摘要:

14 Monosaccharides By J. S. BRIMACOMBE and L. C. N. TUCKER Chemistry Department Dundee University Dundee DD 7 4HN The need and desirability of comprehensive coverage of carbohydrate chemistry in Annual Reports has declined since the publication of the Specialist Periodical Reports on Carbohydrate Chemistry from 1967 onwards. The present Report is confined to some of the publications which in the authors’ opinion are either of general interest or reflect areas of growth in monosaccharide chemistry over the past three years. Occasional reference is made to di- and higher oligo- saccharides. A number of text-books of interest have appeared’ and a summary of Leloir’s illuminating work on the biosynthesis of sugars is available.2 A computerized system of retrieving carbohydrate references from the current literature has been de~eloped.~ 1 Conformation and Structure The applications of n.m.r.spectroscopy to conformational and structural problems in carbohydrate chemistry have been and rules for conformation Qomenclature of five- and six-membered rings in monosaccharides and their derivatives have been approved by the British and US. Carbohydrate Nomen- clat ure Committees.6 The results of ‘H n.m.r. studies of fully acetylated derivatives of pentitols and he~itols,~ pentose dimethyl acetals? glyculose phenylos~triazoles,~ ‘The Carbohydrates. Chemistry and Biochemistry’ 2nd edn. Volumes IIA and IIB ed. W. Pigman and D. Horton Academic Press London 1970; ‘The Carbohydrates. Chemistry and Biochemistry’ 2nd edn.Volume lA ed. W. Pigman and D. Horton Academic Press London 1972; J. F. Stoddart ‘Stereochemistry of Carbohydrates’ Wiley-Interscience London and New York 1971 ; ‘Sugar (chemical biological and nutritional aspects of sucrose)’ ed. J. Yudin J. Edelman and L. Hough Butter- worths London 1971 ;R. J. Ferrier and P. M. Collins ‘Monosaccharide Chemistry’ Penguin Library of Physical Sciences London 1972; MTP International Review of Science Series 1 Vol. 7 ‘Carbohydrates’ ed. G. 0. Aspinall Butterworths London 1973; ‘Methods in Carbohydrate Chemistry’ Volume 6 ed. R. L. Whistler and J. N. BeMiller Academic Press London 1972. * L. L. Leloir Science 1971 172 1299. G. G. S. Dutton and K. B. Gibney Carbohydrate Res. 1971 19 393. T. D. Inch Ann. Reports N.M.R.Spectroscopy 1972 5A 305. R. U. Lemieux Pure Appl. Chem. 1971 27 527. J.C.S. Chem. Comm. 1973 505. ’ S. J. Angyal R. LeFur and D. Gagnaire Carbohydrate Res. 1972 23 121. J. Defaye D. Gagnaire D. Horton and M. Muesser Carbohydrate Res. 1972,21,407. H. El Khadem D. Horton and J. D. Wander J. Org. Chem. 1972 37 1630. 431 432 J. S. Brimacombe and L. C. N. Tucker trans-1-nitro-1-heptenes,loand D-pentononitriles' ' have established that a planar zigzag conformation predominates only in those configurations (e.g. arabino munno and galacto) which do not possess parallel 1,3-interactions between acetoxy-groups on alternate carbon atoms. X-Ray diffraction methods have revealed that allitol D-iditol,' and ~-glucitol' also adopt bent-chain conforma- tions in the crystal although potassium ~-gluconate'~ has a planar extended carbon chain that is stabilized by intramolecular hydrogen-bonding between 0-2 and 0-4.The free energies of aldopyranoses in the 'C and ,C1 conformations have been derived' from theoretical considerations and show fairly good agreement with values previously assigned on a semi-quantitative basis by Angyal. The calculations indicate that all the D-aldopyranoses except a-D-altrose and a-D- idose exist only in ,C conformations whereas all the aldopentoses except xylose bist as a 'C ,C conformational equilibrium in solution. Free-energy calculations predict ' conformations for all the D-aldohexopyranose penta-acetates with the exception of fl-D-idopyranose penta-acetate which should exist as a 'C k,C1conformational mixture in solution.'6 The electronic charge-distribution in mono- di- and oligo-saccharides has also been computed by Rao.17 A fundamental study of the anomeric effect has been reported using both oxygen- and nitrogen-containing heterocycles as model compounds," and ab initio MO theory has been applied to the anomeric effect." New values for the absolute anomeric effect in methyl glycopyranosides have been derived based on the free-radical addition of bisulphite to methyl 6-deoxy-hex-5-eno- pyranosides since proportionality exists between the ratio of epimers formed and the relative conformational stability of the respective hex-5-enopyranosides or the intermediary free-radical methyl 6-deoxyglycopyranoside 6-s~lphonate.~' Horton's group have extended their investigations on the conformational equilibria of monosaccharides in solution to include D-aldopentopyranose tetra-acetates and tetrabenzoates,21 2,3,4-tri-O-acetyl-~-pentopyranosyl benzo-ates and 2,3,4-tri-O-benzoyl-~-pentopyranosyl acetates,22 methyl ethyl iso- propyl and t-butyl fl-D-ribopyranoside tribenzoates and tria~etates,~~ methyl D-aldopentopyranoside triacetates and triben~oates,~ 1-thio-D-aldopentopyranose lo S.J. Angyal R. LeFur. and D. Gagnaire Carbohydrate Res. 1972 23 135. I * W. W. Binkley D. R. Diehl and R. W. Binkley carbohydrate Res. 1971 18 459. N. Azarnia G. A. Jeffrey and M. S. Shen Acta Cryst. 1972 28B,1007. l3 Y.J. Park G. A. Jeffrey and W. C. Hamilton Acta Cryst.1971 27B,2393. l4 G. A. Jeffrey and E. J. Fasiska Carbohydrate Res.,1972 21,187. Is V. S. R. Rao K. S. Vijayalakshmi and P. R. Sundararajan Carbohydrare Res. 1971 17 341; K. S. Vijayalakshmi and V. S. R. Rao ibid. 1972 22,413. l6 K. S. Vijayalakshmi and V. S. R. Rao Carbohydrate Res. 1973 29 427. l7 N. Yathindra and V. S. R. Rao Carbohydrate Res. 1972 25,256. l8 H. Booth and R. U. Lemieux Canad. J. Chem. 1971,49 777. l9 G. A. Jeffrey J. A. Pople and L. Radom Carbohydrate Res. 1972 25,117. 'O J. Lehmann and W. Weckerle Carbohydrate Res. 1972 22,23. P. L.Durette and D. Horton J. Org. Chem. 1971 36 2658. 22 P. L. Durette and D. Horton Carbohydrate Res. 1971 18 389. 23 P. L. Durette and D. Horton Carbohydrate Res. 1971 18 303. 24 P. L. Durette and D.Horton Carbohydrate Res. 1971 18 403. Monosaccharides 433 tetra- acetate^,^ and acetylated aldopentopyranosyl halides.26 Their studies and conclusions regarding substitutional and solvation effects have been collected together in a most enlightening review of conformational analysis applied to pyranoid and other systems.27 From a study of the conformational equilibria of the acetylated methyl D-ribopyranosides (1) and the sulphur-containing analogues (2) (3) and (4) in solution it is concluded that only methyl 2,3,4-tri-O- (1) x = Y = 0 H,YMe (2)X=O; y=s (3) x= s; Y = 0 I 1 OAc OAc (4)X=Y=S acetyl-p-D-ribopyranoside (p-1) exhibits a preference for the C4 conformation whereas the others favour the 4C conformation to various extents.28 The conformational preferences of five methyl thio-D-ribopyranosides in the crystalline state have been determined as follows methyl 1-thio-a-D-ribopyranoside(' C4) methyl 5-thio-n- and -P-D-ribopyranoside (both 4C1) methyl 1,5-dithio-a-~- ribopyranoside ('C4) and methyl 1,5-dithio-p-~-ribopyranoside (4C1).29Only in the 5-thio-derivative does the a-anomer adopt a 4C conformation (ax.C-1 substituent) whereas in the other cases stabilization of the 'C4 conformation by intramolecular hydrogen-bonding between 0-2 and 0-4 overrides the oppos- ing influence of the anomeric effect.Conformational preferences of the methyl 3-deoxy-3-nitropentopyranosides and the corresponding sodium nitronates in aqueous solution have been deter- mined and discussed in terms of the free energies of non-bonded interaction^.^' The interaction between the nitrogen function and an adjacent hydroxy-group (A(1.3)effect) is calculated to be greater than 2 kcal mo1-l for the nitronates.As in other branches of chemistry the use of 13C n.m.r. spectroscopy promises to provide structural and conformational data that are not immediately de- rivable using 'H n.m.r. spectroscopy. The pulse Fourier-transform 13C n.m.r. spectra of twenty methyl and aryl glycosides have been measured and a useful tabulation of chemical shifts has been made; C-1 of glycosides bearing an axial substituent is observed to resonate upfield of its equatorial ~ounterpart.~' The claim32 that equatorial 013CH3 groups of methyl glycosides resonate to higher field than the axial group is contrary to other evidence.The 'H-13C INDOR technique for example has established the 13Cchemical shifts (in p.p.m. from TMS) of ax. and eq. anomeric methoxy-groups in the ranges 55.12-56.63 and 25 P. L. Durette and D. Horton Carbohydrate Res. 1971 18 419. 26 P. L. Durette and D. Horton Carbohydrate Res. 1971 18 57. " P. L. Durette and D. Horton Adv. Carbohydrate Chem. Biochem. 1971 26 49. N. A. Hughes Carbohydrate Res. 1973 27 97. 29 R. L. Girling and G. A. Jeffrey Carbohydrate Res. 1971 18 339; ibid. 1973 27 257. 30 H. H. Baer and J. Kovaf Canad. J. Chem. 1971,49 1940. 31 E. Breitmaier W. Voelter G. Jung and C. Tanzer Chem. Ber. 1971 104 1147. 32 W. Voelter E. Breitmaier R. Price and G. Jung Chirnia (Switz.) 1971 25 168.434 J. S. Brimacombe and L. C. N. Tucker 56.63-58.69 respectively for a series of methyl glyco~ides.~~ Some I3Cn.m.r. data for a number of D-glucobioses allow one to distinguish the C-1' resonances of the a-and /3-linked carbon atoms.34 Fair correlations are found in a-and P-D-glycopyranoses between the C chemical shifts the electron density at the carbon atoms,35 and the rates of oxidation with bromine water.36 Vicinal I3C-lH couplings in monosaccharide derivatives have been demon- strated to exhibit an orientational dependence analogous to that for protons viz. dihedral angles of 60-100" are associated with couplings (0-3 Hz) smaller than those (4.5-5.5 Hz) for angles of 140-180".37 A Karplus-type relationship has been derived for vicinal 13C-lH couplings in cyclonucleosides that should prove invaluable in the conformational analysis of these and related compound^.^ Geminal 13C-l H couplings at the anomeric centre of monosaccharides also show an orientational dependence the 8-anomer generally exhibiting a smaller coupling constant than the a-an~mer.~~ An important paper has appeared on the I3C n.m.r.spectra of di- and poly- saccharides; the fact that the spectra are measurable is heralded as a new and significant method for looking at the conformations of these molecules.40 Although 'H n.m.r. spectroscopy does not readily permit the equilibrium compo- sition of aqueous solutions of D-fructose to be determined it is obtained by I3C n.m.r. Fourier-transform methods as a-pyranose 3 f 1 %; p-pyranose 57 f6 %;a-furanose 9 & 1 %;and /3-furanose 3 1 f3 %.41 Unidentate co-ordination has been demonstrated between suitably protected carbohydrates and lanthanide shift reagents but a cautionary note has been sounded regarding the improper use of the technique.42 An exemplary study with 1,2 :5,6-di-O-isopropylidene-a-~-gluco-and -allo-furanoses and their ace- tates has shown that europium and thulium reagents produce shifts towards low field whereas praseodymium reagents cause shifts towards high field.43 Other applications of shift reagents have been and they have enabled configurational assignments to be made to isomeric branched-chain sugars45 and to such sugar oximes as (5);46 in the latter case the a-proton of the anti-isomer is more deshielded than the corresponding proton of the syn-isomer in 33 R.Burton L. D. Hall and P. R. Steiner Canad. J. Chem. 1971,49 588. 34 N. Yamaoka T. Usui K. Matsuda K. Tuzimura H. Sugiyama and S. Seto Tetra-hedron Letters 1971 2047. 3s N. Cyr A. S. Perlin and M. A. Whitehead Canad. J. Chem. 1972 50 814. 36 A. S. Perlin Canad. J. Chem. 1971 49 1972. " J. A. Schwarz and A. S. Perlin Canad. J. Chem. 1972,50 3667. 38 R. U. Lemieux T. L. Nagabhushan and B. Paul Canad. J. Chem. 1972,50 773. 39 K. Bock I. Lundt and C. Pedersen. Tftrahedron Letters 1973. 1037. 40 D. E. Dorman and J. D. Roberts J. Amer. Chem. SOC. 1971 93,4463. 41 D. Doddrell and A. Allerhand J. Amer. Chem. SOC.,1971 93 2779. 42 I. Armitage and L. D. Hall Carbohydrate Res. 1972 24 221.43 I. Armitage and L. D. Hall Canad. J. Chem. 1971,49 2770. 44 R. F. Butterworth A. G. Pernet and S. Hanessian Canad. J. Chem. 1971 49 981. 45 D. Horton and J. K. Thomson Chem. Comm. 1971 1389; S. D. Gero D. Horton A. M. Sepulchre and J. D. Wander Tetrahedron 1973 29 2963. 46 J. M. J. Tronchet F. Barbalat-Rey and N. Le-Hong Helo. Chim. Acta 1971,54 2615. Monosaccharides 435 the presence of a shift reagent. Salts of the lanthanides cause differential shifts in the spectra of pyranoid compounds in aqueous solution provided that such a XC=NOH (5) R = Me or CH,Ph; X = H or C1 steric arrangement as ax. eq. ax. of the oxygen atoms is available for complex- ing.47 Detailed papers have appeared on the 19Fn.m.r. spectra of fluorinated mono- saccharide~.~~ Measurements of long-range couplings in the acetylated 3-deoxy-3-fluoroaldopyranosyl fluorides have given 4J,, values of ax.ax. + 10.4 ax. eq. + 1.0 and eq. eq. -3.0 Hz.~~ 4J,. values of eq. eq. +4.0 and eq. ax. -1.5 Hz were determined using a series of 3-deoxy-3-fluoro-~-glucosederiva-tive~.~~ A method for determining the configurations of the glycosidic linkages of oligosaccharides is based on measurements of the chemical shift and coupling constant of the anomeric protons of the trimethylsilylated derivative.’ For eight anomeric pairs of pyranose derivatives the axial anomeric proton has a shorter longitudinal nuclear relaxation time (T value) than the equatorial counterpart.’* The most important relaxation pathways for an axially oriented proton involve either 1,3,5-triaxial or vicinal-gauche interactions whereas only the latter type of interaction is effective for an equatorially oriented proton.53 This technique permitss2 the anomeric configuration of D-mannose derivatives to be assigned whereas this is not usually possible using proton-proton couplings and provides a potentially useful basis for assigning the anomeric configurations to both reducing and non-reducing moieties of disa~charides.~~ Angyal’s group in a continuation of earlier studies have used ‘H n.m.r.spectroscopy to examine the tautomeric equilibria of all of the aldopentoses and aldohexoses in deuterium oxide and have discussed each aldose in some detaiL5 47 S. J. Angyal Carbohydrate Res.1973 26 271. 48 L. D. Hall R. N. Johnson J. Adamson and A. B. Foster Canad. J. Chem. 1971 49 11 8; L. Phillips and V. Wray J. Chem. SOC.(B) 1971 1618; P. W. Kent R. A. Dwek and N. F. Taylor Tetrahedron 1971 27,3887. 49 L. D. Hall R. N. Johnson A. B. Foster and J. H. Westwood Canad. J. Chem. 1971 49 236. A. B. Foster R. Hems and L. D. Hall Cunud. J. Chem. 1970 48 3937. 51 J. P. Kamerling M. J. A. DeBie and J. F. G. Vliegenthart Tetrahedron 1972,28 3037. ” L. D. Hall and C. M. Preston J.C.S. Chem. Comm. 1972 13 19. 53 L. D. Hall and C. M. Preston Carbohydrate Res. 1973 27,286. ” L.D. Hall and C. M. Preston Carbohydrate Res. 1973 29 522. 55 S. J. Angyal and V. A. Pickles Austral. J. Chem. 1972 25 1695. 436 J. S. Brimacombe and L. C.N. Tucker Replacement of an oxygen atom by a hydrogen atom at either C-2 or C-3 of an aldose produces an increase in the furanose content of the equilibrium mixture.56 Such ions as Ca2+ Pb2+ and La3+ cause the equilibrium of solutions of D-allose to shift appreciably in favour of the a-anomer~.~’ Although isomeric monosaccharides are not normally distinguishable by mass spectrometry it appears that detailed consideration of the ratios of selected ion-intensities can lead to interpretable differences. This procedure has been used by two gro~ps~~.~~ to identify simple monosaccharides following their conversion into trimethylsilylated forms but the method appears to be dependent on the anomer. The mass spectra of trifluoroacetylated monosaccharides show easily interpretable fragmentation patterns that allow aldoses and ketoses as well as furanoses and pyranoses to be distinguished.60 2 Oxidation and Dicarbonyl Sugars Methods for the oxidation of carbohydrates have been reviewed.61 Continued use has been made of DMSO-based oxidants for the oxidation of monosaccharide derivatives containing an isolated hydroxy-group although epimerization at an adjacent carbon atom bearing an axial substituent sometimes accompanies the oxidation.62 Oxidation followed by reduction of the dicarbonyl sugar with a metal hydride provides a useful method for inverting the configuration of a hydroxy-group in suitably protected derivatives ; these sequences are key steps in recent syntheses of L-lyxose (from ~-glucose),~~ D-tagatose (from ~-fructose),~~ D-psicose (from ~-fructose),~~ and L-psicose (from L-sorbose).66 The introduction of a carbonyl group followed by derivatization has been used in linkage analysis of polysaccharides.Thus oxidation of methanolysates of fully methylated polysaccharides with DMSO-based oxidants produces anomeric mixtures of the corresponding dicarbonyl sugars which are separated and identified as their crystalline 2,4-dinitrophenylhydra~ones.~’ Dicarbonyl sugars obtained by oxidation of monosaccharide derivatives hold considerable interest as synthetic intermediates and their reactions with 56 S. J. Angyal and V. A. Pickles Austral. J. Chem. 1972 25 171 1. ” S. J. Angyal Austral. J. Chem. 1972 25 1957. 58 J. Vink J. H. W. Bruins Slot J.J. de Ridder J. P. Kamerling and J. F. G. Vliegenthart J. Amer. Chem. Soc. 1972 94 2542. 59 S. C. Havlicek M. R. Brennan and P. J. Scheuer Org. Mass Spectrometry 1971 5 1273. 6o W. A. Konig H. Bauer W. Voelter and E. Bayer Chem. Ber. 1973 106 1905. 61 R. F. Butterworth and S. Hanessian Synthesis 1971 70. 62 H. Kuzuhara N. Oguchi H. Ohrui and S. Emoto Carbohydrate Res. 1972 23 217. 63 H. Kuzuhara H. Terayama H. Ohrui and S. Emoto carbohydrate Res. 1971,20 165. 64 A. A. H. Al-Jobore R. D. Guthrie and R. D. Wells Carbohydrate Res. 1971 16,474. 65 R. S. Tipson R. F. Brady jun. and B. F. West Carbohydrate Res. 1971 16 383. 66 A. Armenakian M. Mahmood and D. Murphy J.C.S. Perkin I 1972 63. 67 N. Kashimura KJ. Yoshida and K. Onodera Carbohydrate Res. 1972 25 264.Monosaccharides 437 Wittig reagents,68 toluene-p-~ulphonylhydrazide,~~ dia~oalkanes,~' and di-methyl phosphite' have been examined. Pyranosid-4-uloses undergo Norrish Type I reactions on photolysis the major reaction being decarbonylation. Thus photolysis of the 4-ulose (6) in R' RZ \/ Bu'O2C-C-OOMe R2 "QMe 0\ 0 O\ No ;i cke2 CMez O\ O c6e2 (7) R' = Me; RZ= H (8) R' = H; RZ = Me (9) R1= Me; R2 = H (10) R' = H; RZ = Me Bu'0,C Me3Me Me,C O\ No 0 CMe2 (12) R' = OCHMe,; R2= H (11) (13) R' = H; R2 = Me 0-CH phc/H (,,%Me 0 benzene or pentane solutions affords the pentofuranosides (7) and (8) of Norrish Type I de~arbonylation.~~ In t-butyl alcohol decarbonylation is still J. M. J.Tronchet B. Baehler H. Eder N. Le-Hong F. Perret J. Ponchet and J.-B. Zumwald Helv. Chim. Acra 1973 56 1310; J. M. J. Tronchet J.-M. Bourgeois and D. Schwarzenbach Carbohydrate Res. 1973 28 129; J. M. J. Tronchet and J. M. Chalet ibid. 1972 24 263; J. M. J. Tronchet and G. Graf Helv. Chim. Acta 1972 55 1141; N. Baggett J. M. Weber and N. R. Whitehouse Carbohydrate Res. 1972 22,227; A. Rosenthal and M. Sprinzl ibid. 1971,16,337; A. Rosenthal C. M. Richards and K. Shudo ibid. 1973 27 353; A. Rosenthal and D. A. Baker J. Org. Chem. 1973,38 193; R. W. Lowe W. A. Szarek and J. K. N. Jones Carbohydrate Res. 1973 28 28 1. 69 W. B. Gleason and R.Barker carbohydrate Res. 1972 21,447. 70 A. D. Ezekiel W. G. Overend and N. R. Williams Carbohydrate Res. 1971 20 251; T.D. Inch G. J. Lewis and N. E. Williams ibid. 1971 19 17; T. D. Inch G. J. Lewis and R. P. Peel ibid. p. 29; J. H. Jordaan and S. Smedley ibid. 1971 16 177; B. Flaherty S. Nahar W. G. Overend and N. R. Williams J.C.S. Perkin I 1973 632. '' L. Evelyn L. D. Hall L. Lynn P. R. Steiner and D. H. Stokes Carbohydrate Res. 1973 27 21. 72 P. M. Collins J. Chem. SOC.(0,1971 1960; P. M. Collins and P. Gupta ibid. p. 1965. '0 J. S. Brimacombe and L. C. N. Tucker (18) (19) predominant but minor products (9) and (10) [but not (1 l)] arising from keten formation and trapping by the alcohol are also isolated. Pyranosid-2- and -3-uloses have been observed to undergo Norrish Type I1 elimination on photolysis. Thus photolysis of the pentopyranosid-2-uloses (1 2) and (1 3) in t-butyl alcohol gives the 1,5-anhydro-pent-2-ulose(14) and acetone or f~rmaldehyde.~~ The Type I1 reaction however is strongly dependent on the stereochemistry of the ring substituent that contains the hydrogen atom y to the carbonyl group.Whereas the arubino-derivative (15) eliminates the axial 2-methoxy-group to give (16) (17) and formaldehyde on photolysis the ribo-isomer (18) affords a fused oxetanol derivative (19). All the products formed in these photolyses can be rationalized by conventional biradical mechanisms. The oxidation of acetylated alkyl glycosides with chromium trioxide in acetic has attracted a good deal of interest and a free-radical mechanism has been postulated to account for the conversion of B-glycosides [e.g.(20)] CH20Ac OAc (20) R’= OMe; R2 = H (22) R’ = H; R2 = OMe (23) R’= H; R2 = OCHO into 5-hexulosonates (21) and of a-glycosides [e.g. (22)] into glycosyl formates (23).” Oxidation with chromium trioxide-acetic acid has been applied to linkage analysis of oligo- and poly-saccharides where the possibility of selective degradation Acetals are also oxidized with chromium trioxide-acetic acid;77 thus the cyclic ethylidene acetal(24) is transformed into the hex-3-ulose (25) providing a new route to this class of rare sugar. Oxidation of the methylene acetal(26) by this reagent in the presence of acetic anhydride affords the cyclic carbonate (27) although the yields of cyclic carbonates are decidedly lower when six- and seven-membered methylene acetals are similarly 73 P.M. Collins P. Gupta and R. Iyer J.C.S. Perkin I 1972 1670. 74 S. J. Angyal and K. James Chem. Comm. 1969 617. 75 M. Bertolini and C. P. J. Glaudemans Carbohydrate Res. 1971 17 449. 76 J. Hoffman B. Lindberg and S. Svensson Acra Chem. Scand. 1972 26 661. ” S. J. Angyal and K. James Austral. J. Chem. 1971 24 1219; S. J. Angyal and M. E. Evans ibid. 1972 25 1495. ’’ S. J. Angyal and M. E. Evans Austral. J. Chem. 1972 25 1513. Monosaccharides CH,OAc CH,OAc CH,OAc I AcO -H R AcO AcOt C OT, \C=O Ac 0 OAc +OAc f-OAc CH,OAc CH,OAc CH,OAc (24) R = Me (26) R = H The /I-glycoside (28) is oxidized to the aldonic acid ester (29) with ozone in the presence of acetic anhydride and sodium acetate but the corresponding a-glycoside is ~nreactive.'~ OAc OAc CH,OAc (29) Among other oxidizing agents that have found limited use in carbohydrate chemistry are lead tetra-acetate in pyridine,' t-amyl hydroperoxide and molyb- denum pentachloride,' and the chromium trioxide-bipyridyl complex.'' The unsaturated lactone (30) is formed by oxidation and elimination when either OAc (30) 2,3,4,6-tetra-O-acetyl-/I-~-gluco- or -manno-pyranose is treated with DMSO-triethylamine-sulphur tri~xide.'~ Silver carbonate supported on Celite has been used in boiling benzene to oxidize 2,3-O-isopropylidene-~-ribose and 79 P.Deslongchamps and C. Moreau Canad.J. Chem. 1971,49,2465; P. Deslongchamps C. Moreau D.Frthel and P. Atlani ibid. 1972 50 3402. *O D. J. Ward W. A. Szarek and J. K. N. Jones Carbohydrate Res. 1972 21 305. G. A. Tolstikov U. M. Gemilev and V. P. Yurjev Zhur. obshchei Khirn. 1972,42 161 1. 82 R. E. Arrick D. C. Baker and D. Horton Carbohydrate Res. 1973 26 441. '' D. M. Mackie and A. S. Perlin Carbohydrate Res. 1972 24 67. 440 J. S. Brimucombe and L. C. N. Tucker 2,3 :5,6-di-0-isopropyl~dene-~-allofuranose, etc. into the corresponding aldono- lac tone^,^^ and to convert L-sorbose into ~-threose~’ and L-arabinose into L-erythrose.8 Of biological interest is the formation of mixtures of methyl (6s)- and (6R)- P-~-[6-~H]galactopyranosides~’ and the corresponding methyl a-~-[6-~H]- glucopyranosides’’ by reduction of the appropriate methyl hexodialdo-1,5- pyranoside with sodium borodeuteride ; the D-gluco-epimers could be differen-tiated by deuterium-decoupled H n.m.r.spectroscopy of appropriate derivatives. Use of the ~-[6-~H]galactose derivatives established that dehydrogenation of the primary hydroxy-group by D-galactose oxidase involves removal of the pro-S hydrogen atom.87 3,6-Dideoxy-~-erythro-hexos-4-ulose has been syn- thesized and identified as the component sugar of a nucleotide conjugate in Pasturella pseudotuberculosis concerned with the biosynthesis of the biologically important 3,6-dideoxyhexo~es.~~ 3 Esters The leaves of Protea rubropilosa contain D-allose in the form of the 6-0-cinnamate and 6-0-benzoate :this is the first proven occurrence of this hexose in Nature.” Benzyl 4,6-0-benzylidene-P-~-galactopyranoside is selectively benzoylated at 0-3using N-benzoylimida~ole,~~ and the use of benzoyl cyanide as a benzoylat- ing agent has been advocated.92 A newly developed hydroxy-protecting group 2,2,2-trichloroethoxycarbonyl(Troc) can be removed under mild and non- hydrolytic conditions (zinc dust in 90% acetic acid or methanol).93 Monosaccharide derivatives possessing a cis-configuration at C-2 and C-3 (e.g.2,3-0-isopropylidene-~-ribofuranose) undergo inversion of configuration at C-2 by way of acetoxonium ion intermediates under conditions of acet~lysis.~~ Extensive studies on acetoxonium-ion rearrangements with model diol and trio1 systems have been conducted by Paulsen’s The applications of carbohydrate orthoesters in synthesis have been reviewed.96 Acid-catalysed hydrolysis of 3,4,6-tri-0-methyl-1,2-0-(1-alkoxyethylidene)-a-~-glucopyranose yields the 1-and 2-acetates in proportions depending on the solvent and the concentration of acid low concentrations of acid favouring the 84 S.Morgenlie Acta Chem. Scand. 1972 26 2518. 85 S. Morgenlie Acta Chem. Scand. 1972 26 2146. 86 S. Morgenlie Acta Chem. Scand. 1972 26 1709. A. Maradufu G. M. Cree and A. S. Perlin Canad. J. Chem. 1971 49 3429. 88 D. Gagnaire D. Horton and F. R. Taravel Carbohydrate Res. 1973 27 363. 89 C. L. Stevens K. W. Schultze D. J. Smith P. M. Pillai P. Rubenstein and J. L. Strominger J. Amer. Chem. SOC.,1973 95 5767. 90 G. W. Perold P. Beylis and A. S. Howard J.C.S.Perkin I 1973 643. 91 G. J. F. Chittenden Carbohydrate Res. 1971 16 495. 92 A. Holy and M. SouCek Tetrahedron Letters 1971 185. 93 R. Bugianesi and T.Y. Shen Carbohydrate Res. 1971 19 179. 9A W. Sowa Canad. J. Chem. 1971,49 3292. 95 H. Paulsen and H. Behre Chem. Ber. 1971,104 1264 1281. 96 N. K. Kochetkov and A. F. Bochkov Recent Develop. Chem. Natural Carbon Com- pounds 1971 4 75. Monosaccharides 441 formation of the 2-a~etate.~~ Ethanolysis of the orthoester (31)in the presence of 2,6-dichlorobenzoic acid affords ethyl 2,3,4,6-tetra-O-methyl-~-glucopyranoside (p:o! ratio 29.5 1) (37 %) and 2,3,4,6-tetra-O-methyl-~-glucopyranose (63%).98 CH,OMe LO OMe OEt (31) The proportion of the former product can be substantially increased by con- ducting the solvolysis in the presence of lithium toluene-p-sulphonate but the ratio of o! glycosides is then reduced to ca.2 1. Mesitylenesulphonyl (mesisyl) chloride has been shown to be a useful reagent for the selective sulphonylation of ~ic-glycols.~~ The selectivity towards toluene- p-sulphonyl chloride in pyridine of the hydroxy-groups in trans-fused methyl 4,6-O-benzylidene-~-glycopyranosides is controlled by preferential equatorial reaction and if this is not possible by intramolecular hydrogen-bonding."' Carbohydrate toluene-p-sulphonates are readily removed by 0-S bond cleavage on treatment with sodium naphthalene in THF."' Benzoyloxy-group participation occurs in displacement reactions on the sulphonate (32) to give the rearranged product (33),although direct displacement Tsof& yj>o O, O-CMe2 --CMe2 (32) R = Ac or Ts (33) X = OAc or C1 of the 5-sulphonyloxy-group is accomplished with highly nucleophilic species in dipolar aprotic solvents.'02 A convenient synthesis of L-gulose is based on inverting the configuration at C-5 of the D-mannoside bis(methylsu1phonate) (34)by treatment with sodium acetate in NN-dimethylf~rrnamide.'~~ The unreactivity towards S,2 reactions of sulphonyloxy-groups flanked by a cis-axial substituent is illustrated by the formation of the unsaturated derivative 97 L.R. Schroeder D. P. Hultman and D. C. Johnson J.C.S. Perkin 11 1972 1063. 98 D. P. Hultman L. R. Schroeder and F. C. Haigh J.C.S. Perkin 11 1972 1525.99 S. E. Creasey and R. D. Guthrie Chem. Comm. 1971 801. loo S. E. Creasey and R. D. Guthrie Carbohydrate Res. 1972 22,487. lo' H. C. Jarrell R. G. S. Ritchie W. A. Szarek and J. K. N. Jones Canad. J. Chem. 1973 51 1767. ' 102 M. M'djkovic A. Jokic and E. A. Davidson Carbohydrate Res. 1971 17 155; R. C. Chalk D. H. Ball and L. Long jun. ibid. 1971 20 151. Io3 M. E. Evans and F. W. Parrish Carbohydrate Res. 1973 28 359. J. S. Brimacombe and L. C. N. Tucker ++OMe MsOi':> OMe %;iOMe Me0 Me0 OTs Me0 OTs (35) (36) (37) (35) on reaction of the bis(su1phonate) (36)with sodium benzoate in hexamethyl- phosphortriamide presumably by way of the allylic tosylate (37).'04 Rationaliza-tions have been advanced for the preponderance of elimination over substitution products in the reactions of methyl and benzyl 6-deoxy-2,3-di-O-rnethyl-4-0-methylsulphonyl-a-L-talopyranosides (38)with sodium azide in NN-dimethyl- f~rmamide.'~' It is hardly surprising therefore that the unsaturated sugar (39) tTTR ?-,TMe MsO Me0 OMe 0 O (38) R = Me or CH,Ph &et (39) results when methyl 6-deoxy-2,3-O-isopropylidene-4-~-methylsulphonyl-a-L-talopyranoside is treated with a more basic nucleophile such as ammonia.'06 Products of direct displacement are not observed when methyl 2,3-O-isopropyli- dene-5-0-toluene-p-sulphonyl-a-~-rhamnofuranoside is treated with tetrabutyl- ammonium fluoride in acetonitrile but the internal and terminal olefins formed by elimination of toluene-p-sulphonic acid are isolated instead ;'O7 similar obser- vations have been made with a related nucleoside derivative."* Direct dis- placements on the D-galacturonate sulphonate (40) are circumvented by the A.K. Al-Radhi J. S. Brimacombe L. C. N. Tucker and 0.A. Ching J. Chem. SOC.(0 1971 2305. A. K. Al-Radhi J. S. Brimacombe and L. C. N. Tucker Carbohydrate Res. 1972,22 103. J. Jar); and P. Novak CON.Czech. Chem. Comm. 1971,36 3046. lo' G. Chaves 0.and A. H. Haines Carbohydrate Res. 1972 22 205. L. M. Lerner J. Org. Chem. 1972 37 477. Monosaccharides 443 acidic nature of H-5,which predisposes the system towards formation of the elimination product (41).' O9 C02Me C0,Me MsqF> OMe -$?-)Me OBz OBz (40) (41) The conversion of 1 -0-acet yl-2,3-di-O-benzoyl-4,6-di-0-methylsulphonyl-cr-D-glucopyranose (42) into the 1,4-anhydro-sugar (43) on treatment with azide OBz (43) ion has been suggested"' to take place by a ring-contraction mechanism al- though a mechanism involving deacetylation at C-l initially followed by an intramolecular displacement of the 4-mesyloxy-group is more consistent with the facts.' Displacements of the 4-mesyloxy-group of the 1,6-thioanhydro- derivative (44)proceed by way of the cyclic sulphonium ion (45) which depending on the nucleophilicity of the anion (thiolbenzoate azide halide etc.) leads to different ratios of compounds (46)(pathway a) and (47) (pathway b)."' The formation of benzyl 1,5-dithio-crfl-~-arabinopyranoside on treatment of 5-0-toluene-p-sulphonyl-L-arabinosedibenzyl dithioacetal with sodium iodide in acetone involves dealkylation of the cyclic sulphonium ion (48) formed by intramolecular displacement of the 5-to~yloxy-group.~ l3 lo9 P.L. Gill M. W. Horner L. Hough and A. C. Richardson Carbohydrate Res. 1971 17 213. l lo C. Bullock L. Hough and A. C. Richardson Chem. Comm. 1971 1276. ''' J. S. Brimacombe J. Minshall and L. C. N. Tucker J.C.S. Chem. Comm. 1973 142. " J. Kuszmann and P. Sohhr Carbohydrate Res. 1973,27 157. l l3 J. Harness and N. A. Hughes Chem. Comm. 1971 81 1. J. S. Brimacornbe and L. C. N. Tucker Selective sulphation of the axial hydroxy-group of methyl 2-acetamido-6-0- acetyl-2-deoxy-a-~-galactopyranoside has been achieved with the sulphur trioxide-pyridine complex.' l4 L-Ascorbic acid 3-sulphate is suggested to be an important intermediate in metabolic sulphation and its synthesis has been reported.' 2-Methylthio-4H-l,3,2-benzodioxaphosphorin2-oxide has been advocated as a potentially useful phosphorylating agent for sugars,' l6 and a correlation has been established between the pK value of a reducing sugar and its capability of undergoing cyanogen-induced phosphorylation of the hemi-acetal hydroxy- group.' ' Synthetic ~-[3,3-~H,]glyceraldehyde3-phosphate condenses with 1,3-dihydroxypropan-2-one1-phosphate in a reaction catalysed by rabbit-muscle aldolase to give ~-[6,6-~H,]fructose 1,6-diphosphate in high yield.' ' Carbohydrate phosphonates have been obtained by Arabramov-type reactions on appropriate uloses and by the addition of dialkyl hydrogen phosphites to activated double bond^."^ The configuration at the phosphorus atom in the D-glucopyranoside 4,6-(R)-methylphosphonate (49) and the diastereoisomeric Me (S)-form has been elucidated by their conversion into (S)-and (R)-ethylmethyl- phenylphosphine oxides respectively by sequential additions of phenyl- and ethyl-magnesium bromides.' 2o 'I4 S.Hirano Carbohydrate Res. 1973 27 265. 'Is R. 0. Mumma A. J. Verlangieri and W. W. Weber jun. Carbohydrare Res. 1971 19 127. 'Id M. Eto M. Sasaki M. Iio M. Eto and H. Ohkawa Tetrahedron Letters 1971 4263. 'I7 C. Degani Carbohydrate Res. 1971 18 329. * G. R. Gray and R. Barker Carbohydrate Res. 1971 20 3 1. H. Paulsen W.Greve and H. Kuhne Tetrahedron Letters 1971 2109. I2O T. D. InchandG. J. Lewis J.C.S. Chem. Comm. 1973 310. Monosaccharides 445 4 Glycosides Synthesis.-The search for a reliable stereospecific synthesis of a-glycopyrano- sides continues and Umezawa (Bull. Chem. SOC. Japan 1969,42,529) has opined that 'the preparation of a-glycopyranosides in high yields still remains the most important problem of carbohydrate chemistry.' The problem is accentuated with the solid-phase synthesis of oligosaccharides in prospect. One of the most promising of recent approaches is that of Lemieux in which the synthesis of a-glycosides is based on the reaction of dimeric 3,4,6-tri-O-acetyl- 2-deoxy-2-nitroso-a-~-hexopyranosyl chlorides with alcohols.The resulting alkyl a-D-glycosidulose 2-oxime is capable of a variety of transformations. An eagerly awaited series of papers'21 from Lemieux's group has detailed how this approach can be used in the synthesis of alkyl a-D-glycosides a-linked disacchar- ides amino-sugars and analogues of the amino-glycoside antibiotic kanamycin. In another approach to a-glycosides neighbouring-group participation of groups on sites other than C-2 has been examined under conventional or modi- fied Koenigs-Knorr conditions. Methanolysis of various 6-acylated 2,3,4-tri-O- benzyl-a-D-glucopyranosyl bromides with an excess of the alcohol showed that whereas the p-methoxybenzoate reacts almost exclusively with inversion of configuration at C-1 to give the P-glycoside the p-nitrobenzoate is solvolysed to give greater than 90 % of the a-glycoside.'22 The steric control exerted by the C-6-ester has been attributed to carbonyl participation but the extent of inter- conversion of the anomeric halides prior to alcoholysis remains to be resolved.By contrast solvolyses with low concentrations of methanol in inert solvents give mainly the a-glycosides irrespective of the structure of the C-6 substituent.' 23 However in the presence of either silver tetrafluoroborate or silver hexafluoro- phosphate at -78 "C /I-glycosides are obtained on methanolysis of the same a-D-glucosyl bromides whereas under catalysis by silver trifluoromethane- sulphonate (triflate) the relative amounts of a-and b-D-glycosides formed are influenced by the C-6 substituent and the polarity of the solvent.Glucosyl triflates are suggested as intermediates in the latter reactions whereas a 'push- pull' mechanism seems to operate with the other silver-salt-assisted methanolyses. The glycosyl bromides (50) and (51) react rapidly with ethanol in chloroform solution with pyridine as catalyst to give a-glycosides as the major products. Since the isomeric glycosyl bromide (52) affords a mixture of a-and P-glycosides it is suggested that a mechanism involving participation by Ac0-6 [see (53)] operates in the other cases.124 Determination of the ratio of c1 :P-glycosides lZ1 R. U. Lemieux T. L. Nagabhushan and K. James Cunad. J. Chem. 1973 51 I; R. U. Lemieux Y. Ito K. James and T. L. Nagabhushan ibid. p. 7; R. U.Lemieux R. A. Earl K. James and T. L. Nagabhushan ibid. p. 19; R. U. Lemieux K. James and T. L. Nagabhushan ibid. p. 27; R. U. Lemieux K. James T. L. Nagabhushan and Y. Ito ibid. p.33; R. U. Lemieux K. James and T. L. Nagabhushan ibid. pp. 42 48; R. U. Lemieux T. L. Nagabhushan K. J. Clemetson and L. C. N. Tucker ibid. p. 53. 122 J. M. Frechet and C. Schuerch J. Amer. Chem. SOC.,1972 94 604. 123 F. J. Kronzer and C. Schuerch Carbohydrate Res. 1973 27 379. 24 P. F. Lloyd B. Evans and R. J. Fielder Carbohydrate Res. 1972 22 1 1 1. J. S. Brimacombe and L. C. N. Tucker CH20R3 Me NHC,H,(NO,) (50) R' = Me; R2 = R3 = Ac NHC,HJ(NO~)~ (51) R' = R3 = Ac; R2 = Me (52) R' = R2 = Ac; R3 = Me (53) resulting from Koenigs-Knorr condensations of variously substituted L-fuco- pyranosyl bromides (54) (55) and (56) with the sugar alcohol (57) has demon- strated that the a-directing influence of the 3-and 4-0-acetyl substituents is not less than the P-directing influence of the 2-0-acetyl substituent in these bromides.' 25 R36H1 OR2 NHAc (54) R' = R3= CH2Ph; R2 = AC (55) R' = Ac; R2 = R3 = CH2Ph (57) (56) R' = RZ = CH2Ph; R3 = AC Another novel approach to the synthesis of a-glycosides relies on nucleophilic displacement of a leaving group at C-1 exhibiting a strong conformational preference for the equatorial configuration owing to the operation of the 'reverse anomeric effect'.' Thus 2,3,4,6-tetra-0-benzyl-a-~-glucopyranosyl bromide was converted into either ammonium or phosphonium or sulphonium salts which react with methanol to give the a-glycoside stereospecifically in the first two cases and an a :8-glycoside ratio of ca.6 1with the more reactive sulphonium salt.A potentially versatile synthesis of glycosides is based on the reaction of phenyl 1-thio-D-glucopyranosides(or their benzylated derivatives) with alcohols in the presence of mercury(I1) salts to give alkyl D-glucopyranosides of inverted anomeric configuration. '27 P-Glycosides are produced stereospecifically by this method but a-glycosides are contaminated with a small proportion of the B-isomers. * The use of a solid-phase procedure for the synthesis of di- and oligo-saccharides has well-publicized practical advantages and an informative account relating to this approach has appeared.'28 Schuerch's group have applied a solid-phase 12' M.Dejter-Juszynski and H. M. Flowers Carbohydrate Res. 1972 23 41; M. Dejter-Juszynski and H. M. Flowers ibid. 1973 28 61. 126 A. C. West and C. Schuerch J. Amer. Chem. SOC., 1973,95 1333. 27 R. J. Ferrier R. W. Hay and N. Vethaviyasar Carbohydrate Res. 1973 27 55. 12' C. Schuerch Accounts Chem. Res. 1973 6 184. Monosaccharides 447 method to the synthesis of di- and tri-saccharides using the alcoholysis of 6-O-(p- nitrobenzoy1)- and 6-0-(p-methoxybenzoyl)-2,3,4-tri-O-benzyl-a-~-glucopyrano-syl bromides to form the inter-saccharide linkages.'29 The first sugar unit is anchored glycosidically to a resin via allylic hydroxy-groups wherefrom the product saccharide is released as the 2-ethanal glycoside [(58) +(59)] by ozo-CH20R' $;Po{:> H,OCH,CH=CH-@ R20 R20 OR' (58) O, Me$I 0r2 CH20R' R20 R20 477°4~)H,0C€-12CH0 OR2 0r2 (59) R' = COC6H,N02-p; R2 = CH2Ph nolysis.In a similar synthetic approach smooth release of the saccharide as a reducing sugar is achieved photolytically from a light-sensitive solid support.'30 Other procedures have used a soluble polymer incorporating either an acylated 1,2-orthoester or glycosyl bromide of the m~nosaccharide,'~ while the key step in a solid-phase synthesis of 2-acetamido-6-0-(2-acetamido-2-deoxy-~-D-g~ucopyranosyl)-2-deoxy-D-glucose involves esterification of a 'pop-corn' polymer containing acid chloride groups with benzyl 2-acetamido-4,6-0- benzylidene-2-deoxy-a-~-glucopyranoside.'~~ After hydrolysis with acid to convert the anchored saccharide into the diol(60) the oxazoline (61) is attached CH20H CH ,OAc AcO $76, I NHAc N=CMe J.M. Frechet and C. Schuerch Carbohydrate Res. 1972 22 399. I3O U. Zehavi and A. Patchornik J. Amer. Chem. SOC.,1973,95 5673; U. Zehavi and A. Patchornik J. Org. Chem. 1972 37 2285. R. D. Guthrie A. D. Jenkins and J. Stehlicek J. Chem. SOC.Cc> 1971 2690; R. D. Guthrie A. D. Jenkins and G. A. F. Roberts J.C.S. Perkin I 1973 2414. 13* G. Excoffier D. Gagnaire J. P. Utille and M. Vignon Tetrahedron Letters 1972 5065. 448 J. S. Brimacombe and L. C. N. Tucker to form the non-reducing unit ;displacement of the disaccharide from the resin is achieved with base.Two other reports are of interest. Any of the four methyl glycosides of D-allose can be prepared in good yield by Fischer glycosidation in the presence or absence of calcium or strontium chlorides -complexing with these catlons shifts the equilibrium in favour of the a-furanoid and a-pyranoid forms.'33 A 9 1 ratio of the 8:a-glycosides (62) is produced when the benzyl 1-thioglycoside 2- sulphonate (63) is heated in methanol presumably by competing pathways involving the 1,2-episulphonium ion and the C-1 carbonium ion as inter-mediates.' 34 /,0 SCH2Ph Lo Reactions.-Mechanistic criteria for the hydrolyses of phenyl and methyl ~-glucopyranosides~ and alkyl fi-~-galactopyranosides~ in hydrochloric acid point to a reaction proceeding via carbonium ions generated unirnofecularly from the conjugate acid (A-1 mechanism) although some of the criteria do not correspond with a unimolecular mechanism in other acids.The influence of the acid concentration on the hydrolysis of substituted-phenyl B-D-galactopyrano- sides has been examined in a related st~dy.'~' No relationship was discerned between the rates and steric or electronic effects of the aglycones in the acid- catalysed hydrolysis of alkyl a-D-glucopyranosides which hydrolyse at a lower rate than the corresponding P-glyc~sides.'~~ If as is generally accepted the rate of hydrolysis is primarily a function of the extent of protonation of the glycosidic oxygen atom then the lower rates of hydrolysis (protonation) of alkyl a-D-glucopyranosides are accounted for in terms of the 'reverse anomeric effect'.Etherification of 0-4 lowers the rate of hydrolysis of methyl a- and 8-D-gluco- pyranosides with acid,13 while glycoside 2-sulphates display a much higher susceptibility towards acid than do 3- 4- and 6-s~lphates.'~~ The high rates of hydrolysis of tertiary alkyl glycosides of P-D-galacto- and -gluco-pyranosides are considered to be due to steric acceleration rather than to the generation of a 'stable' tertiary cation even though alkyl-oxygen bond fission is taking ~1ace.l~' 133 M. E. Evans and S. J. Angyal Carbohydrate Res. 1972 25 43. 134 K. J. Ryan E. M. Acton and L. Goodman J. Org. Chem. 1971,36 2646. 13' C. K. De Bruyne and J.Wouters-Leysen Carbohydrate Res. 1971 17 45. C. K. De Bruyne and G. Van Der Groen Carbohydrate Res. 1972 25 59. 13' C. K. De Bruyne and J. Wouters-Leysen Carbohydrate Res. 1972 23 189. 138 J. N. BeMiller and E. R. Doyle Carbohydrate Res. 1971 20 23. 39 J. N. BeMiller and E. R. Doyle Carbohydrate Res. 1972 25 429. 140 P. F. Lloyd and P. F. Forrester Carbohydrate Res. 1971 19 430. 14' D. Cocker and M. L. Sinnott J.C.S. Chern. Comm. 1972,414. Monosaccharides 449 The confusion surrounding the comparative rates of acid hydrolysis of glyc- uronides and the corresponding glycosides at various pH's has been dispelled by dlfferentiating between the rate constants for the hydrolysis of ionized and un-ionized forms of the glycuronide in the observed rate constant^.'^^ Unless the rate constants or activation parameters for the ionized and un-ionized forms can be determined separately any discussion of the reactivities of glycuronides is meaningless.Kinetic data for the alkaline cleavage of methyl a-and b-D-glucopyranosides have confirmed that such reactions are facilitated by anchimeric assistance of the hydroxy-groups at C-6 and C-2 respectively and have provided supportive evidence for the comparable reactivities of both anomers in alkali.'43 A novel mechanism has been proposed for the release of the aglycone from p-nitrophenyl a-D-ghcopyranoside in alkali that involves base-catalysed 0-1 +0-2 and 0-2 -+0-3 migrations of the p-nitrophenyl p-Nitrophenyl p-D-glucopyranoside on the other hand is hydrolysed in alkali by a mixed mechanism involving C-2 oxyanion participation and nucleophilic aromatic substituti~n.'~~ The greater stability to y-radiation of crystalline aryl glycosides compared with alkyl glycosides is attributed to energy transfer which varies in efficiency according to the nature of the aryl ag1yc0ne.l~~ y-Irradiation of aqueous solutions of phenyl p-D-ghcopyranoside leads to D-glucose and phenol by glycosidic scission and to hydrox ylation of the aglycone ;pulse-radiolysis studies indicate that the first intermediate is the radical (64) which reacts by two kinetically distinguishable An extension of these investigations with a series of substituted-aryl glycosides showed that electron-withdrawing groups greatly accelerate the reactions with hydrated electrons but exert only a slight retarding effect on the reactions of hydroxy-radicals ; electron-donating groups have the opposite effect.' 48 A 'H n.m.r.kinetic approach has been used to elucidate the stereochemistry of the enzymic hydrolysis of glycosidic bonds. Thus the enzymic hydrolyses 14* B. Capon and B. C. Ghosh J. Chem. Soc. (B) 1971 739. 143 Y. Z. Lai Carbohydrate Res. 1972 24,57. 144 D. Horton and A. E. Luetzow Chem. Comm. 1971 79. 14' C. S. Tsai and C. Reyes-Zamora J. Org. Chem. 1972 37 2725. 14' J. S. Moore and G. 0.Phillips Carbohydrate Res. 1971 16 79. 14' G. 0. Phillips W. G. Filby J. S. Moore and J. V. Davies Carbohydrate Res. 1971 16 89. 148 G. 0. Phillips W. G. Filby J. S. Moore and J. V. Davies Carbohydrate Res.1971 16 105. 450 J. S. Brimacombe and L. C. N. Tucker of benzyl2-acetamido-2-deoxy-~-~-glucopyranoside (with 2-acetamido-2-deoxy- P-D-glucosidase from boar epididymi~)'~~ and aa-trehalose (with pig-kidney trehalase)lS0 are both observed to proceed with retention of the anomeric con- figuration. 5 Ethers and Acetals Syntheses of the antibiotic components 2-O-methyl-~-lyxose (from evernino- micins B and D)' and 6-deoxy-4-O-methyl-~-altrose(from sordarin)' 52 have been described. Among other naturally occurring methyl ethers 2-and 3-0-methyl-L-rhamnose (L-acofriose) have been found as components of th 2 anti-biotic scopamycin A' 53 and a K Iebsiella lipopolysaccharide,' 54 respectively. Recent syntheses of L-acofriose' " and the isomeric 6-deoxy-3-0-methyl-~- gul~se,''~ -L-altrose (L-vallarose),' 56 and -D-galactose (D-digitalose)' 56 are of interest in view of the occurrence of these sugars as components of the cardiac glycosides.3,6-Di-O-methyl-~-galactosehas been synthesized and is identical with a product from the methylation analysis of polysaccharides related to .+carrageenan.' '' Demethylation of methyl a-cymaroside (methyl 2,6-dideoxy- 3-O-methyl-a-~-ribo-hexopyranoside) and a number of steroidal monomethyl glycosides has been accomplished with lithium in ethylamine without loss of the aglycones.' 58 Benzyl ethers of carbohydrates can be cleaved by using a mixture of boron triffuoride etherate and either ethanethiol or ethane-1,2-dithiol; for example 2,3,4,6-tetra-O-benzyl-a-~-glucopyranose yields ethyl 1-thio-aP-D-glucopyrano-side and dibenzylethylsulphonium tetrafluoroborate when treated with ethane- thiol and the etherate.'59 An alternative method for the debenzylation of sugars involves free-radical bromination to form a stable a-bromobenzyl ether which is hydrolysed by alkali to regenerate the hydroxy-group.'60 Steroidal benzyl ethers have been removed by treatment with trityl fluoroborate and this extremely mild and neutral procedure should be applicable to the deprotection of carbohydrates.' The but-2-enyl ether group offers interesting possibilities for the protection of sugars since it is stable to mild acid and to the basic conditions 149 A.Ya. Khorlin S. E. Zurabyan N. I. Dubrovina V. F.Bystrov G. V. Vikha and E. D. Kaverzneva Carbohydrate Res. 1972 21 316; I. V. Vikha V. G. Sakharovsky V. F. Bystrov and A. Ya. Kho,rlin ibid. 1972 25 143. 150 J. Labat F. Baumann and J.-E. Courtois Carbohydrate Res. 1973 26 341. ''I J. S. Brimacombe A. M. Mofti and L. C. N. Tucker J. Chem. SOC.(C) 1971 291 1. 52 A. M. Spichtig and A. Vasella Helv. Chim. Acta 1971 54 1191. J. B. McAlpine J. W. Corcoran and R. S. Egan J. Antibiotics 1971 24 51. 154 H. Bjorndal B. Lindberg and W. Nimmich Acta Chem. Scand. 1970 24 3414. "' J. S. Brimacombe N. Robinson and J. M. Webber J. Chem. SOC.(C) 1971 613. J. S. Brimacombe I. Da'Aboul and L. C. N. Tucker J. Chem. SOC.(0,1971 3762. ' 57 A. Penman and D. A. Rees J.C.S. Perkin I 1973 21 88. Q. Khuong-Huu C. Monneret I.Kabore and R. Goutarel Tetrahedron Letters 1971 1935. 159 H. G. Fletcher jun. and H. W. Diehl Carbohydrate Res. 1971 17 383. 160 J. N. BeMiller and H. L. Muenchow Carbohydrate Res. 1973 28 253. 161 D. H. R. Barton P. D. Magnus G. Streckert and D. Zurr Chem. Comm. 1971 1109. Monosaccharides 451 required for alkylation but it is readily cleaved with potassium t-butoxide in DMSO at room temperature'62 (cf the 2-methylallyl group' 63). A useful review of the synthesis and ring-opening reactions of sugar epoxides has appeared.' 64 Ring opening of methyl 2,3-anhydro-4,6-0-benzylidene-a-D-allopyranoside with iodine and methanol gives methyl 4,6-0-benzylidene-3-0- methyl-a-D-glucopyranoside (30x)and methyl 4,6-0-benzylidene-2-O-methyl-a-D-altropyranoside (10%) apparently infringing the rule of diaxial opening of conformationally stabilized epoxides.l6 Participation by a vicinal trans-located acetoxy-group has been demonstrated in the solvolyses of sugar epox- ides.'66 In the presence of water the cyclic acetoxonium ion is opened to form a cis-monoester whereas under anhydrous conditions three products are formed by attack at the different sites in the intermediate. Ethanethiolysis of the cyclic acetal (65) has been shown to give the D-allose diethyl dithioacetal(66) by transmission of the alkylthio-group along the carbon chain [see (67)];167 an analogous mechanism also explains the conversion of CH ,OBz BzO I 0-'CMe 3-0-benzoyl- 1,2 :5,6-di-0-isopropylidene-a-~-glucofuranose into ethyl 4-0-benz- oyl-2,3,6-tri-S-ethy1-1,2,3,6-tetrathio-a-~-mannopyranoside.'~~ Treatment of 5-thio-D-ribopyranose with methanethiol and hydrochloric acid affords methyl 1,5-dithio-a~-~-ribopyranosidepreference to the acyclic dithioacetal.' 69 in A new preparation of sugar methylene acetals consists of allowing vicinal diols (or alcohols) to react with N-bromosuccinimide in DMS0,17' while an alternative preparation of benzylidene acetals utilizes the reaction between glycosides and benzal chloride ;' ' only the thermodynamically more-stable diastereoisomer appears to be formed in the latter reaction.D-Glucose and 2-acetamido-2-deoxy-~-glucose,-D-mannose and +galactose yield the corres- ponding 4,6-O-isopropylidenealdopyranosewhen treated at room temperature P.A. Gent R. Gigg and R. Conant J.C.S. Perkin I 1972 1535. P. A. Gent R. Gigg and R. Conant J.C.S. Perkin I 1973 1858. 164 N. R. Williams Adv. Carbohydrate Chem. Biochem. 1970 25 109. 16' J. S. Jewel1 and W. A. Szarek Carbohydrate Res. 1971 16 248. J. G. Buchanan J. Conn A. R. Edgar and R. Fletcher J. Chem. SOC.(0,1971 1515. G. S. Bethel1 and R. J. Ferrier J.C.S. Perkin I 1972 1033. G. S. Bethel1 and R. J. Ferrier J.C.S. Perkin I 1973 1400. 169 C. J. Clayton and N. A. Hughes Carbohydrate Res. 1973 27 89. "O ' ' S.Hanessian P. Lavallee and A. G. Pernet Carbohydrate Res. 1973 26 258. P. J. Garegg L. Maron and C.-G. Swahn Acta Chem. Scad. 1972 26 5 18. J. S. Brimacombe and L. C. N. Tucker with a slight excess of 2,2-dimethoxypropane in DMF in the presence of toluene- p-sulphonic Markedly different products are obtained at 80 “C using this combination of reagents; 2-acetamido-2-deoxy-~-gliicose,for example gives a mixture of the methyl j3-glycosides (68) and (69).173 It is concluded from a comparison of the benzylidenations of D-glucitol under conditions of kinetic and thermodynamic control that Barker and Bourne’s rules are valid only if the acetalization of alditols is carried out under kinetic contr01.l~~ There are important consequences for carbohydrate chemistry in the observation that vicinal oxygen substituents prefer a gauche arrangement in solution.Thus formation of the cis-fused 1,3 :2,4-diacetal (70) in preference to the 2,4:3,s-diacetal (71) with a trans-fused ring-system on condensation of D-arabinitol with formaldehyde under conditions of equilibration is rationalized by the realization that the cis-fused system (70)can adopt a conformation in which onlygauche oxygen-oxygen interactions are present.I7’ The broader implications for carbohydrate chemistry of the orientations of unshared electron pairs and polar bonds on adjacent pyramidal atoms are discussed in a recent review.’76 Partial epimerization at C-2 accompanies acetolyses of 1,2:5,6-di-O-iso-propylidene-@-D-allofuranose,l and furanoid derivatives of D-ribose D-ly~ose,~~~ all of which possess a cis-configuration at C-2 and ~-rhamnose,’’~ and C-3.A. Hasegawa and H. G. Fletcher jun. Carbohydrate Res. 1973 29 209. 173 A. Hasegawa and H. G. Fletcher jun.Carbohydrate Res. 1973 29 223. 174 R. Bonn and I. Dijong Chem. Ber. 1972 105 3833. 75 L. Phillips and V. Wray J.C.S. Chem. Comm. 1973 90. 176 J. F. Stoddart in MTP Internat. Review of Science Series 1 Vol. 7 ‘Carbohydrates’, ed. G. 0.Aspinall Butterworths London 1973 p. 1. 177 W. Sowa Canad. J. Chem. 1972 50 1092. 178 G. J. F. Chittenden Carbohydrate Res. 1972 22 491. P. J. Boon A. W. Schwartz and G. J. F. Chittenden Carbohydrate Res. 1973,30 179. Monosaccharides 453 Details of the synthesis and general properties of a-(dimethylamino)-benzyli-dene and -ethylidene acetals have been reported. These acetals give monoesters on acid hydrolysis with regiospecific formation of the primary monoester when primary centres are involved.'80 Mixtures of isomeric monobenzoates are usually produced by photolysis of carbohydrate benzylidene acetals,18 ' whereas photolysis of the 0-nitrobenzylidene a-glycoside (72) affords only the 2-o-nitro- benzoate (73) after peroxy-acid oxidation of the initial photo-product.'82 AcoG Me 00 \ / NO 6 Halogenated Sugars 2,3,4-Tri-O-acetyl-f-~-arabinopyranosyl bromide has been shown to adopt essentially the same 'C conformation both in solution and in the crystalline state although certain discrepancies are apparent between dihedral angles measured from the crystallographic data and those obtained by n.m.r. spectro- scopy.' A useful method for preparing glycosyl halides involves treatment of either aldose 1,2-0rthoesters'~~ or acetylated aldoses' 85 with a dihalogenomethyl methyl ether although halogenation at C-2 sometimes accompanies prolonged reaction.A kinetic study of the exchange reaction between acetobromo-sugars and lithium bromide in acetone has indicated that the reactions are second order even when there is evidence of neighbouring-group participation. l8 Bimolecular halogen exchange appears to be rate-determining in the hydrolysis of a-aceto- bromo-sugars in aqueous acetone in the presence of alkali-metal halides.' The mechanism of formation of arabinofuranosyl halides has been studied in derivatives protected by such groups as benzyl and p-nitrobenzyl.' 88 Kinetically controlled formation of the a-halide precedes anomerization to the P-halide and S. Hanessian and E. Moralioglu Canad.J. Chem. 1972 50 233. 18' K. Matsuura S. Maeda Y.Araki and Y.Ishido Bull. Chem. Soc. Japan 1971,44,292. P. M. Collins and N. N. Oparaeche J.C.S. Chem. Comm. 1972 532. P. W. R. Corfield J. D. Mokren P. L. Durette and D. Horton Carbohydrate Res. 1972 23 158. 184 I. Farkas Z. Dinya I. F. Szabo and R. Bognar Carbohydrate Res. 1972 21 331. K. Bock C. Pedersen and P. Rasmussen J.C.S. Perkin I 1973 1456. 186 M. J. Duffy G. Pass and G. 0.Phillips J. Chem. Soc. (B) 1971 785. " M. J. Duffy M. Jeffries G. Pass and G. 0.Phillips J.C.S. Perkin ZI 1972 82 1. G. P. J. Glaudemans and H. G. Fletcher jun. J. Org. Chem. 1971 36 3598. 454 J. S. Brimacornbe and L. C.N. Tucker it is suggested that 'participation' by the C-5 benzyloxy-group may be responsible for inducing the formation of the a-halide.Hydroxy-groups in otherwise protected sugars can be replaced by halogen on treatment with triphenylphosphine and a carbon tetrahalide.189. '90 Intro-duction of a chloro-group occurs with inversion of configuration at secondary ~entres,'~' whereas retention of configuration is observed in the bromination of the sugar moiety of certain nu~leosides.'~~ Primary hydroxy-groups in carbo- hydrate derivatives have been selectively halogenated using triphenylphosphine and the appropriate N-halogenosuccinimide in DMF.19' A related reaction in- volves halide displacements on such alkoxyphosphonium salts as (74) which are prepared by reaction of the glycoside with tris(dimethy1amino)phosphine in DMF.192 Terminal chlorodeoxy-sugars [e.g.(75)] can be prepared by treating such diols as (76) with acetylsalicyloyl chloride in the absence of an acceptor for the hydrogen chloride formed.' 93 Chlorodeoxy-sugars [e.g.(77)] can also be prepared by decomposition of the thermally unstable salt (78) that results when CH ,06(NMe2)3CI -CH,R' R30iq> HO(ZJMe OH \ 0-CMe (74) (75) R' = C1; R2 = Ac Ts or CONHPh; R3 = Ac (76) R' = OH; R2 = Ac Ts or CONHPh; R3 = H CH2R OMe (77) R = C1 (78) R = OCO the hydroxy-group is treated with an aryl cyanate in the presence of hydrogen chloride ;replacement of secondary hydroxy-groups by this procedure occurs with inversion of configuration.' 94 The formation of ring-contracted products (79) lE9K.Haga M. Yoshikawa and T. Kato Bull. Chem. SOC.Japan 1970,43 3922; C. R. Haylock L. D. Melton K. N. Slessor and A. S. Tracey Carbohydrate Res. 1971 16 375; F. W. B. Einstein and K. N. Slessor Canad. J. Chern. 1972 50 93. 190 J. P. H. Verheyden and J. G. Moffatt J. Org. Chem. 1972 37 2289. 19' M. M. Ponpipom and S. Hanessian Carbohydrate Res. 1971 18 342; S. Hanessian M. M. Ponpipom and P. Lavallee ibid. 1972 24 45. 19* B. Castro Y. Chapleur B. Gross and C. Selve Tetrahedron Letters 1972 5001. 193 A. A. Akhrem G. V. Zaitseva and I. A. Mikhailopulo Carbohydrate Res. 1973 30 223. Iy4 A. Klemer and G. Mersmann carbohydrate Res. 1972 22 425. 455 Monosaccharides Me 00 00 \/ \/ CMe CMe2 (79) R' =I; R2=H (80) R' =H; R2=I (81) and (SO) in addition to the iodo-compound (81) of retained configuration when methyl 2,3-O-isopropylidene-a-~-rhamnopyranoside is treated with triphenyl phosphite methiodide has been attributed to participation by the ring-oxygen atom in the displacement on the phosphorane intermediate.Ig5 An impressive array of specifically fluorinated sugars has been synthesized in recent years by methods that chiefly include nucleophilic displacements on sugar sulphonates with fluoride salts in (dipolar) aprotic solvents the addition of trifluoro(fluoroxy)methane to acetylated glycals and the opening of sugar epoxides.Deoxyfluoro-sugars synthesized by these methods include 6-deoxy-6- fluoro-~-glucose,'~~3-deoxy-3-fluoro-~-galactose'~~ and -~-idose,"* 4-deoxy-4-fluoro-~-galactose~~~ and -D-glucose,2°0 5-deoxy-5-fluoro-~-xylose,~~~ 2-deoxy-2-fl~oro-~~~ and 1-deoxy-1-fluoro-D- and glycerol,^^^.^'^ 2-deoxy-and 2-fluoro-~-galactose,~~~ the four isomeric 2-deoxy-2-fluoro-~-pent-oses.205,206Addition of trifluoro(fluoroxy)methane to 3,4-di-O-acetyl-~-ara-binal for example affords the cis-adducts (82) (83) and (84) which are converted OAc OAc F (82) R =OCF (84) (83) R =F I95 N.K. Kochetkov A. I. Usov and K. S. Adamyants Tetrahedron 1971 27 549. 196 E. M. Bessell A. B. Foster J. H. Westwood L. D. Hall and R. N. Johnson Carbo-hydrate Res. 1971 19 39. 197 J. S. Brimacombe A. B. Foster R. Hems J. H. Westwood and L. D. Hall Canad. J. Chem. 1970,48 3946. 198 J. S. Brimacombe A. M.Mofti and J. H. Westwood Carbohydrate Res. 1972,21,297. 199 D. M. Marcus and J. H. Westwood Carbohydrate Res. 1971 17 269. 200 A. D. Barford A. B. Foster J. H. Westwood L. D. Hall and R. N. Johnson Carbo-hydrate Res. 1971 19 49. 20 I P. W. Kent and R. C. Young Tetrahedron 1971 27 4057. 202 W. J. Lloyd and R. Harrison Carbohydrate Res. 1971 20 133. 203 G. S. Ghangas and T. P. Fondy Biochemistry 1971 10 3204. 204 J. Adamson and D. M. Marcus Carbohydrate Res. 1972 22 257. 205 E. L. Albano R. L. Tolman and R. K. Robins Carbohydrare Res. 1971 19 63. 206 C. G. Butchard and P. W. Kent Tetrahedron 1971 27 3457. J. S.Brimacornbe and L. C. N. Tucker into 2-deoxy-2-fluoro-~-arabinoseand +-ribose on hydrolysis with acid.205 2-Deoxy-2,2-difluoro-~-~rabino-hexose has been prepared by way of a similar reaction on the fluorinated glycal (85).207 The key steps in an ingenious synthesis of the fluorine-containing antibiotic nucleocidin (86)utilizes the regiospecific addition of iodofluoride (in the form of iodine and silver fluoride) to the un- saturated-sugar nucleoside (87).208 CH,OAc HO OH 00 'CIA, (86) 7 Unsaturated Sugars The general availability of unsaturated sugars in recent years has considerably increased the synthetic applications of this class of sugar.1,5-Diazabicyclo[5,4,0]undec-5-enehas been confirmed as an excellent base for trans-elimination of hydrogen halide from cis-1,2-glycosyl halide^.^".^ trans-1,2-Glycosyl halides can also be converted into 2-hydroxyglycal derivatives using this base in hexamethylphosphortriamide in the presence of lithium bromide presumably following bromide-catalysed anomerization of the starting materiaL2 O A highly stereoselective bishydroxylation of D-galactal to give D-talose is achieved with hydrogen peroxide in the presence of sodium molybdate,21 thereby improving on the selectivity obtained by most other methods.Methoxy- mercuration of the acetates of D-glucal D-galactal L-arabinal and D-xylal results in regiospecific trans-addition to the alkenic bond with the mercury 207 J. Adamson A. B. Foster and J. H. Westwood Carbohydrate Res. 1971 18 345. 208 I. D. Jenkins J. P. H. Verheyden and J. G. Moffatt J. Amer. Chem. SOC.,1971,93,4323. 209 D. R.Rao and L. M. Lerner Carbohydrate Res.1971 19 133; 1972 22 345. 210 N. A. Hughes Carbohydrate Res. 1972 25 242. 'I1 V. Bilik Chem. Zvesti 1972 26 76. Monosaccharides 457 atom adding to C-2 although the proportion of diaxial to diequatorial addition is influenced by the configuration of the group at C-4.212By contrast the cis-adduct (88) is obtained on treatment of 3,4,6-tri-0-acetyl-~-glucalwith mercuric acetate in aqueous acetone and the corresponding a-acetate is formed under anhydrous conditions by way of the intermediate (89).’l3 The 2,3-unsaturated sugar (90) results from iodide-catalysed deoxymercuration of methyl 2-(acetoxy- mercur~)-3,4,6-tr~-0-acetyl-2-deoxy-~-~-glucopyranoside,’ whilst reductive de- mercuration of such adducts to the 2-deoxy-sugar can be achieved either with sodium borohydride’ or by photolysis in methanol.* Equimolar oxy- mercuration of 3,4,6-tri-O-acetyl-~-glucal with mercuric perchlorate has been used in the synthesis of 2’-deoxy-disa~charides.~ l7 CH,OAc CH,OAc CH,OAc Further reports have appeared on the multifarious reactions which glycal esters undergo in liquid hydrogen fluoride.’ l8 Typically treatment of the D-galactal tribenzoate (91)with hydrogen fluoride at -70 “C affords the glycosyl fluorides (92) (93) and (94).Pedersen’s group have also noted that boron trifluoride-catalysed reactions between glycal esters and methanol are influenced CH,OBz cH,OBz CH,OBz CH,OBz CH,OBz (93) Bzod (94) 212 K.Takiura and S. Honda Carbohydrate Res. 1972 21 379. 213 K. Takiura and S.Honda Carbohydrate Res. 1972 23 369. ’14 A. DeBoer G. J. Thanel and G. A. Wilson Tetrahedron Letters 1972 5137. ” S. Honda K. Izumi and K. Takiura Carbohydrate Res. 1972 23 427. ’16 D. Horton J. M. Tarelli and J. D. Wander Carbohydrate Res. 1972 23 440. ’17 S. Honda K. Kakehi H. Takai and K. Takiura carbohydrate Res. 1973 29 477. I. Lundt and C. Pedersen Acta Chem. Scand. 1971,25,2749; K. Bock and C. Pedersen ibid. pp. 1021 2757. J. S.Brimacombe and L. C. N. Tucker by the proportions of the reactant^.^" Thus the glycal ester (95)gives (96) (19%) and (97) (73 %) on brief treatment with two molar proportions of methanol whereas the methyl ethers (98)and (99)result from the non-specific addition of BzO BzO (96) (97) (95) R2 (98) R' = OMe; R2 = H (99) R' = H; R2 = OMe methanol to (97) when more alcohol is used.In a somewhat related biochemical study D-glucal and D-galactal have been treated with p-glucosidase and p-galactosidase respectively in the presence of glycerol to give glyceryl2-deoxy-p- D-hexopyranosides and in the former case a minor proportion of the rearranged product glyceryl2,3-dideoxy-/?-~-erythro-hexopyranoside.~~~ In extending their work on allylic rearrangements of glycal esters Ferrier and his group have established that 3,4,6-tri-0-acetyl-~-glucalgives the 2,3-unsaturated sugar (100) on condensation with substituted purine (B) and that the product is rearranged to the 3-deoxyglycal derivative (101)on heating with acids or in inert high- boiling solvents.221 The formation of (3-deoxyhex-2-enosy1)purmederivatives CH ,OAc CH20Ac (100) B = purine (101) from 2-hydroxyglycal esters and 3-deoxyhex-2-enopyranose esters has also been studied.222 A series of allylic rearrangements of azido- and thiocyanato-sugar derivatives is of interest from a synthetic viewpoint since they enable nitrogen-functions 219 K.Bock,J. K. Christiansen and C. Pedersen Carbohydrate Res. 1971 20 73. 22Q J. Lehmann and E. Schroter Carbohydrate Res. 1972 23 359. 221 R. J. Ferrier and M. M. Ponpipom J. Chem. SOC.(C) 1971 553. 222 R. J. Ferrier and M. M. Ponpipom J. Chem. SOC.(C) 1971 560. Monosaccharides 459 to be introduced at C-2 of pyranoid rings.223 Thus treatment of ethyl 2,3- dideoxy-4,6-di-O-methylsulphonyl-a-~-erythro- and -threo-hex-2-enopyrano-sides with either azide or thiocyanate ions at ambient temperature results in selective S,2 displacement of the allylic sulphonyloxy-group at C-4.The products [e.g.(102)] are isomerized on heating; the azide gives an equilibrium mixture of the two possible products (102; R = N3) and (103; R = N3) whereas the thio- cyanate (102; R = SCN) is completely transformed into the 3,4-unsaturated isothiocyanate (103 ;R = NCS). The branched-chain derivative (104) is obtained CH,OMs CH 20COC6H4N02-p CH,CHO (102) R = -SCN or N (103)R =. NCS or N (104) by Claisen rearrangement of the corresponding 2,3-dideoxy-4-0-vinylhex-2-en~pyranoside.~~~ Formamide225 and acetone226 have been added to 3,4,6-tri-O-acetyl-~-glucal by photochemical processes and similar addition of 2,3-dimethylbut-2-ene to the alkenic bond of the enone (105) yields three cyclobutane adducts and a dimer.227 Base-catalysed cis-eliminations in methyl 4,6-0-benzylidene-a-~-altropyrano-sides containing diaxial 2(3)-phenylthio and 3(2)-methylsulphonyl substituents appear to be highly dependent on the location of the substituents and the solvent.228 The ease of cis-elimination in methyl (methyl 2,3,4-tri-O-methyl-a-~- gluco- and -manno-pyran0sid)uronates to form the 4,5-unsaturated glycosides has been attributed to ring flexibility which allows a change in conformation; both eliminations are suggested to proceed via an Elcb mechanism.229 223 R.J. Ferrier and N. Vethaviyasar J.Chem. SOC.(0,1971 1907. lZ4 R. J. Ferrier and N. Vethaviyasar J.C.S. Perkin I 1973 1791. 22s A. Rosenthal and A. Zanlungo Canad. J. Chem. 1972,50 1192. 226 K.-S. Ong and R. L. Whistler J. Org. Chem. 1972 37 572; K. Matsuura Y. Araki Y. Ishido A. Mural and K. Kushida Carbohydrate Res. 1973 29 459. 227 P. M. Collins and B. R. Whitton J.C.S. Perkin I 1973 1470. 22a S. Hanessian and A. P. A. Staub Carbohydrate Res. 1971 16 419. 229 J. N. BeMiller and G. V. Kumari Carbohydrate Res. 1972 25 419. J. S. Brimacombe and L. C. N. Tucker 8 Deoxy-sugars and Branched-chain Sugars 6-Deoxy-~-altrose has been isolated from the lipopolysaccharide of Yersinia enterocoliti~a,~~~ and 7-deoxy-~-altro- and 7-deoxy-~-g~ycero-~-g~uco-heptose heptulose have been isolated from fermentation broths of Streptornyces set~nensis.~ Useful syntheses of L-fucose (from 2,3 :4,5-di-O-isopropylidene-~-galactose diethyl dithi~acetal)~~ and L-quinovose (by epimerization of ~-rhamnose)~~ have been described.Stereospecfic syntheses of 2-deoxy-(2R)- and -(2S)-deuterio- D-erythro-pentoses have been accomplished ;234 for instance the (R)-isomer (106) is obtained by reaction of the unsaturated glycoside (107) with lithium aluminium deuteride and subsequent treatment of the product (108) with osmium HO D “1 n tetroxide periodate ion and acid. Alternative syntheses of the biologically important dideoxy-sugars paratose (3,6-dideoxy-~-ribo-hexose)and tyvelose (3,6-dideoxy-~-arabino-hexose),~~~ and the trideoxy-sugars L-amicetose (2,3,6- trideoxy-L-erythro-hexose) and L-rhodinose (2,3,6-trideoxy-~-threo-hexose)~~~ have become available.A practical synthesis of 2’-deoxyuridine is based on treatment of 2’,3’-benzyli- deneuridine (109) with N-bromosuccinimide to give the cis-bromobenzoate (1lo) which is subsequently debrominated and de-e~terified.~~~ Another novel 0 0 BzO Br (110) 230 D. C. Ellwood and G. R. A. Kirk Biochem. J. 1971 122 14P. 231 T. Ito N. Ezaki T. Tsuruoka and T. Niida Carbohydrate Res. 1971 17 375. 232 M. Dejter-Juszynski and H. M. Flowers Carbohydrate Res. 1973 28 144. 233 V. Bilik W. Voelter and E. Bayer Annalen 1972 759 189. 234 B. Radatus M. Yunker and B. Fraser-Reid J. Amer. Chem. SOC.,1971 93 3086. 235 E. H. Williams W. A. Szarek and J.K. N. Jones Canad. J. Chem. 1971 49 796. 236 A. H. Haines Carbohydrate Res. 1972 21 99; J. S.Brimacombe L. W. Doner and A. J. Rollins J.C.S. Perkin I 1972 2977. 237 M. M. Ponpipom and S. Hanessian Canad. J. Chem. 1972 50. 246. 253. Monosaccharides 46 1 method of introducing deoxy-functions into the sugar moiety of nucleosides involves treatment with a-acetoxyisobutyryl chloride in the presence of sodium iodide and hydrogenolysis of the resulting iodo-c~mpound.~~~ Reviews23 have appeared on the synthesis chemistry and biochemistry of branched-chain sugars. The structure of the highly methylated branched-chain sugar nogalose (from nogalamycin) has been established as 6-deoxy-3-C-methyl- 2,3,4-tri-O-rnethyl-~-mannose,~~~ and a heptasaccharide produced by hydrolysis of everninomicin B contains a new sugar D-evalose (6-deoxy-3-C-methyl-~- mannose) as one of its components.241 Garosamine the common component of the gentamicin C antibiotic complex has been shown to be 3-deoxy-4-C- methyl-3-methylamino-~-arabinose(1 11),242 and its synthesis243 has been described.Another branched-chain sugar glycoside (1 12) has been isolated from methanoiysates of the antitumour antibiotic ~ibiromycin.’~~ Me H,OH ‘($z?MeHN{kfMe OH HO (1 11) (1 12) A number of new approaches have been made to the synthesis of branched-chain sugars. 2-Lithio-1,3-dithian for example has been added to the 3-ulose (I 13) to give the branched derivative (1 14) which is converted via (1 15) into ~-streptose.~~~ Other examples246 of the use of this and related reagents in the (1 13) ISI (I 14) R = -CHSCH2CH2CH2 (115) R = -CHO 238 M.J. Robins J. R. McCarthy R. A. Jones and R. Mengel Canad. J. Chem. 1973 51 1313. 239 T. D. Inch Adc. Carbohydrate Chem. Biochem. 1972 27 191 ; H. Grisebach and R. Schmid Angew. Chem. internat. Edn. 1972 11 159. 240 P. F. Wiley D. J. Duchamp V. Hsiung and C. C. Chidester J. Org. Chem. 1971 36 2670. 241 A. K. Ganguly and A. K. Saksena J.C.S. Chem. Comm. 1973 531. 242 D. J. Cooper M. D. Yudis R. D. Guthrie and A. M. Prior J. Chem. SOL..(C),1971 960. 243 W. Meyer zu Reckendorf and E. Bischof Chem. Ber. 1972 105 2546. 244 A. S. Mesentsev and V. V. Kuljaeva Tetrahedron Letters 1973 2225. 245 H. Paulsen V. Sinnwell and P.Stadler Chem. Ber. 1972 105 1978. 246 H. Paulsen and H. Redlich Angew. Chem. Internat. Edn. 1972 11 1021 ;A. M. Sepul-chre A. Gateau-Olesker G.Lukacs G.Vass S. D. Gero and W. Voelter Tetrahedron Letters 1972 3945. J. S. Brimacombe and L. C. N. Tucker synthesis of branched-chain sugars including its use in the opening of sugar ep~xides,~~’ have been reported. A Wittig reaction on the 3-ulose (116) has yielded the isomeric cyanomethylene derivatives (1 17) which on bishydroxylation and loss of hydrogen cyanide afford a sugar (118) having the branch on the more (116) X = 0 H / (117) X = C \ CN hindered face of the molecule ;248 other related examples have been reported.249 The sugar derivative (119) containing a functionalized branch-chain has been prepared by base-catalysed cyclization of the malonic ester derivative (120).250 Functionalized branched-chain sugars have also been obtained from the 3-ulose (116) by treatment with ethyl isocyanoacetate in the presence of base followed by either reduction or bishydroxylation of the product (121).251Condensation of nitroethane with periodate-oxidized uridine and reduction of the nitro-derivatives affords a series of branched-chain amino-sugars (122) containing principally the D-gfuco-isomer and smaller proportions of the D-galacto- manno no- and ~-a/fo-isomers.~~~ 24’ A.M. Sepulchre G. Lukacs G. Vass and S. D. Gero Bull. SOC. chim. France 1972 4000. 248 J. M. J. Tronchet and J. M. Bourgeois Helv. Chim. Acta 1972,55,2820; A.Rosenthal and D. A. Baker Carbohydrate Res. 1973 26 163. 249 J. M. J. Tronchet R. Graf and R. Gurny Helv. Chim. Acta 1972 55 613; J. M. J. Tronchet and J. M. Chalet Carbohydrate Res. 1972,24 283. S. Hanessian P. Dextraze and R. Masse Carbohydrate Res. 1973 26 264. 251 A. J. Brink J. Coetzer A. Jordaan and G. J. Lourens Tetrahedron Letters 1972,5353. 252 F. W. Lichtenthaler and H. Zinke J. Org. Chem. 1972,37 1612. Monosaccharides 463 Me {H20p0 N HO H2N Me OH CHO 9 Amino-and Nitro-sugars The equilibrium (123) e(124) established in the presence of antimony penta- chloride lies very much in favour of the oxazolinium ion (124) and this has enabled the acetamido-ester (125) to be converted into the C-2 epimer (126) Me I I i124) Me CH~OAC CH~OAC OAc (125) following hydrolysis of the oxazolinium 2-Amino-2,6-dideoxy-r.-mannose (L-rhamnosamine) -L-glucose (L-quinovosamine) -L( D)-galactose (fuco- samine) and -L(D)-talose (pneumosamine) have been obtained by base-catalysed condensation of nitromethane with the appropriate 5-deo~ypentose.~'~ A number of new amino-sugars have been found as components of antibiotic substances.Ethanethiolysis of the N-acetylated gentamicin C complex25 gave as their diethyl dithioacetals three new sugars (127H129) (purpurosamines 253 H. Paulsen and C.-P. Herold Chem. Ber. 1971 104 131 1. 254 M. B. Perry and V. Daoust Carbohydrate Res. 1973,27,460; Canad. f.Chem. 1973 51 974. 255 D. J. Cooper Pure Appl. Chem. 1971 28 455.J. S. Brimacombe and L. C. N. Tucker NH2 (127) R' = R2 = Me (128) R' = Me; R2 = H (129) R' = R2 = H A B and C respectively) which constitute a new class of naturally occurring amino-~ugar.~~~ Syntheses of methyl purpurosaminide C257and derivatives of 2,6-diamino-2,3,4,6-tetradeoxy-~-threo-hexose (epi-purpurosamine C)258have been described. An unsaturated analogue of purpurosamine C viz. a 2,6-diamino-2,3,4,6-tetradeoxy-hex-4-enose, occurs as a component of sisomicin (from Micrornonospora inyoensis) which also contains deoxystreptamine and the branched-chain sugar garo~amine'~~ (see p. 461). Vancosamine a branched- chain amino-sugar isolated from hydrolysates of the antibiotic vancomycin has been characterized as 3-amino-2,3,6-trideoxy-3-C-methyl-~-lyxoopyran-ose (130).260Ethyl 2,6-diacetamido-2,3,6-trideoxy-a-~-ribo-hexopyranoside ( 131) I FH2NHAc has been synthesized and shown to be identical with the glycoside derived from a diamino-sugar component of the antibiotic nebramycin factor 6,26 and 2,3,6- trideoxy-3-dimethylamino-~-lyxo-hexopyranose (D-rhodosamine)262 has been isolated from the megalomicin complex (a new class of macrolide antibiotic elaborated by Micrornonospora megalornicea).Another new group of antibiotics the validamycins contains inter ah the novel amino-cyclitols validamine (1 32) and hydroxyvalidamine (1 33).263 Other naturally occurring amino-sugars 256 D. J. Cooper M. D. Yudis H. M. Marigliano and T. Traubel J. Chem. Soc. (C) 1971 2876.257 S. Umezawa T. Tsuchiya and k.Okazaki Bull. Chem. Soc. Japan 1971,44 3494. 258 R. D. Guthrie and G. J. Williams J.C.S. Perkin I 1972 2619. 259 D. J. Cooper R. S. Jaret and H. Reimann Chem. Comm. 1971 285; H. Reimann R. S. Jaret and D. J. Cooper ibid. 924. 260 W. D. Weringa D. H. Williams J. Feeney J. P. Brown and R. W. King J.C.S. Perkin I 1972 443; A. W. Johnson R. M. Smith and R. D. Guthrie ibid.,p. 2153. 261 J. Cleophax S. D. Gero J. Leboul and A. Forchioni J.C.S. Chem. Comm. 1973 710. 262 A. K. Mallams J.C.S. PerkinI 1973 1369. 263 S. Horii T. Iwasa E. Mizuta and Y. Kameda J. Antibiotics 1971,24 61 ;K. Kamiya Y. Wada S. Horii and M. Nishikawa ibid. p. 317. 465 Monosaccharides CH,OH OH (132) R = H (133) R = OH to be synthesized include derivatives of 4-amino-2,4,6-trideoxy-3-O-methyl-D-xyb-hexopyranose (~-holacosamine),~~~ a component of the leaves of Holu-rrhena antidysenterica and 2,4-diamino-2,4,6-trideoxy-~-glucose,~~~ a constituent of the polysaccharide from Bucillus licheniforrnis.The nucleoside moiety (C-substance) (134) of gougerotin (135) has been synthesized266 and in a total synthesis of the antibiotic. The 6-hydroxy- methyl analogue (136) of gougerotin has been prepared268 and was shown to OH (134) R' = C02H; R2 = H (135) R' = CONH,; R2 = COCHNHCOCH,NHMe I CH,OH (136) R' = CH20H; R2 = COCHNHCOCH,NHMe I CH20H exhibit biological activity. Cytosinine (1 37) the nucleoside component of blasticidin S has been ~ynthesized,~~' and studies pertaining to the total syntheses of blasticidin S and gougerotin have been ~ummarized.~'~ Other notable achievements have been the synthesis of cytosamine (1313)~~ (thereby formally 264 R.Goutarel C. Monneret P. Choay I. Kabore and Q. Khuong-Huu Carbohydrate Res. 1972 24 297. 265 A. Liav J. Hildesheim U. Zehavi and N. Sharon J.C.S. Chem. Comm. 1973 668. 266 K. A. Watanabe I. M. Wempen and J. J. Fox Carbohydrate Res. 1972 21 148. 267 K. A. Watanabe E. A. Falco and J. J. Fox J. Amer. Chem. SOC.,1972 94 3272. 268 F. W. Lichtenthaler G. Trummlitz G. Bambach and I. Rycklik Angew. Chem. Internat. Edn. 1971,10,334; K. A. Watanabe E. A. Falco and J. J. Fox J. Org. Chem. 1972 37 1198. 269 T. Kondo H. Nakai and T. Goto Tetrahedron Letters 1972 1881."O J. J. Fox and K. A. Watanabe Pure Appl. Chem. 1971,28,475. 271 C. L. Stevens J. Ntmec and G. H. Ransford J. Amer. Chem. Soc. 1972 94 3280. J. S. Brimacombe and L. C. N. Tucker completing the synthesis of the antibiotic plicacetin) and the total syntheses of kas~gamycin~~~ and thymine polyoxin C (139) (a fungal-nucleoside antibiotic).* 73 There has been a resurgence of interest in the deamination of amino-sugars. The action of nitrous acid on 2-amino-2-deoxy-~-g~ucose diethyl dithioacetal affords the rearranged product (140) presumably by way of a 1,2-episulphonium CH,OH ion.274 Participation by the ring-oxygen atom dominates the deaminations of methyl 4-amino-4-deoxy-a-~-glucopyranoside~~~ and methyl 4-amino-4,6-di- 272 Y.Suhara F. Sasaki G. Koyama K. Maeda H. Umezawa and M. Ohno J. Amer. Chem. Soc. 1972 94 6501 ; S. Yasuda T. Ogasawara S. Kawabata I. Iwataki and T. Matsumoto Terrahedron 1973 29 3 141. 273 H. Ohrui H. Kuzuhara and S. Emoto Tetrahedron Letters 1971 4267. 274 J. Defaye T. Nakamura D. Horton and K. D. Philips Carbohydrate Res. 1971 16 133. 275 N. M. K. Ng Ying Kin J. M. Williams and A. Horsington J. Chem. Soc. (0,1971 1578. Monosaccharides 467 deoxy-2,3-O-isopropylidene-a-~-mannopyr~oside,~’~ where the amino-groups are equatorially disposed. In such cases the products are formed stereospecifi- cally by attack of solvent on the bicyclic oxonium ion intermediates. In a related study the products of decomposition of the a-nitrosoamide (141) have been shown to depend on the solvent used.277 Thus in chloroform-ethanol the products (144) arise from the 1,2-acetoxonium ion (143) (pathway a) whereas the alternative pathway (141) *(142)--* (145)+3,4,6-tri-O-acetyl-2,5-anhydro-D-mannose (146) is followed in aqueous acetone.The deaminations of methyl a EtOHor AcO-1 CH,OAc AcOPAc AcOW AcO CHO AcO CH=OAc A AcOc OOAc BOR HI;) + t 146) t 145) (144) R = Ac or Et 4-amino-4-deoxy-a-~-galactopyranoside~~~ and methyl 2-amino-2-deoxy-a-~- mann~pyranoside~~’ yield the products (147) and (148) of hydride migration CH,OH R’0 R2 (ZJMe (147)R’= H; R2 = OH (148)R’= OH; R2= H respectively. 2-O-Methyl-~-glucose is also formed in the latter deamination by way of the 1,2-oxonium ion and a related mechanism via the 1,2-an- hydride is proposed for the stereospecific formation of D-glucose on treatment of 276 A.K. Al-Radhi J. S. Brimacombe and L. C. N. Tucker J.C.S. Perkin I 1972 315. 2’7 J. W. Llewellyn and J. M. Williams Carbohydrate Res. 1973 28 339. 278 N. M. K. Ng Ying Kin and J. M. Williams Chem. Comm. 1971 1123. 279 J. W. Llewellyn and J. M. Williams J.C.S. Perkin I 1973 1997. J. S. Brimacombe and L. C. N. Tucker 2-amino-2-deoxy-~-mannosewith nitrous acid. Although the epimeric amino- sugars (149) and (150) can be considered formally to yield the same carbonium ion on deamination conformational factors need to be invoked to account for differences in the distribution of products and for the formation of the rearranged product (151) from deamination of (149) in aqueous acetic acid.280 Me Me O /OCMe 0 0 (149) R' = NH,; R2 = H (150) R' = H; R2 = NH (151) R = H or Ac ' New routes to nitro-sugars are available from the oxidation of amino-sugars28 or sugar oximes282 with peroxy-acids.Base-catalysed condensation of the dialdehyde (152) with nitromethane yields a mixture of methyl 3-deoxy-3-nitro-a- D-glycopyranosides which are conveniently .separated as their 4,6-O-benzylidene CH,OH CHO derivatives ;the composition of this mixture is manno(42 %) gluco(41%) galacto (9%) and talo(8 %).283 However epimerization of the glycoside nitronates prior to acetalization gives these products in the ratio 15.5 :20 13 :51.5 respectively. In the presence of equimolar proportions of base the order of stability of the methyl 3,6-dideoxy-3-nitro-a-~-hexopyranosides (as the nitronates) is talo > manno > galacto z gluco whereas when traces only of base are present the stability of the nitro-glycosides is gluco > galacto z manno > These findings have been rationalized in terms of interactions.Optically active nitro-inositol derivatives have been prepared by cyclization (i.e. internal Henry addition) of 6-deoxy-3-O-methyl-6-nitro-~-glucose, and the time-dependent formation of the products has been examined.28s 280 J. S. Brimacombe and J. Minshall Carbohydrate Res. 1972 25 267. 281 H. H. Baer and S.-H. L. Ching Canad. J. Chem. 1973,51 1812. 282 T. Takamoto R. Sudoh and T. Nakagawa Tetrahedron Letters 1971 2053; Carbo-hydrate Res.1973 27 135; T. Takamoto M. Ohki R. Sudoh and T. Nakagawa Bull. Chem. SOC.Japan 1973 46 670. 283 H. H. Baer and W. Rank Canad. J. Chem. 1972,50 1216. 284 J. Kovai K. Capek and H. H. Baer Canad. J. Chem. 1971,49 3960. 285 J. Kovai and H. H. Baer Canad. J. Chem. 1973 51 2836. Monosacchar ides 469 Epoxidation of nitro-olefins [e.g. (153)] with hydrogen peroxide in weakly alkaline media gives mainly the or-nitro-oxiran [e.g. (154)] having the three- membered ring located trans to the aglycone.286 Reduction of such nitro-olefins ( 153) as (153) with sodium borohydride affords the saturated compound having the nitro-group equatorially oriented whereas the oxime results if zinc and acetic acid are Halogenation of methyl 4,6-0-benzylidene-3-deoxy-3-nitro-hexopyranosides is highly stereoselective and the gem-halogenonitro-sugar having the C-3 nitro-group in equatorial disposition is formed preferentially.288 286 H.H.Baer and W. Rank Canad. J. Chem. 1971,49 3192. 287 H. H. Baer and W. Rank Canad. J. Chem. 1972,50 1292. H. H. Baer and W. Rank Canad. J. Chem. 1973,51,2001.

ISSN:0069-3030    

DOI:10.1039/OC9737000431

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

15 Heterocyclic Chemistry By M. J. COOK and C. D. JOHNSON School of Chemical Sciences University of East Anglia Norwich NOR 88C The work described is classified in terms of ring size and within this scheme discussion of potentially aromatic or antiaromatic systems normally precedes that of saturated and simple unsaturated compounds. To avoid unnecessary duplication of material presented in other chapters little mention has been made of applications of physical methods and purely mechanistic studies. However the ever-increasing number of photochemical studies on heterocycles would certainly appear to warrant some description here and it is therefore hoped that readers will bear with any overlap that may thus result with Chapter 10. 1 Three-memberedRing Compounds MO calculations on oxiren 1H-azirine and thiiren reveal that these formally antiaromatic analogues of the cyclopropenyl anion should be stable,' an incentive for synthetic attempts and for postulation as reaction intermediates e.g.ref. 2 (see also Section 5). The 2H-azirine moiety figures in a number of interesting investigations its involvement in the formation of aziridines by the action of Grignard reagents on oximes has been sub-ject of further investigation and dis- c~ssion,~ and transitory 2H-azirines arising from the thermolysis of vinyl azides have been intercepted by Diels-Alder reaction (Scheme 1) leading to the formation of 2H-azepines. An interesting analogy to the formation of benzenes by the reaction of cyclopropenium cations with cyclopropene is the reaction of the 2H-azirine (1) to give the pyridine (2).5 The irradiation of 2H-azirines (3) to give the ylide (4)and the subsequent reaction of this with CH,OD established the disubstituted rather than the tri- substituted carbon as the point of highest electron density,6 a key to the regio- selectivity of photoadditions of azirines to dipolarophiles ; thus the products from the irradiation of (3; Ar = Ph R' = Me R2 = H) with methyl acrylate are the A'-pyrrolines (5a) and (5b).7 ' M.J. S. Dewar and C. A. Ramsden J.C.S. Chem. Comm. 1973,688. (a) T. L. Gilchrist G. E. Gymer and C. W. Rees J.C.S. Chem. Comm. 1973 835; (b) T. L. Gilchrist. G. E. Gymer and C. W. Rees J.C.S. Perkin I 1973 555. R. Chaabouni A. Laurent and P.Mison Tetrahedron Letters 1973 1343. D. J. Anderson and A. Hassner J. Org. Chem. 1973 38 2565. R. E. Moerck and M. A. Battiste Tetrahedron Letters 1973 4421. A. Padwa and J. Smolanoff J.C.S. Chem. Comm. 1973 342. A. Padwa M. Dharan J. Smolanoff and S. I. Wetmore J. Amer. Chem. Soc. 1973 95 1945 1954. 47 1 M. J. Cook and C. D.Johnson Me Me 0 R-CH=CH-N -[w]-(R = Ph or But) Me phse R Scheme 1 Br-Ph Ph Ph Ph (1) (2) R' N Ar R' Arc=& < A MeOD \ I hv --+ C=N-C-OMe 1 R2 R' / I + Ar R' ArCrN -C-/ D R2 \ (3) R' R2 = H Me or Ph R2 (4) phfYMe C02Me C02Me (54 (5b) The first proof of methyleneaziridine+yclopropanimine valence bond iso-merism (Scheme 2; R = H or alkyl) has now been provided by n.m.r.investi- gation.* On decomposition the products obtained R,C=CH and RCN are those arising from the chelotropic reaction of the imine (6). * H.Quast and W. Rider Angew. Chem. Internat. Edn. 1973 12 414. Heterocyclic Chemistry Re-R RbN-R R "\\ RYN-R R Scheme 2 Some interesting studies have emerged on the stereochemistry of aziridine synthesis and reactivity. Stereospecific synthesis of N-alkyl- or N-aryl-aziridines (8) can be achieved from the readily available iodo-azides of known configuration (7) by the use of alkyl or aryl dichlorob~ranes.~ Chiral ester functions may be used in the Gabriel synthesis of aziridines (9) permitting the separation of dia- stereomeric chiral aziridines and enabling the induction of asymmetry in their subsequent conversion into amino-acids,' while in related studies full report is now given of the synthesis of optically active N-acylated aziridinones and their use in peptide synthesis.' 'The mechanism and stereochemical control in thermal rearrangement of aziridinyl ketones to pyrroles has been discussed,12 and in contrast to three-membered-ring 'ene' reactions where only the cis-isomer (10) H 'N H ,\R2 /+ I."..I.. I R1 RZ reacts in this case the trans-isomer (11) reacts faster than the cis (12). This is ascribed to reaction via an alternative route i.e. through the azomethine ylides (13) which involves conrotatory ring-opening and in the cis case steric interaction between the nitrogen substituent and one or other of the 2,3-substituents.The A. B. Levy and H. C. Brown J. Amer. Chem. SOC.,1973,95,4067. lo J. W. Lown T. Itoh and N. Ono Cunad. J. Chem. 1973 51 856. " M. Miyoshi Bull. Chem. SOC.Japan 1973,46 212 1489. "A. Padwa D. Dean A. Mazzu and E. Vega J. Amer. Chem. SOC.,1973,95 7168. M. J. Cook and C. D. Johnson deamination of 2-(aminomethy1)aziridineshas also received mechanistic dis- cussion' 3-dual routes involving either carbenes or carbonium ions have been discerned 3-pyrrolines being among the products of the former pathway. t t + \ (13) Ph Ph Me or N + t The first synthesis of l-azaspiro[2,2]pentanes (14) has been described ;IbJ' a modification provides a useful route to the already known l-oxaspiro[2,2]- pentane (15).15 An attempted synthesis of the 2-azabicyclobutane (16) was however unsuccessful ; the substance proved unstable,14b but the analogous reaction with cyclobutenes affords a convenient synthesis of the 5-azabicyclo- [2,l,O]pentanes (17) a structure which unlike other aziridines is very unreactive towards dimethyl acetylenedicarboxylate.14' Ozonolysis of allenes has been used as a route to the novel heterocycles the allene oxides (18) which can be detected by n.m.r. at -78 "Cbut decompose to the oxetan structure (19) at room temperature.I6 Biological involvement of arene oxides has prompted studies on their synthesis," and on the mechanism of oxygen walks." A planar cyclohexane ring in (20) has been detected by X-ray studies," and anti-benzene dioxide (21) the final oxide of the series has now been prepared,*' stimulus being given by the discovery of an antibiotic with this structural unit.Thermally stable,(2l)nevertheless slowly decomposes on standing. l3 G. Szeimies Chem. Ber. 1973 106 3695. l4 (a)J. K. Crandall and W. W. Conover J.C.S. Chem. Comm. 1973 33; (6)D. H. Aue R. B. Lorens and G. S. Helwig Tetrahedron Letters 1973 4795; (c) D. H. Aue H. Iwahashi and D. F. Shellhamer ibid. p. 3719. l5 D. H. Aue M. J. Meshishnek and D. F. Shellhamer Tetrahedron Letters 1973 4799. l6 J. K. Crandall and W. W. Conover J.C.S. Chem. Comm. 1973 340. S. H. Goh and R. G. Harvey J. Amer. Chem. SOC.,1973,95 242; H. Yagi and D. M. Jerina ibid. p. 243. P. Y. Bruice G.J. Kasperek T. C. Bruice H. Yagi and D. M. Jerina J. Amer. Chem. SOC.,1973 95 1673; G. J. Kasperek P. Y. Bruice T. C. Bruice H. Yagi and D. M. Jerina ibid. p. 6041. l9 C. Kabuto M. Yagihara T. Asao and Y. Kitahara Angew. Chem. Internat. Edn. 1973 12 836. *O E. Vogel H.-J. Altenbach and E. Schmidbauer Angew. Chem. Internat. Edn. 1973 12 838. Heterocyclic Chemistry I R' (14) R' = Ph R2= H R' = R2= Ph m-C1C,H,C03H-CH $1,. 20°C(R' = H) p N",;'M." 14 N N-C0,Me @ N3C;,Mi &N-C0,Me But\ Room B u A Bu' But/c=c=c Bu' B,"H Bu' Bu' temp' Bu' 0 (19) (18) 00 a Photo-oxidation of indenes forms the bisepoxyperoxide (22) and on heating (22; R' = Me R2= Ph) collapses to the tetraepoxide (23).21 By contrast the 1-benzoxepin + naphthalene oxide (24)system which exists very predominantly as the former does not epoxidize with singlet oxygen but forms the peroxide (25).22 The irradiation of 9,10-epoxy-9,10-dihydrophenanthrene produces the C.S. Foote S. Mazur P. A. Burns and D. Lerdal J. Amer. Chem. SOC.,1973,95 586. 22 J. E. Baidwin and 0.W. Lever J.C.S. Chem. Comm. 1973 344. M. J. Cook and C. D.Johnson -* 0 :;.?-(_ . R2 Ph o& '-0 '0 previously unknown 2,3 :4,5-dibenzoxepin (26). The mechanism is considered to be an analogue of a photochemical Berson-Willcott rearrangement in which a [1,5] suprafacial shift of oxygen is involved (27).23 In connection with this an unsuccessful attempt to prepare benzoxiren is notable ; the adduct (28) instead of yielding the oxiren by an Alder-Rickert cleavage produced (29).24 Studies have NC NC NC NC also been reported this year of the syrn-oxabicyclo[5,1,0]octa-2,5-dienes (30)and (31) which variable-temperature n.m.r.reveals to be in equilibrium via Cope rearrangement,2 and of the Cope rearrangement in the three bicyclo[6,1,0]- nonadienes (32 ;X = CH ,0,or NCO,Et) which all produce the bicyclic system (33) irreversibly.26 23 N. E. Brightwell and G. W. Griffin J.C.S. Chem. Comm. 1973 37. 24 F.-G. Klarner and E. Vogel Angew. Chem. Internat. Edn. 1973 12 840. 25 H. Klein W. Kursawa and W. Grimme Angew. Chem. Internat. Edn. 1973 12 580. 26 W. Grimme and K. Seel Angew. Chem. Internat. Edn. 1973 12 507. Heterocyclic Chemistry 477 (32) (33) 2 Four-membered Ring Compounds In an extension of the study of the addition of diphenylketen to 2H-azirines reported last year,27 keten addition to azetine (34) to yield (35) has now been Ph Ph Ph Ph (34) (35) reported.2* 4,5-Dihydro-l,3,5-oxazaphosphole with isocyanides gives 3-imino-l- azetine (36),29 a ring system which undergoes photoinduced 1,3-dipolar cyclo- reversion to a nitrile ylide which may be trapped to give 2H-pyrroles or 1-pyrrolines e.g.(37) and (38).30 [2 + 21 Cycloaddition of isocyanates and keteni- (36) a; R' = H R2 = alkyl or Ar RCECR b; R' = Ar R2 = cyclohexyl RCH=CHR J \ Ar Ar (38) R = H or alkyl (37) R = H or alkyl mines gives good yields of 4-iminoacetidin-2-ones (39),3 and the cyanomalondi- hide (40) undergoes thermolysis to the 2,4-dioxa-3-azetidine carbonitrile (41) a precursor to the azetinone (42).32 Fused azetinones may be produced by Ann.Reports (B) 1972 69 429. 28 A. Hassner M. J. Haddadin and A. B. Levy Tetrahedron Letters 1973 1015. 29 K. Burger J. Fehn and E. Miiller Chem. Ber. 1973 106 1. 30 K. Burger W. Thenn and E. Miiller Angew. Chem. Internat. Edn. 1973 12 155. 31 Naser-ud-Din J. Riegl and L. Skattebral J.C.S. Chem. Comm. 1973 271. 32 L. Capuano and R. Zander Chem. Ber. 1973 106 3670. M. J. Cook and C. D. Johnson R' N-C,H,Me-p R'+f CN CNCH(CONHPh) ,,f,, 0J0 CH*N .&*Me N N I I Ph Ph photolysis or pyrolysis of tria~inones,~~ e.g. (43)-+(44),while the production of (47)from the action of heat on N-hydroxytriazonine (45) is taken as evidence for the intermediacy of (46) a valence tautomer of benza~etinone.~~ The azetidinone (48)decomposes on irradiation in methanol to give a compound whose structure has been ascertained by use of lanthanide shift reagents to be (49).35 2-Phenyl- benzazete (50)has been prepared for the first time by the vapour-phase pyrolysis of 4-phenyl-1,2,3-triazine(51);36 it is stable only at -80 "C,readily dimerizing or 33 N.Bashir and T. L. Gilchrist J.C.S. Perkin I 1973 868. 34 P. Ahern T. Navratil and K. Vaughan Tetrahedron Letters 1973 4547. 35 H. L. Ammon P. H. Mazzocchi W. J. Kopecky H. J. Tamburin and P. H. Watts J. Amer. Chem. SOC.,1973 95 1968. 36 B. M. Adger M. Keating C. W. Rees and R.C. Storr J.C.S. Chem. Comm. 1973 19. Heterocyclic Chemistry reacting with nucleophiles but its analogue (52)is stable at room temperature. -&Substituted lH-2,3-benzoxazin-l-ones are reported to yield biphenylenes on pyrolysis,37 presumably via the extrusion of CO to give (50) and then loss of PhCN to give benzyne. Another ni trogen-containing analogue of cyclobutadiene N H (49) Ph Me2PjY7fNMe2 Me,N FN-Me2PjPNMe2 Me,N (53) has been prepared by pyrolysis of tris(dimethylamino)-1,2,3-triazine; this formally antiaromatic structure owes its stability to the canonical form (53b).38 Various aspects of the mechanism of irradiation of a-pyrone to give (54) and thence cyclobutadiene as a matrix in argon at 8 K which thus enables its spectro- scopic investigation have received much attenti~n.~~" Similar treatment of pyridine also leads to cyclobutadiene oia species(55),39bwhile phthaloyl peroxide affords benzpropiolactone (56)and thence ben~yne.~' [2 + 21 Photocycloaddition of unsaturated carbon-carbon linkages to carbonyl groups continues to attract investigation.Irradiation of cis-but-2-ene with acetone yields both stereoisomers (57) and (58) which suggests that the biradical (59) is an intermediate with a sufficiently long lifetime for bond ro- tation ;41 this contention receives support from the isolation of open-chain 37 M. P. David and J. F. W. McOmie Tetrahedron Letters 1973 1361. '* G. Seybold U. Jersak and R. Gompper Angew. Chem. Internat. Edn. 1973 12 847; H.-U.Wagner ibid. p. 848. 39 (a)0. L. Chapman C. L. McIntosh. and J. Pacansky J. Amer. Chem. SOC.,1973 95 614; C. L. McIntosh and 0. L. Chapman ibid.,p. 247; R. G. S. Pong and J. S. Shirk ibid. p. 248; 0.L. Chapman D. De La Cruz R. Roth and J. Pacansky ibid. p. 1337; A. Kranz C. Y.Lin and M. D. Newton ibid.,p. 2744; (b) 0. L. Chapman C. L. McIntosh and J. Pacansky ibid. p. 244. 40 0.L. Chapman C. L. McIntosh J. Pacansky G. V. Calder and G. Orr J.Arner. Chern. Soc. 1973 95 4062; 0.L. Chapman K. Mattes C. L. McIntosh J. Pacansky G. V. Calder and G. Orr ibid. p. 6134. 41 H. A. J. Carless Tetrahedron Letters 1973 3173; J.C.S. Chem. Comm. 1973,316. M. J. Cook and C. D. Johnson 1 compounds such as (60) from the reaction of 2,3-dimethylbut-2-ene.A study of oxetan formation from benzophenone and alkenes suggests initial irreversible formation of a complex with triplet benzophenone before this biradical for- mati~n,~~ whereas participation of ester carbonyls involves the excited singlet state.43 The 2-and E-rotamers (61) arise from the irradiation of benzaldehyde with but-2-yne at 20 "C;44 the oxeten (62) is involved as intermediate and at lower temperatures this leads on to the 2,5-dioxabicyclo[2,2,O]hexanestructure (63a). An oxeten (64) is also involved as an intermediate in the acid-catalysed reaction of 3-chloro-3-dimethylaminopropenoneto give 3-chloro-NN-dimethylacryl-amide.45 A 2,5-dioxabicyclo[2,2,0]hexane(63b) further arises from irradiation of 3-methyl-4-oxa-5-hexen-2-one (65).46 Another novel structure although not (62) (63) a; R' = RZ= Ph R3= Me (64) b; R' = Me RZ = R3 = H Me 42 R.A. Caldwell G. W. Sovocool and R. P. Gajewski J. Amer. Chem. SOC. 1973 95 2549. 43 T. S. Cantrell J.C.S. Chem. Comm. 1973 468. 44 L. E. Friedrich and J. D. Bower J Amer. Chem. SOC.,1973 95 6869. 4s M. Neuenschwander and A. Niederhauser Chimia (Switz.) 1973 27 379. 46 J. C. Dalton and S. J. Tremont Tetrahedron Letters 1973 4025. Heterocyclic Chemistry 481 isolated is tetraoxaspirocycloheptane(66),a plausible intermediate in the for- mation of aldehydes or ketones by irradiation of allenes with singlet oxygen in carbon di~ulphide.~’ The dioxetan (67) reacts quantitatively with triphenyl- phosphine to yield (68) which decomposes on warming to give an ~xiran.~~ 0-0 R 0-0 MewMe 0’ PPh ‘0 +ttRR 0-0 Me Me Me .-!&Me Me Me (66) R = H alkyl or Ph Notable analogues of the carbonyl-alkene reactions discussed above are those of thiophosgene4’ or the thiocarbonate (69)” with 2,3-dimethyibut-2-ene ; in the first case irradiation produces the thietan (70) and thence by hydrolysis the 3hio- lactone (7 l),whereas in the latter the spirothietan (72) arises.Thiacyclobutene or thiet serves as a source of previously unknown thioacrolein. Reaction with iron carbonyl gives the complex (73) and thence the red dicarbonyl- triphenylphosphineiron complex of thioacrolein (74).” The isolation of the first stable a-dithione 4,4’-bis(dimethylamino)dithiobenzilis reported.’ It exists as an equilibrating mixture of (76) and (77) and the position of this equilibrium is co Ar Ar IS>-.“v Ar s Ar (75) Ar = Me2NC6H4-(76) (77) 4’ T. Greibrokk Tetrahedron Letters 1973 1663. 4g P. D. Bartlett A. L. Baumstark and M. E. Landis J. Amer. Chem. SOC.,1973 95 6486. 49 H. Gotthardt Tetrahedron Letters 1973 1221. 50 H. Gotthardt and M. Lid Tetrahedron Letters 1973 2849. 51 K. Takahashi M. Iwanami A. Tsai P. L. Chang R. L. Harlow L. E. Harris J. E. McCaskie C. E. Pfluger and D. C. Dittmer J. Amer. Chem. Soc. 1973 95 61 13. 52 W. Kiisters and P. de Mayo J. Amer. Chem. Soc. 1973,95 2383. M. J.Cook and C.D. Johnson solvent- light- and temperature-dependent. Studies of the activation energy of the processes indicate that the dithiet (77) has a high stability owing to the n-electron delo~alization.’~ Two important studies in the area of Wittig alkene syntheses are the first direct (n.m.r.) observation of the oxaphosphetan (78)’ and in its sulphur analogue a scheme for the formation of alkenes from p-sultines (79).54 0 Ph3P-0 0-Mem MeCH=PPh,+ THF -70°C OH +v+-CHR1-CR2R3I -+ S+-&HR1 c1 +:-cR2R3 0 c1-R’ R2 R3 = alkyl or Ar 0-CR2R3 -so I I R’CH=CR2R3 + //s-CHR1 0 (79) 3 Penams and Cephams The search for details of the biosynthetic pathway from the amino-acids L-valine and L-cysteine to p-lactam antibiotics remains a key interest of obvious impor- tance.Experiments involve the synthesis of (2S,3S)-[4-’3C]valine,55(2RS,3S)-[4-’3C]valine,56 and (2RS,3S)-[4,4,4-2H3]valine57and a study of their incorpora- tion into cephalosporin C (80),55~56 with a particular emphasis on the fate of the isopropyl group.Other work in this area includes a demonstration of the oxi- dation of cysteinyldehydrovaline[81; R’= H,R2= PhCH,CO R3= -C(C0,-Me)=CMe,] and N-phthaloylcystinylvaline [81 R’R2= phthaloyl R3= -C(CO,Me)H-CHMe,] to isothiazolidinones (82),’* new peptide derivatives which may constitute intermediates in the biosynthetic pathway to penam and 53 E. Vedejs and K. A. J. Snoble J. Amer. Chem. SOC.,1973,95 5778. 54 F. Jung N. K. Sharma and T. Durst J. Amer. Chem. SOC.,1973,95 3420. ” H. Kluender C. H. Bradley C. J. Sih P. Fawcett and E. P. Abraham J. Amer. Chem. SOC.,1973 95 6149. 56 J.E. Baldwin J. Loliger W. Rastetter N. Neuss L. L. Huckstep and N. De La Higuera J. Amer. Chem. SOC.,1973 95 3796; N. Neuss C. H. Nash J. E. Baldwin ’’ P. A. Lemke and J. B. Grutzner ibid. p. 3797. D. J. Aberhart and L. J. Lin J. Amer. Chem. SOC.,1973 95 7859. ’* J. E. Baldwin S. B. Haber and J. Kitchen J.C.S. Chem. Comm. 1973 790; see also R. B. Morin E. M. Gordon and J. R. Lake. Tetrahedron Letters 1973 5213. Heterocyclic Chemistry 483 R'R'N 0z!R lR 0 'R3 cepham structures (Scheme 3) which fits in with the experiments on chiral ['3C]valine.56 Not surprisingly the search for interconversions of penams and cephams continues. Last years9 the structure (85) was shown to be an intermediate from RN H RNHg$-RN:n$ 0 'ene' -0 C0,Me C0,Me C0,Me 'Diels-Alder' 0 , C0,Me C02Me Scheme 3 which both antibiotic types could be obtained ;it has now been demonstrated6' that a facile route to (85) is available via halogenation of (84) obtained by the action of 2-mercaptobenzothiazole on penicillin sulphoxide (83).A further noteworthy route from penicillins to cephalosporins involves the conversion of benzyl 6P-(triphenylmethylamino)penicillanate into the azeti- dinone from whence the cepham (87) can be obtained using an intra- 59 Ann. Reports (B) 1972 69 445. 6o T. Kamiya T. Teraji Y.Saito M. Hashimoto 0.Nakaguchi and T. Oku,Tetrahedron Letters 1973 3001. 61 J. H. C. Nayler M. J. Pearson and R. Southgate J.C.S. Chem. Comm. 1973 57; D. H. R. Barton I. H. Coates P. G. Sammes and C.M. Cooper ibid. p. 303. M. J. Cook and C. D. Johnson 0-Ph,CN H SCH,C=CPh CH2CoN :E>CH Ph OE&COZCH Ph CO,H (86) (87) molecular Wittig reaction to construct the dihydrothiazine ring,62 while the synthesis of deacetoxy-cephalosporin S-oxides from penicillins takes advantage of the nucleophilicity of the S atom in sulphenic acids (Scheme 4).63 0-0 I II Ft SO,CI,) Ft OH pz 0 CO2R C02R CO2R / Ft = phthalimido 0-I CO2R Scheme 4 Attention has been paid to the introduction of a C-6 (7) methoxy substituent into penam and cepham nuclei. This can be done stereospecifically by addition of methanol to the cation (88)64 or the kine (89).65 The isolation of p-lactam 62 J. H. C. Nayler. M. J. Pearson and R.Southgate J.C.S. Chem. Comm. 1973 58. '' S. Kukolja and S. R. Lammert Angew. Chem. Internat. Edn. 1973 12 67. 64 L. D. Cama and B. G. Christensen Tetrahedron Letters 1973 3505. 65 J. E. Baldwin F. J. Urban R. D. G. Cooper and F. L. Jose J. Amer. Chem. SOC.,1973 95 2401. Heterocyclic Chemistry RTNlx)( 0 phcH=AE> 0 antibiotics of cepham structure bearing a 7-methoxy-group a functionality previously unknown in such compounds has also inspired a one-step stereo- selective synthesis of 7a-methoxycephalosporin C66(see also ref. 67). A related report68 deals with the direct C-6 epimerization of penicillin V methyl ester through the vicinal dianion (90). I PhCH,-C=N Li+ -o C0,Me Cephalosporin Cefoxitin (91) is unique in possessing not only a 7cx-methoxy substituent but also a 3-carbamoyloxymethyl group.Its synthesis69 exemplifies the use of (92)as a key intermediate in the preparation of p-lactam antibiotics. I C0,Me CO,H (91) (92) Finally in this brief Report which can do scant justice to the wealth of ingenious and novel reactions reported in this field this year an important synthesis of p-lactams by photolytic Wolff rearrangement (93)-(94) which can be ex-panded to cepham and penam preparation is noted.” 0 I1 PhCMe,O,CNHNHC. 0m C02CH,Ph (94) 66 G. A. Koppel and R. E. Koehler J. Amer. Chem. SOC.,1973,95,2403. ‘’ G. A. Koppel and R. E. Koehler Tetrahedron Letters 1973 1943. 68 G. A. Koppel Tetrahedron Letters 1973 4233. 69 R. W. Ratcliffe and B.G. Christensen Tetrahedron Letters 1973 4645 4649 4653. ’O G. Loweand D. D. Ridley J.C.S. Chem. Comm. 1973,328;J.C.S. Perkin I 1973,2024. M. J. Cook and C. D. Johnson 4 Five-membered Ring Compounds Several interesting pyrrole syntheses have appeared. Lithium ethylidenecyclo- hexylamine with P-halogeno-ketones yields a variety of pyrrole structures e.g. (95),71while other one-step routes include anodic dimerization of enamino- ketones or treatment of imines (96)with lithium or Grignard reagent,73 and reaction of alkoxymethyl-substituted bromoallene derivatives (97) with .............. -c=o ether. -78°C [CH,-CH-N-C,Hl,]Lif +(CH,) 1 7 CHX I X = C1 or Br; n = 4-6 CP 1 R' R' R' Li-ether. -70 "C R 1 -CH -CH Pr'MgCI , 0 bRl I I I1 I Br NR2 R2 (96) R' R2 = alkyl benzyl R2 ROCH,C=C=CHCH,CI Bu'NH ROCH,C-CCHCH,NHBu' + I MeCN 120°C I Br NHBu' I (97) Bu' primary amine~.~~ Pyrrole formation by heating the azetidinopyridine (98) in benzene is explained by invoking the formation of a lP-diazocine followed by a [1,3] sigmatropic (C +N).alkyl shift and cyclore~ersion.~~ A variety of new routes to indoles has also been presented pre-eminent of which is a method utilizing N-chloroanilines with ~ulphides,~~ affording a general and viable alternative to the Fischer indole synthesis.The scope of the reaction is shown in Scheme 5 while a modification involves using halogen- sulphide complexes e.g. (99)+( Among other syntheses involving base catalysis is that of (101),which exploits the ability of nitrosoamines to form carb- anionic species,78 and (102) by a process which has a formal analogy to the 71 G.Wittig R.Roderer and S. Fischer Tetrahedron Letters 1973 3517. 72 D. Kock and H. Schafer Angew. Chem. Internat. Edn. 1973 12 245. 73 P. Duhamel L. Duhamel and J.-Y. Valnot Tetrahedron Letters 1973 1339. 74 M. V. Mavrov A. P.Rodionov and V. F. Kucherov Tetrahedron Letters 1973 759. 75 J. W. Lown and M. H. Akhtar Tetrahedron Letters 1973 3727. 76 P. G. Gassman and G. Gruetzmacher J. Amer. Chem. SOC. 1973,95,588; P. G. Gass- man and T. J. van Bergen ibid. p. 590 591 2718. 77 P. G. Gassman T. J. van Bergen and G. Gruetzmacher J. Amer. Chem. SOC. 1973 95 6508. 7a A. Walser and G. Silverman J. Heterocyclic Chem.1973 10 883. Heterocyclic Chemistry (98) R = C,H,, C12H23 or Bu' / Me0,C C0,Me a+ R-N=C=CHPh Ph I R CH2SMe i MeSCHR4C0,R3 i. MeSCH,COR' ii. base R' R' Scheme 5 MeOoNH2 ii. Et,N Me (99) H M. J. Cook and C. D. Johnson Ph ,Me -K0Bu'-THF c ' ~ ~Ph o HTi,H,-RaNi "a7JphI I \ I NO I NO i H (101) Fischer synthesis. 79 Other starting points are the dihydroquinoline [( 103)-+ ( 104)],'0 arylhydroxylamines [( 105)+(106)],'1 and N-2-chloroallylanilines [(107)-+ (108)],82 while a convenient synthesis of 4,5,6,7-tetrafluoroindole(109) has also been gi~en.'~ hv I C0,Et (103) A note that the action of p-chlorobenzoyl chloride and pyridine on 3,3-dimethyl-3H-indole yielded stereoisomers of structure (1 was later corrected" to show that the compounds were in fact (11l),the first diastereomeric atropisomers to be isolated involving the heterocyclic ring of an indole and arising from restricted rotation about the bond indicated.3- 4- and 6-substituted indoles (1 13)-(115) are available by Fries-type photochemical rearrangement of 1-substituted indoles (112) where R' is a wide variety of groups e.g. CO,Et COMe PhCH ,etc.,'6 and vinylogous Favorskii reactions of 3-(a-halogenoacyl)- 79 L. N. Yakhontov and M. F. Marshalkin Tetrahedron Letters 1973 2807. 8o M. Ikeda S.Matsugashita H. Ishibashi and Y. Tamura J.C.S. Chem. Comm. 1973 922. K. Okamoto and K. Shudo Tetrahedron Letters 1973 4533. 82 B. McDonald A. McLean and G. R.Proctor J.C.S. Chem. Comm. 1973. 208. 83 R. Filler S. M. Woods and A. F. Freudenthal J. Org. Chem. 1973 38 81 1. 84 K. Takayama M. Isobe K. Harano and T. Taguchi Tetrahedron Letters 1973 365. 85 V.Dave J. B. Stothers and E. W. Warnhoff Tetrahedron Letters 1973 4229. M. Somei and M. Natsume Tetrahedron Letters 1973 2451. Heterocyclic Chemistry (105) R' = H Me or C1 R2 = H or Me OH 0 F F indoles (1 16) under mildly basic conditions lead to the formation of indole acetic acids (118) in good yield presumably via the intermediate (117).87 A simple one-step high-yield route to isoindoles and related compounds is illustrated by the first synthesis of a pyrrolo[3,4-b]quinoline heterocycle (1 19).88 Isoindole derivatives (122) whose structure have been confirmed by X-ray crystallography have also been derived from dimerization of nitrile ylides (121) J.Bergman and J.-E. Backvall Tetrahedron Letters 1973 2899. ** M. J. Haddadin and N. C. Chelhot Tetrahedron Letters 1973 5185. M. J. Cook and C. D. Johnson R' QT&r NaOH-EtOH ' -H,O I H J I H mz CH,NH,-EtOH-NaBH; 0 Ph (119) Heterocyclic Chemistry 49 1 formed from oxazaphospholes ( while the first stable 2-azapentalene (124) has been derived from the lactam (123).90 The synthetic utility of the ylide salt (125) has been demonstrated in the preparation of the pyrazine (126) and the pyrazole (127),” and another method for preparation of pyrazoles e.g. (129) is / (121) (120) X = H Me or OMe CF3 CF NPX e- X CF CF NMe NMe NMe, I I I 0 OEt OEt (123) (124) + Br -Ph,P-CH -C-CH=PPh3 II N-N=CHCOPh CH,PPh Br-1 CH,COPh the reaction of hydrazidic bromides (128) and anions of acetylacetone dibenzoyl- methane ethyl acetoacetate etc.in ethanol at room ternperat~re.~~ A good route 89 K. Burger K. Einhellig G. Suss and A. Gieren Angew. Chem. Internat. Edn. 1973 12 156; A. Gieren K. Burger and K. Einhellig ibid. p. 157. 90 K. Hafner and F. Schmidt Angew. Chem. Internat. Edn. 1973 12 418. 91 E. E. Schweizer C. S. Kim 6.S. Labaw and W. P. Murray J.C.S. Chem. Comm. 1973 7. 92 A. S. Shawali and H. M. Hassaneen Tetrahedron 1973 29 121. M. J. Cook and C. D. Johnson to the pyrazolopyridine (130) is provided by action of primary aromatic amines HCI or EtOH on 2-arylaminomethy1-3-nitro-pyridine~,~~ and pyrazoles (132) arise from a spontaneous [1,5] acyl migration of the intermediate in the reaction of (131) with alkyne~.~~ R'-C LNHAr/Br R' COR' N,9 R r (128) I Ar X (129) (130) X = ArNH CI or EtO Very simple routes have been described for the synthesis of aryl-substituted imidazoles (133),95 and also for N-amir~o-~~ and N-hydroxy-benzimida~oles,~~ N-hydroxybenzimidazolones,972-aminoben~imidazole,~* and polychlorobenz- imida~oles.~~ In the realm of imidazole reactivity it has been shown that the reaction of phenylenediamine and cyclohexanones leads to an electron-transfer complex between dihydrobenzimidazole and isobenzimidazole (134) a novel oxidation-reduction system of potential synthetic utility.O0 + Phosgeneimmonium chloride Cl,C=NMe,CI -,has been shown to react with dinucleophiles in a number of useful syntheses."' Thus with arylhydrazines amidrazones and hydrazides indazoles triazoles and oxadiazoles are formed respectively and o-aminophenols or o-aminothiophenols yield benzoxazoles or benzothiazoles. The diazo-compound (135) formed from 2-amino-4,5-dicyanoimidazole readily eliminates nitrogen to form a highly zlectrophilic intermediate that inserts the 4,5-dicyanoimidazole moiety into a substrate ; e.g. with trifluoromethylbenzene it yields (136).'02 Other notable features of 93 H. E. Foster and J. Hurst J.C.S. Perkin I 1973 319. 94 M. Franck-Neumann and C. Buchecker Angew.Chem. Internat. Edn. 1973 12 240. 9s U. Lang and H. Baumgartel Chem. Ber. 1973 106 2079. D. W. S. Latham 0. Meth-Cohn and H. Suschitzky J.C.S. Chem. Comm. 1973 41. 97 D. B. Livingstone and G. Tennant J.C.S. Chem. Comm. 1973,96. S. Weiss H. Michaud H. Prietzel and H. Krommer Angew. Chem. Internat. Edn. 1973 12 841. 99 J. Martin 0.Meth-Cohn and H. Suschitzky Tetrahedron Letters 1973 4495. loo J. A. L. Herbert and H. Suschitzky Chem. and Ind. 1973 482. lol F. Hervens and H. G. Viehe Angew. Chem. Internat. Edn. 1973 12 405. lo* W. A. Sheppard and 0.W. Webster J. Amer. Chem. SOC.,1973,952695. Heterocyclic Chemistry R2 R' R2 (134) R' R2 = H or Me diazole reactivity are the synthetically useful thermal rearrangements (137)-(138)'03 and the novel transformation (139)-(l4O),lo4 the latter particularly surprising since aromaticity is lost in the process.The synthesis of triazoles has also commanded attention this year. An elusive cyclic azo-compound 1,2,4-triazoline-3,5-dione,has now been prepared in solution by oxidation of urazole and its spectral characteristics and reactivity have been examined.lo5 sym-Triazoloazines fused at the N-2-C-3 bond of the triazole ring can now be readily prepared from the corresponding aminoazines.' O6 Compound (142),the product of reaction of cyanogen bromide with (141),gives rise to a number of noteworthy compounds-to (143) a previously unknown derivative of benzimidazole and to (144) and (145),both new ring sy~terns."~ '03 J. W.A. M. Janssen H. J. Koeners C. G. Kruse and C. L. Habraken J. Org. Chem. 1973,38 1777. lo4 F. T. Boyle and R. A. Y.Jones J.C.S. Perkin I 1973 167. lo5 J. E. Herweh and R. M. Fantazier Tetrahedron Letters 1973 2101. lo6 S. Polanc B. VerEek B. Stanovnik and M. TBler Tetrahedron Letters 1973 1677. lo' R. I.-F. Ho and A. R. Day J. Org. Chem. 1973,38 3084. M. J. Cook and C.D. Johnson RR RR C N ''3. t3N N H Me Me Me Me OMe (139) NHCOR' I i. (R2C0),0 MeCOCOMe ii H+ or OH-I I Benzotriazole 1-oxides are produced by irradiation of 1-(0-nitropheny1)pyr-azoles,'08 and the synthesis of a range of H-l,2,3-triazoles by the action of azide on acetylenes demonstrates the versatility of this rarely exploited reaction.log The stability of polyaza-rings is illustrated by the preferential ring-opening of the pyridine ring in (146) on attack by nucleophiles such as borohydride morpholine and methoxide.' Two other intriguing reactions of polyaza- indolizine derivatives are the reversible Dimroth-style rearrangement (147) (148)' ' and the 1,3-photocycloaddition of alkenes to syrn-triazolo[4,3-b]pyr-idazine to give products (149) and (150) presumably via the nitrene (151).l12 P.Bouchet C. Coquelet J. Elguero and R. Jaquier Tetrahedron Letters 1973 891 Y.Tanaka S. R. Velen and S. I. Miller Tetrahedron 1973 29 3271. 'lo A. Gellkri and A. Messmer Tetrahedron Letters 1973 4295. 'I1 D. R. Sutherland G. Tennant and R. J. S. Vevers J.C.S. Perkin I 1973 943. J. S. Bradshaw B. Stanovnik and M.TiSler Tetrahedron Letters 1973 2199. Heterocyclic Chemistry 495 RcN+y .pN*? NaBH, \ N-N Ar / N-N Ar Me (147) Two groups' l3 have stressed the utility of the reaction of thiomethylisocyanides with carbonyl compounds to form substituted oxazoles and oxazolines while isoxazoles are prepared by a facile cyclization of orb-unsaturated ketoximes with the palladium complex [(Ph,P),PdCl,].' ' Two isoxazole conversions receive mechanistic interpretation :the photoisomerization of indoxazene to benzoxazole proceeds via the isocyanide (152) rather than through an azirine intermediate as previously thought,' ' and the conversion of isoxazoles to pyridones by treat- ment with diphenylcyclopropenone' ' involves the key rearrangement (153).Dioxazoles may be synthesized from hydroxamic acids and acetylenic com-pounds,' ' while selective reduction of the oxides (154) accessible as indicated leads to benzothiazoles with a wide variety of substituent groups many previously unknown.' 'I3 A. M. van Leusen and H. E. van Gennep Tetrahedron Letters 1973,627; U. Schollkopf and E. Blume ibid. p. 629; U. Schiillkopf and R. Schroder ibid. p. 633. 'I4 K. Maeda T. Hosokawa S.4. Murahashi and I. Moritani Tetrahedron Letters 1973 5075. '' J. P. Ferris F. R. Antonucci and R. W. Trimmer J. Amer. Chem. SOC.,1973 95 919. 'I6 R. Grigg R. Hayes J. L. Jackson and T. J. King J.C.S. Chem. Comm. 1973 349. F. M. F. Chen and T. P. Forrest Canad. J. Chem. 1973,51 1368. K. Wagner H. Heitter and L. Oehlmann Chem.Ber. 1973,106 640. M. J. Cook and C. D. Johnson R' R' Other syntheses worthy of mention in the realm of five-membered nitrogen- and oxygen- or sulphur-containing rings include a general method for isothiazolo- [2,3-a]pyridinium salts,' several novel isothiazolopyridines,120 5-amino-1,2,4thiadiazoles from 1-amino-3-iminoisoindolenines,' and thiadiazoles e.g. (156) and (157) from electron-depleted thiocarbonyl compounds (155) with diazoalkanes. ' Dithiolans thiadiazolines and thiirans are also available from this reaction mode. Lithio-thiazoles -thiadiazoles and -0xadiazoles (158) are reported to undergo rearrangement to ketenimines (159) which are not isolated but recognized as dimers such as (160).'23 The naturally occurring furans perillene and dendrolasin are among the 3- and 3,4-substituted furans (161) synthesized by the general route shown,'24 and a one-step synthesis of 2-substituted benzofurans by the action of palladium complexes on sodium salts of 2-allylphenols' 25 echoes the previously mentioned generation of isoxazoles.'l4 The attempted preparation of 2-amino-3-cyano-4-methylfuran (162) by the action of malononitrile on MeCOCH,OH a method l9 G.G. Abott and D. Leaver J.C.S. Chem. Comm. 1973 150. A. Taurins and V. T. Khouw Canad. J. Chem. 1973 51 1741. K. Leverenz Angew. Chem. Znternat. Edn. 1973 12 237. 12' S. Holm and A. Senning Tetrahedron Letters 1973 2389. '' A. I. Meyers and G. N. Knaus J. Amer. Chem. SOC.,1973 95 3408. 24 M. E. Garst and T. A. Spencer J. Amer.Chem. SOC., 1973,95 250. ''' T. Hosokawa K. Maeda K. Koga and 1. Moritani Tetrahedron Letters 1973 739. Heterocyclic Chemistry 497 SII (155) MeS02CNMe2 N-N CHzNz Etzo ' (S)jNMe Me,N (156) (157) (161) previously advocated,' 26q yields instead the first member of the 4,7-epoxybenzo- furan ring system (163) by a novel Diels-Alder reaction.126b 3-0xabicyclo[3,2,0]hepta-1,4-diene(165) has now been prepared from (164 ; X = 0)by partial hydrogenation,'27 and their differences in spectral properties have been ascribed to the fact that whereas the former is a perturbed furan the latter is a truly antiaromatic planar 8x-system ;in the sulphur system (164;X = S) this instability is reflected by its ready dimerization to bisthienocyclo-octatetraene (166).'** Treatment of the system (167; R' = R2 = Ph R3 = COPh) with P2S (a) K.Gewald. Chem. Ber. 1964 99 1002; (6) J. L. Isidor M. S. Brookhart and R. L. McKee J. Org. Chem. 1973,38 612. Iz7 R. G. Bergman and K. P. C. Vollhardt J.C.S. Chem. Comm. 1973,214. K. P. C. Vollhardt and R. G. Bergman J. Amer. Chem. SOC.,1973 95 7538. M. J. Cook and C.D.Johnson Ex 1 I 1 1 -( 164) (165) ( 166) in pyridine leads to thieno[3,4-f]benzo[c]thiophen (168),a non-classical 14n-electron system.129 Benzo[c]thiophen (167;R' = CO,Me R2 = R3 = H) can conveniently be prepared by alkali-induced decomposition of 1,Cdimethoxy-carbonyl-2,3-benzodithiane,'30 benzo[b]thiophens by thiophenol addition to R' F2 Ph ph Ph (167) (168) activated triple bonds,13' and thieno[3,2-b]quinoline (169)by nitrene insertion into thiophen rings.' 32 The mechanism of the oxidation of P-phenylpropanoic acids with thionyl chloride to give benzo[b]thiophens has now been inves- tigated.Arsadiazole (171)has been prepared from the hydrazine (170)and its spectral characteristics have been examined ;'34 the photoelectron spectra of phospholes and arsoles reveal that the lone pairs do not participate in cyclic conjugation and thus that they are non-aromati~.'~~ PhNH-N=CRMe "h N ,As (170) R = Me Et or Ph N I Ph (171) K. T. Potts and D. McKeough J. Amer. Chem. Soc. 1973,954 2750. I3O G. Cignarella and G. Cordella Tetrahedron Letters 1973 1871. 13' K. Undheim and R. Lie. Acta Chem. Scand. 1973 27 595.132 G. R. Cliff G. Jones and J. M. Woollard Tetrahedron Letters 1973 2401. 133 A. J. Krubsack and T. Higa Tetrahedron Letters 1973 125 4515. 13* G. Markl and C. Martin Tetrahedron Letters 1973 4503. W. Schafer A. Schweig G. Markl H. Hauptmann and F. Mathey Angew. Chem. Internat. Edn. 1973 12 145; cf. Ann. Reports (B) 1972 69 435. Heterocyclic Chemistry 499 Notable among preparation of other non-aromatic five-membered heterocycles reported this year are a general and versatile method illustrated by the conversion (172)-P (173)136andthepreparationoftriazolidines,pyrrolidines,andimidazolin-4-ones and -4-thiones by the reaction of lithium salts (174)with azo-compounds alkenes isocyanates and isothiocyanates respectively.' With carbon disulphide the spiro-compound (175)is formed.Other syntheses in this area include the I NH,(CH,),XH RNC-AgC% N' NCdX+ RNH2 (172) X = 0 NH,or S (173) n=2or3 H H H I Ph Ph (174) Ph I H photochemical formation of 3-oxazolidines from aryl ketones and aliphatic imines,' 38 2-oxazolidinones (177)with 8-hydroxy-amides (1 76)as intermediates in a Hofmann-style reaction,' 39 stable 1,4,2-dioxaphospholaniumsalts (1 78)140 prepared for the first time 3,4-dimethyIenethiolan and its I-oxide and I,1- dioxide,'41 and thiolactone systems (179) formed by cleavage of o-metallated cornplexe~,'~~ which constitute a potential entry into the benzo[c]thiophen ring system. Vinylketens are implicated in the photolysis of pyrazolenines and the detailed mechanistic pathways have been eiu~idated'~~ (Scheme 6 is an example).2-Phenyl-(180)and 2-thiono-1,3-dioxol-4-en (181)appear to be useful alternatives to acetylenes as dienophiles in Diels-Alder rea~ti0ns.l~~ Finally in this section 136 Y. Ito Y.Inubushi M. Zenbayashi S.Tomita and T. Saegusa J. Amer. Chem. Sac. 1973,95.4447. 13' T. Kauffmann A. Busch K. Habersaat and B. Scheerer Tetrahedron Letters 1973 4047 T. Kauffmann and R. Eidenschink Angew. Chem. internat. Edn. 1973. 12 568 T. Kauffmann. A. Busch. K. Habersaat and E. Koppelmann. ibid. p. 569. 138 A. A. Baum and L. A. Karnischky J. Amer. Chem. SOC.,1973 95 3072. 139 S. S. Simons J. Org. Chem. 1973 38 414. I4O N. J. De'Ath J. A. Miller and M. J. Nunn Tetrahedron Letters 1973 5191.I4I S. Sadeh and Y. Gaoni Tetrahedron Letters 1973 2365. 142 H. Alper and A. S. K. Chan J. Amer. Chem. SOC.,1973,95,4905. 143 A. C. Day A. N. McDonald B. F. Anderson T. Bartczak and 0.J. R. Hodder J.C.S. Chem. Comm. 1973 247; M. Franck-Neumann and C. Buchecker Tetrahedron Letters 1973 2875. 144 W. K. Anderson and R. H. Dewey J. Amcr. Chem. SOC., 1973,95 7161. M. J. Cook and C. D.Johnson Ar I Ph 0 (178) R = Phz or -CMe2CHzCMe2-COMe COMe COMe COMe hv Et,O GN Scheme 6 Heterocyclic Chemistry 50 1 we may note the high stereoelectronic control of the stepwise addition of triplet SO generated from thiiran oxide to dienes to form 3-thiolen S-oxides demon- strating that stereochemical integrity is not necessarily proof of a concerted mechanism.' 45 5 Six-memberedRing Compounds Research into heteroaromatic rings containing a Group V atom has produced the first 2-phosphanaphthalene (1 82),14(j a route to 4-substituted phospha- and arsa-benzenes (Scheme 7),147and has shown that there is still scope for novel R OMe R Scheme 7 syntheses of pyridinoid systems.A new route to 3,5-dialkylpyridines using compounds based on simple petrochemicals is illustrated in Scheme 8,14* and variously substituted pyridines are available by treating alkynes with nitriles MeC(CH,OH) CH,=C-CH,OH I CH,OH Scheme 8 over a catalytic amount of the cobalt complex (183) or indeed by treating nitriles with (183) dire~t1y.l~~ 2-Phenoxy- and 2-alkoxy-quinolines (185) are obtained 145 P.Chao and D. M. Lemal J. Amer. Chem. SOC.,1973 95 920; D. M. Lemal and P. Chao ibid. p. 922. 146 H. G. de Graaf 3. Dubbeldam. H. Vermeer and F. Bickelhaupt,Tetrahedron Letters 1973 2397. 14' G. Mark1 and F. Kneidl Angew. Chem. Infernat. Edn. 1973 12 931. 148 D. Dieterich H. Reiff H. Ziemann and R. Braden Annalen 1973 11 1. 149 Y. Wakatsuki and H. Yamazaki Tetrahedron Letters 1973,3383; J.C.S. Chem. Comm. 1973,280. M. J. Cook and C. D. Johnson from 2-azidocinnamates (184) via phosphorimidates in an elegant high-yield pathway,' 50 and quinoline-8carboxylic acids arise on treatment of 3,l -benzox- azin-4-ones with enamines.' 51 In an intriguing one-step reaction (but involving a number of mechanistic steps !) 2-bromopyridine reacts with lithium piperidide OR OR to yield 8-cyanoquinoline.' 52 Decomposition of 1-alkyltriazines (186) to imino- carbenes provides a novel synthesis of isoquinolines.2" Significantly both (186b) and (186c) afford 3-methylisoquinoline demonstrating that the intermediate imino-carbenes are in an equilibrium presumably involving the 1H-azine cf.ref. 2b. Me (186) a; R' = R2 = Ph b; R' = Ph R2 = Me c; R' = Me R2= Ph Substituent reactivity studies show that alkylpyridines surprisingly undergo deuteriation of the alkyl group in organic and that in KNH,-liquid ammonia 4-methylpyridine is more acidic than the 2-methyl isomer.' 54 Related to the latter observation is the report that 2,4-lutidine 2,3,4-collidine and 2,4- dimethylquinoline metallate exclusively at the 4-methyl group with alkali amides in ammonia or lithium di-isopropylamide in ether-hexane but at the 2-methyl I5O S.A. Foster L1. J. Leyshon and D. G. Saunders J.C.S. Chem. Comm. 1973 29. ls1 W. Steglich and 0.Hollitzer Angew. Chem. Internat. Edn. 1973 12 495. lS2 H. N. M. van der Lans and H. J. den Hertog Terrahedron Lerters 1973 1887. 153 W. E. Parham and P. E. Olson Tetrahedron Letters 1973 4783. Is4 J. A. Zoltewicz and L. S. Helmick J. Org. Chem. 1973 38 658. Heterocyclic Chemistry 503 group with n-b~tyl-lithiurn.'~~ Unlike the methylation of 3-amino- and 2- methylamino-pyridine which occurs at the ring nitrogen methylation of 3- amino-2-methylaminopyridineis now shown to occur exclusively at the 3-amino- group.' 56 Methylation of 2,3-diaminopyridine takes place at both basic sites'56 whereas alkylation of 4-and 5-aminoquinolines occurs at either or both depending upon the alkylating agent.' 57 A novel method of selectively alkylating 2-amino- pyridines at the 3-position has been described (Scheme 9);'58 using p-carbonyl sulphides azaindoles are obtained (cf.refs.76 and 77). H H 1 Scheme 9 2-Pyridyl acetate has been converted in one step into the quinolizinone (187),' 59 and the bispyridyl compound (188) undergoes smooth acid-catalysed rearrange- ment to (189).160 Sodium hydride has now been found to reduce quinolines and 155 E. M. Kaiser G. J. Bartling W. R. Thomas S. B. Nichols and D. R. Nash J. Urg. Chem. 1973,38 71. 156 K. Oyama and R.Stewart J.C.S. Perkin I 1973 673. 57 C. Feller and J. Renault Bull. SOC.chim. France IZ 1973 11 12; J. Berlot and J. Renault ibid. p. 2866. P. G. Gassman and C. T. Huang J. Amer. Chem. SOC. 1973,95 4453. G. R. Newkome J. M. Robinson and N. S. Bhacca J. Org. Chem. 1973 38 2234. 160 G. R. Newkome R. A. Martin and N. S. Bhacca Tetrahedron Letters 1973. 2541. M. J. Cook and C. D Johnson isoquinolines and provides a route to dihydroheteroaromatics not readily accessible previously,'6 ' while the reducing properties of N-alkyl- 1,4-dihydro- nicotinamides have been exploited to reduce the double bond of unsaturated nitriles.'62 Among papers on six-membered rings containing two or more nitrogen atoms are notes on the formation of the novel pyrrolo[l,2-d]triazine (190)163 and the dehydropyridazine system (191).lh4 The latter was trapped as the adduct (192) during oxidation of (193) in the presence of furan.Pyrolysis of both (192) and the pyridazinotriazine (194) afforded the butadiyne (195) considered to be the fragmentation product of (191).'64 (1931 Ph(CFC),Ph (195) The pyrimidine derivative (196) is unexpectedly formed during the Leuckart reaction on (197),16' and a new pathway for the thermolytic isomerization of the pyridazine nucleus to the pyrimidine nucleus is reported during the conversion of (198) into (199).'66 A facile H-D exchange in the n-deficient heterocycle (200) occurs in both basic and neutral media ;it is suggested that under the latter con- ditions exchange proceeds via the covalent hydrate (2Ol).' 67 Electrophilic bromination of the tetra-azacycl[3,3,3]azines (202a) and (202b) occurs at C-9 in the former and at C-6 in the latter.16' 16' M.Natsume S. Kumadaki Y. Kanda and K. Kiuchi Tetrahedron Letters 1973,2335. 16* K. Wallenfels W. Ertel and K. Friedrich Annalen 1973 1663. 163 J. P. Cress and D. M. Forkey J.C.S. Chem. Comm. 1973 35. T. L. Gilchrist G. E. Gymer and C. W. Rees J.C.S. Chem. Comm. 1973 819. 165 D. T. Hill and B. Loev J. Org. Chem. 1973 38 2102. 166 R. D. Chambers M. Clark J. R. Maslakiewicz and W. K. R. Musgrave Tetrahedron Letters 1973 2405. 16' W. W. Paudler J. Lee and T.-K. Chen Tetrahedron 1973 29 2495. 0.Ceder and K. Rosen Acra Chem. Scand. 1973 27 359 2421. Heterocyclic Chemistry (202) a; X = CH Y = N b;X = N Y = CH Heterocyclic N-oxides re a continuing source of intriguing chemistry.R action of quinoxaline dioxide with acetyl chloride chlorinates the benzene ring and deoxygenates the N+-0-function (Scheme the benzotriazine oxide (203) reacts with PhMgBr to form the ring-contraction products (204) and (205),'70 and 2-azidopyridine N-oxides undergo thermolytic ring contraction to the pyrroles (206).' 71 Photochemical studies of N-oxides have again been numer- ous. Further details of photolysis of pyridazine N-oxides are reported ; thus (207; R' = H R2 = Me) decomposes into (208; R' = H R2 = Me) and (209) Y. Ahmad M. S. Habib M. I. Qureshi and M. A. Farooqi J. Org. Chem. 1973 38 2 176. "O H. Igeta T. Nakai and T.Tsuchiya. J.C.S. Chem. Comm. 1973 622. R. A. Abramovitch and B. W. Cue J. Org. Chem. 1973 38 173. M.J.Cook and C.D.Johnson oQAcf OAc Scheme 10 OH (211) R = H or Me Heterocyclic Chemistry and (207; R' = R2 = Ph) into (208; R' = R2 = Ph) and (210).172 Interestingly the carbonanalogue of (207) uiz.the ylide (21 l) undergoes photolysis by pathways formally similar to those for the N-0~ides.I~~ In the benzo-fused series the phthalazine (212) photodecomposes to the isobenzofuran (213) [cf (207)-+ (208)],'72 and the cinnoline N-oxides (214) and (215) hitherto considered to be photochemically inert give among other compounds the ring-contracted products indi~ated.'~~ The anthranil(216) is also formed on photolysis of (217; R = Me); the analogue (217; R = Ph) however is converted into (218) and (219).175 Me Me Me Me H H "* K.B. Tomer N. Harrit. 1. Rosenthal 0. Buchardt P. L. Kumler and D. Creed J. Amer. Chem. Soc. 1973 95 7402; T. Tsuchiya H. Arai and H. Igeta Tetrahedron 1973,29 2741. 73 H. Arai H. Igeta and T. Tsuchiya J.C.S. Chem. Comm. 1973 521. W. M. Horspool J. R. Kershaw and A. W. Murray J.C.S. Chem. Comm. 1973,345. W. M. Horspool J. R. Kershaw A. W. Murray and G. M. Stevenson J. Amer. Chem. SOC.,1973 95 2390. M. J. Cook and C.D. Johnson 1,3-Cycloadditions involving ylides derived from pyridinoid rings have again been reported'76 (cf. last year's Report'") and of interest this year is the first report of 1,3-cycloaddition to an azoxy-compound ;thus (220) with DMAD forms (222) presumably via the adduct (221).' 78 The compound previously assigned the structure (223) has now been shown to be (224).'79 The betaine itself rapidly rearranges into (224) but can be trapped with methyl acrylate to form the adducts (225).' 79 .NO,rJo-No (223) Anumber of papers on pyridinium pyrylium thiapyrylium and related cations have appeared; synthetic studies include a novel route to pyrylium cation'" and the isolation of the stable thianthrene dication (226) obtained by oxidation of the corresponding thianthrene.' '' Addition of -CCl to pyridinium cations yields both 2- and 4-addition products,' ** while the action of amines on thiapy- rylium causes ring cleavage.' 83 2,4,6-Triarylpyrylium salts (227) undergo attack by nitrite in alcohols to yield the dihydropyran (228) the nitro-group being the oxidation product of the nitroso-group initially formed.In boiling acetic acid (228) is converted into (229).la4 176 E.g. Y. Hayasi H. Nakamura and H. Nozaki Bull. Chem. SOC. Japan 1973,46 667; N. S. Basketter and A. 0.Plunkett J.C.S. Chem. Comm. 1973 188. 177 Ann. Reports (B),1972,69 453. S. R. Challand C. W. Rees and R. C. Storr J.C.S. Chem. Comm. 1973 837. 179 N. Dennis B. Ibrahim A. R. Katritzky and Y. Takeuchi J.C.S. Chem. Comm. 1973 292. J. Andrieux J.-P. Battioni M. Giraud and D. Molho Bull. SOC. chim. France 11 1973 2093. R. S. Glass W. J. Britt W. N. Miller and G. S. Wilson J. Amer. Chem. SOC. 1973 95 2375. V. Mann G. Schneider and F.Krohnke Tetrahedron Letters 1973 683. lB3 Z. Yoshida H. Sugimoto T. Sugimoto and S. Yoneda. J. Org. Chem. 1973,38 3990. lS4 C. L. Pedersen 0. Buchardt S. Larsen and K. J. Watson Tetrahedron Lefters 1973 2195. Heterocyclic Chemistry + The photochemistry of pyrylium salts has been the subject of a series of studies. Photodecomposition of trialkylpyrylium cations e.g. (230) appears to proceed by way of an oxoniabenzvalene (231)18' and such intermediates have been in- voked in the photoisomerization (232)-+ (233).'86 (233) itself undergoes photorearrangement to (234) possibly via the intermediate indicated.' 86 Closely related to these studies are the photoisomerizations of 4-pyrones into 2- pyrones' 86b*' "where rearrangement is reported to be facilitated by increasing solvent polarity and the conversion of hindered 4-pyridones into 2-pyridones.' 88 (For discussion of the photochemistry of 2-pyrones see ref.39 and Section 2.) Further evidence has been presented which demonstrates that the 2-pyri- done *2-hydroxypyridine equilibrium favours the latter tautomer in the gas J. A. Barltrop K. Dawes A. C. Day S. J. Nuttall and A. J. H. Summers J.C.S. Chem. Comm. 1973 410. J. W. Pavlik and E. L. Clennan J. Amer. Chem. SOC.,1973,95 1697; J. W. Pavlik and J. Kwong ibid. p. 7914. N. Ishibe M. Sunami and M. Odani J. Amer. Chem. SOC.,1973 95 463. la' N. Ishibe and J. Masui J. Amer. Chem. SOC.,1973,95 3396. 5 10 M. J. Cook and C. D. Johnson phase,'89 and new routes to both 2- and 4-pyridones have been described.Thus the isocyanate (235) from sorbic acid undergoes electrocyclic ring closure to (236) which rearranges to the pyridone,' 90 and 2-and 4-halogeno-pyridinium and -quinolinium salts readily react with DMSO to form the corresponding pyridones and q~inolones.'~~ 4-Pyridones are also available through the sequence (237)-(238),'92 or by treating (239; X = 0)with the amido-acid phfih ~ RNH acid or base NaO ONa RNH RNH I (237) R (238) MeN(CPhOJCHPhC0,H ' (240) Ph A Ph ph)AJph Ph Ph (239) I Me The sulphur analogue (239; X = S) provides access to the corresponding py- ridthione.lg3 The reactivity of 2-pyridthione has been exploited in syntheses of thiazolopyridinium salts as exemplified by the sequence (241) -+(242).194 MeCH=CBrCO,H+ -+ os I H Ho2c2 Me Br-+Np;e (241) Br CO,H (242) lE9P.Beak and F. S. Fry J. Amer. Chem. SOC. 1973,95 1700. 190 J. H. MacMillan and S. S. Washburne J. Org. Chem. 1973 38 2982. 19' R. E. Lyle and M. J. Kane J. Org. Chem. 1973 38 3740. 192 I. El-S. El-Kholy M. M. Mishrikey and R. F. Atmeh 1. Heterocyclic Chem. 1973 10 665. 193 K. T. Potts and J. Baum J.C.S. Chem. Comm. 1973 833. 194 K. Undheim and R. Lie Acta Chem. Scand. 1973 27 1749; R. Lie and K. Undheim ibid. p. 1756; J.C.S. Perkin I 1973 2049. Heterocyclic Chemistry 511 The reaction of diketen with (243) and (244) provides simple routes to the pyrone derivatives (245) and (246) respectively. 19' A convenient synthesis of alkylated 4-hydroxy-2-pyrones has also been reported196 while in the sulphur series the dithioacetate (247) reacts with (248) to form (249) in neutral medium ; however in the presence of pyridine the 2-thiopyranthione (250) is ~btained.'~' s-s-s Ph+SMe S PhC=CH-C-SMeII I OH + A \ COPh (249) (247) (248) pJPh Ph (250) Pathways to cyclic thiazine S-oxides and benzothiadiazine S-oxides have been described,' 98 and in one paper optically pure derivatives were prepared e.g.(251).19" N.m.r. data indicate negligible aromatic character in these systems. Addition of sulphenes to thiomide vinylogues provides access to 1,2-dithiin-l,1- dioxide (252),19' and reaction of (253) with BF afforded a route to (254) which apparently exists as the potentially aromatic tautomer (254b).200 Further 195 R.Gompper and J. Stetter Tetrahedron Letters 1973 233. 196 E. Suzuki. H. Sekizaki and S. Inoue J.C.S. Chem. Comm. 1973 568. 19' F. Clesse J. P. Pradere and H. Quiniou Bull. Soc. chim. France II 1973 586. 198 (a)T. R. Williams and D. J. Cram J. Org. Chem. 1973 38 20; (6) Y. Tamura T. Miyamoto H. Taniguchi K. Sumoto and M. Ikeda Tetrahedron Letters 1973 1729; A. C. Barnes P. D. Kennewell and J. B. Taylor J.C.S. Chem. Comm. 1973 776. '99 M. Bard J. C. Meslin and H. Quiniou J.C.S. Chem. Comm. 1973 672. H. Zinnes and J. Shavel J. Heterocyclic Chem. 1973 10 95. M. J. Cook and C. D. Johnson evidence has been presented for aromatic stabilization of anions of type (255) systems electronically analogous to (252) and the heterocyclic ring of (254b).Thus the conjugate acid of (255)is a stronger acid than open-chain analogues,201 and structures of type (256)show partial dipolar character.202 \ \/ -N H Ar (252) Me Me I 1 (256) Chlorosulphonyl isocyanate adds to ketones to give both (257) and (258),203 and the salt of methoxycarbonylsulphamoyl chloride (259) reacts with nitriles to form (260).204 The latter undergoes thermal decomposition to the nitrile "' G. Gaviraghi and G. Pagani J.C.S. Perkin II 1973 50. 202 G.Pagani J.C.S. Perkin II 1973 1184; G. D. Andreetti G.Bocelli and P. Sgarabotto ibid. p. 1189. '03 J. K. Rasmussen and A. Hassner J. Org. Chem. 1973 38 21 14. '04 E. M. Burgess and W. M. Williams J. Org. Chem. 1973 38 1249; J.K. Rasmussen and A. Hassner Tetrahedron Letters 1973 2783. 513 Heterocyclic Chemistry and MeO,CN=SO, which adds to alkenes to provide access to the oxathia-zine (261). Conformational analysis of six-membered rings has advanced on ‘various fronts. Theoretical approaches have been described for calculating the ‘strain 02 02 o/s NH N/s\ N R1+0 Me LoL OMe R2 (257) R4 R3so:N RYoyoMe ‘ energy minimized’ geometry of heterocycle^'^^ and the preferred pathway for conformational inversion :’06 the former has been applied to heterocycles with one to three heteroatoms and the latter to the IC CI inversion of a-D-glucose. Results of a photoelectron spectroscopic study of 172-dimethylhexahydro-pyridazine have been interpreted in terms of a predominance of conformer (262),207and in the 0.r.d.x.d.field measurable Cotton effectsarising from hetero-atoms in b-hetero-cyclohexanones have been observed.208Further c.d. studies on y-lactones and lactams have also been rep~rted.”~ The effect of heteroatoms on ring-inversion barriers continues to attract study. Barriers for inversion of selenan selenan monoxide and dioxide and telluran have been determined using variable-temperature n.m.r. and correlate well with 205 I. D. Blackburne R. P. Duke R. A. Y. Jones A. R. Katritzky and K. A. F. Record J.C.S. Perkin II 1973 332. 206 A. A. Lugovskoy V. G. Dashevsky and A. I. Kitaigorodsky Tetrahedron 1973 29 287. 207 S. F. Nelson and J. M. Buschek J. Amer. Chem.SOC.,1973 95 201 1 ; S. F. Nelson J. M. Buschek and P. J. Hintz ibid. p. 2013. 208 M. M. Cook and C. Djerassi J. Amer. Chem. SOC.,1973 95 3678. 209 0.cervinka L. Hub F. Snatzke and G. Snatzke CON.Czech. Chem. Comm. 1973 38. 897. M. J. Cook and C.D. Johnson torsional properties of the carbon-heteroatom bond.21 1.3.2-Dioxathian has a lower barrier than 1,2,3-trithian but a higher barrier than 1,3-dioxan. These comparisons and others support the general contention tnat substitution of 0 for S lowers ring-inversion barriers and that lone pairs on adjacent atoms hinder the inversion process.21 Similarly the barrier to inversion of (263) is substantially higher than that of cyclohexene.212 Microcalorimetric measurements of the equilibrium (264a) S(264b) have provided the basis of an estimate of the enthalpy difference (37.3 kJmol-') between the chair and 1,4-twist conformations of 1,3-dio~an,~'~ and n.m.r.has \A-Me Me (264a and b) revealed an unusual slow (on the n.m.r. time-scale) chair-boat equilibrium viz. (265a) (265b).214 In the latter study signal integration of the spectrum at 0 "C showed that (265a) is marginally favoured in CCl whereas (265b) predominates (265) a; n = 9 (265) b; n = 9 (266) a;n = 8 (266) b;n = 8 in (CD3),C0 and CDC1,. The homologue (266) was isolated as conformer (266b) from the reaction of furan with 2,1l-dibromocycloundecanone,and did not ring-invert into (266a) below 140 0C.214 Studies on cis fused bicyclics have shown that the 'heteroatom inside' conformer (i) is favoured for (267; R = H) whereas the 'heteroatom outside' form (0)is *lo J.B. Lambert C. E. Mixan and D. H. Johnson J. Amer. Chem. Soc. 1973,95 4634. 211 G. Wood R. M. Srivastava and B. Adlam Cunud. J. Chem. 1973,51 1200. *I2 M. L. Kaplan and G. N. Taylor Tetrahedron Letters 1973 295. R. M. Clay G. M. Kellie and F. G. Riddell J. Amer. Chem. SOC.,1973 95 4632. *I4 J. G. Vinter and H. M. R. Hoffmann J. Amer. Chem. Soc. 1973,95 3051. Heterocyclic Chemistry preferentially adopted for (267; R = CD,CH,).Z’S In the series (268 269; n = 4) conformer (i) predominates but for (268 269; n = 5) the equilibrium is X ‘3 0 (4 (268) X = 0,Y= NH (269) X = NH Y = 0 reversed.’I6 Similar results were reported independently for bicyclic 1,3-dioxan~.~’ ’ The conformational equilibrium in (270) shows a temperature dependence favouring the equatorial methyl conformer at low temperature and the axial methyl one at room temperature.’18 In the series (271) the sub-stituent on the nitrogen preferentially adopts the equatorial site (at -82 0C),219 and a dipole moment study showed that the equatorial S=O conformer of (272) predominates at 25 0C,220a reversal of the normal preference of the S=X bond (see last year’s Report221).(271) R = H or Me Details of a methylation of rigid thian oxides and a thorough investigation of the chlorination of both mobile and fixed thian oxides have been reported. Thus monomethylation (BuLi-MeI) of both (273)and (274)introduced the methyl ‘I5 H.Boothand D. V. Griffiths J.C.S. Chem. Comm. 1973 666. 216 G. Bernhth Gy. Gondos K. Kovhcs and P. Sohhr Tetrahedron 1973 29,981. ’I7 A. K. Bhatti and M. Anteunis Tetrahedron Letters 1973 71. S. I. Featherman and L. D. Quin J. Amer. Chem. Soc. 1973 95 1699. 2L9 R. A. Y.Jones A. R. Katritzky A. R. Martin and S. Saba J.C.S. Chem. Comm. 1973 908. 220 M. J. Cook and A. P. Tonge Tetrahedron Letters 1973 849. 221 Ann. Reports (B) 1972 69 440. M. J. Cook and C. D.Johnson group trans to the S=O bond,222 whereas chlorination (CI in pyridine) con- verted (273) and (274) into the same product (275).223 H/D Exchange of the a-methylene protons in (276) and (277) has been compared;224 the reactivity ratio 0 & (273) Me Me OMe I I 0 (276) for the two pairs of diastereotopic hydrogens in (276) is ca.1 1 but in the five- membered ring it is ca. 12 l.224 Stereochemical studies on certain 1,3,2-dioxaphosphorinans have shown an unusual retention of configuration in the displacement of chlorine by methylmagnesium iodide22 and confirmed that oxidation of the two isomers of (278) occurs with retention of configuration.226 In the synthetic field the intermediacy of 4,5-dihydropyridazine (280) has been postulated in the conversion of (279) into (281),227 and the first synthesis of a 5,6-dihydropyridazine (282) is described.228 The latter undergoes a thermal [1,5] sigmatropic shift to give (283) whereas on photolysis the ring opens to give diazatrienes.228 The rate of the [2,3] sigmatropic rearrangements (284) -+(285) is slow compared with acyclic ylides and suggests bonding in the transition state consistent with a concerted mechanism.By contrast smooth rearrangement of (286) into (287) is interpreted in terms of a non-concerted Further studies on tetra-azabicyclononanes (288) show that dinitrogen tetroxide smoothly cleaves the molecule to give (289).230 Syntheses of 9-azabarbaralane (290)23 and the intriguing bridgehead alkenes (291) and (292) have been described.232 Spectral and chemical properties of 222 R. Lett S. Bory B. Moreau and A. Marquet Bull. SOC.chim. France II 1973 2851. 223 J. Klein and H. Stollar J. Amer. Chem. SOC.,1973 95 7437. 224 0. Hofer and E. L. Eliel J. Amer. Chem. Soc.,1973 95 8045 see also A. Garbesi G. Barbarella and A.Fava J.C.S. Chem. Comm. 1973 155; G. Barbarella A. Garbesi A. Boicello and A. Fava J. Amer. Chem. SOC.,1973 95 8051. 225 T. D. Inch and G. J. Lewis Tetrahedron Letters 1973 2187. 226 J. A. Mosbo and J. G. Verkade J. Amer. Chem. SOC.,1973,95,4659. 227 B. K. Randlish J. N. Brown J. W. Timberlake and L. M. Trefonas J. Org. Chem. 1973 38 1102. 228 P. de Mayo and M. C. Usselman Canad. J. Chem. 1973,51 1724 1729. 229 S. Mageswaran W. D. Ollis and I. 0. Sutherland J.C.S. Chem. Comm. 1973 656; W. D. Ollis I. 0.Sutherland and Y. Thebtaranonth ibid. p. 657. 230 H. Yoshida G. Sen and B. S. Thyagarajan J. Heterocyclic Chem. 1973 10 279 725. 231 A. G. Anastassiou A. E. Winston arid E. Reichmanis J.C.S. Chem. Comm. 1973 779. 232 C. B. Quinn and J.R. Wiseman (a) J. Amer. Chem. SOC.,1973 95 1342; (6) ibid. p. 6120. Heterocyclic Chenz istry 517 -(3coph X 'Rl I-R'CCOPh (285) (284) X = NMe or S R' RZ = H Et Bu' or Ph A n Ph NO NO (289) K = COMe (291)232"show the expected absence of conjugation while in (292) the structure inhibits overlap between the double bond and the sulphur 3p-orbitals but allows interaction with 3d-0rbitals.~~'~ Sulphur participation has been invoked to explain the solvolytic elimination reactions (293) -+(294),233 and an intra- 233 P. H. McCabeand C. M. Livingston Tetrahedron Letters 1973. 3029. M.J. Cook and C. D.Johnson molecular aldol condensation to account for the equally unexpected acetylation product (296) of (295).234 CN (291) X = 0 (292) X = S C1BC1 (293) (294) s 5 OWS More conventional routes than the above to heteroadamantanes as well as to heterotwistanes continue to command attention.Reports include details of the syntheses of 2,6-dia~a-adarnantanes,~~~ oxabenzo-2-0xa-6-aza-adarnantane,~~~ horn~adamantenes~~~ and [eg (297)] 2-oxa-7-azatwistane and isot~istane,~~~ the first heterotwistene and twistadiene (298).239 Methanolysis of (299) is shown to give solely (300),240and through-bond interaction is proposed to account for modified carbonyl character in l-aza-adamantan-4-0ne~~' and some diaza- derivatives.242 234 P. H. McCabe and W. Routledge Tetrahedron Letters 1973 3919. 235 R.-M. Dupeyre and A. Rassat Tetrahedron Letters 1973 2699; R.E. Portmann and C. Ganter Helu. Chim. Acta 1973 56. 1986. 236 R.E. Portmann and C. Ganter Helv. Chim. Acta 1973 56 1962. 237 B. Fohlisch U. Dukek. I. Graessle B. Novotny E. Schupp G. Schwaiger and E. Widmann Annalen. 1973 1839. 238 R. E. Portmann and C. Ganter Heh. Chim. Acta 1973 56 1991. 239 P. Ackermann and C. Ganter Helv. Chim. Acta. 1973 56 3054. 240 H. Teufel E. F. Jenny and K. Heusler Tetrahedron Letters 1973 3413; H.-C. Mez and G. Rihs ibid. p. 3417. 24 1 A. W. J. D. Dekkers J. W. Verhoeven and W. N. Speckamp Tetrahedron 1973 29 1691. 242 T. Sasaki S. Eguchi T. Kiriyama and Y. Sakito J. Org. Chem. 1973 38 1648. Heterocyclic Chemistry C1 (299) 6 Medium-sized Ring Compounds A number of novel potentially aromatic or antiaromatic compounds have been investigated this year.The oxonin derivative (302) prepared from (301) shows instability and reactivity indicative of antiaromatic destabilization ;243 such destabilization in benzo[b]thiepin may well account for the stability of its valence tautomer (303) now synthesized.244 The synthesis of the cyc1[4,3,2]azine (304) (302) is described and n.m.r. reveals that the system sustains a paramagnetic ring current.245 Among potentially aromatic medium-sized rings are the aza-azulenone (305),which protonates to form a diatropic cation,246 the hydrazine- bridge [14lannulene(306),which evidently supports a diamagnetic ring current,247 and the first examples ofthe monobenzo-fused analogues ofthe previously reported heteronin~.~~~ None of the derivatives in the last series sustains a ring current.Fluxional behaviour of the tricarbonyliron complex of 1-( lH)-2-diazepine (307) has been detected by variable-temperature n.m.r.,249 and reactions of the 243 M. P. Cava and K. T. Buck J. Amer. Chem. SOC.,1973 95 5805. 244 1. Murata T. Tatsuoka and Y. Sugihara Tetrahedron Letters 1973 4261. 245 W. Flitsch and B. Muter Angew. Chem. Internal. Edn. 1973 12 501. 246 W. Flitsch B. Muter and U. Wolf Chem. Ber. 1973 106 1993. 247 W. Flitsch and H. Peeters Chem. Ber. 1973 106 1731. A. G. Anastassiou E. Reichmanis and R. L. Elliott Tetrahedron Letters 1973 3805. 249 A. J. Carty R. F. Hobson H. A. Patel and V. Snieckus J. Amer. Chem. Soc. 1973 95 6835. 520 M. J. Cook and C.D. Johnson (MeOC),N @ AN/-(COMe)* NC -(306) R ““’3Fen N’ I H (307) R = H or Me free N-substituted diazepines include [2 + 21 cycloaddition with ketens and acid-catalysed dirneri~ation.~” The 1,3-oxazepin (309a) obtained by photolysing (3081 undergoes acid-catalysed hydrolysis to the pyrrole (3 10) and the hydroxy- pyridine (31 1).251in an independent acid hydrolysis of (309b) afforded the pyrrole corresponding to (3 10) but thermal or base-catalysed hydrolysis gave predominantly (312). Basic hydrolysis of the benzodiazepine (313) in- triguingly affords a benzimidazole (314) a further benzodiazepine (315) or a benzotriazepine (316) depending upon the condition^.^'^ d N R +Rc’kPh -+ c>+ ooHPh 0 (308) \o R (309) a; R = H b;R = Ph I COPh (310) (311) Ph COPh Ph aPh I H (312) 250 J.P. Luttringer and J. Streith Tetrahedron Lptters 1973 4163; B. Willig and J. Streith ibid. p. 4167. 251 T. Mukai and H. Sukawa Tetrahedroti Letters 1973 1835. C. L. Pedersen and 0.Buchardt Acta Chem. Scand. 1973 27 271. Y. Okamoto and T. Ueda J.C.S. Chem. Comm.. 1973 367. Heterocyclic Chemistry 521 In the realm of saturated and simple unsaturated medium rings a number of preparations elegant in their simplicity have been described. The reactive oxacycloheptyne (317a)254 and silaheptyne (317b)255 have been obtained from (317) a; X = 0,R = Me b; X = SiMe, R = H the corresponding acyloins as outlined and the bisalkyne (318) is precursor to the dihydrophosphepin and dihydroarsepin (319a) and (319b).2s6 The reaction of hydroxylamine with phorone originally believed to give the piperidone (320) is now shown to provide a convenient access to the oxazepinone ring system (321).257 Thermal rearrangement of both syn-and anti-2-azatricyc10[4,1,0,0,~~~]-heptanes (322) and (323) affords the dihydroazepine (324).Higher temperatures &/-7N PhXHz) cxF% & 0GMe (318) (319) a; X = P I b;X =AS OH (321) (320) 254 A. Krebs and G. Burgdorfer Tetrahedron Letters 1973 2063 255 S. F. Karaev and A. Krebs Tetrahedron Letters 1973 2853. 256 G. Mark1 and G. Dannhardt Tetrahedron Letters 1973 1455. 257 K. C. Rice and U. Weiss Tetrahedron Letters 1973 1615. 522 M. J. Cook and C. D. Johnson C0,Me I (324) are required for the conversion of (323) into (324) than for that of (322) into (324) the difference in reactivity being rationalized in terms of the ease of formation of the ylide transition state (325).2s8 Details of a general synthesis of 3H-azepines have been describedzs9 and a new synthetic entry into benzodiazepines has been realized through base-catalysed cyclization of di-imines e.g.(326)-+(327).z60 Bu' (327) An interesting route to an eight-membered ring involves an 'anti-Markovnikoff addition of H2Sto the bisalkene (328) to give (329) an addition induced photo- lyti~ally.~~~ Further routes to eight- as well as nine- and ten-membered rings (329) are exemplified by the additions of alkynes to enamines (Scheme 11),z62 the addition of alkenes and dienes to the 1,2-dithian derivative (330) (Scheme 12),263 and the thermolysis of (331) the adduct from reaction of arylnitrile oxides with hexamethyl-Dewarbenzene to give the nine-membered ring (332).264 Oxidation of (333) with rn-chloroperbenzoic acid gives (334) and is but one of several N-oxide rearrangements reported during the year.Here the reaction is suggested to proceed as indicated.265 A study of the Polonovsky rearrangement S. R. Tanny and F. W. Fowler J. Amer. Chem. SOC.,1973,95 7320. 239 F. R. Atherton and R. W. Lambert J.C.S. Perkin I 1973 1079. 260 J. A. Deyrup and J. C. Gill Tetrahedron Letters 1973 4845. 261 K. E. Koenig and W. P. Weber Tetrahedron Letters 1973 3151. 262 D. N. Reinhoudt and C. G. Kouwenhoven Tetrahedron Letters 1973 3751.263 N. E. Hester and G. K. Helmkamp J. Org. Chem. 1973 38 461. 264 G. Briintrup and M. Christl Tetrahedron Letters 1973 3369. 265 D. L. Trepanier S. Wang and C. E. Moppett J.C.S. Chem. Comm. 1973 642. Heterocyclic Chemistry 523 R3 X=SorN ~ OR3 NR'R2 R3 Scheme 11 TNBs-TNBs-TNBs-(330) Scheme 12 Me Me Me (331) Me Me (332) of prochiral substrates (335a) with chiral reagent has led to the conclusion that the rearrangement is a non-concerted one,266 while in the same area the sub-strate (335b) under Polonovsky conditions unexpectedly forms (336).267 266 V. SunjiC F. KajfeB D. Kolbah H. Hofman and M. Stromar Tetrahedron Letters 1973 3209. 26' A. Walser G. Silverman and R.I. Fryer J.Org. Chem. 1973 38 3502. 5 24 M. J. Cook and C. D. Johnson (335) a; R' R2 = H or Me b; R' = Me R2 = CH,CH=CH (336) 7 Large-ringCompounds The synthesis and properties of heteroannulenes remains an active area of research. Irradiation of (338) one of several products of addition of N-(ethoxycarbony1)- nitrene to (337) afforded an aza[l3]annulene to which the configuration (339) N (337) (338) I C0,Et (339) has been assigned.268 The compound is sensitive to air and chemical shifts of the ring protons are typical of a polyolefin ;variable-temperature n.m.r. spectra suggest that it exists in more than one conformation.268 Details of the prepara- tions of various potential 16~-systems have been reported this year and include those of the oxa[l5]annulene (340),269 the [16]annulene dioxide (341),270 and the (340) (342) a; R R = 0,X = NH 0,or S b;R =H,X =NH,O,orS series of [17]annulenones (342).27' Compounds (340) and (341) sustain a para- magnetic ring current and the separation of the inner and outer proton resonances in the latter is greater than in [16]annulene itself.Comparison of the proton 268 G. Schroder G. Frank and J. F. M. Oth Angew. Chem. Internat. Edn. 1973 12 328. 269 H. Ogawa and M. Kubo Tetrahedron 1973 29 809. 270 H. Ogawa M. Kubo and I. Tabushi Tetrahedron Letters 1973 361. 271 T. M. Cresp and M. V. Sargent J.C.S. Perkin I 1973 2961. Heterocyclic Chemistry shifts in the series (342) with those of the homoannulenes (343) show that (342; X = 0)and (342; X = NH) but not (342; X = S) are paratropic; the bulky S atom in (342; X = S) presumably forces the compound into a nonplanar con- formation.271 Syntheses are also described for the didehydroaza-[19]- and -[21]- annulenes (343) and (344).272 Proton shifts relative to those in open-chain C0,Et C0,Et I (343) (344) analogues reveal that the former is paratropic and the latter diatropi~,~'~ although the manifestation of diatropy of (344) is less marked than in the corresponding smaller [17lannulene reported last year.273 N.m.r.is not helpful in establishing the presence of a ring current in the [26]annulene (345) formed in a remarkable NH HN (345) quantitative yield by condensing 2,2'-diaminobiphenyl with diphenyl-2,2'-dicarboxyaldehyde.74 Chemiluminescence of the paracyclophane (346) on oxidation with 0,-KOBu' in DMSO has been investigated ;275 the emission of light is some 25 times 272 P. J. Beeby and F. Sondheimer Angew. Chem. Internat. Edn. 1973 12,410 41 1. 273 Ann. Reports (B),1972 69 457. 274 I. Agranat Tetrahedron 1973,29 1399. *" K.-D. Gundermann and K.-D. Roker Angew. Chem. Internat. Edn. 1973,12,425. M. J. Cook and C. D. Johnson t-s-l 0 SMe Me 0 that emitted from a mixture of (347) and (348). Syntheses of cyclophanes include those of (349)276and new multibridged systems,277 while further template syn- theses of macrocycles (cyclization promoted by metal ions) have also been (349) announced. The latter are exemplified by the formation of the furan-acetone condensation product (350),”* and 22- 33- 44- and 55-membered macrocycles (353) from the bisalcohol (351) and the dibromide (352).279 In the absence of (351) (352) (353) n = 1-4 metal ions the yield of macrocycle drops at the expense of linear products.An improved synthesis of cryptates has also been described which involves a flow 276 T. Umemoto T. Otsubo Y. Sakata and S. Misumi Tetrahedron Letters 1973 593. 277 F. Vogtle G. Hohner and E. Weber J.C.S. Chern. Cornm. 1973 366. 278 M. Chastrette and F. Chastrette J.C.S. Chem. Comm. 1973 534. 279 G. R. Newkome and J. M. Robinson J.C.S. Chem. Comm. 1973 831. Heterocyclic Chemistry technique.280 Related to cryptates are the novel tri- and tetra-cycles (354a) and (354b) and these form metal cation and molecular complexes.281 Examples of the appropriate-sized binaphtho-crown ethers (355) reported this year,28 LO\lOd (354)a; Y =CH, 0,or NH b; Y-Y =NCO(CH,),,CON or N(CH,),,N solubilize arenediazonium tetrafluoroborate and benzoyl hexafluorophosphate salts2824 in non-polar medium and also complex metal salts and a-amino- acids.282bA feature of certain members of the series is the incorporation of counter-ions (e.g.R =CH20CH2C0,-)within the system and in an important innovation,282c optically pure valine was shown to resolve racemic host crown ether in liquid-liquid chromatography.Conversely optically pure crown provides a tool for the resolution of amino-acids. J. L. Dye M. T. Lok F. J. Tehan J. M. Ceraso and K. J. Voorhees J.Org. Chem. 1973,38 1773. J.-M. Lehn J. Simon and J. Wagner Angew. Chem. Internat. Edn. 1973,12 578 579. '"(a)G. W. Gokel and D. J. Cram J.C.S. Chem. Comm. 1973 481 ;(6)R. C. Helgeson J. M. Timko and D. J. Cram J. Amer. Chem. SOC., 1973,95 3023; (c) R. C. Helgeson, K. Koga J. M. Timko and D. J. Cram ibid. p. 3021; (6)E. P. Kyba M. G. Siegel L. R. Sousa G. D. Y. Sogah and D. J. Cram ibid. p. 2691.

ISSN:0069-3030    

DOI:10.1039/OC9737000471

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

16 Alkaloids By H. F. HODSON The Wellcome Research Laboratories Beckenham Kent BR3 3BS 1 Introduction For a comprehensive survey of the whole alkaloid field the reader is again referred to the latest volume’ of the Specialist Periodical Reports on Alkaloids which covers the period from July 1971 to June 1972. Biosynthetic aspects are also treated in the companion volume’ on biosynthesis which following the pattern of last year includes a tabular survey of all tracer incorporations into alkaloids reported during 1972. 2 Pyridine and Imidazole Alkaloids A fungal alkaloid (1 ;or enantiomer) from Rhizoctonia legminicola is a unique example of a natural 1-pyrindene ; like slaframine (2) previously isolated from the same source it is biosynthesized via pipecolic acid from lysine.3 It has been noted that the structures (3) and (4) previously assigned4 to iso- longistrobine and dehydroisolongistrobine,are inconsistent with the published spectroscopic data.Syntheses have confirmed the revised structures (5) for isolongistrobine and (6) for dehydroisolongistrobine. ‘The Alkaloids’ ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 1973 Vol. 3. ‘Biosynthesis’ ed. T. A. Geissman (Specialist Periodical Reports) The Chemical Society London 1973 Vol. 2. F. P. Guengerich S. J. Di Mari and H. P. Broquist J.Amer. Chem. SOC.,1973,95,2055. Ann. Reports (B) 1969 66 471. M. A. Wuonola and R. B. Woodward J. Amer. Chem. SOC.,1973.95 284. 529 5 30 H. F. Hodson 0 Me I (5) X = H,OH (3) (4) (6) X = 0 3 Acridone Alkaloids Nearly thirty acridone alkaloids have been isolated to date all from plants of the Rutaceae family.Among new examples this year are the novel ether-linked bis-acridones ataline (7) and atalantine (8) from Atalantia ceylanica;6 the C-5'-C-6 position of the ether link was not rigorously established but is bio- genetically reasonable. Mono-acridone alkaloids were also isolated from the same species. * 4 Isoquinoline Alkaloids During recent years much of the interesting work in this area has been concerned with the in uiuo and in uitro transformations of benzylisoquinolines and phenyl- ethylisoq~inolines~ into the derived systems such as aporphines morphinandie- nones erythrina alkaloids and their homologues.The key step in these trans- formations is an intramolecular aryl-aryl coupling reaction and for the bio- synthetic routes the evidence suggests oxidative coupling of appropriate di- phenolic precursors. Much ofthe in uitro work has therefore involved the reaction of such precursors with a variety of one-electron oxidizing agents with coupling of the resultant diphenoxyl radical." The current year sees two significant M. A. Wuonola and R. B. Woodward J. Amer. Chem. SOC.,1973.95 5098. ' A. W. Fraser and J. R. Lewis J.C.S. Chem. Comm. 1973 615. A. W. Fraser and J. R. Lewis J.C.S. Perkin I 1973 1173. T. Kametani in 'The Alkaloids' Academic Press New York 1973 Vol. 14 p. 265. lo T. Kametani and K. Fukumoto Synthesis 1972 657. Alkaloids 531 departures in this area of intramolecular oxidative coupling both of which could have biogenetic implications.The first of these" is illustrated in a synthesis (Scheme 1) of the colchicine precursor (f)-0-methylandrocymbine (10) by a route which involves a two-electron oxidation with thallium(Ir1) trifluoroacetate of a mono-phenolic pre-cursor (9) the novel use of the N-BH protecting group is noteworthy. Previous attempts to prepare (10) by oxidative coupling of the appropriate diphenol had failed. N Me HO ' HO OMe OMe .. ... II 111 J OMe OMe Reagents i BH in THF-CHCl,; ii TTFA in CH,Cl,; iii Na,CO,-MeOH reflux. Scheme 1 Another example of oxidative coupling of a monophenolic substrate is pro- vided by the conversion" of the fully aromatic isoquinoline (11) into the quinonoid oxoaporphine (13); this transformation is mediated by a variety of reagents including both recognized one-electron and two-electron oxidants in yields of 10-60%.Alkaloid (13)was also isolated from a Pschorr cyclization of the diazonium salt (12); presumably the expected product (14) suffers im- mediate aerial oxidation to the fully conjugated (13).13 'I M. A. Schwarz B. F. Rose and B. Vishnuvajjala J. Amer. Chem. SOC.,1973,95 612. l2 S. M. Kupchan and A. J. Liepa J. Amer. Chern. SOC.,1973,95,4062. See also M. P. Cava I. Noguchi and K. T. Buck,J. Org. Chem. 1973 13,2394. 5 32 H. F. Hodson I I OMe OMe OMe (11) R' = R2 = H (14) (12) R' = Ac R2 = N,+ The second departure' involves the intramolecular coupling of non-phenolic benzylisoquinolines mediated by vanadium oxytrichloride.With this reagent in the presence of trifluoroacetic acid (-t)-N-formylnorlaudanosine (15) was converted into a mixture of the aporphine N-formylnorglaucine (16) and the spirodienone (17) the structure of which was established by X-ray analysis. Under the same conditions (+)-laudanosine (18) gave (rt)-glaucine (19) in 43% yield. A likely mechanism for the formation of (17) involves the oxidative demethylation. Hydride reduction of the dimethylacetal from (17) gave 0-methylerybidine (21) with the dibenzazonine structure established as an in uitro and in uivo precursor of the Erythrina alkaloids. '9~~0 MeoFR formation [ct (15) path b] of (20) followed by rearrangement (20; arrows) and \ Me0 M b...Y .;.-' /.o R Me0 \ e ' ' ' Me0 Me0 Me0 OMe OMe OMe (15) R = CHO (18) R = Me (16) R = CHO (19) R = Me (17) OMe OMe M e< Me03 \-Me0 ' 1 NCHO M e O k p'NMe Me0 OMe OMe 0 (20) (21) (22) l4 S.M. Kupchan A. J. Liepa V. Kameswaran and R. F. Bryan J. Amer. Chem. SOC. 1973 95 6862. Alkaloids 533 The only previous example of the coupling of non-phenolic substrates is provided by the anodic oxidation of (f)-laudanosine (18) first reportedI5 two years ago and now described in detail for (18) and several analogues;16 very similar results under somewhat simpler conditions are independently reported.” In contrast to the chemical oxidations discussed above [cf.(18) routes a and b] the electroxidative cyclizations follow route c exclusively to give high yields (up to 86 %) of products e.g.(22) from (18) with the morphinandienone skeleton. The prohomoerythrinadienone (23) prepared for the first time by a standard phenol oxidation procedure readily undergoes acid-catalysed dienone-phenol rearrangement to the homoaporphine (24) in 75% yield.I8 This is in striking contrast to the behaviour of the corresponding proerythrinadienone system cf. (25) which has never been rearranged to an aporphine presumably because of steric constraints ;’ the rearrangement normally takes a different course to give a dienone of type (17) ;cf. (20)-+(17). This year however the aporphine (27) has been obtained2’ from the dienol(26) but in less than 1 % yield the major product being an enone of skeletal type (17).Me0 Ho~NcOCFI HO Q OMe OH Ann. Reports (B) 1971,68 497. l6 L. L. Miller F. R. Stermitz and J. R. Falck J. Amer. Chem. Soc. 1973 95 2652. ” E. Kotani and S. Tobinga Tetrahedron Letters 1973 4759. J. P. Marino and J. M. Samanen Tetrahedron Letters 1973 4553. ‘ M. Shamma in ref. 1 p. 136 and T. Kametani K. Takahashi T. Honda M. Ihara and K. Fukumoto Chem. and Pharm. Bull. (Japan) 1972 20 1973. ’O T. Kametani K. Takahashi K. Ogasawara and K. Fukumoto Chem. and Pharm. Bull. (Japan) 1973 21 662. 5 34 H. F. Hodson Me0 \ xpo2Et Meopco2Et Me0 Me0 ' OMe OMe (25) X = 0 (26) X = H,OH (27) An amorphous green base nandazurine (29) has the same zwitterionic meso- meric structure2' as the hitherto unique alkaloid corunnine (28).Both alkaloids have been synthesized22 by a route which employs a photocyclization to complete the aporphine system; corunnine has also been prepared via a conventional Pschorr ring-cl~sure.~~ R R (28) R = Me0 (29) RR = OCHZO A new route24 to protoberberine alkaloids is exemplified by a synthesis of (+)-xylopinine (32) in which the key step is photocyclization of the enamide (30) to give (31)accompanied by its dehydro-derivative. Me0 OMe OMe (30) (31) X = 0 (32) X = H l' J. Kunitomo M. Ju-Ichi Y. Yoshikawa and H. Chikamatsu Experientia 1973 29 518. l2 S. M. Kupchan and P. F. O'Brien J.C.S. Chem.Comm. 1973,915. 23 I. Ribas J. SBa and L. Castedo Tetrahedron Letters 1973 3617. 24 I. Ninomiya and T. Naito J.C.S. Chem. Comm. 1973 137. Alkaloids 535 Another synthesis of the protoberberine system makes use of the recently described’ thermolysis of benzocyclobutenes to o-quinodimethide intermediates. Thus in bromobenzene at 150-16OoC (33) and (34) gave about 90% yield of the protoberberinium salts (35)26and (36),’’respectively;the extra unsaturation was presumably introduced oxidatively during work-up. Me0 OMe OMe (33) R = Me (35) R = Me (34)R = PhCHz (36) R = PhCH A quinodimethide intermediate is also probably implicated in a photochemical synthesis ** of the spiroisoquinoline (38). Irradiation of a basic solution of the oxotetrahydroberberinium salt (37) gave (38) in 45 % yield presumably /I+ Me q Q 0 /-o/ OMe 1 (37) by the steps indicated.The reverse process has also been effected photo- ~hemically;~~ irradiation of (39) in neutral solution gave the berberinium salt (35). ’’ Ann. Reports (B) 1971 68 494. 26 T. Kametani K. Ogasawara and T. Takahashi Tetrahedron 1973 29 73; J.C.S. Chem. Comm. 1972,675. ” T. Kametani Y. Hirai F. Satoh K. Ogasawara and K. Fukumoto Chem. and Pharm. Bull. (Japan) 1973 21 907. 28 B. Nalliah R. H. F. Manske R. Rodrigo and D. B. MacLean Tetrahedron Letters 1973 2795. *’ H. hie K. Akagi S. Tani K. Yabusaki and H. Yamane Chem. and Pharm. Bull. (Japan) 1973 21 855. 536 H. F. Hodson Three new alkaloids3' from Corydalis incisa corydalic acid methyl ester (40),3 corydamine (41),3zand N-f~rmylcorydamine,~~ are 3-arylisoquinolines and formally of a new structural type although their biogenetic affinities with protoberberine alkaloids e.g.(42) which occurs in the same species,30 are obvious ;note that the isoquinoline ring in (40)and (41)is not the biosynthetically original isoquinoline nucleus. O'Me OMe (40) Although it has generally been presumed that alkaloids are end-products of plant metabolism during recent years there have been sporadic reports33 indicating that in at least some cases they may play an important dynamic functional role in plant metabolic processes. Such a report this year is concerned with the fate of morphine (43)in Pupaver sornniferurn where it is shown to be converted irreversibly into normorphine (a), now identified as a natural alkaloid ; normorphine is in turn degraded to non-alkaloidal metabolite^.^^ Morphine is biosynthesized via thebaine (45)and codeine (46)and it is now clear that throughout the lifecycle of the plant there is a high rate of turnover in the sequence from thebaine to normorphine and beyond a sequence involving successive demethylation steps.This leads to the hypothesis34 that the morphine alkaloids in this sequence are acting as specific methylating agents. 30 G. Nonaka H. Okabe I. Nishioka and N. Takao Yakugaku Zasshi 1973,93 87. 3' G. Nonaka Y. Kodera and I. Nishioka Chem. and Pharm. Bull. (Japan) 1973 21 1020. 32 G. Nonaka and I. Nishioka Chem. and Pharm.Buff.(Japan) 1973,21 1410. 33 E. Leete in ref. 2 p. 1 1 1. 34 R. J. Miller C. Jolles and H. Rapoport Phyrochemistry 1973 12 597. Alkaloids 537 R'O NR2 (43) R' = H R2 = Me (45) (44) R' = R2 = H (46) R' = R2 = Me Significant findings of another kind are also associated with morphine. For some time pharmacologists have been building up a compelling body of evidence for the existence of a specific opiate receptor which recognizes morphine and related opiates and also morphine antagonists [e.g. (-)-naloxone]. Now from various mammalian species there have been isolated membrane fractions of nervous tissue which selectively form complexes with opiate drugs at very low concentrations (down to 1 x moll-for naloxone).The binding is highly stereospecific and correlates well with known pharmacological potencies. These res~lts~~-~~ should give greater insight into the mode of action of opiate drugs. A synthesis of cephalotaxine (47)reported4' last year incorporated a cyclization of the anion (48; X = C1 Br or I) to (49) under benzyne-forming conditions; yields were less than 10%. A reinvestigation4' of this step has shown that the conversion can be effected most efficiently through a photo-stimulated intra- molecular SR,l reaction;42 irradiation of (48; X = I) in liquid ammonia in the presence of potassium t-butoxide produced an astonishing 94 % of (49). " c.B. Pert and S. H. Snyder Science 1973 179 1011; Proc. Nat. Acad. Sci. U.S.A. 1973,70 2243. 36 L.Terenius Acta Pharmacol. Toxicol. 1973 32 317. '' E. J. Simon J. M. Hiller and I. Edelman Proc. Nar. Acad. Sci.U.S.A.,1973,70 1947. " M. J. Kuhar C. B. Pert and S. H. Snyder Nature 1973 245 447. 39 C. B. Pert G. Pasternak and S. H. Snyder Science 1973 182 1359. 40 Ann. Reports (B) 1972 69 494. 4' M. F. Semmelhack R.D. Stauffer and T. D. Rogerson Tetrahedron Letters 1973 4519. 42 R.A. Rossi and J. F. Bunnet J. Org. Chem. 1973. 38 1407. 538 H. F. Hodson 5 Amaryllidaceae Alkaloids Aryl-aryl coupling of non-phenolic substrates by electro-oxidative methods employed so effectively in the benzylisoquinoline series has now been applied to the synthesis43 of (f)-oxocrinine (52) and (+)-oxomaritidine (55) with yields of 60% in the coupling reactions (50) to (51) and (53) to (54).The well-trodden phenol oxidation procedure e.g. (56) to (57) has been effected in 35% yield with yet another reagent the iron-DMF complex [Fe(DMF),Cl,] [FeC14].44 A synthesis45 of the lactonic alkaloid (f)-clivonine (60) commenced with a cycloaddition reaction to give (58); conversion to (59) was followed by two oxidative steps as indicated. COCF (51) R'R' = CH, (50)R'R2 = CH,,R3 = Me / (54)R' = R2 = Me (53) R' = R2 = R3 = Me (57)R' = Me R2 = H (56)R' = Me,R2 = R3 = H R20 R1o&o (52) R'R~= CH (55) R' = R2 = Me 6 Terpenoid Indole Alkaloids Strychnos angustijlora an Asian species has furnished the three closely related yellow angustoline (61) angustine (62) and angustidine (63).further4' examples of pyridines closely related to the seco-iridoid precursor(s) of the many indole alkaloids so far isolated from this genus. The new bases were obtained in an ammonia-free work-up and are not therefore artefacts. The assigned structures followed mainly from spectroscopic data and in two cases have been confirmed by synthesis. In one synthetic study48 the aglycone (64) from dihydrovincoside lactam was converted with aqueous ammonia into an unstable product formulated as (65) ; 43 E. Kotani N. Takeuchi and S. Tobinga J.C.S. Chem. Comm. 1973 550. 44 E. Kotani N. Takeuchi and S. Tobinga Tetrahedron Letters 1973 2735. 45 H. hie Y. Nagai K. Tamoto and H. Tanaka J.C.S. Chem. Comm. 1973 302. 46 T. Y. Au H. T. Cheung and S. Sternhell J.C.S.Perkin I 1973 13. 47 cf. Ann. Reports (B) 1972 69 498. ** R.T. Brown A. A. Charaiambides and H. T. Cheung Tetrahedron Letters 1973,4837. A lkaloids 539 0 (60) Reagents i Os0,-Et,O; ii sepn. of isomers; iii Mn0,-CHCI dehydration and oxidation then furnished dihydroangustine [cf (62)] identical with the reduction product of angustine. The other ~ynthesis:~ of angustidine (63) exploited the enamide photo- cyclization first employed in a synthesis of (f)-crinane full details of which have NH Et * OH (64) (65) 49 I. Ninomiya. H. Takasugi and T. Naito J.C.S. Chem. Comm. 1973 732. 540 H. F. Hodson appeared this year.50 Irradiation of (66) gave two isomeric bases one of which (20%) was identical with natural (63); the other base was the product of the alternative cyclization on to the pyridine 6-position.~ T ! N J Ho2cPH \o /6 Me0,C Some years ago the structure (67) was assigned to the naturally occurring antiviral compound elenolic acid. On spectroscopic grounds this is now re- formulated'' as (68) which was confirmed by a total synthesis of the racemic methyl ester.52 The depicted (68) absolute stereochemistry was established" by a stereorational conversion (Scheme 2) into (-)-ajmalicine (69). H ,,Me H i-iii T HO,C CHO ee H-' H MeOzC'bo Reagents i esterification; ii tryptamine; iii NaBH,; iv POC1,-PhH reflux; v NaBH Scheme 2 50 I. Ninomiya T. Naito and T. Kiguchi J.C.S. Perkin I 1973 2261. 5L F. A. MacKellar R. C. Kelley E.E. van Tamelen and C. Dorschel J. Amer. Chern. SOC.,1973 95 7155. 52 R. C. Kelley and I. Schletter J. Amer. Chem. SOC.,1973 95 7156. Alkaloids 541 Adina rubescens the source of so many interesting tryptophan-derived indole alkaloids (i.e. those retaining the carboxylate function) has provided still two more both with unique structural features but both clearly very close to a precursor such as 5-carboxystrictosidine (70).53One of these alkaloids de- soxycordifoline lactam (7 1) incorporates an unprecedented seven-membered indole lactam; it was isolated as the tetra-acetate and could be converted into the known deoxycordifoline (70; ring c aromatic). Rubenine (72) the second alkaloid has a unique N(b)-C-18 bond in a seven-membered ring; most of the structural features were recognized in a detailed n.m.r.and mass spectral study of (72) and its derivative^.^^ H Me0,C bo Me Q o0 (72) (73) R = C0,Me (74) R = H A tryptophan-derived structure (73) is also proposed55 for cannagunine B from the cranberry Vucciniurn oxycoccus. This structural assignment however relies heavily on an earlier assignments6 of the novel structure (74) to canna- gunine from the same source and the evidence as then presented for the latter structure was not wholly convincing; the U.V. maximum for example was reported at 338 nm ! The dehydroyohimbane system (76) has been prepared in 70% yield by thermolysis of the appropriate benzocyclobutene (75),5 ' a route analogous to that described on p. 535 for the protoberberine system." R. T. Brown and S. B. Fraser Tetrahedron Letters 1973 841. s4 R. T. Brown and A. A. Charalambides J.C.S. Chem. Comm. 1973 765. 55 K. Jankowski Experientia 1973 29 519. 56 K. Jankowski J. Boudreau and I. Jankowska Experientia 1971 27 1141. 57 T. Kametani M. Kajiwara and K. Fukumoto Chem. and Ind. 1973 1165. 542 H. F. Hodson OMe OMe (75) Four years ago it was shown that in Strychnos nux vornica tryptophan and geraniol were as expected both incorporated into strychnine (82) the additional two-carbon bridge being provided by acetate. In these short-term hydroponic experiments it was not possible to demonstrate the incorporation of more advanced intermediates such as geissoschizine(78) Wieland-Gumlich aldehyde (79) or diaboline (80).Now prolonged feeding experiments have shown that both geissoschizine and W-G aldehyde but not diaboline are significantly incorporated into ~trychnine.~~ H‘ Me0,C 3 I OH (79) R = H (78) (80) R = AC In two short-term experiments after feeding with labelled tryptamine or with acetate modified work-up furnished a new base-soluble (amphoteric) alkaloid which could be converted into strychnine on warming with dilute acid. This alkaloid which would be converted into strychnine during normal work-up was named prestrychnine and was plausibly formulated as (81).58 58 S. I. Heimbergerand A. I. Scott J.C.S. Chem. Comm. 1973 217. Alkaloids 543 The interesting but biosynthetically unexceptional structure (83) has been assigned to geissovelline a new alkaloid from Geissospermum uellosii by a combination of classical degradation and spectroscopic studies.59 The U.V. spectrum in neutral solution exhibits both N-acylindoline and afl-unsaturated ketone chromophores. In acidic solution the latter disappears leaving a pure N-acyldialkoxyindoline spectrum ; the transannular interaction between the amino and carbonyl functions ensures that protonation occurs on the oxygen to give (84). {fie HH Ac (84) (83) The novel lactam rhazinalam (86) described last year has now been neatly synthesized (Scheme 3) by a route6' in which the full carbon-nitrogen skeleton was incorporated into the pyrrole-lactam (85) produced by an N-alkylation of the appropriately substituted pyrrole.The methoxycarbonyl function served to direct the cyclization of (85) and was removed in the terminal stages to give racemic (86). The depicted (86) absolute stereochemistry followed from a partial synthesis6* by oxidation of ( k)-1,2-dehydroaspidospermidineof known con- figuration. % Il-v 3 &! CO,Me N u I CO,H H Reagents i AlC1,-MeNO,; ii H,-Adams catalyst; iii DCC-DMF; iv NaOH-H,O-MeOH; v decarboxyiation Scheme 3 I3C N.m.r. spectroscopy has played a predominant role in the structural elucidation of several alkaloids newly isolated this year. These include the s9 R. E. Moore and H. Rapoport J. Org. Chem. 1973,38 215. 'O A. H. Ratcliffe G. F. Smith and G. N. Smith Terrahedrorl Letrers 1973 5179. 544 H.F.Hodson bis-indole alkaloid criophylline (87),61 from Crioceras dipladenijlorus and the tabersonine-like vandrikidine (88) vandrikine (89),and hazuntinine (90). These last three bases were examined as part ofa detailed analysis,62 usinga combination H I C0,Me H (89) of decoupling techniques of a number of Aspidosperma bases. Further63a information is now provided63b on the existence of two distinct stereochemical series within this family a consequence of the involvement of a common achiral biosynthetic precursor such as (92). The new work includes a number of 0.r.d. comparisons and provides another absolute standard by an X-ray analysis of natural (*)-coronaridhe (91) the enantiomer of the natural coronardine of last year's63a study.There is still no resolution of the controversy surrounding the claimed inter- conversion in refluxing acetic acid of indole alkaloids of the coryanthe aspido- 61 A. Cave J. Bruneton A. Ahond A. M. Bui H.-P. Husson. C. Kan G. Lucacs and P. Potier Tetrahedron Letters 1973 508 1. 62 E. Wenkert D. W. Cochran E. W. Hagaman F. M. Scheii N. Neuss A. S. Katner P. Potier C. Kan M. Plat M. Koch H. Mehri J. Poisson N. Kunesch and Y. Rolland J. Amer. Chem. SOC.,1973 95 4990. 63 (a) Ann. Reporrs (B) 1972 69 501 ;(b)J. P. Kutney K. Fuji A. M. Treasurywala F. Fayos J. Clardy A. I. Scott and C. C. Wei J. Amer. Chem. Soc. 1973 95 5407 Alkaloids 545 sperma and iboga skeletal types.64 A note6’ comments on the work reported last year by Scott and Wei.64 It emphasizes the fact that although this work showed that interconversions of the three skeletal types can be achieved in vitro the transformations were effected under specific conditions quite remote from those originally described and with yields very much lower than claimed earlier.It was not therefore a vindication of the earlier work as described,66 work which others have been unable to duplicate and for which full experimental details have still not been published. 7 Quinoline Alkaloids Biogenetically Derived from Indoles The interest in camptothecin (93b),67 particularly in the total synthesis of the alkaloid and of analogues has continued unabated although it now appears that the initial high hopes for its utility as an anticancer agent have dwindled.Despite the fact that six total syntheses had been reported by the end of 1972 new ones reported this year are again sufficiently different in approach to be worthy of comment. One synthesis68 depended on the prior assembly of the complete CDE ring system in (94) ; in a Friedlander quinoline synthesis with anthranilaldehyde this gave ( f)-deoxyde-ethylcamptothecin (93a) which had previously6’ been converted into ( +)-camptothecin. (93) a; R’= RZ= H (94) b; R’= OH R2 = Et 64 Ann. Reports (B) 1972 69 501. 65 R. T. Brown G. F. Smith J. Poisson and N. Kunesch J. Amer. Chem. Soc. 1973 95 5778. 66 A. A. Qureshi and A. I. Scott Chem. Comm. 1968 947. 67 A. G.Schultz Chem. Rec. 1973 73.385. 68 M. Shamma D. A. Smithers and V. St.Georgiev Tetrahedrori 1973 29 1949. 69 Ann. Reports (B) 1972 69 503. 546 H. F. Hodson Alkaloid (93a) also featured in another synthe~is,’~ which commenced with the intact ABC ring system in (96) ;successive acylation and Michael reactions gave the completely functionalized intermediate (95) in which the elements of the pentacyclic lactone are readily recognized. A third synthesis7’ arrived at the tetracyclic ester (101) which had been converted into (+)-camptothecin in one of the early routes.69 The key inter- mediate (99) was prepared from (98) via (97) the latter being obtained from furfural in six steps. Although (99) has the full carbon skeleton of deoxyde- ethylcamptothecin (93) attempts at a direct conversion were fruitless ;alkaline hydrolysis of (99) in fact produced (100) via ring-opening and deformylation.Compound (100) was therefore converted into (101) from which following the earlier work the ‘lost’ carbon could be reintroduced by a formylation step. /!. (101) (100) (99) ’O A. I. Meyers R. L. Nolen E. W. Collington T. A. Narwid and R. C. Strickland J. Org. Chem. 1973 38 1974. ” A. S. Kende T. J. Bentley R. W. Draper J. K. Jenkins M. Joyeux and I. Kubo Tetrahedron Letters 1973 1309. A lkaloids 547 8 TerpenoidBases The common carbon skeleton of the complex C22 and C30 Daphniphyllum alkaloids suggests a mevalonoid origin and feeding experiments have now ~onfirmed’~ that six molecules of mevalonic acid are incorporated into the C30 alkaloids daphniphylline (102) and codaphniphylline (103) ; squalene was also incorporated to the extent of 0.008% and a plausible origin from a squalene-like intermediate is suggested.It is likely73 that the CZ2bases such as daphnilactone B (104) are derived from a C, precursor by oxidative loss of an eight-carbon unit. Me (102) R = OAc (103) R = H Me (104) 9 Miscellaneous Alkaloids Three alkaloid^'^ (105) (106) and (107) from the leaves of Homliurn pronyense are closely related to the principal alkaloid homaline (108) the structure of \NAc / R2 R’ (105) R’= [CH,],Me R2 = [CH2],Me (106) R’= [CH,],Me R2= CH,CH(OH)[CH i (107) R’= Ph R2 = CH,CH(OH)[CH,],Me (108) R’= RZ= Ph 0 H I Ph NH[CH2],-N[CH2],-NH 72 K. T. Suzuki S. Okuda H.Niwa M. Toda Y.Hirata and S. Yamamura Tetrahedron Letters 1973 799. ” H. Niwa Y. Hirata K. T. Suzuki and S. Yamamura Tetrahedron Letters 1973 2129. 74 M. Pais R. Sarfati F.-X. Jarreau and R. Goutarel Tetrahedron 1973 29 1001. 548 H. F. Hodson which was confirmed by synthesis two years ago. These bases are presumably biogenetically derived from spermine and various orb-unsaturated carboxylic acids and it is interesting to note that the alkaloid maytenine first isolated 35 years ago has now been identified’’? ’‘ as di-trans-cinnamoylspermidine (109). Another example of this increasing group of spermine- and spermidine- derived alkaloids is the macrocyclic alkaloid chaenorine (1 ’* G. Englert K. Klinga Raymond-Hamet E. Schlittler and W.Vetter Helv. Chim. Acta 1973 56 474. 76 E. Schlittler U. Spitaler and N. Weber Helv. Chim. Acra 1973 56 1097. ” H. 0. Bernhard I. Kompis S. Johne D. Groger M. Hesse and H. Schmid Helv. Chim. Acta 1973 56 1266.

ISSN:0069-3030    

DOI:10.1039/OC9737000529

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

17 Terpenoids and Steroids By B. A. MARPLES Department of Chemistry The University of Technology 1oughborough Leicestershire LEI I 3TU 1 Introduction The fourth annual volume of the Chemical Society’s Specialist Periodical Report on Terpenoids and Steroids,’ giving comprehensive literature cover from September 1972 to August 1973 will be available during 1974. Of general relevance to this section are reviews on biogenetic syntheses of terpenes,2 insect pheromone^,^ and sex attractants of plants and animal^.^ 2 Monoterpenoids It is agreed by two groups that the tetrahomomonoterpene (1) from the codling moth has the (6Z)-~onfiguration.~*~ However despite two independent synthese~,~~*~~ the configuration of the 2,3-double bond is in doubt. A synthesis of (+)-grandis01 (2) a constituent of the male boll weevil pheromone employs zerovalent nickel to catalyse the dimerization of isoprene.’ Regioselective cycloaddition of yy-dimethylaconic acid with isoprene leads to a novel synthesis of (f)-menthone,8 and total syntheses of (&)-a-and (+)-Q-pinene employ the ‘Terpenoids and Steroids’ ed.K. H. Overton (Specialist Periodical Reports) The Chemical Society London 1974 vol. 4. T. Money ‘Progress in Organic Chemistry’ ed. W. Carruthers and J. K. Sutherland Butterworths London 1973 p. 29. (a) D. A. Evans and C. L. Green Chem. SOC.Rev. 1973 2 75; (6) J. G. MacConnell and R. M. Silverstein Angew. Chem. Internat. Edn. 1973 12 644. L. Jaenicke and D. G. Muller Fortschr. Chem. org. Nafurstofle 1973 30,62.(a) S. B. Bowlus and J. A. Katzenellenbogen Tetrahedron Letters 1973 1277; (b) S. B. Bowlus and J. A. Katzenellenbogen J. Org. Chem. 1973 38 2733. (a) M. P. Cooke jun. Tetrahedron Letters 1973 1281; (6) M. P. Cooke jun. ibid. p. 1983. ’ W. E. Billups J. H. Cross and C. V. Smith J. Amer. Chem. SOC.,1973,95 3438. S. Torii T. Oie and H. Tanaka Tetrahedron Letters 1973. 2471. 549 B. A. Marples conversion of the benzylidene tosylate (3) into the bicyclo[3,1,1 Iheptane (4)with NaH-MeOCH,CH,OMe.' Cyclization of the enantiomers of dihydromyrcene with AcOH-H,SO unexpectedly gave cyclohexanes [e.g. (5)+(6)] stereo-specifically." Citral may be converted viu an optically active pyrrolidine enamine into optically active a-cyclocitral.' ' Treatment of a-pinene with IN,-RCN leads to the azidotetrazole (7) by a 'Hassner-Ritter' reaction.' The reactions of a-pinene (inter alia) with chloro- sulphonyl isocyanate are rep~rted,'~ and the conversion of camphor to nopinone (9)is achieved uia the mesylate (8) which rearranges readily in MeO-MeOH.' Junionone (10) is the first monocyclic cyclobutane monoterpenoid to be isolated from vegetable sources (Juniperus cornrnunis L.).The novel mono- terpene (11) was isolated from the same source.I6 Two novel chorine- and CH,OTs 0 (3) (4) R = CHPh (9) R = H H. T. Thomas and A. G. Fallis Tetrahedron Letters 1973 4687. lo H. R. Ansari Tetrahedron 1973 29 1559. ' I S. Yamada M. Shibasaki and S. Terashima Tetrahedron Letters 1973 377; 381.(a)S. Ranganathan D. Ranganathan and A. K. Mehrotra Tetrahedron Letters 1973 2265; (6) D. Ranganathan S. Ranganathan and A. K. Mehrotra Synthesis 1973 356. I3 T. Sasaki S. Eguchi and H. Yamada J. Org. Chem. 1973 38 679. l4 J. V. Pankstelis and B. W. Macharcia Tetrahedron 1973 29 1955. ' A. F. Thomas and M. Ozainne J.C.S. Chem. Comm. 1973 746. l6 A. F. Thomas Helv. Chirn. Acta 1973 56 1800. Terpenoih and Steroids 55 1 bromine-containing monoterpenes (12)' and (13)18 have been isolated from the sea hare Aplysia californica which feeds on the halogen-containing species of algae. Rose oxide is reported in the secretions of an insect for the first time.Ig 3 Sesquiterpenoids Further evidence is presented in favour of the endo-structure for isolongifolene epoxide,20 from which the kinetic product of rearrangement is the ketone (14).Paradisiol (15) and intermedeol are shown to be identical rather than epimeric at C-4 as originally supposed.21 The proposed (9-configuration for ( +)-cis-and (+)-trans-abscisic acid22e is supported by c.d.22n and 0.r.d. spectra.226 and other data.22c*d Resolution of ( f)-trans-abscisic acid via the brucine salts followed by U.V. trans-to-cis isomerization provides an improved resolution of the cis-enanti~mers.~~ Confirmation of the absolute configuration (S)of the asymmetric ring carbon of blumenols A (16)and B (17) is established by chemical correlation with ( +)-abscisic and the side-chain asymmetric carbon is shown to have the (R)-config~ration.~~' Reassignment of absolute configurations I1 (a) D.J. Faulkner and M. 0. Stallard Tetrahedron Letters 1973 1171; (b) M. R. Willcott R. E. Davis D. J. Faulkner and M. 0.Stallard ibid.. p. 3967. I8 D. J. Faulkner M. 0.Stallard J. Fayos and J. Clardy J. Amer. Chem. SOC. 1973 95 341 3. 19 G. Vidari M. De Bernardi M. Pavan and L. Ragozzino Tetrahedron Letters 1973 4065. 20 (a) G. Mehta and S. K. Kapoor Tetrahedron Letters 1973 497; (6) cf. Ann. Reports (B) 1972 69 512. 21 J. W. Huffman and L. H. Zalkow Tetrahedron Letters 1973 751. 11 (a) G. Ohloff E. Otto V. Rautenstrauch and G. Snatzke Hefu. Chim. Acta 1973 56 1874; (6)N. Harada J. Amer. Chem. SOC.,1973,95,240; (c)M.Koreeda G. Weiss and K. Nakanishi ibid. p. 239; (d)K. Mori Tetrahedron Letters 1973 2635; (e) cJ Ann.Reports (B) 1972 69 512. 23 J. C. Bonnafous J.-C. Mani J.-L. Olivk and M. Mousseron-Canet Tetrahedron Letters 1973 11 19. 24 (a) M. N. Galbraith and D. H. S. Horn J.C.S. Chem. Comm. 1973 566; (6) cf. Ann. Reports (B) 1972 69 512; (c) G. Weiss M. Koreeda and K. Nakanishi J.C.S. Chem. Comm. 1973 565. 552 B. A. Marples are reported for ( -)-campherenone (18) and the related ( +)-epicampherenone ( -)-P-santalene and ( +)-epi-P-~antalene.~' Several new approaches to a-methylenebutyrolactones are reported.26 The butyrolactones are a-carboxylated or a-formylated and then suitably modified.26"*b9',d An interesting alternative is exemplified by the rearrangement of the cyclopropylmethanol ester (19) to the a-methylenebutyrolactone (20).26r Routes to hydroazulenes continue to be of interest and are exemplified by the formic acid-catalysed cyclization of the chloro-olefin (21) to the hydroazulene (22),27and by a photochemical conversion of the By-unsaturated ketone (23) to the hydroazulene (24).28A biogenetic-type cyclization of the germacrone (25) to the guaiane (26) is achieved with acetic acid in thi~phenol.~' Syntheses of the non-isoprenoid B-gorgene (28) are rep~rted,~' including a one-step biogenetic transformation from maaliol (27).30bThe biogenetic-type conversion of the bicyclic olefin (29) into ( f)-cedrone (30) provides a synthesis of ( f)-cedrene and (_+)-~edrol.~' Two groups report the synthesis of the bicyclic compound (31) as a key intermediate in a general non-annelation approach to e~desrnanes.~~ A synthesis of (i-)-nootkatone does not employ the Robinson 25 G.L. Hodgson D. G. MacSweeney R. W. Mills and T. Money J.C.S. Chem. Comm. 1973 235. 26 (a) K. Yamada M. Kato and Y. Hirata Tetrahedron Letters 1973 2745; (6) P. A. Grieco and K. Hiroi J.C.S. Chem. Comm. 1973 500; (c) A. D. Harmon and C. R. Hutchinson Tetrahedron Letters 1973 1293; (d)R. C. Ronald ibid. p. 3831 ;(e) P. F. Hudrlik L. R. Rudnick and S. H. Korzeniowski J. Amer. Chem. SOC. 1973 95 6848. 27 (a)P. T. Lansbury P. M. Workulich and P. E. Gallagher Tetrahedron Letters 1973 65; (6)CJ Ann. Reports (B) 1972 69 513. 28 R. E. Carlson R. L. Coffin W. W. Cox and R. S. Givens J.C.S. Chem. Comm. 1973 501. 29 M. Iguchi M.Niwa and S. Yamamura Tetrahedron Letters 1973 1687. 30 (a) R. K. Boeckman jun. and S. M. Silver Tetrahedron Letters 1973 3497; (b)S. K. Paknikar and V. K. Sood ibid. p. 4853. 31 E. J. Corey and R. D. Balanson Tetrahedron Letters 1973 3153. 32 (a)R. B. Miller and R. D. Nash J. Org. Chem. 1973 38 4424; (6) G. H. Posner and G. L. Loomis ibid. p. 4459. Terpenoids and Steroids (25) (29) (30) annelation but involves cyclization of the intermediate trienone (32) to the bicyclic compound (33).33 The cyclopentane (34) is converted stereospecifically into the enol acetate (35) and thence to guai01.~~ Syntheses of #?-vetivone and (32) (33) related compounds are rep~rted,~'as are syntheses of a-ac~renol,~~'' B-and y-and a-a~oradiene.~ ac~renol,~~",~ ' A novel lactone spiroannelation procedure involving the reaction of the thioester (36) with selenious acid in benzene gave (+)-bakkenolide A (37).38 Two groups report the synthesis of gyridinal the norsesquiterpene recently isolated from gyrinid beetle^.^' 33 K.P. Dastur J. Amer. Chem. SOC.,1973 95 6509. 34 N. H. Andersen and H.-S. Uh Tetrahedron Letters 1973 2079. 35 (a) P. M. McCurry jun. and R. K. Singh Tetrahedron Letters 1973 3325; (b) P. M. McCurry jun. R. K. Singh and S. Link ibid. p. 1155; (c) G. Stork R. L. Danheiser and B. Ganem J. Amer. Chem. SOC.,1973 95 3414; (d)K. Yamada H. Nagase Y. Hayakawa K. Aoki and Y. Hirata Tetrahedron Letters 1973,4963; (e)K. Yamada K. Aoki H. Nagase Y. Hayakawa and Y. Hirata ibid. p. 4967.36 (a)1. G. Guest C. R. Hughes R. Ramage and A. Sattar J.C..S. Chem. Comm. 1973 526; (b)W. Oppolzer Helu. Chim. Acra 1973 56 1812. 37 J. N. Marx and L. R. Norman Tetrahedron Letters 1973 4375. 38 D. A. Evans and C. L. Sims Tetrahedron Letters 1973 4691. 39 (a)J. Meinwald K. Opheim and T. Eisner Tetrahedron Letters 1973 281 ;(b) C. H. Miller J. A. Katzenellenbogen and S. B. Bowlus ibid. p. 285; (c) cf. Ann. Reports (B) 1972 69 516. 554 B. A. Marples HI (ia CHOAc A number of new halogenated sesquiterpenes isolated4* from Laurencia species of algae include prepacifenol (38),40"a precursor of the recently reported pacifenol and oppositol (39),40bwhich is a member of a new skeletal class. A new JH (40) is reported from the tobacco hornworm Chlorochrymorin (41)42 and arteannuin B (42)43 are two new types of sesquiterpene lactones and cyclo- seychellene(43),"4 a-pompene (44),45and ( + )-2,idiepi-B-cedrene (45)46 are new hydrocarbon members.a-Cedrene is the first example of a sesquiterpene to be isolated from fossil 40 (a) J. J. Sims W. Fenical R. M. Wing and P. Radlick J. Amer. Chem. SOC.,1973 95 972; (b) S. S. Hall D. J. Faulkner J. Fayos and J. Clardy ibid. p. 7187; (c)A. G. Gonzalez J. Darias and J. D. Martin Tetrahedron Letters 1973 3625; (d) A. G. Gonzalez J. Darias and J. D. Martin ibid. p. 2381. 41 K. J. Judy D. A. Schooley L. L. Dunham M. S.Hall B. J. Bergot and J. B. Siddall Proc. Nat. Acad. Sci. U.S.A. 1973 70 1509. 42 T. Osawa A. Suzuki S. Tamura Y.Ohashi and Y.Sasada Tetrahedron Letters 1973 5 135.43 D. JeremiC A. JokiC A. Behbud and M. Stefanovic Tetrahedron Letters 1973 3039. 44 S. J. Terhune J. W. Hogg and B. M. Lawrence Tetrahedron Letters 1973,4705. A. Matsuo T. Maeda M. Nakayama and S. Hayashi Tetrahedron Letters 1973 4131. T. Norin and S. Sundin Tetrahedron Letters 1973 17. 47 A. G. Douglas and P. J. Grantham Chem. and fnd. 1973 37. Terpenoids and Steroids 4 Diterpenoids The quassinoid bitter principles are reviewed.48 The revised structure (46) is presented for isoincensole oxide.49 Fusicoccin H (47) is isolated and shown to be a biogenetic precursor of fusicoccin suggesting that the latter is a diterpene rather than a degraded sester-terpene as previously thought. ’O Corrected structures are presented for products of the reductive backbone-rearrangements of certain resin acid derivatives.’ * a-D-gluCOSyl I (48) R’ = H,R2 = Me (47) (49) R1= Me,R2 = H Chlorosulphonic acid-catalysed rearrangement of levopimaric acid’2a gave mixtures of the trienes (48) and (49) whereas the previously reported reaction with sulphuric acid gave ring-contraction produ~ts.’~~ The rearrangement of the tosylate (50)to the diene (51)is analogous to that proposed for the biosynthetic 48 J.Polonsky Fortschr. Chem. org. Naturstofle 1973 30 101. 49 M. L. Forcellese R. Nicoletti and C. Santarelli Tetrahedron Letters 1973 3783. 50 K. D. Barrow D. H. R. Barton Sir E. Chain U. F. W. Ohnsorge and R. P. Sharma J.C.S. Perkin I 1973 1590. 51 J.W. Huffman and J. J. Gibbs J. Org. Chem. 1973.38 2732. 52 (a)G. Mehta and S. K. Kapoor Tetrahedron Letters 1973 2385; (b) cJ Ann. Reports (B) 1972 69 518. B. A. Marples do. C0,Me transformation of atisine diterpenoid alkaloids to the aconitine type.53 The ent-beyer-15-ene-l2-p-tosylhydrazone (52)is converted with sodium borohydride into the en?-atis-13-ene (53)via a 1.2-vinyl shift.54 A 1,2-vinyl shift occurs in the rearrangement5’ of the pimarane (54)into the cleistanthane (55). However NNHTs (52) (53) OH (54) attempts to rearrange a pimarane into a cassane were unsucce~sfuI.~~ Progress has been made in a new general approach towards the inversion of the C-4-substituents in isopimaric acid,57 which is converted through the cyclobutanone (56) into the nitrile (57).The boron trifluoride-catalysed rearrangement of the epoxide (58) to the lactone (59) is the key step in a synthesis of rosenonolactone from podocarpic 53 W. A. Ayer and P. D. Deshpande Canad. J. Chem. 1973 51 77. 54 K. H. Pegel L. P. L. Piancenza L. Phillips and E. S. Waight J.C.S. Chem. Comm. 1973 552. ” G. A. Ellestad M. P. Kunstmann and G. 0.Morton J.C.S. Chem. Comm. 1973 312. ” J. P. Johnston and K. H. Overton J.C.S. Perkin I 1973 853. ’’ J. P. Tresca J. L. Fourrey J. Polonsky and E. Wenkert Tetrahedron Letters 1973 895. Terpenoids and Steroids ,,, (57) CN BF3 ' d A ' CO,H (59) acid.58 Two syntheses of trachylobane are reported.59 Conversion of the mesylate (60) into the ketone (61) and the alcohol (62) by treatment with one equivalent of methylsulphinyl carbanion in DMSO is a key step.59b A model stereospecific synthesis of the A and B rings of gibberellic acid involves the intramolecular Diels-Alder reaction of the acetylenic diene (63).60 An improved procedure is (60) (63) reported for the intramolecular keto-carbene addition to double bonds leading to the bicyclo[3,2,1]octanones.6' This reaction is also employed in the synthesis of (+)-kaurene and (+)-phyllocladene from (-)-abietic acid.62 A synthesis of miltirone is reported.63 58 W.S. Hancock L. N. Mander and R. A. Massey-Westropp J. Org. Chem. 1973 38 4090. 59 (a) R. B. Kelly J. Eber and H.-K. Hung Cunad. J. Chem. 1973 51 2534; (b) R. B. Kelly J.Eber and H.-K. Hung J.C.S. Chem. Comm. 1973 689. 6o E. J. Corey and R. L. Danheiser Tetrahedron Letters 1973 4477. 6' U. R. Ghatak P. C. Chakraborti B. C. Ranu and B. Sanyal J.C.S. Chem. Comm. 1973 548. 62 A. Tahara M. Shimagaki S. Ohara T. Nakata and R. Kenkyusho Tetrahedron Letters 1973. 1701. " D. Nasipuri and A. K. Mitra J.C.S. Perkin I 1973 285. B. A. Marples Concinndiol (64),which was isolated from the red alga Laurencia concinna is only the second example of a natural bromine-containing diterpen~id.~~ The first of this kind was isolated from a sea hare thus providing further support for the suggestion that the sea hares are capable of concentrating the halogen- containing compounds present in their diet." Cyathin B and Cyathin C are further examples of the diterpenoid class first reported last year from Cyathus l~elenae.~~ Several compounds with novel carbon skeletons include leucothol B (65)66and leucothol D,66stemodin (66)67and ~temodinone,~~ which resemble aphidocolin and pachydictyol A (68).68The latter may be derived from geranyl- geranyl pyrophosphate (67) as shown or from farnesyl pyrophosphate followed by isoprenylation.The full report of tle isolation of cembrene-A and the related mukulol from Cornrniphora rnukul is now a~ailable.~~" Cembrene-A is identical with the termite trail pheromone named ne0~embrene-A.~~~ Borjatriol (69) is the first example of a diterpenoid from the Sideritis genera with the normal steroidal A/B-trans ring j~nction.~' 64 J.J. Sims G. H. Y. Lin R. M. Wing and W. Fenical J.C.S. Chem. Comm. 1973 470. 65 W. A. Ayer and L. L. Carstens Canad. J. Chem. 1973,51 3157. 66 H. Hikino S. Koriyama and T. Takemoto Tetrahedron 1973 29 773. 67 P. S. Manchand J. D. White H. Wright and J. Clardy J. Amer. Chem. SOC.,1973 95 2705. 68 D. R. Hirschfield W. Fenical G. H. Y. Lin R. M. Wing P. Radlick and J. J. Sims J. Amer. Chem. SOC.,1973 95 4049. 69 (a) V. D. Patil U. R. Nayak and S. Dev Tetrahedron 1973 29 341; (6) cf. Ann. Reports (B) 1972 69 520. 'O B. Rodriguez and S. Valverde Terrahedron 1973. 29. 2837. Terpenoids and Steroids H 5 Sesterterpenoids Deoxoscalarin (70) a relative of cheilanthatriol and scalarin has been isolated from Spongia q$cinalis. 71 Variabilin is a further linear furanosesterterpene from Ircinia variabili~.~’ 6 Triterpenoids The structure of dendropanoxide (71) has been ~larified,’~‘’ and shown to be similar to that of baccharis It has been suggested that the configuration at C-16 in certain oleane-16a,28-diols should be amended owing to their ready OH HH formation of acetonides.74 However under the reaction conditions employed more recent work shows that both 16a,28- and 16B-28-diols are capable of acetonide formation.” The driving force for the necessary distortion of the D-ring appears to be the interaction between the 16a-hydroxy-group and the l4a-methyl group and the 2la-hydrogen. Corrected structures are presented for faradiol and arnidiol. 76 The ready acid-catalysed rearrangement of the side chain of the 3,23-dihydroxylanosta-8,24-diene(72) to the 25-substituted-A’ 3-compounds suggests that similar rearranged compounds previously isolated in 71 G.Cimino S. de Stafano and L. Minale Experientia 1973 29 934. 72 D. J. Faulkner Tetrahedron Letters 1973 3821. 73 (a)J. D. White J. Fayos and J. Clardy J.C.S. Chem. Comm. 1973 357; (b)cf. Ann. Reports (B) 1972 69 521. 74 R. Segal and A. Taube Tetrahedron 1973 29 675. 75 J. St. Pyrek J.C.S. Chem. Comm. 1973 787. 76 J. St. Pyrek and E. Baranowska Tetrahedron Letters 1973 809. 560 B. A. Marples (72) nature may be artefact^.'^ The (S)-configuration at C-24 is established for the 24,25-epoxytriterpene aglaicol and suggests that it may arise from the cyclization of (3S,22S)-22,23-diepoxy-squalene.The (R)-configuration is reported for each 78 of the cyclopropane ring carbons of presqualene An improved route to A2-triterpenes is available through nickel boride- desulphurization of A2-3-thiobenzyl ethers." An improved synthesis of 32-oxygenated lanostanes involves the formation of the 32-nitrate ester by irradiation of the 7a-nitrite in the presence of oxygen.81 A route to the highly functionalised side chain of some cucurbitacins is described.82 The total synthesis of pyrangolensolide (73) a close relative of fraxinellone is reported.83 An interesting preparation of B-amyrin by the enzymic cyclization of the bicyclic epoxide (74) is reported.8" Somewhat different results were obtained (73) (74) from a chemical cyclization last year.84b A radical induced biogenetic-type cyclization of the aromatic substrate (75) leads to the tetracyclic compound (76).8s A stereospecific synthesis of (+)-taondiol methyl ether (78; R = Me)86" is reported from the epoxide (77).86b 77 N.Entwistle and A. D. Pratt J.C.S. Perkin. I 1973 1235. 78 R. B. Boar and K. Damps J.C.S. Chem. Comm. 1973 11 5. 7v G. Popjak J. Edmond and S.-M. Wong J. Amer. Chem. SOC.,1973 95 2713. R. B. Boar D. W. Hawkins J. F. McGhie and D. H. R. Barton J.C.S. Perkin I 1973,654. J. Allen R. B. Boar J. F. McGhie and D. H. R. Barton J.C.S. Perkin I 1973 2402. 82 F. de Reinach-Hirtzbach and G. Ourisson Tetrahedron Letters 1973 1363. 83 Y. Fukuyama and T. Tokoroyama Tetrahedron Letters 1973 4869.'' (a) H. Horan J. P. McCormick and D. Arigoni J.C.S. Chem. Cumm. 1973 73; (b) c.f.Ann. Reports (B) 1972 69 523. *' J. Y. Lallem M. Julia and D. Mansuy Tetrahedron Letters 1973 4461. (a) A. G. Gonzalez J. Darias J. D. Martin and C. Pascual Tetrahedron 1973. 29 1605; (h) A. G. Gonzalez J. D. Martin and M. L. Rodriguez Tetrahedron Letters 1973. 3657. Terpenoidsand Steroids 561 (75) (76) Treatment of taondiol (78; R = H) with methanolic potassium hydroxide leads to the epimeric compound (79).8 A free-radical mechanism involving an intermediate p-quinone is proposed. Partial backbone rearrangement of the friedelenone (80) gave (inter ah) the As-compound (81).88 It appears that neither contraction of ring A nor expansion of ring D changes the course of backbone rearrangement in the euphol series8’ The acid-catalysed rearrange- ment of the dienone (82) to the phenol (83) involves an initial methyl shift to the oxygen-bearing carbon followed by a second shift to C-2.” Further base- induced fragmentations of some swietenine derivatives show the critical depen- dence of the reaction course on substit~tion.~’ The 23-oxygenated lactone (84) is reported in a sea c~cumber.’~ Glabretal (85)is one of several compounds of a new skeletal class which may arise by capture ” A.G. Gonzalez M. A. Alvarez J. Darias and J. D. Martin J.C.S. Perkin I 1973 2637. *’ T. Kikuchi M. Niwa M. Takayama T. Yokoi and T. Shingu Tetrahedron Letters 1973 1987. 89 J. L. Zundei G. Wolff and G. Ourisson Bull.SOC.chim. France 1973 3206. O0 J. R. Bull and A. J. Hodgkinson Terrahedron 1973 29 1109. ’’ J. D. Connolly R. Henderson R. McCrindle K. H. Overton and N. S. Bhacca J.C.S. Perkin I 1973 865. 92 I. Rothberg B. M. Tursch and C. Djerassi J. Org. Chem.. 1973 38 209. 562 B. A. Marples HOy$ 'OAc of the 13-methyl group by a C-14 carbonium ion in a step subsequent to the tirucallol to apotirucallol-type of rearrangement.93 Cyclofuntumienol (86)94u and cyclotrichosantol (87)94bare new isomeric 3 1-nortriterpenes. Botryococcene 9J G. Ferguson P. A. Gunn W. C. Marsh R. McCrindle R. Restivo J. D. Connolly J. W. B. Fulke and M. S. Henderson J.C.S. Chem. Comm. 1973 159. 94 (a) L. Mukam G. Charles J. Hentchoya Th. Njimi and G. Ourisson Tetrahedron Letters 1973 2779; (6)M.KoCor and J. St. Pyrek J. Org. Chem. 1973 38 3688. Terpenoitis and Steroids (88)is a major metabolite of the alga Botryococcus br~unii.~' A number of quinone methides related to pristimerin are reported.96 Tingenone (89) maitenin and tingenin A all have the same struct~re.~~'~~*~ The other compounds reported are 20-hydro~ytingenone,~~" tingenin B,96cand disperm~quinone.~~~ 7 Steroids The chemistry and biology of ~aponins,~' and microbiological hydro~ylation,~~ steroid acids in petroleum99 are reviewed. The contaminent in ergosterol 5a,8a-peroxide which was claimed to be the epimeric 5/?,8/?-peroxide is now shown to be 9,ll-dehydroergosterol peroxide."' The 12a- and 12~-mesylates (90) are converted into the c-nor-D-homo- compounds (cholajervanes) (91) and (92).Acetolysis of the D-homo-compound 95 R.E.Cox A. L. Burlingame D. M. Wilson G. Eglinton and J. R. Maxwell J.C.S. Chem. Comm. 1973,284. 96 (a) P. M. Brown M. Moir R. H.Thomson T. J. King V. Krishnamoorthy and T. R. Seshadri J.C.S. Perkin I 1973 2721 ;(b) F. D. Monache G. B. M. Bettblo 0. G. de Lima 1. L. d'Alberquerque and J. S. de B. Cdlho ibid. p. 2725; (c) K. Nakanishi V. P. Gullo I. Miura T. R. Govindachari and N. Viswanathan J. Amer. Chem. SOC.,1973 95 6473; (d)J. D. Martin Tetrahedron 1973 29 2997. '' R. Tschesche and G. Wulff Fortschr. Chem. org. Nutursroffe 1973 30 462. 98 E. R. H. Jones Pure Appl. Chem. 1973 33 39. 99 W. K. Seifert Pure Appl. Chem. 1973 34 633. loo M. H. Fisch R.Ernst B.H.Flick J. Arditti D. H. R. Barton P. D. Magnus and I. D. Menzies J.C.S. Chem. Comm. 1973 530. lo' R. C. Ebersole and F. C. Chang J. Org. Chem. 1973 38 2579. 564 B. A. Marples (93) is accompanied by inversion at C-13 and the 13a,l7aa-acetate (94) is a product.'02 A similar result is obtained in the formolysis of the D-homotosylate (95) which leads in part to the 13a-17aa-formyl-l7~-methyl compound (96).'03 Treatment of 5a-and 5P-pregnane-3,20-dione with HF-SbF gives the corres- ponding 13a,l7/3-isomer as the major product.' O4 Oestrone is converted by HF-SbF into 9,ll-dehydro-oestrone via a C-9 carbonium ion. The phenol- dienone rearrangement product oestra-4,9-diene-3,17-dione,' O5 is a minor product. The previously reported rearrangement of (19R)- 19-hydroxy- 19- methyl-3-oxo-5a-steroids into 3a-hydroxy- 19-methyl- 19-0x0-%steroids has been shown by 'H-labelling studies to involve an intramolecular hydride transfer.lo6 The iodo-aldehyde (97) is converted into the cyclic ether (98) by an alumina- induced cyclization accompanied by a hydride shift from the solvent (hexane). lo' OAc H (94) (93) OTs P H H (96) (95) Treatment of the ene reaction product (99) with lithium aluminium hydride remarkably gave the A-ring aromatized compound ( 100).'08 Neighbouring group participation by a 7a-hydroxy-group accelerates the nucleophilic opening of 4a,5a-epoxides. 'O9 Direct P-epoxidation of cholesterol is preponderant using hydrogen peroxide and ferric acetylacetonate in aceto- nitrile.' lo Further studies on long-range substituent effects are reported." ' Io2 I.Khattak D. N. Kirk C. M. Peach and M. A. Wilson J.C.S. Chem. Comm. 1973 341. Io3 F. B. Hirschmann and H. Hirschmann J. Org. Chem. 1973 38 1270. Io4 J.-C. Jacquesy R. Jacquesy S. Moreau and J.-F. Patoiseau J.C.S. Chem. Comm. 1973 785. Io5 J. P. Gesson J.-C. Jacquesy and R. Jacquesy Brtll. SOC. chim. France 1973 1433. Io6 J. Wicha and E. Caspi J. Org. Chem. 1973 38 1280. lo' H. Suginome and K. Kato Tetrahedron Letters 1973 4143. lo8 H. de Nijs and W. N. Speckamp Tetrahedron Letters 1973 3631. lo9 D. H. R. Barton and Y. Houminer J.C.S. Chem. Comm. 1973 839. I lo M. Tohma T. Tomita and M. Kimura Tetrahedron Letters 1973 4359. 'I' (a) I.G. Guest and B. A. Marples J.C.S. Perkin I 1973 900; (6) V. V. Egorova A. V. Zakharychev and S. N. Ananchenko Tetrahedron 1973,29,301; (c) G. C.Wolf E. L. Foster and R. T. Blickenstaff J. Org. Chem. 1973,38 1276; (6)J. B. Jones and P. Price Tetrahedron 1973 29 1941. Terpenoids and Steroids 17 4 H Evidence is presented in favour of inductive,' 'layb conformational,' 'lb and steric effects.' 'Ic However variation of C-17-substituents does not appear to affect the course of homologations of 3-0x0-5a-steroids.' 'Id The addition of hypobromous acid to A4-steroids gives a significant quantity of 4P-bromo-5a-hydroxy-compound in contrast to similar reactions with A'-steroids.' Func-tionalization of 17a-methylsteroids is readily achieved by photolysis of the 12a-nitrite esters or by reaction of the 12a-hydroxy-compounds with lead tetra- acetate.' l3 Epoxidation of the 9,lO-double bond of Westphalen's diol derivatives provides improved yields in the similar functionalization of the 5P-methyl group.' l4 Mercuric acetate oxidation of a A14-steroid provides the A8(14)-1 5-0x0- compound.' ' ' The interest in biogenetic-type synthesis of tetracyclic compounds continues." 6*1l7 Syntheses of progesterone' '6a,b and oestrone' 16' by this means are reported. Cyclization of the acetylenic alcohol (101) in 2-nitropropane affords a route to 17-oxygenated pregnanes as the intermediate C-20-vinyl cation is trapped by the solvent and leads to the oximino-ether (102).'16d3e Evidence for some degree of concertedness in these cyclizations is provided by a study of the aromatic substrates (103) in which the reaction rate is dependent on substituents in the aromatic ring and the ortho to para product ratio is dependent on the nature of the leaving group (OR2).''' ' '' P.Morand and A. Polakova-Paquet Canad. J. Chem. 1973 51 4098. 'I3 Ch. R. Engel D. Mukherjee and G. J. Beaudoin Sreroids 1973 21 857. J. G. L1.Jones and B. A. Marples J.C.S. Perkin I 1973 1143. 'I5 E. C. Blossey and P. Kucinski J.C.S. Chem. Comm. 1973 56. 'I6 (a)R. L. Markezich W. E. Willy B. E. McCarry and W. S. Johnson J. Amer. Chem. SOC.,1973 95 4414; (6)B. E. McCarry R. L. Markezich and W. S. Johnson ibid. p. 4416; (c) P. A. Bartlett and W. S. Johnson ibid. p. 7501 ;(4D. R. Morton M.B. Gravestock R. J. Parry and W. S. Johnson ibid. p. 4417; (e)D. R. Morton and W. S. Johnson ibid. p. 4419. 'I7 P. A. Bartlett J. I. Braceman W. S. Johnson and R. A. Volkmann J. Amer. Chem. Soc. 1973 95 7502. 566 B. A. Marples Poriferasterol and stigmasterol may be synthesized from the (22R)- and (22s)- allylic alcohols (104) respectively.' l8 A Claisen rearrangement allows the stereospecific introduction of the 24-ethyl group. Lithium-ammonia reduction of A8~'4~-7-oxo-compounds provides a route to the unnatural 14/3-steroids.l OH Reduction of 14-dehydro-8,19-epoxy-compounds with zinc-acetic acid exclu- sively provides the 14-dehydro-l9-hydroxy-8/3-compounds.'Syntheses of 9a-2o and 9fi-methyl-19-norsteroidsare reported.' Resibufogenin is readily converted by acid treatment into 14a-and 14/3-arteb~fogenin.'*~ Direct conversion of 14-dehydrobufalin into bufalin employs the direct reaction of the 14,15-d0uble bond with hypohalous acid rather than proceeding through the epoxide resi- bufogenin.' 23 An improved procedure for sulphur dehydrogenation of the 'I8 W.Sucrow P. P. Caldeira and M. Slopianka Chem. Ber. 1973 106 2236. I l9 I. Midgley and C. Djerassi J.C.S. Perkin I. 1973. 155. G. Kruger and G. I. Birnbaum Tetrahedron Lerrers 1973 501. R. V. Coombs,J. Koletar R. Danna H. Mah and E. Galantay J.C.S. Perkin I 1973 2095. "* Y. Kamano and G. R. Pettit Canad. J. Chem. 1973,51 1973. Y. Kamano and G. R. Pettit J. Org. Chem. 1973.38 2202. Terpenoids and Steroids lactone ring is used in a synthesis of re~ibuf0genin.l~~ The conversion of the starfish aglycone (105) into A9(' ')-progesterone provides a synthesis of cortico-steroids from marine sources.125 Interest has focused on the partial'26 and tota112' synthesis of la-hydroxy- cholecalciferol which exhibits potent antirachitic activity.The partial syntheses proceed through the irradiation of la,3~dihydroxycholesta-5,7-diene or its esters whereas the total synthesis employs the combination of the acetylenic ditrimethylsilyl ether (106) with the appropriate cD-fragment as a key step. OSiMe HO * A synthesis of (22s)-hydroxyvitamin D4is also reported but this compound has no significant antirachitic activity.' 28 The structures of the marine sterols 24,28-didehydroaplysteroland aplysterol are supported by synthesis of the former and the X-ray crystal structure of the latter.' 29 The principal aglycones from the saponins of the starfish Marthasterias glacialis are the unusual natural 23-0x0-cholestanes (107) and (108).' 30 The W.Haede W. Fritsch K. Radscheit and U. Stache Annalen 1973 5. lZ5 J. E. Gurst Y. M. Sheikh and C. Djerassi J. Amer. Chem. SOC.,1973 M,628. (a) D. H. R. Barton R. H. Hesse M. M. Pechet and E. Rizzardo J. Amer. Chem. Soc. 1973 95 2748; (b) A. Furst L.Labler W. Meier and K. H. Pfoertner Helu. Chim. Acra 1973 56 1708; (c) C. Kaneko S.Yamada A. Sugimoto M.Ishikawa ' S.Sasaki and T. Suda Tetrahedron Letters 1973 2339. R. G. Harrison B. Lythgoe and P. W. Wright Tetrahedron Letters 1973 3649.lZ8 D. R. Crump D. H. Williams and B. Pelc J.C.S. Perkin I 1973 2731. lZ9 (a) P. De Luca M. De Rosa L. Minale R. Puliti G. Sodano F. Giordano and L. Mazzarella J.C.S. Chem. Comm. 1973 825; (b) cf. Ann. Reports (B) 1972 69 529. IJoD. S. H. Smith A. B. Turner and A. M. Mackie J.C.S. Perkin I 1973 1745. 568 B. A. Marples related 6'-deoxyglucoside (109) is also reported in Acasthaster planci,' 31 and the 3-sulphate of compound (105) is reported in asterosaponin New phytoecdysones include calonysterone (1 lo),'33 the related kaladsterone (1 1 l),' 34 and dacrysterone. '35 The synthesis of 16-oxopregnanes is achieved by microbiological oxidation of diosgenone. 36 Microbiological dehydrogenation of 5P-androstane-3,17-dione at C-1 C-2 and C-4,C-5 involves the stereospecific removal of the 21-and the 4a-hydrogens.' 37 A number of studies are reported on the microbiological hydroxylation of androstanes,' 38a*b7c oestranes,' 38a and pregnanes'38" with I 0-~-~-6'-deoxyglucosyl ( 109) OH I3l Y.M. Sheikh and C. Djerassi Tetrahedron Letters 1973 2927. 13' (a) S. Ikegami Y. Kamiya and S. Tamura Tetrahedron Letters 1973 731; (6)S. Ikegami Y.Kamiya and S. Tamura Tetrahedron 1973 29 1807. '33 L. Canonica B. Danieli G. Ferrari J. Krepinsky and G. Rainoldi J.C.S. Chem. Comm. 1973 737. '34 L. Canonica B. Danieli G. Ferrari M. A. Haimova and J. Krepinsky Experientia 1973 29 1062. 135 G. B. Russell and J. G. Fraser Austral. J. Chem. 1973 26 1805. 136 E. Kondo and T. Mitsugi Tetrahedron 1973 29 823.13' S. Ikegawa and T. Nambara Chem. and Ind. 1973 230. IJ8(a) J. W. Browne W. A. Denny Sir E. R. H. Jones G. D. Meakins Y. Morisawa A. Pendlebury and J. Pragnell J.C.S. Perkin I 1973 1493; (b) V. E. M. Chambers W. A. Denny J. M. Evans Sir E. R.H. Jones A. Kasal G. D. Meakins and J. Pragnell ibid. p. 1500; (c) A. M. Bell I. M. Clark W. A. Denny Sir E. R. H. Jones G. D. Meakins W. E. Miiller and E. E. Richards ibid. p. 2131 ;(4A. S. Clegg W. A. Denny Sir E. R. H. Jones G. D. Meakins and J. T. Pinhey ibid. p. 2137. Terpenoids and Steroids OH Rhizopus and Aspergillus strains. Microbiological oxygenation of B-norsteroids with Rhizopus nigricans and Absidia orchidis is also re~0rted.I~’ lJ9 J. Joska 2. Prochazka J. Fajkos and F.Sorm CON.Czech. Chem. Comm. 1973 38 1398.

ISSN:0069-3030    

DOI:10.1039/OC9737000549

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

18 Alicyclic Chemistry By J. M. MELLOR Department of Chemistry University of Southampton Southampton SO9 5NH Traditionally this Report has attempted to highlight important contributions throughout the area of alicyclic chemistry. In view of the publication of the Chemi- cal Society Specialist Periodical Reports’ giving comprehensive coverage of this area and of the difficulty of containing an effective critique of the notable con- tributions within the required length this Report is not in accordance with tradi- tion. Two topics synthesis and methods ofannelation and the study of structural properties and orbital interactions are discussed in detail. This discussion is preceded by a list of reviews concerning contributions outside those areas re- viewed in more detail.New texts on alicyclic chemistry are available.2 Reviews concern various aspects of organometallic synthesis3 written by different members of Wilke’s group the nature of protonated cyclopropane intermediate^,^ Brown’s view of a-bridging in norbornyl system^,^ valence isomerization in bullvalene and related systems,6 an analysis of stereochemical control in concerted processes,’ and a further discussion of the uses of photoelectron spectroscopy.8 A reappraisal of Bredt’s Rule has appeared’ and the nature of bridgehead olefins has been further examined.lo ‘Aliphatic Alicyclic and Saturated Heterocyclic Chemistry’ ed. W. Parker (Specialist Periodical Reports) The Chemical Society London Vol. 1 1973; Vol. 2 1974. * L. N. Ferguson ‘Highlights of Alicyclic Chemistry’ Franklin 1973.’ K. Fischer K. Jonas P. Misbach R. Stabba and G. Wilke Angew. Chem. Infernaf. Edn. 1973 12 943; B. Bogdanovic ibid. p. 954 H. Bonnemann ibid. p. 964; P. Heimbach ibid. p. 975. ‘M. Saunders P. Vogel E. L. Hagen and J. Rosenfeld Accounts Chem. Res. 1973,6 53. H. C. Brown Accounts Chem. Res. 1973,6 377. B. Decock B. Le Reverend and P. Goudmand Bull. SOC.chim. France II 1973 389. ’ J. Mathieu Bull. SOC.chim. France II 1973 807. H. Bock and B. G. Ramsey Angew. Chem. Internat. Edn. 1973 12 734. G. Kobrich Angew. Chem. Internat. Edn. 1973 12 464. lo H. H. Grootveld C. Blomberg and F. Bickelhaupt J.C.S. Chem. Comm. 1973 542 C. Batich 0.Ermer E. Heilbronner and J. R. Wiseman Angew. Chem. Internar. Edn. 1973 12 312; J.E. Gano and L. Eizenberg J. Amer. Chem. SOC.,1973,95 972; A. H. Alberts H. Wynberg and J. Strating Tetrahedron Letters 1973 543 3047; C. B. Quinn J. R. Wiseman and J. C. Calabrese J. Amer. Chem. SOC. 1973 95 6121; B. L. Adams and P.Kovacic ibid. p. 8206; M. Farcasiu D. Farcasiu R. T. Conlin M. Jones and P.von R. Schleyer ibid. p. 8207; A. D. Wolf and M. Jones ibid. p. 8209. 57 1 572 J. M. Mellor 1 Synthesis Three-and Four-memberedRings.-An outstanding series of papers has elabora- ted upon the preparation and uses of cyclopropyldiphenyl sulphonium fluoro- borates. The preparation" of the ylide (1) can be effected in high overall yield in situ (Scheme 1) but (1) readily undergoes thermal decomposition to give Reagents i Ph,S-MeN02-AgBF,; ii NaH-THF; iii LiNPr' Scheme 1 cyclopropyl phenyl sulphide.However under suitable conditions (1) may be trapped and affords an excellent synthesis of oxaspiropentanes,' spiropentanes,' and cyclobutanones' and hence y-butyrolactones' by subsequent peroxidative attack (Scheme 2). The synthetic procedures are appropriate to substituted Rif R2 R2 R' Reagents i KOH-DMSO->O; ii KOH-DMSO-PhCH =CHCOPh; RZ R' iii KOH-DMSO->O ;iv H'; v Na0,H. R2 Scheme 2 B. M. Trost and M. J. Bogdanowicz J. Amer. Chem. SOC.,1973,95 5298. " B. M. Trost and M. J. Bogdanowicz J. Amer. Chem. SOC.,1973,954 531 1. l3 B. M. Trost and M. J. Bogdanowicz J. Amer. Chem. SOC.,1973,95 5307. l4 B. M. Trost and M. J. Bogdanowicz J. Amer. Chem. SOC.,1973,95 5321 ; M.J. Bog-danowicz T. Ambelang and B. M. Trost Tetrahedron Letters 1973 923. A 1icyclic Chemistry ylides thus (2) is transformed into (3) on reaction with acetone indicating a re- tention of configuration at the carbanion followed by inversion of configuration in the displacement. Both the oxaspiropentanes and cyclobutanones are valuable synthetic intermediates. Although acid-catalysed rearrangement of the oxaspiropentanes gives cyclo- butanones in high yield rearrangement under basic conditions e.g.lithium diethyl- amide gives allyl alcohols. From (4) derived from cyclopentanone two allyl alcohols (5)and (6)might be formed but work-up of the reaction with trimethyl- chlorosilane affords12.' (7) in 94 % yield. Thermolysis of (7) at 330 "C gives (8) and this sequence is an important method of general applicability for the prepa- ration of cyclopentanones.The group of Conia have noted16 the opening of oxaspiropentanes by trimethylchlorosilane to give intermediates readily trans- formed into cyclobutanones (Scheme 3). The ready synthesis of cyclobutanones CISiMe KosiMe3 ~ lOO% ao ~ CH,CI,. 20°C CH2CI Scheme 3 has led to a studyI7 of their subsequent transformations to afford an efficient method of geminal alkylation [see synthesis of methyl desoxypodocarpate (9) (Scheme 4)]. Is B. M. Trost and M. J. Bogdanowicz J. Amer. Chem. SOC.,1973,95,289. l6 J. P. Barnier B. Garnier C. Girard J. M. Denis J. Salaun and J. M. Conia Tetra-hedron Letters 1973 1747. " B. M. Trost and M.J. Bogdanowicz J. Amer. Chem. SOC.,1973,95,2038; B. M. Trost and M. Preckel ibid. p. 7862. 574 J. M. Mellor 1iii-v 90% Reagents i ;Ph,BF,-KOH-DMSO; ii LiBF,-PhH; iii (Me,N),CHOCMe,; iv TsS(CH,),STs; v NaOMe-MeOH; vi MeI-MeCN-H,O 50 "C; vii (Ph P)3RhCI-MeCN. Scheme 4 Of the above reactions of diphenylsulphonium cyclopropylides only the addition to ap-unsaturated carbonyl compounds to give spiropentanes and addition to highly hindered saturated ketones are inefficient with respect to attack at the carbonyl centre. However the alternative approach'* shown in Scheme 5 leads Scheme 5 to an efficient formation of a cyclopropylmethanol and hence by acid-catalysed rearrangement to a cyclobutanone. Either spiropentanes or oxaspiropentanes can be prepared from conjugated ketones by suitable choice of reagent.These reagents are also easier to prepare than cyclopropylides of sulphoximines the use of which has now been reviewed. B. M. Trost D. Keeley and M. J. Bogdanowicz J. Amer. Chem. Soc. 1973.95 3068. l9 C. R. Johnson. Accounts Chem. Res. 1973 6 341. Alicyclic Chemistry A full report” gives the preparation of (10) (43 % yield 97 % purity) (1 1) (70% yield 99 % purity) and (12)(30% yield 99% purity) by treatment of the appro- priate methallylchloride with an alkali amide. A novel pyrolysis2’ converts furfuryl benzoate at 700°C into (13) (40%yield). A more lengthy route22 by retro-Diels-Alder reaction gives the substituted analogue (14) by pyrolysis of (15) at 400°C.Full details23 are now published of the photocyclization of a-methylene-ketones proceeding viaType I1 biradicals to give either cyclobutanones or cyclopropanones (Scheme 6) but yields are rather low. .O .O Scheme 6 Following the syntheses of cyclobutadienes reported last year the first tri- alkylcyclobutadiene (16) stable at room temperature has been prepared.24 The absence of a band in the U.V. spectrum above 300 nm was used to conclude a singlet ground state with rapid valence isomerization between (16a) and (16b). In contrast further st~dy~’,~~ of the i.r. spectrum of cyclobutadiene obtained in a low-temperature matrix suggests D, symmetry and a triplet ground state is suggested and supported by new ab initio calculations. 2o R. Koster S.Arora and P. Binger Annalen 1973 1219. *’ W. S. Trahanovsky J. Amer. Chem. SOC.,1973,95 5412. 22 R. C. De Selms and F. Delay J. Amer. Chem. SOC.,1973,95 274. 23 R. A. Cormier W. L. Schreiber and W. C. Agosta. J. Amer. Chem. SOC.,1973,95,4873. 24 G. Maier and A. Alzerreca Angew. Chem. Internat. Edn. 1973,12 1015; S. Masamune N. Nakamura M. Suda and H. Ona J. Amer. Chem. SOC.,1973,95 8481. ’’ 0. L. Chapman C. L. McIntosh and J. Pacansky J. Amer. Chem. SOC.,1973,95,614. 26 A. Krantz C. Y. Lin and M. D. Newton J. Amer. Chem. SOC.,1973,95,2744. 576 J.M. Mellor The synthesis of faur-membered rings by [2 + 2]cycloadditions continues to be a subject of great interest but few procedures of synthetic importance have been recently developed.Ethylene adds to acrylonitrile to give cyclobutyl cyanide27 but not under conditions that suggest a useful laboratory preparation. Weak catalysis of this addition by nickel(0) is suggested but is not clearly established to be of importance. Further cycloadditions of ketones to olefins28 and to acety- lene~~’ are shown in Scheme 7. Scheme 7 Five-membered Rings.-Methods of synthesis of five-membered rings have for long been overshadowed by the greater interest in developing methods for six- membered rings. Now the stimulus of attempted synthesis of prostaglandins has led to considerable success. The epoxide (17) is converted3’ into the lactone (18) with boron trifluoride. As the mode of cyclization in the biosynthesis of prostaglandins is still not clarified it is too early to call this a ‘biogenetically patterned synthesis’.However the above example (yield 15%) suggests an im- portant route to cyclopentenyl cations from dienyl cations. The synthesis of cyclopentenones has been re~iewed,~ of cyclo- and an effective ~reparation~~ pentenones from 1,3-dienes is described in Scheme 8. An alternative route to cyclopentanones is afforded by the ring c~ntraction~~ of boracyclanes on bro- ’’ H. K. Hall C. D. Smith and D. E. Plorde J. Org. Chem. 1973 38 2084. P. W. Jeffs and G. Molina J.C.S. Chem. Comm. 1973 3. 29 H. H. Wasserman J. U. Piper and E. V. Dehmlow J. Org. Chem. 1973 38 1451. 30 E. J. Corey G. W. J. Fleet and M. Kato Tetrahedron Letters 1973 3963. 31 R. A. Ellison Synthesis 1973 397. 32 E.J. Corey and S. W. Walinsky J Amer. Chem. SOC.,1972 94 8932. 33 Y. Yamamoto and H. C. Brown J.C.S. Chem. Cornm. 1973 801. Alicyclic Chemistry Scheme 8 mination (Scheme 9) but this route has less general applicability. A limitation is posed by the required formation of the boracyclane from the appropriate diene. a) Brz:: H,O,-NaOH ' OH I 0 OMe Scheme 9 An elegant synthesis34 of /?-vetivone (19) (Scheme 10) depends upon the preferred site of alkylation of the enolate anion of the enol ether of a 1,3-diketone. CH,Cl (19) Reagents i n -HMPA-THF-LiNPr', -78 "C; ii MeLi; iii H' CH ,CH ,C1 Scheme 10 G. Stork R. L. Danheiser and B. Ganem J. Amer. Chem. Soc. 1973,95 3414. 578 J. M. Mellor The stereochemistry is controlled by the preference of the methyl group for a pseudo-axial orientation.As a method of spiroannelation this route would appear to have considerable versatility. Since the early days of steroid synthesis the construction of trans-fused hydrin- danes has proved difficult. Typically on hydrogenation (20; R = H) gives the thermodynamically preferred cis-product. However the ether (20; R = But) on catalytic hydr~genation,~’ because of steric hindrance on the p-face gave a higher percentage of trans-product (21). Using this approach with further sub- stitution at C-4 a synthesis of 19-nor-steroids is described. Novel ~yntheses~~,~’ of cis-hydrindanones are described in Scheme 11 but neither has a likely utility. The formation of five-membered rings by cycloaddition reactions has been extended.Last year [Ann. Reports (B) 1972 69 4121 the allowed [,2 + .4,] H ko Ac,O-ZnCI,-CH,CI Ref. 36 30% Br Br Br Br H H Ref. 37 0 H o Scheme 11 thermal cycloaddition of olefins to allyl carbanions was reported. Now the effective thermal cycloaddition of allyl carbonium ions to olefins which is not symmetry-allowed has been achieved.38 Addition of [Fe,(CO),] to aa’-dibromo- ketones generates oxyallyl cationic intermediates which undergo cycloaddition with aryl-substituted olefins in a stereospecific manner in high yield (Scheme 12). ’’ Z. G. Hajos and D. R. Parrish J. Org. Chem. 1973,38 3239 3244. 36 L. W. Boyle and J. K. Sutherland Tetrahedron Letters 1973 839. ” H. J. Liu and T.Ogino Tetrahedron Letters 1973 4937. R. Noyori K. Yokoyama and Y.Hftyakawa J. Amer. Chem. SOC.,1973,95 2722. Alicyclic Chemistry Ar Me Scheme 12 Simple aliphatic olefins cannot be used. The use of ally1 cations in the synthesis of seven-membered rings has been discussed in detail,39 and their application to the synthesis of cyclopentanes noted. Last year the application of thermal cyclization of unsaturated ketones to give cyclohexanones was noted. The above work is fully discussed4' and Conia's group now report4' the use of the ene reac- tion in the construction of five-membered rings (Scheme 13). Scheme 13 Six-memberedRings.-Both outstanding modifications of well known processes such as the Robinson annelation procedure and the Johnson cationic cyclizations and also the development of novel cyclization procedures are reported.The use of a-hal~geno-acetals~~ in cyclization processes is considerable. Halogeno-acetals are available from the halogeno-ketones prepared either from carboxylic acids by diazomethane addition or by addition to terminal olefins. Subsequent cycli- zations are illustrated in Scheme 14. A number of interesting points stem from this study. Cyclization to give either (22) or (23) is controlled by the nature of the cation. Study of a number of systems shows that in the absence of special con- straints cyclization with an axially held halogeno-acetal chain is preferred and hence this constitutes an important new synthesis of cis-decalins. When a tight ion pair is involved as with the lithium salt in benzene an equatorial conforma- 39 H.M. R. Hoffmann Angew. Chem. Internat. Edn. 1973 12 819. 40 J. Brocard G. Moinet and J. M. Conia Bull. SOC.chim. France II 1973 1711. 41 G. Mandville F. Leyendecker and J. M. Conia Bull. SOC. chim. France II 1973 963; M. Bortolussi R. Bloch and J. M. Conia Tetrahedron Letters 1973 2499. 42 G. Stork J. 0. Gardner R. K. Boeckman and K. A. Parker J. Amer. Chem. SOC. 1973 95 2014; G. Stork and R. K. Boeckman ibid. p. 2016. 580 J.M. Mellor n n i 70-85 % + OyO ___) NCg NCm 92 % 8% Br OJ 70-85% ~ “62 Reagents i sodium hexamethyldisilazane ;ii potassium hexamethyldisilazane ;iii lithium hexamethyldisilazane. Scheme 14 tion is adopted and hence a trans-decalin results.trans-9-Cyano-2-decalones are available by addition to o~talones.~~ The Robinson annelation of 2-alkylcyclohexanones with methyl vinyl ketone is limited in application by the extensive competing polymerization of the vinyl W. Nagata M. Yoshioka and T. Teresawa J. Amer. Chem. SOC.,1972,94 4612. Alicyclic Chemistry 58 1 ketone and by the formation of products from both enolate anions of the cyclo- hexanone. Two important developments have overcome these limitations and suggest many uses for this modified annelation. With methyl vinyl ketone the base strength and reactivity of the enolate anion is comparable to that of the cyclohexanone. Use44 of or-silylated enones (Scheme 15)overcomes this problem. OLi n Reagents i SiEt3 ;ii 5 % NaOMe-MeOH; iii SiEt 0 Scheme 15 Addition of a cyclohexenone to lithium dimethylcuprate gives45 an organo-copper enolate which fails to equilibrate by proton transfer from the vinyl ketone.Hence in contrast to the lithium enolates highly regiospecific addition with a kinetically stable organo-copper enolate is possible. Even direct annelation of cyclopen- tanones is possible (Scheme 16). 0 ocu nA j$120y)+o~ 97 % 3 76 Reagents i. LiCuMe,-Et,O; ii SiMe Scheme 16 44 G. Stork and B. Ganem J. Amer. Chem. SOC.,1973.95 6152. 45 R. K. Boeckman J. Amer. Chem. SOC.,1973,95,6867. 582 J. M. Mellor The use of the Lansbury chloro-olefin annelation procedure has been further adapted to the synthesis of hydroa~ulenones~~ and of cycloalkanecarboxylic acids4’ (Scheme 17).Construction of bridged systems by ad-bisalkylation of 03- C02H CI Reagents i ; ii CH =CHMgBr; iii HCO,H A 40 ”/’,. dc, Br Scheme 17 enamines is not an efficient process. However the use of palladium complexes48 leads to catalysis by reversible formation of n-ally1 complexes and a moderately efficient annelation(Scheme 18).Thead-annelation ofenamines by ap-unsaturated 0 0 Q AcOCH ,CH=CHCH .OAc &+ $,. 30 % 34 % Scheme 18 acid chlorides has previously proved an efficient method of synthesis of bridged bicyclic diketones. Now the reaction is adapted4’ to the synthesis of polyfunc- tional adamantanones (Scheme 19). Dauben and Ipaktschi’’ have developed n 29 % Scheme 19 46 P.T. Lansbury P. M. Wovkulich and P. E. Gallagher Tetrahedron Letters 1973 65. ‘’ P. T. Lansbury and R. C. Stewart Tetrahedron Letters 1973 1569. 48 H. Onoue I. Moritani and S.I. Murahashi Tetrahedron Letters 1973 121. 49 P. W. Hickmott H. Suschitzky and R. Urbani J.C.S. Perkin I 1973 2063. W. G. Dauben and J. Ipaktschi. J. Amer. Chem. SOC.,1973,95 5088. Alicyclic Chemistry an elegant and efficient synthesis of bridged olefins (Scheme 20). In spite of the strain imposed by cyclization the efficient loss of triphenylphosphine oxide in-duces closure. Even closure to give a bicyclo[3,3,l]nona-1,3-diene(trapped but 6 + 0 PhCH=CH-CH=PPh, / Ph I Ph 57 % Scheme 20 not isolated) is possible. The reaction is generally applicable to the synthesis of cyclohexa-1,3-dienes from acyclic ketones" and to the annelation of cyclic ketones e.g.synthesis of occidol(24) from (25) in three steps. "OWMe02C,o-e Useful developments of the Diels-Alder reaction still continue (see Scheme 21).53-56 Synthesis of the fragrant a-dama~cone~~ (26) and of P-damascenoneS4 (27)shows that catalysis of the cycloaddition may proceed by effective activation of either dienophile or diene. Control of the stereochemistry has been clarified both by experimental observation^^^ concerning the relative importance of secondary orbital overlap and steric effects and by PMO calculation^^^ con-cerning regiospecificity and syn-anti specificity. W. G. Dauben D. J. Hart J. Ipaktschi and A. P. Kozikowski Tetrahedron Lerters 1973,4425.s2 E. Sonveaux and L. Ghosez J. Amer. Chem. SOC.,1973,95 5417. 53 P.G. Sammes and T. W. Wallace J.C.S. Chem. Comm. 1973 524. 54 K. S.Ayyar R. C. Cookson and D. A. Kagi J.C.S. Chem. Comm. 1973 161. 55 R.C. Cookson and R.M. Tuddenham J.C.S. Chem. Comm. 1973,742. 56 E. J. Corey and R. L. Danheiser Tetrahedron Letters 1973 4477. " D. W. Jones and G. Kneen J.C.S. Chem. Comm. 1973,420; D. W. Jones and R.L. Wife ibid. p. 421; H. Takeshita M. Shima and S. Ito Bull. Chem. SOC. Japan 1973 46. 2915 C. K. Bradsher F. H. Day A. T. McPhail and P. Wong J.C.S. Chem. Comm. 1973 156; E. T. McBee. M. J. Keogh R.P.Levek and E. P.Wesseler J. Org. Chem. 1973 38 632; K. Seguchi A. Sera and K. Maruyama Tetrahedron Letters 1973 1585; B.M. Jacobson J. Amer. Chem. SOC. 1973,95,2579. K. N. Houk J. Amer. Chem. SOC. 1973 95 4092; K. N. Houk and R. W. Strozier ibid. p. 4094; N. D. Epiotis ibid. p. 5624; P. V. Alston R. M. Ottenbrite and D. D. Shillady J. Org. Chem. 1973 38 4075; 0.Eisenstein and N. T. Anh Bull. SOC. chim. France II 1973 2721 2723; N. T. Anh Tetrahedron 1973 29 3227; M. N. Paddon-Row P. L. Watson and R. N. Warrener Tetrahedron Letters 1973 1033. 584 J. M. Mellor H'-H,O/ 95 % Ref. 52 Ph 0-Mf Me0 OH \ Ref.53 0+ Meek + a% ;1''( -6 AlCl,-CH,CI Ref. 55 \ "y* 9 Ac20.135"C Ref. 56 70 % o, 0 The potential of cationic cyclizations in the synthesis of steroids has been shown by Johnson's group. Now they show the flexibility of the approach by total syntheses of oestrone," optically active progesterone,60 17-hydroxy-5fl-pregnan- 59 P.A. Bartlett and W. S. Johnson J. Amer. Chem. Soc. 1973 95 7501. 6o R. L. Markezich W. E. Willy B. E. McCarry and W. S. Johnson J. Amer. Chem. SOC. 1973 95 4414; B. E. McCarry R. L. Markezich and W. S. Johnson ibid. p. 4416. Alic-vclic Chemistry gg \ (26) (27) 20-0ne,~' and testosterone benzoate.62 Details are given elsewhere in this volume but two general points may be noted here. The novel use of nitro-alkanes permits the trapping of vinyl cations to give derivatives of a-hydroxy-ketones (Scheme 22). Studies related to the synthesis of oestrone that in the cyclization of H / OH +AH-J/ Scheme 22 (28)to give (29)and (30)the ratio (29):(30)depends upon the nature of the leaving group X.This result is best interpreted as evidence for a concerted mode of (28) (29) (30) 6' D. R. Morton M. B. Gravestock R. J. Parry and W. S. Johnson J. Amer. Chem. SOC. 1973 95 441 7. 62 D. R. Morton and W. S. Johnson J. Amer. Chem. SOC.,1973,95,4419. 63 P. A. Bartlett J. I. Brauman W. S. Johnson and R. A. Volkmann J. Amer. Chem. SOC. 1973,95 7502. 586 J. M. Mellor cyclization. Full details are given of the cyclization of unsaturated acetal~,~~ the use of allene participation6' to give six-membered rings and the influence of substitution upon the stereochemistry of the ring junction. Cyclization of (31) give#' the cis-decalin (32). Cationic cyclizations are of greater synthetic im- portance than their radical analogues.Nevertheless impressive stereospecificity is observed67 in the radical cyclization of(33) which gives (34)(12 % yield) as the only tetracyclic product. (33) (34) Seven-memberedRings.-Problems in the synthesis of sesquiterpenoids particu- larly highly functionalized lactones have exposed a lack of methods. Successful syntheses of bulnesol and guaioP8 depend upon cationic cyclization [(35) --* (36)]. Two fresh approaches have promise. &Unsaturated ketones typically undergo 1,3-rearrangement from the first excited singlet state. Ph~torearrangement~' of (37) efficiently gives (38). The easily prepared and stable ylide (39) can be trans- formed7' via a vinylcyclopropane into a cycloheptadiene (Scheme 23).A route 64 A. van der Gen K. Wiedhaup J. J. Swoboda H. C. Dunathan and W. S. Johnson J. Amer. Chem. SOC.,1973 95 2656. '' M. H. Sekera B. Weissman and R. G. Bergman J.C.S. Chem. Comm. 1973 679. 66 K. E. Harding R. C. Ligon C. Tseng and T. Wu J. Org. Chem. 1973 38 3478. '' J. Y. Lallemand M. Julia and D. Mansuy Tetrahedron Letters 1973 4461. 68 N. H. Anderson and H. Uh Tetrahedron Letters 1973 2079. 69 R. G. Carlson R. L. Coffin W. W. Cox and R. S. Givens J.C.S. Chem. Comm. 1973 501. 'O J. P. Marino and T. Kaneko. Tetrahedron Letters 1973 3971 3975. Alicyclic Chemistry (37) H,C=PPh, 1 0 0 Scheme 23 more appropriate to the synthesis of azulenes concerns' the catalysed decompo- sition of diazoketones (Scheme 24).Routes based upon addition of ally1 cations to dienes have been reviewed3' and further studied72 and cyclizations using chloro-olefins described.73 CuCl PhH Scheme 24 71 L. T. Scott J.C.S. Chem. Comm. 1973 882. l2 S. Ito M. Ohtani and S. Amiya Tetrahedron Letters 1973 1737; R.Noyori Y. Baba S. Makino and H. Takaya ibid. p. 1741; A. E. Hill G. Greenwood and H. M. R. Hoffmann J. Amer. Chem. SOC.,1973,95 1338. 73 P. T. Lansbury Accounts Chem. Res. 1972 5 31 1. 588 J. M. Mellor Miscellaneous Syntheses.-A novel synthesis74 of macrocycles proceeds in quantitative yield by the ene reaction of (40)to give (41) and (42). Photore-arrangement7’ of By-epoxy-ketones leads to iactones and thereby affords a novel macrolide synthesis. \ Ref.76 I (43) Ref. 77 I Br i. Hi Ref. 78 ii p-TsC1-py I (45) ‘OTs AICI,-CH,CI,-MeNO ~ 4% 00 i AIH ii. SOCI,1 Scheme 25 74 J. B. Lambert and J. J. Napoli J. Amer. Chem. SOC.,1973 95 294. ’’ R. G. Carlson J. H. Huber and D. E. Henton J.C.S. Chem. Cumm. 1973 223. Alicyclic Chemistry 589 Collected in Scheme 25 are the ~yntheses~~-~~ of different spirocyclic systems the properties of which are discussed in the next section. Further attempts have been made to synthesize ~entalene,~' and spectroscopic observation of the mono- mer generated at -196 "C was possible. However the highly substituted pentalene (47)was stable" at room temperature (synthesis in Scheme 26). Scheme 26 The first [2,2,2]propellane (48) has been prepared" by successive ring con- tractions of a-diazoketones.The final keten is trapped as the amide (48) which has t+ -28 min at 25 "C. A compound of surprising thermal stability is prismane (48) (?+ -11 h at 90°C). Synthesis82 from the now readily available benzvalene proceeds in three steps (Scheme 27). Following last year's report of the synthesis of the trioxides of benzene [Ann. Reports (B),1973,69,416]more recent work has concerned a study of their reactivity to nucleophilic a preparati~n~~ of anti-benzene dioxide (49),and the synthesis85 of the cis-benzene tri-imine (50). 76 H. Durr B. Ruge and H. Schmitz Angew. Chem. Internat. Edn. 1973 12 577. 77 A. de Meijere and L. Meyer Angew. Chem. Internat. Edn. 1973,12 858; R. D.Miller M. Schneider and D. L. Dolce J. Amer. Chem. SOC.,1973 95 8468. '' M. F. Semmelhack J. S. Foos and S. Katz J. Amer. Chem. SOC.,1973 95 7325. 79 K. Hafner R. Donges E. Goedecke and R. Kaiser Angew. Chem. Internat. Edn. 1973 12 337. 'O K. Hafner and M. U. Suss Angew. Chem. Internat. Edn. 1973,12 575. P. E. Eaton and G. H. Temme J. Amer. Chem. SOC.,1973,95 7508. 82 T. J. Katz and N. Acton J. Amer. Chem. SOC.,1973 95 2738. 83 R. Schwesinger H. Fritz and H. Prinzbach Angew. Chem. Internat. Edn. 1973 12 993 994. 84 E. Vogel H. J. Altenbach and E. Schmidbauer Angew. Chem. Internat. Edn. 1973,12 838. 85 R. Schwesinger and H. Prinzbach Angew. Chem. Internat. Edn. 1973 12 989. 590 J. M. Mellor Ph i KOH 65 7’ ii C~CI,-OH I N=N Scheme 27 0 (49) 2 Structural Properties and Orbital Interactions The early discussions of the consequences of orbital interactions either through bonds or through space emphasized the effects upon spectral properties.These theoretical analyses have received ample experimental verification from photo- electron spectroscopy particularly from the work of Heilbronner’s group. Recently such studies have been made on for example the spirocyclic systems whose syntheses are discussed above and hence spiroconjugation has been es- tablished. It is now clear that orbital interactions can have profound consequences upon the chemical reactivity of both ground and excited states. Accordingly we discuss the consequences of such interactions in spiroconjugated homoconjugated antiaromatic and hyperconjugated systems.Spiroconjugatiom-Spiroconjugation has recently been examined in three types of system (a)systems having a cyclopropyl or cyclobutyl ring fused to a cyclic n-system having either (4n + 2) or 4n n-electrons; (b) systems having a cyclic mystem of a polyene fused to another n-system of an olefin or polyene ;and (c) systems having a cyclic n-system of a polyene fused by the spiro-centre to an acetal. In case (a) interaction might be expected between the appropriate MO of the n-electron system and the Walsh orbitals of the cycloalkyl ring. In 4n n-electron systems this would imply interaction with the LUMO and with (4n + 2) Alicyclic Chemistry 59 1 n-electron systems with HOMO.Conflicting results have been obtained in searching for experimental verification in case (a). Electron-diffraction resultse6 with (51) suggest that there is little interaction between the three- and five-membered rings in contrast to earlier conclusions made from n.m.r.87 and photoelectron spectra." Conjugative interaction in (44)is expected to be less and this view is supported by a preliminary of chemical and spectral properties but it is suggested that the photoelectron spec- trum indicates a little interaction. Staley has probed the concepts of homoaromaticity and spiroaromaticity by examining the properties of carbanions. Anion (52) has a (4n + 2) n-electron system and should therefore undergo charge donation from the HOMO to the cyclopropyl ring.Anion (52)cannot be isolated" and even at -65 "Cis converted into the carbanion of ethylbenzene. In contrast anion (53) with a 4n n-electron 8 system is more table'^*^^ and n.m.r. evidence suggests a ring current in the n-system attributable to spiroconjugation with charge donation from the cyclo- propyl group. Spiroconjugation of type (b)has been explored in the olefins (43) and (46) and in the anion (54). Neither polarography nor measurements of acidityg1 indicated that anion (54)was more stable than analogues of type (55). Anion (54)is therefore c1 (54) not spiroaromatic but this may be due to an alternative and preferred mode of stabilization by the chlorines. The related olefin (43) can spiroconjugate by interaction of the 4n-system either with the 2n-system or with the Walsh orbitals.The observed U.V. spectrum [I,, 239nm for (43) and I,, 257nm for (Sl)] is inter~reted~~ as evidence for spiroconjugation. The magnitude of this spiro- 86 J. F. Chiang and C. F. Wilcox J. Amer. Chem. SOC.,1973,95 2885. R. A. Clark and R. A. Fiato J. Amer. Chem. SOC.,1970,92,4736. R. Gleiter E. Heilbronner and A. de Meijere Helu. Chim. Acla 1971,54 1029. 89 S. W. Staley G. M. Cramer and W. G. Kingsley J. Amer. Chem. SOC.,1973,95 5052. 90 S. W. Staley and W. G. Kingsley J. Amer. Chem. SOC.,1973.95 5804. 91 M. F. Semmelhack R. J. Defranco Z. Margolin and J. Stock J. Amer. Chem. SOC. 1973 95 426. 592 J. M. Mellor conjugation will be better assessed by photoelectron spectroscopy. The tetraene (46)has two bands in the U.V.spectrum at A,, 218 and 276 nm whereas the triene (45) has a single band at 254 nm. The conclusion78 of a spiroconjugative inter- action is confirmed92 by photoelectron spectroscopy which also reveals spiro- conjugation in (56),93 (57),94 and (58).95 The third type of spiroconjugation (c) requires interaction of the p-orbitals of the acetal oxygens with a nsystem and has previously been recognized in acetals of cyclopentadienone. The rate of Diels-Alder dimerization and the U.V. spectrum of (59) indicate96 a further case of spiroconjugation. Ph Ph Homoconjugated and Antiaromatic Species.-Not only has the cyclopentadienyl cation (C5H5+) been shown97 to be highly destabilized as expected of an anti- aromatic species but the cation prepared by treatment of the bromide with SbF gives an e.s.r.spectrum establishing that the ground state is a triplet and not a singlet species. The novel homoaromatic systems (60),98 (61),99*'00 and (62)99*'00 have been prepared. It is agreed that both (61) and (62) are stabilized by homoconjugative 92 C. Batich E. Heilbronner and M. F.Semmelhack Helv. Chim. Acta 1973 56 21 10. 93 A. Schweig U. Weidner J. G. Berger and W. Grahn Tetrahedron Lefters 1973 557. 94 A. Schweig U. Weidner D. Hellwinkel and W. Krapp Angew. Chem. Internat. Edn. 1973 12 310. 95 A. Schweig U. Weidner R. K. Hill and D. A. Cullison J. Amer. Chem. SOC.,1973 95 5426. 96 J. M. Holland and D. W. Jones J.C.S. Perkin I 1973 927. 9' R.Breslow and S. Mazur J. Amer.Chem. SOC.,1973,95 584; M. Saunders R. Berger A. Jaffe J. M. McBride J. O'Neill R. Breslow J. M. Hoffman C. Perchonock E. Wasserman R. S. Hutton andV. J. Kuck ibid. p. 3017. 98 G. B. Trimitsis E. W. Crowe G. Slomp and T. L. Helle J. Amer. Chem. SOC.,1973 95 4333. 99 M. V.Moncur and J. B. Grutzner J. Amer. Chem. SOC.,1973,95 6449. loo M. J. Goldstein and S. Natowsky J. Amer. Chem. SOC.,1973 95 6451. Alicyclic Chemistry interactions but there is disagreement in the assessment of the importance of laticyclic stabilization in (62). Analysis"' of the anion (63) further implies the lack of bishomoantiaromatic character in the 7-norbornenyl anion but preparationlo2 of the anion (64) has not indicated whether it has significant homoantiaromatic character.Observation oftheions(65)lo3 and(66)'04shows that by bond fixationin(65)andconformational twisting in (66) the destabilizing antiaromaticity of a 4n-system is minimized. Anion (67) has a (4n + 1)n-electron system is defined as an atropic system and observation by n.m.r. indicates'05 that it supports at best only a minor ring current in contrast to the above diatropic or paratropic species. A further novelty is the organic sandwich species (68) obtainedlo6 from (69) in FS0,H. The n.m.r. spectrum is best interpreted on the basis of a species with degeneracy atrributed to a double rotation and not on the basis of equilibrating species. The diol(70) in FS0,H gives a dication to which the structure (71) has been assigned,lo7 and solution of (72) or (73) in superacid media"* gave the cation (74).lo' D. D. Davis and W. B. Bigelow Tetrahedron Letters 1973 149. lo' S. W. Staley and N. J. Pearl J. Amer. Chem. SOC.,1973 95 2731. '03 S. W. Staley and A. W. Orvedal J. Amer. Chem. SOC.,1973,95 3382. lo' S. W. Staley and A. W. Orvedal J. Amer. Chem. SOC.,1973 95 3384. lo' S. W. Staley and G. M. Cramer J. Amer. Chem. SOC.,1973,95 5051. Io6 M. J. Goldstein and S. A. Kline J. Amer. Chem. SOC., 1973 95 935. lo' H. Hogeveen and P. W. Kwant Tetrahedron Letters 1973 1665. lo' S. Masamune M. Sakai A. V. Kemp-Jones H. Ona A. Venot and T. Nakashima Angew. Chem. Znternaf. Edn. 1973 12 769. 594 J. M. Mellor H OH H I Cl (74) (73) Hyperconjugation.-The expectation [Ann.Reports (B) 1972 68 4041 that a study of orbital interactions through bonds and through space would lead to a recognition of their great importance in controlling chemical reactivity is being realized. Interactions which lead to a reversal in ordering of n-levels will determine reactivity in symmetry-controlled cycloadditions. In (75) a dominant through- bond intera~tion"~ through the strained a-system places the symmetric 7~ combination above the antisymmetric n combination in energy. Hence a photo- chemical closure of (75) to cubane is not expected. Less drastic interactions which lead not to an actual reversal of energy levels but only to more minor displacements control the reactivity in for example log R. Gleiter E. Heilbronner M. Hekman and H.D. Martin Gem. Ber. 1973 106 28. Alicyclic Chemistry Diels-Alder additions. With electron-rich dienes rate is largely determined by interaction of the HOMO of the diene with the LUMO of the dienophile. This interaction will be increased by any increase in energy of the HOMO of the diene. Experimental rate studies havebeen made withdienes for which the HOMOenergy is modified by spiroconj~gation,~~*~~ and by other orbital interactions."' Orbital interactions between a functional group and the a-framework modify reactivity conformation and control of stereochemistry by an attacking reagent. Carbonium ion stability is increased by a conjugative interaction in simple acycliccases. The7-norbornylcationisabnormallyunstable :anew explanation' ' attributes the lack of stability to a lack of interaction between the highest occupied a-orbital of the cyclohexane framework and the cationic centre [see (76)].Similar symmetry constraints stabilize the no-and %-orbitals in the ether (77)' and the sulphide (78)' ' relative to acyclic examples. Solution of 1,4-dichlorobicyclo- [2,2,2]octane in superacid generates' ' the dication (79). The unusual stability of this dication is due to the symmetry-allowed hyperconjugative interaction with the three carbon bridges. Cation (80) is stabilized by extensive cyclopropane a-participation''4 and preliminary results suggest that (81) may also be stable. H (76) (78) X = S The anomeric effect,' l5 the preference of methyl groups for adopting an eclipsed rather than staggered conformation with respect to a vinylic group,'16 and the concept of steric attraction by a remote group in a transition state'17 have all 110 W.L. Jorgensenand W. T. Borden J. Amer. Chem. SOC.,1973,956649; M. N. Paddon-Row Tetrahedron Letters 1972 1409. 111 R. Hoffmann P. D. Mollere and E. Heilbronner J. Amer. Chem. SOC.,1973,95,4860. 112 J. C. Bunzli D. C. Frost and L. Weiler J. Amer. Chem. SOC.,1973 95 7880. 113 G. A. Olah G. Liang P. von R. Schleyer E. M. Engler M. J. S. Dewar and R. C. Bingham J. Amer. Chem. SOC.,1973,95 6829. 114 A. de Meijere and 0.Schallner Angew. Chem. Internat. Edn. 1973 12 399. 115 S. David 0.Eisenstein W. J. Hehre L. Salem and R. Hoffmann J. Amer. Chem. SOC. 1973,95 3806. 116 W. J. Hehre and L. Salem J.C.S.Chem. Comm. 1973 754. 111 N. D. Epiotis and W. Cherry J.C.S. Chem. Comm. 1973 278; N. D. Epiotis J. Amer. Chem. SOC.,1973 95 3087; R. Hoffmann C. C. Levin and R. A. Moss ibid. p. 629. 596 J. M. Mellor been attributed to hyperconjugative interactions. Such interactions can induce a dissymmetry in for example the n-cloud of a carbonyl group. A fresh inter- pretation"* of Cram's Rule argues that the preferred face for nucleophilic attack is determined by such an interaction and new light is cast upon the vexed problem of the control of stereochemistry in reductions of cyclohexanones by the view' l9 that interaction of the o-framework with the carbonyl group induces dissymmetry in the n-system. A more detailed analysis is required of recent experimental results concerning nucleophilic attack at cyclohexanones' 2o before the importance of hyperconjugative interactions can be fully assessed but results12' shown in Scheme28 might be explained by such effects.Both '3C-H coupling constants' 22 R R R R = Et R = Ph R = Me R= Pr' 50 % 68 % 72% 5% 50 % 32 % 28 % 95 % Scheme 28 and 13C chemical shifts'23 have been used to establish the magnitude and pre- ferred pathways for hyperconjugative effects. The contribution of through-bond effects to the phenomenon of 'conformational transmission' is still unresolved and recent solvolytic studies' 24 and calculations' 25 are indeterminate. l8 N. T. Anh 0.Eisenstein J.-M. Lefour and M.-E. Tran Huu Dau J. Amer. Chem. SOC. 1973,95 6146. l9 J.Klein Tetrahedron Letters 1973 4307. 120 J. Laemmle E. C. Ashby and P. V. Roling J. Org. Chem. 1973,38,2526;E. C. Ashby J. R. Boone and J. P. Oliver J. Amer. Chem. SOC.,1973,95 5427; E. Volpi G. Biggi and F. Pietra J.C.S. Perkin 11 1973 571. D. Varech and J. Jacques Tetrahedron Letters 1973 4443. IZ* N. H. Werstiuk R. Taillefer R. A. Bell and B. Sayer Cunad. J. Chem. 1973,51 3010. * 23 I. Morishima K. Yoshikawa K. Okada T. Uonezawa and K. Goto J. Amer. Chem. SOC.,1973 95 165. 124 H. Tanida S. Yamamoto and K. Takeda J. Org. Chem. 1973 38 2077. P. A. Kollman D. D. Giannini W. L. Duax S. Rothenberg and M. E. Wolff J. Amer. Chem. SOC.,1973,95 2869.

ISSN:0069-3030    

DOI:10.1039/OC9737000571

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

19 Biosynthesis By E. McDONALD University Chemical Laboratory Lensfield Road Cambridge CB2 1EW 1 Monoterpenoids Chrysanthemic acid (1) bears a close structural relationship to presqualene pyrophosphate and prephytoene pyrophosphate the important biosynthetic precursors of the steroids and carotenoids.' Each of the three compounds has a pair of isoprene units which are not linked in a head-to-tail manner and this irregularity gives a special interest to studies of their biosynthesis. Doubly labelled [(4R)-4-3H]mevalonic acid (MVA) (2) was incorporated' (0.4 %) into (1) (2) chrysanthemic acid (1) by Chrysanthemum cinerariaefolium without a change in the ratio of 3H to 14C. The isolated monoterpenoid was purified as a crystalline amide and a straightforward degradation showed that all of the tritium was located at C(4).Clearly MVA in this experiment is providing only half of the carbon skeleton of chrysanthemic acid a result often found in the monoterpenoid area.lb In a parallel experiment [(4S)-4-3H]MVA lost its tritium during bio- synthesis of chrysanthemic acid and so the stereospecificity of hydrogen removal in this study parallels that found in other system^.^ In the same plant ''C-labelled chrysanthemic acid (1) was shown to be specifically incorporated4 (0.08%) into pyrethrin I1 (3). Me02CII ' (a)E. McDonald Ann. Reports (E) 1971 68 395; (b)E. McDonald Ann. Reports (E) 1972 69 467. ' G. Pattenden and R. Storer Tetrahedron Letters 1973 3473. J. W. Cornforth Chem. SOC.Rev. 1973 2 1. S.A. Abou Donia C. F. Doherty and G. Pattenden Tetrahedron Letters 1973 3477. 597 598 E. McDonald 2 Sesquiterpenoids Farnesol(4) is the parent of the sesquiterpene family but its conversion into the 2-cis-isomer (5) is frequently postulated in biogenetic schemes. The isomers of farnesol had identical labelling ratios when they were biosynthesized’ from (4) (5) [(4R)-or (4S)-4-3H,2-I4C]MVA by an enzyme system from Andrographis pani- culata. However when the incubation was carried out using [S3H, 2-I4C]MVA (6),all-trans-farnesol was formed without a change in the 3H 14C ratio but the 2-cis-isomer had lost one sixth of its tritium. Essentially the same result has been obtained by another research group who incubated6 labelled all-trans-farnesol with a cell-free system from Tricothecium roseurn.Their farnesol (prepared biosynthetically using pig liver) was tritiated randomly at C(1) C(5) and C(9) and it lost one sixth of its tritium during isomerization to 2-cis,6-trans-farnesol. It seems therefore that the 2-cis-isomer is formed from 2-trans-farnesol with obligatory loss of a hydrogen atom from C(1). The aldehydes corresponding to (4)and (5)are probably intermediates as suggested last yearlb for the isomeri- zation in Helminthosporium sativum. Although the insect juvenile hormones (7)and (8) are closely related to farnesol (4),they are not derived from it by direct methylation. A cell-free extract from the corpus allatum of Manduca sexta on incubation with S-adenosylmethionine tritiated in the S-methyl group does give labelled juvenile hormone (7),but all the tritium activity is confined to the ester methyl group.7 This result is in full K.H. Overton and F. M. Roberts J.C.S. Chem. Comm. 1973 378. R. Evans A. M. Holtom and J. R. Hanson J.C.S. Chem. Comm. 1973 465. ’ D. Reibstein and J. H. Law Biochem. Biophys. Res. Comm. 1973.55 266. Biosynthesis 599 (7) R' = R2 = Me (8) R' = Me R2 = H (9)R' = R2 = H agreement with earlier worklb using intact Hyalophora cecropia. The reason for these negative results has become clear from the outstanding experimental study of the Zoecon group8 [2-I4C]MVA was converted by gland cultures of Manduca sexta into juvenile hormones I1 (8) and I11 (9). After purification the hormones were each degraded and the carbons of the epoxide terminus were isolated and counted in the form of the crystalline derivatives (10)and (11).The NH (10) R' = Me (11) R' = H derivative (11)carried one third of the activity of hormone I11 (9),but derivative (10) from hormone I1 (8) was completely inactive. This clearly indicates that hormone I11 is a regular sesquiterpenoid but that hormone I1 is biosynthesized from only two MVA molecules and a C unit possibly homomevalonic acid (12). HOHZC COZH (12) Further experiments showing that hormone I11 incorporates nine acetate mole- cules but hormone I1 incorporates eight acetates and one propionate are con- sistent with the homo-MVA proposal. A regular farnesyl unit can be discerned as part of the skeleton of cochlio- quinone (13)and it has now been showng that [2-14C]MVA is incorporated only * D.A. Schooley K. J. Judy B. J. Berget M. S.Hall and J. B. Siddall Proc. Nut. Acud. Sci. U.S.A. 1973 70 2921. L. Canonica B. M. Ranzi B. Rindone A. Scala and C. Scolastico J.C.S. Chem. Comm. 1973 213. 600 E. McDonald HO.. HOpo into this C unit by CochlioboIus miyabeunus. The methyl groups marked a are derived from [Me-14C]methionine and the quinone ring and its attached side- chain are probably of acetate origin. The labelling pattern illustrated for dendrobine (14) was obtained" from feeding [5-3H,, 2-14C]MVA (6) to Dendrobium nobile the location of tritium at C(5)and C(8)being obtained by specific degradations to (15) and (16),respectively.T (14) The tritium at C(8) must have migrated from either C(3) or from C(5) and the authors assume that this happened at an early stage of the biosynthesis during interconversion of cations (17)and (18). If so then the isomerization of 2-trans- to 2-cis-farnesol must have occurred without loss of tritium a suggestion in conflict with results now discovered in three different organisms (uide supra). The alter- native possibility that tritium migrates from C(3) to C(8) later in the pathway lo A. Corbella P. Gariboldi and G. Jommi J.C.S. Chem. Comm. 1973 729. Biosyn thesis 601 nicely accounts for the presence of oxygen at C(3) and a feeding of specifically labelled farnesol should make the necessary distinction. Labelled illudin M (19) was obtained" after incubating the mushroom Clitocybe illudens with [2-14C]MVA.Further studies show that [(4R)-4-3H]MVA provides one tritium at C(1) or C(11) while [2-3H,]MVA gives illudin M with three tritium atoms only one of which is located in the cyclopropane ring. This shows that one of the CH groups of the cyclopropane changed its oxi- dation level during the biosynthesis and (20)is suggested as an intermediate. Incubation of [2-' 3C]MVA with Helicobasidium mompa gave' * a 3C-enriched sample of helicobasidin (21). This was converted into the diacetate before running the 13C n.m.r. spectrum in the presence of the relaxation reagent chromium trisacetylacetonate. Comparison of the spectrum with that of a natural-abundance sample revealed the enhancement of three carbon resonances assigned as C(4) C(12) and either one of the equivalent atoms C(8) or C(10).No justification is given for the distinction which is made between the pairs C(8),C(10) and C(7) C(11) (both remain singlets during off-resonance decoupling) or between C(2) and C(4) (both triplets) or between C(12) C( 13) and C(14)(all quartets). In all cases the differences in 13C chemical shift seem too small to be significant. J. R. Hanson and T. Marten J.C.S. Chem. Comm. 1973 171. l2 M. Tanabe K. T. Suzuki. and W. C. Jankowski Tetrahedron Letters 1973 4723. 602 E. McDonald 3 Diterpenoids (-)-Kaurene (22),biosynthesized from [(SS)-S-3H,2-14C]MVA,is converted by Gibberellufujikuroi (1.4%)into gibberellic acid (23) without loss of 3H.In the present work13 the stereochemistry of the 3H at C(11) was assigned from the rate of base-catalysed exchange of tritium from the rearranged ketone (24). T9'-*T HO W 11 H H T' C0,H (23) H py I Me0,C OH Preliminary experiments with D,O had shown that the exo-9-H exchanges faster than endo-9-H in (24). [17-' 4C]Kaurene (22) is poorly incorporated' (0.003-0.004%) by leaves from lsodon juponicus into the highly oxygenated diterpenoid enmein (25) and Sugar R CH,OH (26) R = CH,OH (27) R = CH oridonin but degradation of these compounds showed that all of their radio- activity was located in their vinyl methylene group. Both fusiococcin (26) and fusiococcin H (27) have a skeleton of twenty carbon atoms and are structurally l3 R.Evans J. R. Hanson and L. J. Mulheirn J.C.S. Perkin I 1973 753. l4 T. Fujita S. Takao and E. Fujita J.C.S. Chem. Comm. 1973 434. Biosynthesis 603 related to the CZ5 sesterterpenoids. It seemed possible that oxidative cleavage of the side-chain of a sesterterpene might give rise to the CH,OH residue in fusiococcin. Fusiococcin H might then be formed by reduction of fusiococcin. In fact such a reduction does not occur1’ in Fusiococcurn amygddi but rather fusiococcin H is oxidatively transformed (2%) into fusiococcin. This result strongly supports the classification of these compounds as true diterpenoids rather than degraded sesterterpenoids. The dilactone (28) with a c16 skeleton is very probably a degraded diterpene.The evidence for this comes from feeding experiments’ with Acrostalagrnus. 0 [2-13C]Acetate gave a sample of dilactone enriched as shown. The enrichment at C(12) and C(15) particularly precludes the possibility that the compound might be a methylated sesquiterpenoid. Furthermore the results obtained from feeding doubly labelled MVA were consistent with the incorporation of four rather than three molecules of MVA. 4 Triterpenoids The text of Professor Cornforth’s Robert Robinson lecture3 should not be missed by anyone interested in mechanistic studies of biosynthetic processes and it provides a background for many of the stereochemical results reported in these pages. For example the mechanism of the biosynthesis of squalene is such that [(5S)-5-3H 2-I4C]MVA (29) should lead to the labelling pattern illustrated in (30).The unsymmetrical labelling at the central pair of carbons C(12) and C(13) might in principle be maintained if squalene oxidase were to operate on only one of the terminal double bonds but because of the symmetry of the molecule it would be necessary for newly biosynthesized squalene to be transferred from one enzyme to another without release into the medium. To test this hypothesis the appro- priate MVA (29) was fed” to intact growing Fusidiurncoccineum,and [14C6,3H4]-fusidic acid (31) was isolated. Careful degradation established that one of the K. D. Barrow D. H. R. Barton Sir E. Chain U. F. W. Ohnsorge and R.P. Sharma J.C.S. Perkin I 1973 1590.l6 H. Kakisawa M. Sato T. Ruo,and T. Hayashi J.C.S.Chem. Comm. 1973 802. R. C. Ebersole W. 0. Gotfredsen S. Vangedal and E. Caspi J. Amer. Chem. SOC. 1973,95 8 133. 604 E. McDonald four tritium atoms is equally distributed between C(11) and C(12) so that the asymmetry of squalene is not transferred to later biosynthetic stages. The absence of tritium at C(16) suggests that hydroxylation took place with retention of configuration as expected. T i several steps HO (33) Biosynthesis 605 P-Amyrin (32) is formed in peas (Pisumsatiuurn)in high yield (13 %)from squalene oxide. The ion (33) (which is similar to that implicated in lanosterol biosynthesis) might be cyclized by the pea enzyme and transformed into (34).Support for the intermediacy of the tetracyclic ion (34) comes'* from the transformation of the synthetic compound (35) by the pea enzyme into p-amyrin (32) (0.006%). Oxidation of the P-amyrin to the 1 1-oxo-derivative established the specificity of labelling in the product. Oleanolic acid (36) and maslinic acid (37) were isolated from lsodon japonicus tissue culture after inc~bation'~ with [(4R)-4-3H 2-14C]MVA (2). The labelling ratio in the two acids was the same as that of the precursor and the pattern illus- trated can be deduced from earlier studies. In contrast 3-epi-maslinic acid iso- lated from the same experiment had retained five rather than six tritium atoms i (36) R = OH (37) R = H and degradation showed that the discrepancy is entirely at C(3).Thus 3-epi- maslinic acid must be biosynthesized via a 3-ox0 precursor. After feeding [2-I4C]MVA to Convallaria majalis degradation of convallamarogenin (38) established" that the exocyclic methylene group carries one sixth of the radio- activity and that C(26) is radioinactive. The same result has been observed in other sapogenins. H. Horan J. P. McCormick and D. Arigoni J.C.S. Chem. Comm. 1973 73. l9 Y. Tomita and S. Seo J.C.S. Chem. Comm. 1973 707. *O F. Ronchetti and G. Russo J.C.S. Chem. Comm. 1973 184. 606 E. McDonald HO (38) From two independent studies of the biosynthesis of the ecdysone hormones the sequence cholesterol (39)+ (40)-B (41) has been established. 6,7&0xido- cholestanol was reduced by borotritide and the product converted into cholesterol (39) (41) R = H ; a-ecdysone R = OH ; P-ecdysone (ecdysterone) stereospecifically labelled at C(7).In the insect Calliphora erythrocephala the tree Tuxus baccata and the fern Polypodium vulgare ecdysone and ecdysterone were formed from cholesterol and in every case the 7/3-hydrogen was lost.” Furthermore [3-3H]-(40) was incorporated22 by larvae of Calliphora stygia into ’’ I. F.Cook J. G. Lloyd-Jones H. H. Rees and T. W. Goodwin Biochem. J. 1973 136 135. M. N. Galbraith D. H. S.Horn E. J. Middleton and J. A. Thomson J.C.S. Chem. Comm. 1973 203. Biosynrhesis 607 a- and P-ecdysone (41),and degradation showed that the tritium of each hormone was exclusively located at C(3).Several pathways for ergosterol biosynthesis seem to operate in yeast and the complexities have been described by two different research gro~ps.~~,~~ The biosynthesis from [(4R)-4-3H 2-14C]MVA (2) of the plant sterols which carry an ethyl group at C(24) proceeds via cholesterol (39) and the ion (42) having tritium at C(25). It has now been shown that in four different plants stigmasterol (43)and a-spinasterol (44),produced in this way do not carry 3H at C(25),and ...TAT ..T& Jw 25 Jw. (43) cholesterol nucleus (42) (44) 5-a A8.9-cholestene nucleus therefore a 24-eth~l-A~~.~~-intermediate is likely as discussed earlier for p-sitosterol biosynthesis. The Liverpool studied a-spinasterol biosynthesis in leaves from Spinacea oleracea and Medicago sativa while the Osaka group26 used tissue cultures of Nicotiana tabacurn and Dioscorea tokoro and isolated stigmasterol.The biosynthetic origin of the highly complex Daphniphyllurn alkaloids has been a fascinating problem for some years and it may not surprise others who have given it some thought that squalene is in~orporated~~ into daphniphylline (45) by Daphniphyllurn rnacropodurn. Further support for the suggestion that this alkaloid is a triterpenoid comes from feeding [2-14C]-and [5-14C]-MVA and degrading the radioactive products to (46)and (47)having a specific activity ratio of 2.0 and 5.0 respectively. Daphnilactone (48) carried one quarter of its radio- activity at the site marked 0 after feeding” [2-I4C]MVA to Daphniphyllurn D.H. R. Barton J. E. T. Corrie P. J. Marshall and D. A. Widdowson Bio-org. Chem. 1973,2 363. 24 M. Fryber A. C. Oehlschlager and A. M. Unrau J. Amer. Chem. Soc. 1973,95 5747. 25 W. L. F. Armarego L. J. Goad and T. W. Goodwin Phyrochemistry 1973 12 2181. ” Y. Tomita and A. Uomori J.C.S. Perkin I 1973 2656. ’’ K. T. Suzuki S. Okada H. Niwa M. Toda Y. Hirata and S. Yamamura Tetrahedron Letters 1973 799. 28 H. Niwa Y. Hirata K. T. Suzuki and S. Yamamura Tetrahedrorr Letters 1973 2129. 608 E. McDonald & &co2H -N Me (47) teijsrnanii,and this suggests that four molecules of MVA have been incorporated. The alkaloid is presumably a degraded relative of daphniphylline (49 and a possible biosynthetic pathway is outlined in Scheme 1.Scheme I 5 Polyketides More detailst9 of the biosynthesis of the highly unsaturated fatty acids found in the Cornpositae have appeared one example*'" being the conversion (3%) by Anthernis austriaca of synthetic (49) into pyrone (50). 29 (a) F. Bohlmann and P.-D. Hopf Chem. Ber. 1973 106 3772; (6) F. Bohlmann and D. Weber ibid. p. 3020. Biosynthesis 609 Samples of [l-"C]-and [2-' 3C]-acetate have been incorporated into several metabolites and the labelling patterns deduced by '3C n.m.r. are summarized in the accompanying formulae (51)-(58). The carbon skeleton of nigrifactin (51) is formed3' entirely from acetate by Streptomyces nigrifaciens whereas several related compounds in plants are derived from lysine and acetate.2 G3C0 *aH fiO a 15 11 a (51) 0 (52) (58) A notable feature observed3' in the 13C n.m.r. spectrum of avenaciolide (52) was the 75 Hz '3C(1 lk' 3C(15) coupling which demonstrates clearly a deviation from the alternating pattern of enrichment in the remainder of the molecule. The 30 T. Terashima E. Idaka Y. Kishi andT. Goto J.C.S. Chem. Comm. 1973 75. 31 M. Tanabe T. Hamasaki Y. Suzuki and L. F. Johnson J.C.S. Chem. Comm. 1973 212. 610 E. McDonald authors conclude that the three-carbon unit is formed from acetate via succinate. The absence of I3C-enrichment in the three-carbon unit [C(l) C(2) C(21)] of thermozymocidin (53) and the incorporati~n~~ of [I4C]serine together reveal the nature of its biosynthesis. In addition to the ['3C]acetate incorporations [14C]-(54) is in~orporated~~ very well (25%) by Phyllosticta into epoxydon (59,and the same hydroquinone (54) may well be involved34 in the biosynthesis of patulin (56) by Penicilliurn patulurn.Nybomycin (57) an antibiotic produced by a strain of Streptornyces incorporates four acetate units as shown and the atoms marked were labelled after feeding ['4CH3]methionine.35 The central aromatic ring is not labelled by acetate thus demonstrating that nybomycin is a compound of mixed biosynthetic origin. This is true also for the ansa antibiotics rifamycin S (58) and strepto- varicin D (59). Prelog has shown36 by feeding various radioactive propionate samples to Streptomyces rneditterranei that 23 of the 37 carbon atoms are derived from propionate.The results from feeding Nocardia rnediterranei with [' 3C]-acetate and ['3C]propionate now make it clear3' that the polyketide chain is built up in a clockwise manner since [l-13C]acetate provides enrichment at C(17) rather than C(19) in rifamycin S (58). The assignment of the I3C resonances for C(17) and C(19) has been established by specific single proton decoupling. Rinehart's group has found3' the same clockwise growth for the polyketide chain of streptovaricin D (59)in Streptornyces spectabilis. The crucial observation was "bH Oe -rut c-CH ,CH,CO,H n"Y II the enrichment of C(15) and C(19) rather than C(17) when the antibiotic was biosynthesized from [l-'3C]propionate. Ring B in these antibiotics is not of polyketide origin.32 F. Aragozzini M. G. Beretta G. S. Ricca C. Scolastico and F. W. Wehrli J.C.S. Chem. Comm. 1973 788. 33 K. Nabeta A. Ichihara and S. Sakamura J.C.S. Chem. Comm. 1973 814. 34 A. I. Scott L. Zamir G. T. Phillips and M. Yalpani Bio-org. Chem. 1973 2 124. 35 W. M. J. Knoll R. J. Huxtable and K. L. Rinehart jun. J. Amer. Chem. Sac. 1973 95 2703. 36 M. Brufain D. Kluepfel G. C. Lancini J. Leitich A. S. Mesentsev V. Prelog F. P. Schmook and P. Sensi Helv. Chim. Acra 1973 56 2315. 37 R. J. White E. Martinelli G. G. Gallo G. Lancini and P. Beynon. Nature 1973 243 273. 38 B. Milavetz K. Kakimuna K. L. Rinehart jun. J. P. Rolls and W. J. Haak. J. Amer. Chem. Soc. 1973,9S 5793. Biosynthesis 61 1 The final 13C biosynthetic experiment in this section is rather different.[1,2-13C,]Acetate was converted3' by Mollisia caesia into mollisin (60). In the 3C n.m.r. spectrum of the enriched mollisin (60)the resonances assigned to C(3) C(6) C(12) and C(14) appeared as doublets (J = 45 52 61 and 47 Hz respec-tively) whereas that for C(11) was a clean singlet. The remaining carbon reson- ances could not be observed because they have long relaxation times. c1 ,\,.-J F''.0 go 0 P'...(.../ 00 (60) (604 The high enrichment of the precursor (90% at each carbon so that 81 % of acetate molecules have two ad.jacent 3C atoms) together with the dilution of the precursor with endogenous ['2C,Jacetate has ensured that only the carbon atoms of C units which have remained intact throughout the biosynthesis will appear as doublets a singlet methyl reveals a site at which decarboxylation has occurred.So on the 13C assignments made by the authors C(12) and C(14) represent the methyl ends of two separate chains while C( 11) is the degraded end of the chain. The illustrated arrangement (60a) of two acetate chains then accounts for the results and requires that C(1) should be a singlet. The use of Cr(acac) might reveal the fully substituted carbon resonances and allow this point to be checked. [There are alternative schemes in which C(8) or C(l0) but not C(l) would appear as singlets]. 6 Shikimate Metabolites In Mycobacterium phlei [7-14C]shikimate (61) was incorporated4' into mena- quinone (62) and a subtle degradation gave the quinoxalines (63) (radioactive) and (64) (inactive) proving that the I4C was located specifically at C(4).Clearly any naphthoquinone precursors of menaquinone have to be unsymmetrically substituted. ~-[6-'~C]Shikimic acid was in~orporated~~ very efficiently (36 %) by Pseudomonas aureofaciens into phenazine-1 -carboxylic acid (65). Oxidative degradation served only to restrict the label to four possible sites leaving a num- ber of possibilities for the biosynthesis. '3C-Techniques would surely help to solve this problem. The labelling pattern found42 in chloramphenicol (66) after '' H. Seto L. W. Cary and M. Tanabe J.C.S. Chem. Comm. 1973 867. 40 R. M. Baldwin C. D. Snyder and H. Rapoport J. Amer. Chem. Soc. 1973,95 276. 41 K. Hollstein and D.A. McCamey J. Org. Chem. 1973. 38 3415. 42 W. P. O'Neill R. F. Nystrom K. L. Rinehart jun. and D. Gottlieb Biochemisiry 1973,12,4775. 612 E. McDonald OH 0 N0 feeding [6-4C]glucose to Streptomyces venezuelae suggests that the glucose is first converted into [2,6-'4C,]shikimate and thence into triply labelled prephenate (67). C02H C02H The radioactive oxime (68)can be isolated43 from Sorghum vulgare after feeding [U-'4C]tyrosine. Further the oxime is converted in high yield (44%)into the cyanogenic glucoside dhurrin (69). Since p-hydroxyphenylacetonitrileis 6-7 times less effective as a precursor of dhurrin it is concluded that hydroxylation occurs at the oxime stage. Using tyrosine stereospecifically tritiated at C(3),it has been shown44 that the biosynthesis of mycelianamide (70) in Penicilliurn 43 K.J. F. Farnden M. A. Rosen and D. R. Liljegren Phytochemistry 1973 12 2673. 44 G. W. Kirby and S. Narayanaswami J.C.S. Chem. Comm. 1973 322. Biosynthesis 613 griseojiilvum involves loss of the 3-pro-S-hydrogen from the (2S)-amino-acid a formal cis-dehydrogenation. OGlucose 0 0 (70) Stereospecifically deuteriated tyramine (71) was converted45 by Williaanornala into tyrosol (72) whose stereochemistry was established by comparison with a sample synthesized by deuterioboration of the monodeuteriostyrene (73). Clearly BzO the transformation involves subsequent oxidation-reduction at C(l) and the reductive step (perhaps catalysed by an alcohol dehydrogenase) is stereospecific.The oxidative step was next studied by measuring the tritium retention in tyrosol formed from various tyramine derivatives randomly tritiated at C(1). In each case a high (70-96 %) retention of tritium was observed and this result is inter-preted to mean that the oxidative step (monoamine oxidase) is non-stereospecific which seems rather unlikely. When [4-3H]phenylalanine is hydroxylated to tyrosine (in this case by Pseudo-monas) appreciable amounts of 3H are retained having migrated to the adjacent 45 C. Fuganti D. Ghiringhelli P. Grasselli and A. Santopietro-Amisano,J.C.S. Chem. Comm. 1973 862. 614 E. McDonald ring position (so-called NIH shift). In principle the isotope effect k,/kT (or kJkD) can be calculated from the percentage retention of 3H(or 2H) at completion of the reaction but in practice the calculation is very sensitive to error.It is now reported46 that (74) is converted into tyrosine with 74% retention of 3H. This D (74) corresponds to a value of kD/b= 2.8 k0.1 and from this k,/k can be calculated as 10 & I. The value is so close to that observed in studies of purely chemical enolization reactions that it is apparent that the final step of the NIH shift mechanism (75) -P (76) is not under enzymatic control. 7 Aliphatic Amino-acid Metabolism Miscellaneous.-Proline serine alanine and methionine each labelled with I3C were incorporated4' into prodigiosin (77) by Serratia marescens. All the remaining carbon atoms come from acetate as discussed in the 1971 Annual Report [where incidentally formula (82) is in error].Q H 4c W. R. Bowman W. R. Gretton and G. W. Kirby J.C.S. Perkin I 1973,218. 47 H. H. Wasserman R. J. Sykes P. Peverada C. K. Shaw R. J. Cushley and S. R. Lipsky J. Amer. Chem. SOC.,1973,95 6874. Biosynthesis 615 Va1ine.-Valine (78) has a prochiral centre at C(3) and during the year not less than four syntheses have appeared of valine derivatives having a true chiral centre at C(3)by virtue of isotopic substitution in one of the methyl substituents. In three of the syntheses the key intermediates have only one chiral centre which has been elaborated from an optically pure starting material. The labelled cyclopropanecarboxylic acid (79) was prepared48 from the corresponding Grignard reagent and 3C0, and was resolved by fractional crystallization of the diastereoisomeric quinine salts.The key intermediate (80)was then prepared as shown. several MeO,C&H phQ. steps ‘50,H p 3 Optically active isopropyl alcohol has been prepared earlier and a clean sN2 displacement on the benzenesulphonate gave4’ the required ester (81). Optically C0,Et active epoxymethacrylate (82) was opened cleanly in an sN2 displacement by methyl-lithium and gaves0 the diol(83). Possible racemization by enolization of the aldehyde (84) was avoided by converting it directly into the Strecker a-amino-nitrile. CD,LI CH3 OH H CH ’ &t-H -* YL.CHO H C02H H CH,OH CD3 CH20H CD3 48 J. E. Baldwin J.Loliger W. Rastetter N. Neuss L. L. Huckstep and N. De la Higuera J. Amer. Chem. SOC.,1973,95,3796. 49 R. K. Hill S. Yan and S. M. Arfin J. Amer. Chem. SOC.,1973,95,7857. D.J. Aberhart and L. J. Lin J. Amer. Chem. SOC.,1973,95,7859. 616 E. McDonald In the fourth synthesis (Scheme 2) both chiral centres of valine are set up5' in optically pure form by the action of the enzyme /?-methylaspartase on acid (85). C0,Me ox::;; LiCuGe 1 Ill I C0,Me /*eps enzyme H3?fC02H -H3?fCH2D H3Y02H H0,C ' H2N CO2H H2N A CO2H H (85) Scheme 2 Deuterium may be introduced during reduction of the carboxy-group to afford the (3-R)-valine derivative while 3C-labelled (3-S)-valine may be prepared from ['3C]methyl iodide by the route illustrated.The chiral valines (86) have been used by two group^^'*^^ to investigate the biosynthesis of penicillin (87) and cephalosporin (88) in Cephdosporiurn acre-rnoniurn. Their valine precursors were fortuitously enantiomeric at C(3) and the results were therefore complementary as illustrated. So in the overall conversion of valine into penicillin sulphur is introduced with retention of configuration,* 0 II RCNH H 0 3, yJ-2 C02H (87) 0 Rgp>&o*c C02H (88) H. Kluender C. H. Bradley C. J. Sih P. Fawcett and E. P.Abraham J. Amer. Chem. SOC.,1973 95 6149. '' N. Neuss C. H. Nash J. E. Baldwin P. A. Lemke and J. B. Grutzner J. Amr . Chem. SOC.,1973 95 3797. * The assignment of the appropriate 13C resonances to the a-and 8-methyl groups is ultimately based on the difference between the NOE's of H(3) observed during irradiation of the r-and fi-methyl 'Hresonances.Biosynthesis 617 while the biosynthesis of cephalosporin involves a formal cis-dehydrogenation of L-valine. The biosynthesis of valine proceeds from dihydroxyisovaleric acid (89) and the diastereotopic methyl groups of (89) have been distinguished4' by the OH OH H,C>-\-H CDj CO2H CH H (3R) CD,-CrC-CO,R L'CuMez P CD3 COlR cD3y-{ OH CO,H(3s) (89) synthesis of deuteriated derivatives as shown. Each compound was incubated with the specific dehydrase-transaminase system from E. coli and gave a sample of valine chirally substituted at C(3). These could be distinguished by 'H n.m.r.spectroscopy and their stereochemistry was assigned by comparison with the synthetic specimens described above showing that the replacement of OH by H at C(3)happened with overall retention of configuration and that the proto- nation of enol(90) was a stereospecific reaction. Me \_pH Me C02H Lysine.-Quite frequently racemic labelled compounds are used for biosynthetic studies and the results can be readily interpreted because one enantiomer is completely rejected by the enzyme system in question. Thus (3R)-MVA has never been found to be utilized for terpenoid biosynthesis. With a-amino-acids it is more difficult to ascertain that only one enantiomer is being used because the configuration may be inverted via the corresponding keto-acid. An elegant method has now been described53 for determining which enantiomer is meta-bolized even during studies in intact plants.The resolved [3H]-precursor should be fed mixed with racemic [''C]-precursor the technique is best under- stood by considering one of the examples rep~rted.~ ~-[4,5-~H,]Lysinewas mixed with ~L-[6-'~C]lysine to give (91) with a 3H/'4C ratio of 6.8. Any products formed entirely from L-lysine should therefore have a 3H/'4C ratio of 13.6 whereas those formed only from D-lysine will carry only I4C radioactivity. Clearly the tritium label must not be located at the chiral centre and it must 53 E. Leistner R. N. Gupta and I. D. Spenser J. Amer. Chem. Soc. 1973 95 4040. 618 E. McDonald first be established that the 3H/'4C ratio remains unchanged after feeding DL material.Using the technique it seems that pipecolic acid (92) is formed only from D-lySine in three different plants whereas in the same three plants other alkaloids are formed exclusively from L-lysine. T C02H NH2 NH Another interesting feature of lysine metabolism is that C(2) and C(6)do not become equivalent during the bioconversion into sedamine (93) yet the sym- metrical molecule cadaverine (94) acts as a precursor for sedamine is present in ,n NH NH the plant and is biosynthesized from lysine in the plant. The authors conclude54 on the basis of these facts and the non-incorporation of alternative precursors that cadaverine is a normal intermediate but that it maintains the distinction between C(2)and C(5)by staying bound to the enzyme (cf.the randomization of squalene during fusidic acid biosynthesis). An enantiomeric pair of stereospecifically labelled [1 -3H]cadaverine (94) molecules was prepared from lysine (91) by the decarboxylase from Bacillus cadaveris. Each was then mixed with [l-14C]cadaverine and fed to Sedurn sarrnentosurn. The N-methylpelletierine (95) from sample A had retained all its s4 E. Leistner and I. D. Spenser J. Amer. Chem. Soc. 1973 95 4715. Biosynthesis 619 tritium while that from sample B had lost one half. These results show that conversion of cadaverine into N-methylpelletierine involves stereospecific enzymatic oxidation at C(l)[C(6)]. Also by comparison with the results obtained from lysine feedings it appears that the lysine decarboxylases of B.cadaveris and of S. sarrnentosurn are of opposite stereospecificity. 6-Aminolaevulinic Acid.-The review lecture55 by Neuberger provides a brief background to many of the following topics. 6-ALA synthetase operates on succinyl-coenzyme A and glycine as substrates. Glycine randomly tritiated at C(2) and both enantiomers of [2-3H]glycine have now been incubated’ with 600-fold purified enzyme from Rhodopseudo- rnonas spheroides and the results clearly show that the 2-pro-R-hydrogen of glycine is lost during the formation of 6-ALA (96). The enzyme is known to pyridoxal (96) require pyridoxal phosphate as cofactor and is deactivated by sodium boro- hydride only in the presence ofsubstrate. It seems reasonable therefore to consider the enzymatic mechanism illustrated.The nature of the intermediates in the biosynthesis of uroporphyrinogen I11 (97)from four molecules of PBG (98) is still uncertain. All four pyrromethanes (99),(loo),(101) and (102) have been ~ynthesized,’.’’,~~ and the chemical studies reported by two independent group^^',^' are in agreement in showing some surprising differences in the behaviour of isomers. Both groups also report enzymatic studies but in different biological systems and no clear conclusion can yet be drawn concerning the possible intermediacy of the pyrromethanes. In contrast the nature of the rearrangement which results in the ‘reverse’ substitu- tion pattern in ring D of the natural macrocycles is now quite clear the carbon skeletons of three PBG molecules remain intact and provide rings A B and c and the 6- a- and P-meso-carbons respectively.A fourth PBG molecule suffers a 55 R. C. Davies A. Gorchen A. Neuberger J. D. Sandy and G. H. Tait Nature 1973 245 15. 56 T. Zaman P. M. Jordan and M. Akhtar Biochem. J. 1973 135 257. ” A. R. Battersby D. A. Evans K. H. Gibson E. McDonald and L. Nixon J.C.S. Perkin I 1973 1546. ’* A. R. Battersby J. F. Beck and E. McDonald J.C.S. Perkin I 1974 160. ’’ R. B. Frydman A. Valasinas and B. Frydman Biochemistry 1973 12 80. ‘O A. R. Battersby K. H. Gibson E. McDonald L. N. Mander J. Moron and L. Nixon J.C.S. Chem. Comm. 1973 768. 620 E. McDonald rearrangement intramolecular with respect to itself and provides ring D and the y-meso-carbon.AP (97) A = CH2C02H P = CH2CH2C02H R' R2 R3 R4 R' R2 R3 R4 (99) A (100) A P P A P P A (101) P A A P (102) P A P A A = CH2C02H P = CH2CH2C02H This situation was revealed61 by using diluted doubly 13C-labelled PBG. [5-' 3C]6-ALA (90% enrichment) (96) was synthesized from sodium [13C]-cyanide by a new route,62 and then converted into PBG (103)by the dehydratase from ox liver. 81% of the molecules actually* carry two 13C atoms and the 3Cn.m.r. spectrum revealed a long-range 13C-13Ccoupling of -4 Hz. The doubly labelled material was diluted four-fold with PBG of natural abundance and incubated with an enzyme system- from chicken blood. The (103) A = CH2CO2H; P = CH2CH2C02H A. R. Battersby E. Hunt and E.McDonald J.C.S. Chem. Comm. 1973 442. 62 A. R. Battersby E. Hunt E. McDonald and J. Moron J.C.S. Perkin I 1973 2917. * The reader should appreciate that structures drawn elsewhere e.g. (30) as multiply labelled molecules are in fact assemblies of singly labelled molecules and unlabelled molecules. Biosynthesis 621 3Cn.m.r. spectrum of the dimethyl ester of the isolated protoporphyrin-IX (104) had three doublets (J = 5 Hz) corresponding to the a- p- and &carbon atoms and one doublet (J = 72 Hz) corresponding to the y-carbon atom. Manipulation C0,Me C0,Me I C0,Me CO,Me I + C0,Me C0,Me C0,Me C0,Me of the spectrum by lanthanide shift reagents and by conversion of both vinyl side-chains into acetyl groups served to increase the separation of the carbon resonances which were unambiguously assigned63 by the total synthesis of protoporphyrin-IX specifically 3C-labelled at the p- y- and 6-meso-carbon atoms respectively.At least 19 proposals have been published concerning the mechanism of the rearrangement but the vast majority are inconsistent with the facts just described. The timing of the rearrangement remains to be ascertained and the pyrromethane results described above demonstrate that future experiments will need to be very carefully designed. Neuberger reports64 that the ‘intermediates’ which accumulate when por- phyrin macrocycle biosynthesis is inhibited by ammonia hydroxylamine and methoxylamine actually incorporates these inhibitor molecules into their structures.They appear to be ‘Type I’ tetrapyrroles (105) and each cyclizes 63 A. R. Battersby G. L. Hodgson M. Ihara E. McDonald and J. Saunders J.C.S. Perkin I 1973 2923. ‘‘ R. C. Davies and A. Neuberger Biochem. J. 1973,133,471. 622 E. McDonald chemically to uroporphyrinogen I releasing the appropriate RNH molecule. The significance of these findings for uroporphyrinogen 111 biosynthesis is rather uncertain. AP AP AP AP (105) A = CH2C02H; P = CH2CH2C02H Three independent research teams have obtained ' 3C-enriched vitamin B (106) after feeding [ ''Clrnethionine to Propionibacterium shermanii. All three teams agree that the same seven carbon resonances in the vitamin show enrich- ment and that these resonances are due to seven of the eight methyl groups in (106) A = CH2C02H; P = CH2CH2C02H vitamin B12.The methyl group which is not enriched is one of those at C(12) but there is some confusion about the distinction between the 12a- and 12B-methyl resonances. The Cambridge group6' degraded their corrin to the imide (107) whose optical activity demonstrates that the stereochemistry at C( 13) remains unaltered. P (107) P = CH2CHzCOzH In the 'H n.m.r. spectrum of this imide in both CDC1 and C6D6 the high-field CH resonance was diminished in intensity and had 13C satellite signals [J('H-13C) = 128 Hz]. The high-field signal has been unambiguously assigned to the a-methyl group by Eschenmoser through the synthetic reactions (108) -P (109) (Scheme 3). The other two groups of workers based their conclusions on 65 A.R. Battersby M. Ihara E. McDonald J. R. Stephenson and B. T. Golding J.C.S. Chem. Comm. 1973,404. Biosynthesis 623 the chemical-shift values of the enriched signals in the corrin spectrum. Scott argues66 that the methyl groups at C(2) C(7) C(12a) and C(17) are all in similar environments and should have similar chemical shifts owing to the y-effect of P = CH2CH2CO2H Reagent i K0Bu'-ButOD; ii (R,P),RhCI; iii 0 Scheme 3 the syn propionate side-chain while that at C(12B) should be shifted downfield. Good support for this analysis was obtained by inspection of the 13Cn.m.r. spectra of the enriched corrin after epimerisation at C( 13) when one of the enriched signals [presumably C12a))I moved downfield by -12 p.p.m.Shemin and Katz have reached the opposite concl~sion.~~ They have by careful single-frequency 'H-decoupling correlated each of the enriched '3C resonances with the corresponding 'H resonance and then based their assignment on 'H n.m.r. assignments including those of Brodie and Poe.68 Unfortunately these 'H assignments appear to the reviewer to be uncertain in respect of the crucial methyl signals. The reviewer has attempted to set out clearly the experimental evidence and he must declare his interest of being involved in the Cambridge effort before suggesting that the 'H n.m.r. assignments have probably led Shemin and Katz to the wrong conclusion. If so then it is the C(12a)methyl resonance which is derived from methionine and a consistent pattern of formal trans-addition of CH3-H can be seen in all four pyrrole rings of vitamin B, .bb A. I. Scott C. A. Townsend E. Lee and R. J. Cushley J. Amer. Chem. SOC. 1973,95 5159. 67 C. E. Brown D. Shemin and J. J. Katz J. Biol. Chem. 1973 248 8015. 60 J. D. Brodie and M. Poe Biochemistry 1971 10 914.

ISSN:0069-3030    

DOI:10.1039/OC9737000597

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

20 Nucleic Acids By R. T. WALKER Department of Chemistry Birmingham University Birmingham B 15 2TT For the first time for many years there has been no significant change in the num- ber of papers published in 1973 when compared with the previous year' and this is no doubt a result of the cut-back in basic research. This year three main subjects can be singled out for special mention re- striction repression and X-ray crystallography. The first two subjects will be dealt with later and the advance in X-ray crystallography this year is due almost entirely to Rich and his co-workers.2-8 Several papers by this team on the struc- ture of tRNA have appeared almost in the reverse order to that in which they were written because as the results got more exciting so the speed of publication was increased.The polymorphic nature of yeast tRNAPhe was made apparent when it was found to crystallize in five different crystal systems involving eight different space groups.2 The orthorhombic form was found to occur in two forms ;3 they had identical unit cell dimensions in two directions but the distances in the third direction differed by 35%. The longer form changed to the shorter when the crystal was dried and this suggested that the tRNA molecules could slide together along the c-axis without a substantial change in internal structure. The breakthrough came when isomorphous heavy-atom derivatives were obtained for these orthorhombic crystal^.^ The data obtained at 5.5 8 resolution resulted in a model for tRNA which was quickly proved by the data at 4%1to be in~orrect.~ The model predicted from the 5.5 %1 data was a long thin molecule but it was not possible to trace unambiguously the phosphate backbone and 1 'Nucleic Acids Abstracts' ed.E. S. Krudy and A. Williamson Information Retrieval Ltd. London 1973. 2 S. H. Kim G. Quigley F. L. Suddath A. McPherson D. Sneden J. J. Kim J. Weinzierl and A. Rich J. Mol. Biol. 1973 75,421. 3 S. H. Kim G. Quigley F. L. Suddath A. McPherson D. Sneden J. J. Kim J. Weinzierl and A. Rich J. Mol. Biol. 1973 75,429. 4 S. H. Kim G. Quigley F. L. Suddath A. McPherson D. Sneden J. J. Kim J. Weinzierl P. Blattmann and A. Rich Proc. Nar. Acad. Sci. U.S.A. 1973 69 3746. 5 S. H. Kim G. J. Quigley F. L. Suddath A. McPherson D. Sneden J.J. Kim J. Weinzierl and A. Rich Science 1973 179 285. 6 S. H. Kim H. M. Berman N. C. Seeman and M. D. Newton Acra Crysr. 1973 B29 703. 7 J. M. Rosenberg N. C. Seeman J. J. P. Kim F. L. Suddath H. B. Nicholas and A. Rich Nature 1973 243 150. 8 R. 0.Day N. C. Seeman J. M. Rosenberg and A. Rich Proc. Nut. Acad. Sci. U.S.A. 1973 70,849. 624 Nucleic Acids 625 with hindsight it can be seen that at one point the chains of two adjacent mole- cules were muddled. The 4A map gave what is now widely accepted to be the correct structure for this tRNA which is in the form ofan 'L'.' The result obtained by interpreting the data collected at 3%1resolution is now eagerly awaited as this should enable the position of the bases to be determined so that those bases capable of forming hydrogen bonds can be identified.Many other .people are working on the structure of this and other tRNAs and it will be interesting to see whether these results are confirmed and whether other tRNAs have similar structures because already there are signs of disagreement.' The work on the structure of dinucleoside phosphates is probably of as great a fundamental importance as the determination of tRNA structures. The seven basic conformations for these molecules are described6 and in particular adeno- sinyl-3',5'-uridine phosphate (APU)~ and guanylyl-3',5'-cytidine phosphate (GpC)* both crystallize to give right-handed antiparallel double helices in which the ribose phosphate backbones are held together by Watson-Crick hydrogen- bonding between the base residues.The resolution could be obtained at 0.84.98 and thus the atomic details of structures likely to be very similar to those of double-helical nucleic acids are now available. The unit cell of ApU contains 26 water molecules and GpC contains 36. When they have all been accurately located it should be possible to understand how hydrophobic forces lead to a stabilization of nucleic acid double helices. There is one sodium ion per ApU molecule and the two ions in each asymmetric unit occupy distinct sites. One is as expected between phosphate groups but the other lies in the minor groove of the helix and has octahedral co-ordination to two uracil oxygen atoms and to water molecules. In GpC each phosphate group is associated with two sodium ions each of which has octahedral co-ordination to additional water molecules.To complete a successful year Rich and his colleagues have reported pre- liminary X-ray analysis data from the crystalline complex formed between polypeptide elongation factor Tu and GDP." Large crystals have been obtained using the same method as was used to crystallize tRNA. The complex of phenyl- alanyl-tRNAPhe elongation factor Tu and GTP has also been crystallized,' but the crystals were too small for X-ray crystallographic analysis. To set the record straight the results reported last year," that guanine and cytosine contain appreciable quantities of minor tautomers have been shown to be incorrect and it has been suggested that the presence of paramagnetic impu- rities in the solutions led to the misinterpretation of the n.m.r.spectra.13 Inter- calation of ethidium bromide into DNA is claimed to cause the DNA helix to unwind not wind.I4 To prove a point made last year neither of the sequences of M. Levitt J. Mol. Biol. 1973 80 255. lo D. Sneden D. L. Miller S. H. Kim and A. Rich Nature 1973 241 530. I' K. Arai M. Kawakita S. Nishimura and Y. Kaziro Biochim. Biophys. Acra 1973 324,440. '*G. C. Y. Lee J. H. Prestegard and S. I. Chan J. Amer. Chem. SOC.,1972 94 951; G. C. Y. Lee and S. 1. Chan ibid. p. 321 8. l3 Y. P. Wong K. L. Wong and D. R. Kearns Biochem. Biophys. Res. Comm. 1972 49 1580; Y. P. Wong J. Amer. Chem. SOC.,1973,95 3511. l4 W. J. Pigram W. Fuller and M. E. Davies J. Mol.Biol. 1973 80 361. 626 R. T. Walker the 'renaturable' yeast tRNAL'" independently determined by two laboratories' was correct and a third version has now appeared.'6 The chromosomal location of human repetitive satellite DNA continues,' ' but work claiming to have located the structural genes for haemoglobin" has been seriously q~estioned,'~ as calculations from the specific activity of the mRNA used and the known number of cistrons for these genes per genome show that the hybrid molecules could not have been detected under the conditions used. The same group also claims to have detected regions in human metaphase chromosomes exhibiting complementarity with labelled RNA isolated from RD 114 virus'O-the virus announced in a blaze of publicity at a news conference as the prime candidate for the human cancer virus.*' Unfortunately seven papers which were published simultaneously by a total of no fewer than 22 people,22 came to the unanimous conclusion that RD 114 virus is of feline origin.It has also been pointed out2' that all this similar work was funded by the National Cancer Institute and that it would be interesting to know how much money has been wasted on this viral equivalent of a 'wild goose chase'. Viruses are however continuing to be found in association with tumour cells and other oncogenic cell lines. Rauscher leukaemia virus (RLV) RNA has been found associated with Burkitts lymphomas and nasopharyngeal carcinoma^.^^ The DNA-containing Epstein-Barr virus (EBV) has also been found associated with both these neopla~ia.~~*~~ In particular the RLV RNA is a 70s RNA25 and is associated with an RNA-instructed DNA polymerase in a particle having the density of an RNA tumour virus.However the genetic information contained in the RNA of the particle still has to be found in the DNA of the tumour cells and the aetiological role of EBV or RLV in the pathogenesis of Burkitts disease cannot be assumed. Hybridization studies have failed to show the presence of virus-related sequences in normal human cells which could be detected in human leukaemic cells.26 These experiments do not support the virogene-oncogene theory which postulates the inclusion of at least one complete copy of oncogenic information in the genomes of every normal cell and thus more Is S.Kowalski T. Yamane and J. R. Fresco Science 1971 172 385; S. H. Chang N. R. Miller and C. W. Harmon F.E.B.S. Letters 1971 17 265. l6 S. H. Chang S. Kuo E. Hawkins and N. R. Miller Biochem. Biophys. Res. Comm. 1973 51 951. K. W. Jones J. Prosser G. Corneo and E. Ginelli Chromosoma 1973 42 445. P. M. Price J. H. Conover and K. Hirschhorn Nature 1972 237 340. l9 J. 0.Bishop and K. W. Jones Nature 1972,240 149; W. Prensky and G. Holmquist Nature 1973 241. 44. 2o P. M. Price. K. Hirschhorn N. Gabelman and S. Waxman Proc. Nut. Acad. Sci. U.S.A. 1973,70 11. See Nature 1973 244 252. 22 See Nature New Biol. 1973 244 51-64; R. M. Ruprecht N. C. Goodman and S. Spiegelman Proc. Nut. Acad. Sci. U.S.A. 1973.70 1437. 23 D. Kufe R.Hehlmann and S. Spiegelman Proc. Nut. Acad. Sci. U.S.A. 1973 70 5. ?* H. Wolf H. zur Hausen and V. Becker Nature New Biol. 1973 244 245. 25 D. Kufe I. T. Magrath J. L. Ziegler and S. Spiegelman Proc. Nat. Acad. Sci. U.S.A. 1973 70 737. 26 W. G. Baxt and S. Spiegelman Proc. Nut. Acad. Sci. U.S.A. 1972 69 3737. iVucleic Acids 627 hopeful pathways leading to the control and cure of cancer can perhaps be entertained. Among the stranger reports this year is one which finds that patients with severe organic memory defects did not improve when given tRNA (no doubt microbial in rigi in).^' However a diet of DNA and ATP provides radioprotection (and gout?) for radiologists.28 The team working on the DNA content of the blood of a live coelacanth had little danger of being pre-empted2’ and finally there is a report that one team has been using its money to induce the production of monster ‘lollipops’ from T-even phages,30 no doubt as their contribution to the world protein shortage! 1 Bases Nucleosides and Nucleotides Treatment of thymine and uracil with trialkyl phosphates in molar proportions has been found to give high yields of the N-l-alkylated base.31 An excess of the phosphate results in the production of 1,3-dialkyl derivatives although the reac- tion rate decreases as the length of the alkyl chain increases.An improved pro- cedure for the synthesis of 9-alkyladenines has been reported.32 5-Vinyluracil has been prepared by no fewer than four different methods the first of which involves the decarboxylation of trans-3-(5-uracilyl)propenoicacid33 (l) but the overall yield is low (<20%).Base-catalysed elimination of esters of 5-(2-hydroxyethyl)uracil(2) failed3 as the substitution reaction was preferred. Attempts to dehydrate the alcohol under acidic conditions led to an intramol- ecular displacement reaction and the formation of the bicyclic compound (3). In asecondmethod ofpreparation,5-( l-hydroxyethyl)uraci1(4)can bedeh~drated~~ under acidic conditions to give 5-vinyluracil but the yield is low owing to the competing reaction resulting in the production of trans-1,3-bis(uracil-5-yl)but-l-ene (5). 5-Vinyluracil can also be prepared by the base-catalysed elimination of the methanesulphonyl ester of (4) in -80% yield,35 and a method involving ” A.Britton L. L. Bernstein A. J. Brunse M. W. Buttiglieri A. Cherkin J. H. McCor-mack and D. J. Lewis J. Geronroi. 1972,27 478. V. Goyanes-Villaescursa Lancet 1973 2 575. 29 K. S. Thomson J. G. Gall and L. W. Coggins Nature 1973 241 126. 30 D. J. Cummings V. A. Chapman S. S. Delong and N. L. Couse Virology 1973 54 245. 3’ K. Yamauchi and M. Kinoshita J.C.S. Perkin I 1973 391. 32 T. Fujii S. Sakurai and T. Uematsu Chem. and Pharm. Buil. (Japan) 1972 20 1334. 33 J. D. Fissekis and F. Sweet J. Org. Chem. 1973. 38 264. ” C. H. Evans A. S. Jones and R. T. Walker Tetrahedron 1973 29 161 1. 35 A. S. Jones G. P. Stephenson and R. T. Walker Nucieic Acids Res. 1974 1 105. 628 R.T. Walker synthesis of the pyrimidine ring36 has the sole merit that the starting materials are cheap as the yield is <10%.5-Vinyluracil has been incorporated into the DNA of a thymine-requiring mutant of Escherichia ~oli.~~ 5-Lithiouracil has been used as an intermediate in the preparation of several 5-alkylated uracil~.~~ Thiols particularly 2-mercaptoethanol and cy~teine,~~ dehalogenate 5-iodo- and 5-bromo-uracil under physiological conditions to give uracil while 5-bromo- 2’-deoxyuridine has been found to give 2’-deoxyuridine and s-[5-(2’-deoxyuridyl)]- cysteine (6):’ Thus 5-bromouracil may not be as stable as has previously been thought particularly when in bacterial growth media. The reaction is thought to proceed via addition of the thiol across the 5,6-double bond. 0 I 2'-Deoxyribosy l (6) A similar reaction has been used to label uracil by isotope exchange at the 5-position at a pH of 8.9 by cysteine-catalysed hydrogen-deuterium exchange.41 The reaction conditions are very mild and could be used at the nucleic acid level.The kinetics of hydrogen exchange at the 5-and 6-positions of uracil catalysed by Pt-black have been inve~tigated.~~ The 6-position of pyrimidine nucleosides can be labelled by treating them in DMSO solution with labelled base.43 In the cases where the sugar hydroxyls can easily participate in the saturation of the 5,6-double bond quantitative incorporation of the label at C-5 can also be obtained. The mechanism of H-6 exchange is thought to involve the direct 36 J. D. Fissekis and F. Sweet J. Org.Chem. 1973 38 1963. 37 E. T. J. Chelton C. H. Evans A. S. Jones and R. T. Walker Biochim. Biophys. Acta 1973 312 8. 38 D. M. Mulvey R. D. Babson S. Zawoiski and M. A. Ryder J. Heterocyclic Chem. 1973 10 79. 39 F. A. Sedor and E. G. Sander Biochem. Biophys. Res. Comm. 1973,50 328. 40 Y. Wataya and H. Hayatsu Biochemistry 1973 12 3992. 41 Y. Wataya H. Hayatsu and Y. Kawazoe. J. Biochem. 1973. 73 871. 42 T. Ido M. Tatara and Y. Kasida Internat. J. Appl. Radiation Isotopes 1973 24 81. 43 J. A. Rabi and J. J. Fox J. Amer. Chem. Sor. 1973 95 1628. Nucleic Acids 629 abstraction of H-6 by base. The reactions of thymine irradiated in aqueous solution in the presence of cy~teine,~~ and the photoaddition reactions of nucleo- philes to uracil have been studied.45 The photoaddition of bisulphite under these conditions takes place at much lower concentrations (lo-' moll-') of bisulphite than is required for the thermal addition and the addition is sterochemically random.The major product of y-irradiation of thymine in aerated aqueous solution is cis-5-hydroxy-6-hydroperoxy-5,6-dihydrothymine (7).46 Apart from the ionic reactions of bisulphite which take place more readily at high bisulphite concentrations (usually 1-3 moll-') bisulphite also reacts under free-radical conditions at concentrations of 10-* moll-'. These reactions require the presence of oxygen and are accompanied by the oxidation of bisulphite to sulphate. Several reactions of this type have previously been reported and it has now been used to convert 2-thiouracil into uracil in 60% yield.47 The bisulphite- oxygen system also results in the rapid cleavage of the glycosidic bond in uridine cytidine and their homopolynucleotides (with concomitant chain scission for the latter).48 The fate of the sugar moiety is unknown but it can be argued from the substrate specificity of the reaction that the initial attack is possibly that of a free radical on the 2'-OH group.The reaction is clearly different from that of the hydrogen peroxide or the hydroxylamine-oxygen system as deoxynucleosides purine glycosides and their phosphate esters do not react. People using bi- sulphite to modify nucleic acids chemically should be aware of this type of radical reaction which can occur unless steps are taken to prevent it.The reaction of adenine derivatives with chloroacetaldehyde to give the cor- responding 'etheno'-derivatives (E) first described by Kochetkov et ~1.:~and further exploited by Leonard and co-workers as described last year,50 has ob- viously appealed to many people. The fluorescent adenine derivatives so produced (8) are potential probes of enzymatic mechanisms and structure. The energy of &-AMP fluorescence has been shown not to be highly sensitive to the environment of the molecule so that large fluorescent shifts are unlikely. However thequantum yield of fluorescence is more sensitive and is likely to fall when the analogue is 44 '' A. J. Varghese Biochemistry 1973 12 2725. W. A. Summers C. Enwall J. G. Burr and R. L. Letsinger Phorochem.and Photobiol. 1973 17 295. 46 B. S. Hahn and S. Y. Wang Biochem. Biophys. Res. Comm. 1973,54 1224. 47 M. Sono and H. Hayatsu Chem. and Pharm. Bull. (Japan) 1973 21 995. 48 N. Kitamura and H. Hayatsu Nucleic Acids Res. 1974 1 75. 49 N. K. Kochetkov V. N. Shibaev and A. A. Kost Tetrahedron Letters 1971 1993. 50 R. T. Walker Ann. Reports (B) 1972 69 534. 630 R. T. Walker bound to a macromolecule.51 The kinetic and fluorescence behaviour of E-ADP and E-ATPwith the enzyme pyruvate kinase has been studied in detail.52 The analogues substitute very well for ADP and ATP in terms of reaction rates and the binding of the analogues to the enzyme can be observed by fluorescence polarization techniques. The same analogues have been used as substrates for photophosphorylation reactionss3 and inevitably the 3’,5‘-cyclic AMP analogue has been ~repared.’~ At a more complex level E-DPN’ and &-FAD have been prepared and their physicochemical and biological properties studied.” E-Adenylated glutamine synthetase has been used as an internal fluorescence probe for enzyme confor- mati~n.’~ Chloroacetaldehyde reacts with both adenine and cytosine bases in denatured DNA so that 1.5% of these residues are modified in 5 minutes at pH 4.5 and 53 0C.57The melting point of the DNA is lowered by 1.3 “Cfor each base modified per 100 base pairs which corresponds to a 2.8 kcal destabilizing free energy per mismatched base pair.Poly(rA) when treated with chloro- acetaldehyde can give a range of degrees of substitution of &-residues in the poly- mer.’* Highly substituted polymers with more than 80% .+A residues give no indication of a co-operative transition at acid pH.However the homopoly- nucleotide poly-( 1,N6-ethanoadenylic acid) has been prepared from E-ADP and polynucleotide phosph~rylase,’~*~~ but this polymer is claimed to possess an organized secondary structure at acidic but not at neutral PH.~’ Poly-(&-A) does not complex with poly(U) or poly(1). The polymer is more resistant to hydrolysis by pancreatic RNase and snake venom phosphodiesterase than the corresponding natural polynucleotide. 51 G. R. Penzer European J. Biochem. 1973 34 297. 52 J. R. Barrio J. A. Secrist Y.-H. Chien P. J. Taylor J. L. Robinson and N.J. Leonard F.E.B.S. Letters 1973 29 215. 53 Y. Shahak D. M. Chipman and N. Shavit F.E.B.S. Letters 1973 33 293. 54 G. H. Jones D. V. K. Murthy D. Tegg R. Golling and J. G. Moffatt Biochem. Biophys. Res. Comm. 1973 53 1338. 55 C.-Y. Lee and J. Everse. Arch. Biochem. Biophys. 1973 157 83. 56 P. B. Chock C. Y. Huang R. B. Timmons and E. R. Stadtman Proc. Nat. Acad. Sci. U.S.A. I973,70 312. 57 C. H.Lee and J. G. Wetmur Biochem. Biophys. Res. Comm. 1973,50 879. 58 R. F. Steiner W. Kinnier A. Lunasin and J. Delac Biochim. Biophys. Acta 1973,294 24. 59 H.Lehrach and K. H.Scheit Biochim. Biophys. Acta 1973,308 28. 60 B. Janik R. G. Sommer M. P. Kotik D. P. Wilson and R. J. Erickson Physiof. Chem. Phys. 1973,5 27. Nucleic Acids 631 Poly-(3,N4-ethenocytidylicacid)60 has been similarly prepared and it does not complex with poly(1).Poly-(E-C) does not significantly fluoresce. Fluorescent derivatives of cytidine have been made by reaction with pyridinium and quino- linium hydrazides at pH 4.2 and 37°C.61 The fluorescence of the modified cytidines showed structure and environment dependence. Compounds (9) and (lo) by their ultraviolet absorption and fluorescence emission characteristics Ribosyi (9) R = H (10) R = Ph present favourable possibilities for energy-transfer studies with other fluorescing molecules particularly in single-stranded oligo- and poly-nucleotides and nucleic acids. p-Nitrophenol has been found to activate the fusion of an acylated sugar with a purine derivative.62 In an attempt to clarify the mechanism of acidic catalysis of the fusion reaction p-nitrophenol was added to compete with the heterocyclic base for the acylated sugar.The result was the formation of a high yield of nucleoside at a lower temperature than usual. The a-anomer of the carbohydrate moiety gave no nucleoside at all but resulted in a quantitative yield of (11). When the acidic catalyst was omitted the reaction continued as before. However the phenol exerts no catalytic effect and has to be present in molar quantities. It was deduced that for activating agents of this type the purine has to be acti- vated by polarization bonding with the activating agent. It was also concluded that in the normal fusion reaction the catalyst resulted in the activation of the purine base (12).61 J. R. Barrio and N. J. Leonard J. Amer. Chem. SOC.,1973,95 1323. 62 M. Sekiya T. Yoshino H. Tanaka and Y. Ishido Bull. Chem. SOC.Japan 1973,46 556. 632 R.T. Walker -$A? 0-C-Me The useful intermediate in nucleoside synthesis 2,3-@isopropylidene-~- ribofuranosylamine has now been isolated in high yield in a stable crystalline form as the toluene-p-sulphonate (13) and has been used in the synthesis of nucleosides such as Sacetyluridine by reaction with ethyl-N-(a-acetyl-P-ethoxyacryloy1)carbamate (14)? Both a- and P-anomers are produced but their relative amounts depend upon the solvent used and the p-anomer cafi usually be obtained in crystalline form from the reaction mixture. M I O,SC,H,Me-p c=oI EtOCH=C -NHCO,E t 0 0 (14) MeXMe The first successful functionalization of a purine 2‘-deoxynucleoside is repor- ted.64 Previous attempts had failed owing to the acid- and heat-lability of purine 2’-deoxynucleosides but it was argued that substitution of strongly electronegative groups (trifluoroacetyl) on the sugar moiety would destabilize the postulated glycosyl carbonium ion intermediate and thus retard base cleavage.2’-Deoxyino- sine when treated with trifluoroacetic anhydride followed by thionyl chloride in refluxing methylene chloride gave 6-chloropurine-2-deoxyriboside(15)in 80% yield with only 8 % cleavage to hypoxanthine. Quantitative cleavage of the giyco- sidic bond results if 3’,5’-di-O-acety1-2’-deoxyinosine is used.This compound is a useful intermediate in the preparation of 6-substituted purine deoxynucleosides several of which are useful in cancer chemotherapy. ‘’ N. J. Cusack B. J. Hildick D. H. Robinson P. W. Rugg,and G. Shaw J.C.S. Perkin I 1973 1720. 64 M. J. Robins and G. L. Basom Canad. J. Chem. 1973,51 3161. Nucleic Acids 633 C-C-Linked p-D-ribofuranosyl nucleosides have been synthesized in four steps6’ [the yields were :good excellent almost quantitative and 65 %(ascending order?)] from 2,3-O-isopropylidene-~-ribofuranose. The preparation of 5-(2’,3’-O-isopropylidene-5’-O-trityl-~-~-ribofuranosyl)barb~turic acid (16) is re-ported. The ct :p ratio of the anomeric mixture of C-glycosides can be altered 0 0WONa 2’-Deoxyribosyi (15) Me OX0Me by prolongation of the reaction time,more of the p-isomer being produced as the time increases.The mechanism is explained in terms of the thermodynamically more stable p-(‘trans’)isomer being favoured in an equilibrium situation which is possible because of an ‘active’ proton on C-5. Nucleoside phosphates can be easily synthesized by the reaction of an inter- mediate formed between phosphorous acid mercuric chloride and N-methylimi- dazole with a suitably blocked nucleoside such as 2’,3’-O-isopropylideneadeno-sine.66 Yields are between 70 and 80% for all the common nucleotides. 8-Mercaptoadenosine nucleotides can be prepared by the reaction of the corres- ponding 8-bromo-compounds with NaSH in DMF-water at room ternperat~re.~~ 7-Methylguanine can be demethylated under conditions which should be suitable for tRNA by reaction with a new powerful nucleophilic reagent lithium 2-methylpropane-2-thiolate in hexamethylphosphoramide.68 The hazards of using diethyl pyrocarbonate as an enzyme inhibitor because of its reaction with the nucleic acid bases under physiological conditions have been re-empha~ized,~~ but to read the biochemical literature one can only conclude that either biochemists are still unaware of its effects or that they don’t care or don’t believe it.An interesting series of reactions of 2-acyloxyisobutyryl halides (17) with nucleosides has belatedly been de~cribed.~’.~~ Uridine reacts with (17a) in the 65 H. Ohrui and J. J. Fox Tetrahedron Letters 1973 1951. 66 H.Takaku Y.Shimada and H. Oka Chem. and Pharm. Bull. (Japan) 1973,21 1844. ”M. Ikehara E. Ohtsuka and S. Uesugi Chem. and Pharm. Bull. (Japan) 1973,21,444. 68 S. M. Hecht and J. W. Kozarich J.C.S. Chem. Comm. 1973 387. 69 A. Vincze R.E. L. Henderson J. J. McDonald and N. J. Leonard J. Amer. Chem. SOC.,1973,95,2677; R.E. L. Henderson L. H. Kirkegaard and N. J. Leonard Biochim. Biophys. Acta 1973 294 356. ’O S. Greenberg and J. G. Moffatt J. Amer. Chem. Sac. 1973 95,4016. ” A. F. Russell S. Greenberg and J. G. Moffatt J. Amer. Chem. SOC.,1973 95 4025. 634 R. T. Walker absence of solvent to give (18a) and in acetonitrile to give (18b) both of which on treatment with sodium methoxide give 2’-chloro-2‘-deoxyuridinein high yield.7 O The reaction proceeds by a rapid intramolecular participation of the C-2 carbonyl group of the uracil ring with the initial acetoxonium ion (19) giving the proto- nated species (20) which is then opened up by chloride ion to give (21).Me \ Me /I OAc c-cox OAc C1 (17) a; X = C1 b;X = Br II I(18) a; R = C-C-Me 0 OAc ROHZ OAc CI Adenosine when treated with (17a) in acetonitrile gives (22a) which on de- blocking gives 3’-deoxy-3’-chloro-~-~-xylofuranosyladenos~ne.~~ The reaction goes via the cyclic acetoxonium ion which in the absence of participation from the base is opened by chloride ion which on steric grounds prefers attack at C-3’. Reaction of (22a) with sodium methoxide gives (23). If the acyl bromide (17b) is used in the initial reaction a similar product (22b) is formed which can be catalytically debrominated to give 2,3’-dideoxyadenosine and 3’-deoxy-adenosine (Cordycepin) each in 40% yield.Deacetylation of (22a) followed by catalytic debromination results in a high yield of 3’-deoxyadenosine only. Similar reactions have been used to produce analogues of the drugs tubercidin and formycin. 2’,3’-O-Methoxyethylideneadenosine,when heated under reflux with pivalic acid chloride in pyridine gives a mixture from which (24a) could be isolated. On treatment with sodium methoxide 2’,3’-anhydroadeno- sine (23) was formed. Hydrogenolysis of the iodo-ester (24b) gives the correspond- ing 3’-deoxyadenosine derivative and treatment of (Nb) with the non-saponifying 72 T. C. Jain A. F. Russell and J. G. Moffatt J.Org. Chem. 1973 38 3179. 73 M. J. Robins R.Mengel and R.A. Jones J. Amer. Chem. SOC.,1973,95,4074. Nucleic Acids 635 0 \\O Me I OAC (22) a; X = C1 b;X = Br NHR I R = COCMe (24) a; X = C1 b;X=I base 1,5-diazabicyclo[4,3,0]non-5-enegives the corresponding 3’-ene-derivative. 5’-Deoxy-5’-halogenouridines can be prepared by the reaction of 2‘,3’-0-iso- propylidene-02,5’-cyclouridinewith acyl halides at room temperat~re.~~ The syntheses of 2’-0- 3’-0- and 5’-0-benzylcytidine have been described75 and the 2’-0-and 3’-O-benzyl ethers of the four common ribonucleosides can be prepared in a one-step reaction of the free nucleoside with phenyldiazomethane in the presence ofa Lewis acid catalyst.76 2’-O-Methyluridine can be synthesized directly by standard procedures from the carbohydrate l-O-acetyl-3,5-di-O- benzoyl-2-O-methyl-Q-~-ribofuranose.~ Mono- di- and tri-0-alkyl derivatives of cytidine and uridine can be prepared using dialkyl sulphates in a strongly alkaline medium.78 Treatment of nucleoside 3’,5’-cyclic phosphates with an alkyl iodide followed by cleavage of the phosphate enzymatically or chemically gives 2’-O-alkyl 3’(5’)-nucleotides in high yield.79 The 5’-nucleotides can be further phosphorylated to the 5’-diphosphates which are substrates for poly- nucleotide phosphorylase in the preparation of poly 2’-O-alkyl nucleotides.A synthesis of 8-bromo-2’-O-tosyladenosine illustrates the use of the 5‘-carboxylate group as a protecting agent.*’ Its production from and regeneration 74 Y.Fujisawa and 0. Mitsunobu J.C.S. Chem. Comm. 1973,201. 75 W. Hutzenlaub and W. Pfieiderer Chem. Ber. 1973 106 665. 76 L. F. Christensen and A. D. Broom J. Org. Chem. 1972 37 3398. ” A. H. Haines Tetrahedron 1973 29 2807. 78 J. T. Kusmierek J. Giziewicz and D. Shugar Biochemistry 1973 12 194; J. Giziewicz and D. Shugar Acta Biochim. Polon. 1973 20 73. 79 I. Tazawa S. Tazawa J. L. Alderfer and P. 0.P. Ts’o Biochemistry 1972 11 4931. B. R. Schmidt R. Machat and U. Scholz Chem. Ber. 1973 106 1256. 636 R. T. Walker to the 5’-hydroxymethyl group is nearly quantitative and its use is claimed to be more effective than that of the conventional 5’-blocking groups. The 5’-nitrates of uracil- and cytosine-containing nucleosides have been prepared by the action of 90 % nitric acid at 70 “C for 1.5 h on the free nucleosides.81 Many hundreds of papers on the synthesis of new potential drugs have been published.Among the most interesting is the synthesis of 1,2-dihydro-1- (~-deoxy-~-~-erythro-pentofuranosy~)-~-oxopyraz~ne(25) which has 4-oxide been shown to be a potent deoxyuridine analogue.’* The base moiety is an anti- bacterial compound in its own right but the deoxynucleoside is lo5times more effective an inhibitor of Streptococcus faecium and E. coli than either the base or the ribonucleoside. If the weight of publications dealing with Virazole (1-P-~-ribofuranosyl-1,2,4-triazole-3-carboxamide) (26) is any g~ide,~~-~ this compound could be very 0 0 t II 0111 I I 2’-Deoxyribosy1 Ribosyl useful to the medical profession as it has broad-spectrum antiviral proper tie^.^^ X-Ray crystallographic data indicate that Virazole is similar in structure to g~anosine,~~ and results of biochemical experiments to determine its mechanism of action suggest that this is due to the inhibition of GMP biosynthesis at the step involving the conversion of IMP into xanthosine S-pho~phate.~~ 02,2’-Cyclocytidine has antitumour activitys6 due it is thought to its trans- formation in solution into ma-cytidine and it can be synthesized in 33% yield by the action of toluene-p-sulphonyl chloride on cytidylic acid.8 3’,5‘-Cyclic ma-CMP is also an active antiviral compound and in oiuo is more reactive than ara-C probably because it cannot be deaminated by deoxycytidylic acid de- aminase which is responsible for the loss of activity of ~ra-C.~~ Attempts are being made to synthesize derivatives of biologically active compounds which can F.W. Lichtenthaler and H. J. Muller Angew. Chem. Internat. Edn. 1973 12 752. 82 P. T. Berkowitz T. J. Bardos and A. Block J. Medicin. Chem. 1973 16 183. 83 J. H. Huffman R. W. Sidwell G. P. Khare J. T. Witkowski L. B. Allen and R. K. Robins Antimicrob. Agents Chemother. 1973 3 235. 84 P. Prusiner and M. Sundaralingam Nature New Biol. 1973,244 116. 85 D. G. Streeter J. T. Witkowski G.P. Khare R. W. Sidwell R. J. Bauer R. K. Robins and L. N. Simon Proc. Nut. Acad. Sci. U.S.A. 1973,70 1 174. 86 A. Hoshi M. Yoshida F. Kanzawa K. Kuretani T.Kanai and M. Ichino Chem. and Pharm. Bull. (Japan) 1972 20 2286. M. Ikehara and S. Uesugi Chem. and Pharm. Bull. (Japan) 1973 21 264. R. W. Sidwell L. N. Simon J. H. Huffman L. B. Allen R. A. Long and R. K. Robins Nature New Biol. 1973 242 204. Nucleic Acids 637 penetrate cells and liberate the compound once inside the cell over a period of time. 3’,5’-Cyclic phosphoramidates have been synthesized but these appear to be too stable.89 The water-soluble N6-dimethylaminomethyleneanalogue of ara-A has been used to provide the relatively insoluble ara-A in a sustained fashion.’O 2 Oligonucleotidesand Polynucleotide Analogues The year has been one of consolidation for those working on oligonucleotide synthesis with the methods becoming more widely used and the technique of isolation” and the condensation yields 92 having been improved.The announce- ment of the synthesis of the gene for tRNATy‘ from Escherichia coli is still awaited but the aim is now the synthesis of not only the DNA corresponding to the pre- cursor tRNA but also that for the promoter and terminator regions as well. Much interest has centred on the development of new methods for sequencing oligonucleotides on a micro scale. Low-resolution mass spectrometry has been used to determine the sequence of oligodeoxynucleotides.93 The 3’- and 5’- termini of the oligonucleotides can be identified and in combination with limited enzymatic digestion the sequence of a hexanucleotide has been obtained. A continuous directional degradation in the 3‘ +5’ direction for polyribonucleo- tides involves incubating the polynucleotide (10-’moll-’) with periodate and alkaline phosphatase at an alkaline pH.94 Dialdehyde derivatives are sequentially liberated from the 3’-terminus and these are removed and reduced with [3H]KBH4.Successive treatment of oligodeoxyribonucleotides with phosphatase and then phosphodiesterase can give information about the chain length base composition and identity of the terminal nu~leotides.~~ Polynucleotide kinase can be used to label the 5’-terminus of oligo- rib^-,^^ and de~xyribo-~’ nucleotides. Polynucleotide phosphorylase has been used to label the 3’-end of oligoribonucleotides either by phosphorolysing the oligo- nucleotides in the presence of [32Pi] to nucleoside diphosphates9* in a non- processive manner or by using oligoribonucleotides obtained from a T1 digestion as primers for the reaction of primer-dependent polynucleotide phosphorylase 89 R.B. Meyer D. A. Shuman and R. K. Robins Tetrahedron Letters 1973 269. 90 S. Hanessian J. Medicin. Chem. 1973 16 290. P. J. Cashion M. Fridkin K. L. Agarwal E. Jay and H. G. Khorana Biochemistry 1973,12 1985; N. Katagiri C. P. Bahl K. Itakura J. Minchniewicz and S. A. Narang J.C.S. Chem. Comm. 1973 803. 92 Y.A. Berlin 0. G. Chakhmakhcheva V. A. Efimov M. N. Kolosov and V. G. Korobko Tetrahedron Letters 1973 1353. 93 J. L. Wiebers Analyt. Biochem. 1973 51 542. 94 K. Randerath F.E.B.S. Letters 1973,33 143. 95 N. W. Y. Ho and P. T. Gilham Biochim.Biophys. Acta 1973 308 53. 96 M. Simsek J. Ziegenmeyer J. Heckman and U. L. RajBhandary Proc. Nut. Acud. Sci. U.S.A. 1973,70 1041. 97 K. Murray Biochem J. 1973 131 569. 98 G. Kaufmann H. Gosfeld and U. Z. Littauer F.E.B.S. Letters 1973 31 47. 638 R.T. Walker with [LZ-~~PIGDP This results in the 3'-hydroxy- in the presence of T1 RN~s~.~~ group of each fragment becoming phosphorylated (Scheme). This method99 and the previously mentioned kinase method" for the labelling of the 5'-end of PY A G OH Phosphatase HO OH P' HO Py = pyrimidinyl Scheme oligonucleotides ought to complement each other in the sequence determination of tRNAs from a wide variety of sources which cannot be sufficiently labelled in uiuo so that a complete sequence might be obtainable with only 2mg of tRNA.Much work continues on oligonucleotide synthesis on a polymer support but the first requirement seems to be a knowledge of German! The search for a suit- able support continues and candidates this year have included highly cross- linked polystyrene-containing supports,"' soluble polymers,"' and poly-peptides."* Although the polymer-support methods suffer from low yields at the condensation steps which lead to chains of different lengths and sequences being produced it is now realized that unlike polypeptide synthesis only short oligonucleotides need be prepared by chemical synthesis as these can be joined enzymatically. It is also possible to separate the different short-chain oligomers synthesized.The advantages of the method include the ease of manipulation of reactants and the speed at which successive condensations can be performed. A new approach to the sequential synthesis of oligodeoxyribonucleotides involves the selective removal of an acid-labile 5'-protecting group phosphory- lation with POCl in 2,6-lutidine and tetrahydrofuran followed by condensation with a deoxynucleoside containing a free 3'-OH group and an acid-labile 5'-protecting group.lo3 Other oligodeoxynucleotides to be synthesized include an octanucleotide complementary to a section of 16s rRNA,lo4 four undecanucleotides comple- 99 K. S. Szeto and D. So11 Nucleic Acids Res. 1974 1 171. 100 R. Glaser U. Sequin and C. Tamm Helv. Chim. Acta 1973 56 654; H. Koster and F.Cramer Makromol. Chem. 1973 167 171; V. K. Potapov V. V. Zvezdina M. N. Kochetkova Z. A. Shabarova and M. A. Prokofiev Doklady Akad. Nauk S.S.S.R. 1973,209 364. 101 F. Brandstetter H. Schott and E. Bayer Tetrahedron Letters 1973 2997; H. Seiiger and G. Aumann ibid. p. 291 1. 102 T. M. Chapman and D. G. Kleid J.C.S. Chem. Comm. 1973 193. 103 H. Koster and W. Heidmann Angew. Chem. Internat. Edn. 1973 12 859. I04 V. N. Kagramanov V. D. Smirnov A. A. Bogdanov Z. A. Shabarova and M. A. Prokofiev Doklady Akad. Nauk S.S.S.R. 1973 208 858. Nucleic Acids 639 mentary to a region of the coat protein cistron of fd phage,lo5 and a dodecanu- cleotide complementary to a section of the lysozyme gene of phage T4.'06 It is reportedlo7 that only the 2'-O-(a-methoxyethyl)nucleoside5'-diphosphates are substrates for polynucleotide phosphorylase in the enzymatic synthesis of oligoribonucleotides described two years ago.O8 A chemical synthesis of poly- riboguanylic acid is rep~rted,''~ although it appears that 84 % of the products have a chain length of between four and six units and it hardly qualifies for the title 'poly'. The 3'-terminal nonanucleotide and 5'-terminal hexanucleotide of yeast tRNAA'" have been synthesized by conventional techniques.' ' ' The triester approach to oligonucleotide synthesis is gradually gaining favour as the advantages of the method particularly the ease of isolation of the products are realized. A hexadecamer of thymidylic acid has been prepared" ' and the techniques used are now almost at the stage where they can be applied to the synthesis of oligoribonucleotides of defined sequence in high yield.The phenyl group is used to make the phosphotriester."' Other people have used the tri-chloroethyl group,' although this becomes increasingly more difficult to remove as the length of the chain increases. In the analogue field poly-( 1-vinyluracil) can complex with poly(A) and com- pletely block poly(A)-stimulated formation of polylysine in an E. coli subcellular protein synthesis system.'13 Poly-(3'-O-carboxymethyl-2'-deoxyadenosine)'14 has been shown to have a similar effect to poly-(9-vinyladenine)' l3 and reduces the poly(U)-stimulated formation of polyphenylalanine. Poly-(1-vinyluracil) has been found to inhibit the in uitro translation of rabbit globin mRNA pre- sumably by interacting with the poly(A) sequences on the mRNA as poly- (9-vinyladenine) has no effect.' l5 Both vinyl polymers inhibit acute murine leukaemia virus infection in mouse embryo cells.' l6 3 Photochemistry and Physical Chemistry of Polynucleotides There is an increasing interest in the influence of conformation of a polynucleotide chain upon its photochemistry and the related subject of how the presence of different photoproducts alters the conformation of polynucleotide structures.From a comparison of the effects of pyridimine dimerization and ethidium bromide H. Schott and H. Kossel J. Amer. Chem. SOC.,1973 95 3778. lo6 M. T. Doe1 and M. Smith F.E.B.S. Letters 1973 34 99. lo' G.N. Bennett J. K. Mackey J. L. Wiebers and P. T. Gilham Biochemistry 1973 12 3956. R. T. Walker Ann. Reports(B) 1971 68 420. log D. B. Strauss and J. R. Fresco .I.Amer. Chem. Soc. 1973,95 5025. 'lo E. Ohtsuka M. Ubasawa S. Morioka and M. Ikehara J. Amer. Chem. SOC.,1973,95 4725. I" N. J. Cusack C. B. Reese and J. H. van Boom Tetrahedron Letters 1973 2209. 'I2 J. C. Catlin and F. Cramer J. Org. Chem. 1973 38 245. 'I3 F. Reynolds D. Grunberger J. Pitha and P. M. Pitha Biochemistry 1972 11 3261. 'I4 A. S. Jones M. MacCoss and R. T. Walker Biochim. Biophys. Acta 1973 294 365. 'Is F. Reynolds D. Grunberger P. M. Pitha and J. Pitha in the press. P. M. Pitha N. M. Teich D. R. Lowy and J. Pitha Proc. Nat. Acad. Sci. U.S.A. 1973 70 1204. 640 R.T.Walker intercalation on the sedimentation coefficient of superhelical DNA,' '' it has been concluded that each dimer unwinds the helix by 54".From the effect of a central thymine photodimer on the stability of the double helix dAlo.dTlo it has been estimated that each dimer disrupts four base pairs those of the dimerized thymines and those of their immediate neighbours.' '* The influence of the conformation of poly(U) and poly(C) on their photochemistry has been studied' l9 and the photo- hydration and photodimerization reactions of uracil have been used to charac- terize the local environment of extra-helical uridine residues in the copolymer strand of poly(AU).poly(U) helices.'2o The occurrence and stability of cytosine photohydrates in DNA have been studied12' using a newly developed reduction assay.These lesions are sufficiently stable to interfere with the in viuo function of DNA. Hitherto purines in comparison with pyrimidines have proved very resistant to photochemical change and accordingly have been considered to have little importance in photobiology. The discovery' 22 that poly(dA) [but not poly(A)] undergoes a specific photoreaction with high quantum efficiency upon irradiation at 248 nm should herald a new interest in the photochemistry of purines. The contrast in the reactivity of the two polyadenylic acids is ascribed to the known difference in their single-stranded conformations. Investigations into the effects of heavy atoms on the photochemistry of nucleic acids have been initiated.Thymine dimerization and biological inactivation of transforming DNA are enhanced by complexed silver ions'23 but reduced by complexed mercuric ions.' 24 The enzymology of cellular mechanisms for repairing photolesions in DNA is being actively explored. Photoreactivation which is the simplest cellular repair mechanism is achieved by an enzyme which monomerizes pyrimidine photodimers in DNA upon illumination at wavelengths of ca. 400nm. The photoreactivating enzymes from blue-green alga' 25 and yeast' 26 have been extensively purified and a fluorescent cofactor has been implicated in their func- tion. Now that milligram amounts of the E. coli en~yrne'~'can be prepared from a strain carrying the photoreactivation gene as part of a transducing phage the detailed characterization of this remarkable enzyme will be possible.'H N.m.r. (220 and 300 MHz) has been used to study hydrogen-bonded ring protons in Watson-Crick base pairs in oligonucleotide model systems,' 28 11' D. T. Denhardt and A. C. Kato J. Mol. Biol. 1973 77 479. 118 F. N. Hayes D. L. Williams R. L. Ratliff A. J. Varghese and C. S. Rupert J. Amer. Chem. SOC. 1971 93,4940. A. J. Lomant and J. R. Fresco J. Mol. Biol. 1972 66 49. A. J. Lomant and J. R. Fresco J. Mol. Biol. 1973 77 345. Iz1 J. Y. Vanderhoek and P. A. Cerutti Biochem. Biophys. Res. Comm. 1973,52 1156. D. Porschke Proc. Nut. Acad. Sci. U.S.A. 1973 70 2683. Iz3 R. 0.Rahn and L. C. Landry Photochem. and Photobiol. 1973 18 29. lz4 R. 0.Rahn J. K. Setlow and L. C. Landry Photochem.and Photobiol. 1973 18 39. * '' S. Minato and H. Werbin Photochem. and Photobiol. 1972 15 97. lZ6 J. S. Cook and T. E. Worthy Biochemistry 1972 11 388. l '' B. M. Sutherland M. J. Chamberlin and J. C. Sutherland Biochemistry 1973,12,4200. 12* D. M. Crothers C. W. Hilbers and R. G. Shulman Proc. Nut. Acad. Sci. U.S.A. 1973 70 2899. Nucleic Acids 641 5s RNA,12' and tRNA.'30-'34 tRNA?" from bakers' yeast in going from the denatured to the native form gains 3-5 G-C pairs and loses 0-2 A-U pairs.'30 No evidence can be found for additional Watson-Crick base pairs apart from those occurring in the clover-leaf In a detailed study of tRNAPhe from yeast the CCA stem is shown to form a continuous helix with the T+C stem and this result agrees with the structure determined from X-ray studies.'33 No difference in conformation between the charged and uncharged tRNAPhe can be detected and it is concluded that the secondary and tertiary structures of these molecules are probably the same.134 Conformational changes in tRNA have also been investigated by temperature-jump techniques.'35 Polynucleotide complexes involving non-Watson-Crick base-pairing and possibly left-handed helices have been described. Poly-(2-dimethylaminoadenylic acid) forms hydrogen bonds through N6and N-7 with poly(U) and poly-(5- brom~uracil).'~~ Wobble base-pairing between G and T occurs in the stable helical secondary structure of poly(dT-G).' 37 The hydrogen-bonding pattern in the hairpin secondary structure of poly(U) has been established by i.r.spectro- scopy.' 38 Poly-(2-thiouridylic acid) forms a similar but much more stable hairpin helix.' 39 Although the spectroscopic and hydrodynamic properties of the alter- nating copolymer poly[d(A-s4T).d(A-s4T)] are consistent with a left-handed double helix incorporating reversed Hoogsteen base-pairing between adenine and 4-thi0thyrnine,'~~ this is not supported by a small-angle X-ray scattering study.141 Poly-(2-methyladenylic acid) forms a 1 1 complex with poly(U) to give a double-stranded complex with Hoogsteen-type h~dr0gen-bonding.l~~ Oligonucleotides containing 6,2'-anhydro-6-oxy-1-/3-~-arabinofuranosyluracil (Uo)have been prepared143 and have been found to give a 1 :1 complex with oligo 8,2'-S-cycloadenosine (A').The duplex probably has a left-handed con- formation and since poly(A') could not form complexes with poly(U) nor could poly(Uo) form complexes with poly(A) it seems that the torsion angle of the bases has to be identical before a double-stranded complex can form. Anomalous 0.r.d. lZ9 Y. P. Wong D. R. Kearns B. R. Reid and R. G. Shulman J. Mol. Biol. 1972,72 741. I3O Y. P. Wong D. R. Kearns R. G. Shulman T. Yamane S. Chang J. G. Chibikjian and J. R. Fresco J. MoI. Biol. 1973 74 403. '" R. G. Shulman C. W. Hilbers D. R. Fearns B. R. Reid and Y. P. Wong J. Mol. Biol. 1973 78 57. 132 D. R. Lightfoot K. L. Wong D. R. Kearns B. R. Reid and R. G. Shulman J. Mol. Biol. 1973 78 71. 133 R. G. Shulman C. W. Hilbers Y. P. Wong K. L. Wong D. R. Lightfoot B.R. Reid and D. R. Kearns Proc. Nut. Acad. Sci. U.S.A. 1973 70 2042. 134 Y. P. Wong B. R. Reid and D. R. Kearns Proc. Nat. Acad. Sci. U.S.A. 1973,79,2193. 13' P. E. Cole and D. M. Crothers Biochemisrry 1972 11 4368; S. K. Yang and D. M. Crothers. ibid.. p. 4375. 136 F. Ishikawa J. Frazier F. B. Howard and H. T. Miles J. Mol. Biol. 1972 70 475; F. Ishikawa J. Frazier and H. T. Miles Biochemistry 1973 12 4790. 13' A. G. Lezius and E. Domin Nature New Biol. 1973 244 169. 13' D. Bode M. Heinecke and U. Schernau Biochem. Biophys. Res. Comm. 1973,52,1234. W. Bahr P. Faerber and K. Scheit European J. Biochem. 1973,35 535. I4O E. M. Gottschalk E. Kopp and A. G. Lezius European J. Biochem. 1971 24 168. 14' P. Zipper European J. Biochem. 1973,39,493. 14' M.Ikehara M. Hattori and T. Fukui European J. Biochem. 1972 31 329. '43 M. Ikehara and T. Tezuka J. Amer. Chem. Soc. 1973,95,4054. 642 R.T. Walker spectra suggestive of unusual polynucleotide conformation are shown by the complexes of poly(A) with formycin and 7-methyl~anthine.'~~ X-Ray diffraction studies have shown the triple-stranded polynucleotides p~ly(U).poly(A).poly(U)'~~and poly(I).poly(A).poly(I)'4' to have diameters only very slightly greater than those of the corresponding double helices. In agreement with other physical studies,'48 the two poly(U) [and poly(I)] strands are antiparallel. The properties of the triplex dT .dA .rU have been investi- gated149 and the structures of p~ly(I),'~~ poly-(1-deaza- 3-deaza- and 7-deaza- adenylic acid),I5 'and poly-(7-deazainosinic acid)' 52 determined.A method for estimating the most stable secondary structure of an RNA mole- cule from its sequence has been refined and used to predict the secondary structure of a 55-base fragment of R17 RNA.ls3 The free energy of the RNA conformation is considered to be determined by contributions from helical base-paired regions internal loops bulge loops hairpin loops and single-stranded regions. Recent thermodynamic investigations of model systems incorporating internal loops,' 54 bulge 100ps,'55 and hairpin 100ps'~~*'~' have allowed the contributions of these features to the over-all free energy of the nucleic acid structure to be estimated more accurately. However a study of the thermodynamic kinetic and optical properties of the double helices formed by the series of self-complementary oligonucleotides (Ap),GpC(pU) shows that the shortest helix containing just six base pairs is much less stable than would be predicted from the properties of larger rn~lecules.'~~ Apparently one cannot assume that base-pair free energies and extinction-coefficient changes are independent of size.The temperature-jump relaxation method has been used to study the transition in a variety of oligonucleotides containing G-C base pair^."^+'^^ The initial nucleation of about three base pairs is rate-limiting for helix growth in oligo- nucleotides containing A-A A-U and A-T base pairs. Once such a stable nucleus has formed the helix 'zips up' at a rate of 10'-lo8 base pairs per second.With the oligonucleotides containing G-C base pairs formation of one or perhaps two base pairs is sufficient for rapid helix growth and the rate of reaction 144 R. J. H. Davies J. Mol. Biol. 1973 73 317. 14' R. J. H. Davies Biochem. Biophys. Res. Comm. 1973 52 1115. 146 S. Arnott and P. J. Bond Nature New Biol. 1973 244 99. 14' S. Arnott and P. J. Bond Science 1973 181 68. 148 J. Thrierr and M. Leng Biochim. Biophys. Acta 1972 272 238. 149 N. L. Murray and A. R. Morgan Canad. J. Biochem. 1973,51,436. 'O D. Thiele and W. Guschlbauer Biophysik 1973 9 277. L. Hagenberg H. G. Gassen and H. Matthaei Biochem. Biophys. Res. Comm. 1973 50 1104. lS2 M. Ikehara T. Fukui T. Koide and J. Inaba Nucleic Acids Res. 1974 1 53. I. Tinoco P.N. Borer B. Dengler M. D. Levine 0.C. Uhlenbeck D. M. Crothers and J. Gralla Nature New Biol. 1973 246 40. J. Gralla and D. M. Crothers J. Mol. Biol. 1973,78 301. lS5 T. R. Fink and D. M. Crothers J. Mol. Biol. 1972,66 1. lS6 0.C. Uhlenbeck P. N. Borer B. Dengler and I. Tinoco J. Mol. Biol. 1973 73 483. Is' J. Gralla and D. M. Crothers J. Mol. Biol. 1973,73 497. "* J. Ravetch J. Gralla and D. M. Crothers Nucleic Acids Res. 1974 1 109. S. K. Podder European J. Biochem. 1971 22,467. D. Porschke 0. C. Uhlenbeck and F. H. Martin Biopolymers 1973 12 1313. Nucleic Acids 643 is markedly dependent upon the base sequence. The importance of single- stranded stacking interactions in determining the stability of these complexes has been stressed’60 and it is therefore appropriate that investigations of the dynamics of the conformational changes of single-stranded polynucleotides have been initiated with a study of oligoadenylates and poly(A).16’ 4 tRNA tRNA is still the only readily available source of a homogeneous nucleic acid and thus there are many hundreds of papers each year dealing with various aspects of the chemistry and biochemistry of these molecules.Happily the number of such reports dealing with unfractionated tRNA is now very small and there really is little excuse for not first fractionating the tRNA now that an RPC-5 column (1 1) has been used to fractionate 1.5g of a partially-purified tRNA in 4.5 h with a flow rate of 10ml min-1.’62 One of the most interesting experiments reported this year has at last solved the problem as to which hydroxy-group of the 3’-terminal adenosineof tRNA is aminoacylated.Using nucleotidyl transferase 2‘-and 3’-deoxyadenosine were in turn incorporated into this terminal position in the tRNAPhe from yeast.’63 Only the 3’-deoxyadenosine-terminated molecule could be aminoacylated (i.e.on the 2’-OH group) but the product could not take part in protein ~ynthesis.’~~ The tRNA terminating in 2‘-deoxyadenosine could not be aminoacylated but acts as a competitive inhibitor of the phenylalanyl-tRNA synthetase and it can be concluded that tRNA is normally aminoacylated on the 2’-OH group which is followed by a rapid acyl-group migration to the 3’-position before it can be active in protein biosynthesis.3’-Deoxy-3’-aminoadenosine has also been incor- porated into the 3’-terminal position of tRNAPh‘ from yeast.’65 This tRNA can be aminoacylated; the amino-acid is attached to the 3’-NH2 group and the product is very stable. Thus the tRNA has acceptor but not donor activity and the kinetics for the aminoacylation are the same as for a normal tRNA which is no doubt due to the fact that it is the acylation of the common 2’-OH group which is the rate- determining step. It has been shown that mischarged initiator tRNAs such as Phe-tRNAp‘ can be formylated showing that the formylation depends upon the tRNA and not the amino-acid.’66 Several more tRNA sequences have been published during the year and they include for E. coli tRNAAsp,167 tRNAggG,168 and tRNAS,”;16’ for yeasts 16’ D.Porschke European J. Biochem. 1973 39 117. ’‘* B. Roe K. Marcu and B. Dudock Biochim. Biophys. Am 1973 319 25. M. Sprinzl K. H. Scheit H. Sternbach F. von der Haar and F. Cramer Biochem. Biophys. Res. Comm. 1973,51 881. 164 M. Sprinzl and F. Cramer Nature New Biol. 1973 245 3. 165 T. H. Frazer and A. Rich Proc. Nat. Acad. Sci. U.S.A. 1973 70 2671. R. Giege J. P. Ebel and B. F. C. Clark F.E.B.S. Letters 1973 30,291. F. Harada K. Yamaizumi and S. Nishimura Biochem. Biophys. Res. Comm. 1973 49 1605. C. W. Hill G. Combriato W. Steinhart. D. L. Riddle and J. Carbon J. Bioi. Chem. 1973 248,4252. 169 (u)D. Ish-Horowicz and B. F. C. Clark J. Bid. Chem. 1973,248,6663;(6)Y.Yamada and H. Ishikura F.E.B.S. Letters 1973. 29 231.644 R.T. Walker tRNALys,190 tRNAGIy,' 71 and tRNA;4i'g;172 for rabbit liver tRNAPhe for Salmonella typhimurium tRNAGIy;168 for phage T4 coded tRNAG'y,' 74 tRNALe",'75 and tRNASer.176 When bacteriophage T4177 (and probably T2 and T6)178infect E. coli,the phage genome directs the synthesis of at least eight tRNAs and two stable RNA species of low molecular weight whose function is unknown. Two groups of workers have determined the sequences of several of these tRNAs and have compared them with those of the corresponding E. coli tRNAs. In particular tRNAGIY from the phage probably recognizes both GGG and GGA and contains a 5-methylamino-2-thiouridineresidue at the 5'-end of the anticodon.' 74 This tRNA has a very high mobility on gel electrophoresis suggesting a chain length of only 66 nucleotides but in fact the molecule contains 74 nucleotides and it may have a more compact shape than other tRNAs.The T4 system has been used to synthesize tRNA in uitro in a p~rified'~' and in a crude system.'80 The tRNAs are identical to those synthesized in uiuo except for the absence of modified bases. An RNA molecule of 140 nucleotides has also been sequenced from T4- infected cells and the nucleotides 46-140 can be arranged in the form of a clover leaf with a CCA 3'-termin~s.'~~ Precursors of the T4-coded tRNAs have also been found which consist of polynucleotide chains containing two tRNA species. At least six of the tRNAs can be accounted for in three such dimeric species.'81 Eukaryotic initiator tRNA from mouse myeloma cells lacks Tp$p in loop IV,18* and in tRNAp' from wheat germ,96 rabbit li~er,'~*'~~ and sheep mammary gland,96 the normal GT$CG is replaced by a sequence GAUCG so that the lack of rT is not because of the non-modification of a U residue.An oligonucleotide fragment from the 3'-terminus to the 7-methylguanosine residue of these tRNAs can be obtained following a specific mild alkaline cleavage at m7Gand separation of the products. The base sequences in loop IV of yeast mouse myeloma rabbit liver wheat germ and sheep mammary gland are identical'84 and it is probable 170 C. J. Smith H.-S. Teh A. N. Ley and P. D'Obrenan J. Biol. Chem. 1973 248,4475. M. Yoshida Biochem. Biophys. Res. Comm. 1973 50 779. J. Weissenbach R.Martin and G. Dirheimer F.E.B.S. Letters 1972 28 353. G. Keith F. Picaud J. Weissenbach J. P. Ebel G. Petrissant and G. Dirheimer F.E.B.S.Letters 1973 31 345. 174 S. Stahl G. Paddock and J. Abelson Biochem. Biophys. Res. Comm. 1973 54 567; B. G. Barrell A. R. Coulson and W. H.McClain F.E.B.S. Letters 1973 37 64. 175 T. C. Pinkerton G. Paddock and J. Abelson J. Biol. Chem. 1973 248,6348. 176 See reference 169a. 177 W. H. McClain C. Guthrie and B. G. Barrell Proc. Nut. Acad. Sci. U.S.A. 1972 69 3703. 178 G. Paddock and J. Abelson Nature New Biol. 1973 246 2. 179 D. P. Nierlich H. Lamfrom A. Sarabhai and J. Abelson Proc. Nut. Acad. Sci. U.S.A. 1973,70 179. H.Lamfrom A. Sarabhai D. P. Nierlich and J. Abelson Nature New Biol. 1973,246 1 I. 181 C.Guthrie J. G. Seidman S. Altman B. G. Barrell J. D. Smith and W. H.McClain Nature New Biol. 1973 246 6. P. W. Piper and B. F. C. Clark F.E.B.S.Letters 1973 30 265. G. Petrissant Proc. Nut. Acad. Sci. U.S.A. 1973 70 1046. M. Simsek G. Petrissant and U. L. RajBhandary Proc. Nat. Acad. Sci. U.S.A. 1973 70 2600. Nucleic Acids that the total sequences of the cytoplasmic initiator tRNAs from mouse rabbit and sheep have the same sequence. The sequence T+CG in non-initiator tRNAs has been directly implicated in the binding of the tRNA to the ribosome.'85 Other tRNA species have been found to lack rT. A tRNATy' from a mutant E. cofistrain lacking rT is able to support protein synthesis at a rate equivalent to that observed with normally methylated tRNA.'86 Using an E.cofi uracil methylase assay five specific tRNAs in wheat embryo and also tRNAs in foetal calf calf liver and beef liver have been found to lack rT.ls7 In tRNALY" from rabbit liver 2'-O-methylribothymidine has been identified.'88 This tRNA is fully active in protein synthesis. When Bacillus stearothermophilus is cultured at 70" C a three-fold increase in the amount of 2'-O-methylation of tRNA has been found compared with that when the bacterium is cultured at 50 "C. Little difference in the amount of base methylation was found.189 Two particularly interesting tRNA molecules have been found in mutant bacteria. In frameshift mutants of Salmonelfa typhimurium a new tRNAGIy has been found which has an identical sequence to the tRNAGIy from the wild-type strain except for an additional C in the anticodon l00p.'~~ The anticodon now comprises the quadruplet CCCC and presumably the mutant suppresses frame- shift mutations by reading a quadruplet codon.A new series of 'Smith' mutants has been These are Su; mutants of E. coli selected for their ability to suppress an amber mutation in the p-galactosidase gene of E. cofi fac~ooo which is suppressed by the glutamine-inserting suppressor Sui. Five such mutants have been isolated the tRNATY' isolated and all have been found to contain a different single base substitution in the amino-acid stem. Four of the five mutant tRNAs have been shown to accept glutamine and to insert this in vivo at an UAG site. The results clearly implicate the amino-acid acceptor stem of the tyrosine tRNA as a site of synthetase recognition.The modification of 5-methylaminomethyl-2-thiouridine in the anticodon of E. coli tRNAG1" with BrCN results in a much lowered reaction of the tRNA with its cognate synthetase.' 93 The incorporation of a 2-thiocytidine into the penulti- mate position of the 3'-end of tRNAPhe from yeast does not affect the amino- acylation of the tRNA.Ig4 The addition of UGG to bind to the CCA stem of a tRNA prevents aminoacylation whereas oligonucleotides binding to the anticodon loop do not prevent aminoacylation.' 95 An investigation of homologous and D. Richter V. A. Erdmann and M. Sprinzl Nature New Biol. 1973 246 132. S. Yang E. R. Reiniz and M. L. Gefter Arch. Biochem. Biophys. 1973 157 55.I87 K. Marcu R. Mignery R. Reszelbach B. Roe M. Sirover and B. Dudock Biochem. Biophys. Res. Comm. 1973 55 477. H. J. Gross M. Simsek M. Raba K. Limburg J. Heckman and U. L. RajBhandary, Nucleic Acids Res. 1974 1 35. P. F. Agris H. Koh and D. Soll Arch. Biochem. Biophys. 1973 154 277. I9O D. L. Riddle and J. Carbon Nature New Biof. 1973 242 230. 19' J. D. Smith and J. E. Celis Nature New Biol. 1973 243 66. 19* J. E. Celis M. L. Hooper and J. D. Smith Nature New Biof. 1973 244 26i. 193 P. F. Agris D. So11 andT. Seno Biochemistry 1973 12 4331. M. Sprinzl K. H. Scheit and F. Cramer European J. Biochem.. 1973 34 306. 19' C. J. Bruton and B. F. C. Clark Nucleic Acids Res. 1974 I 217. 646 R. T. Walker heterologous aminoacylation with the yeast phenylalanyl-tRNA synthetase (PRS) has shown that 11 tRNAs can be amin~acylated.'~~ These fall into three classes fast intermediate and slow.Those in the slow class all contain nine bases in the dihydrouridine loop whereas the other two classes all contain eight. All the members of the fast group contain an N'-methylguanosine at position 10 from the 5'-end and those in the intermediate group lack this modification. Specific methylation of one of the intermediate class tRNAPhe from E. coli at position 10 by an enzyme preparation from rabbit liver results in an increased rate of aminoacylation of this tRNA by the PRS confirming that the synthetase requires this position to be methylated for rapid aminoacylation to occur.197 However specific methylation of tRNAp' from E.coli has no effect upon its aminoa~ylation'~~ and it is going to be very important that all experiments in this field are done on pure tRNAs that the modifications claimed are specific and that the positions of modification are identified by sequencing the tRNAs so modified. A three-point attachment for the synthetase has been proposed'99 which includes the amino-acid stem the anticodon loop and the extra loop in tRNAy' but although much progress is being made in this field it is clearly going to be some time if ever before all the apparently conflicting data are rationalized and a uniform recognition system is obtained. Little work of much significance involving chemical modification of tRNAs has appeared during the year.Exceptions to this include the experiments in which tRNAF' from E. coli undergoes photo-oxidation in the presence of methy- lene blue which results in the modification of two guanosine residues at positions 2 and 71.'" It has been shown that the lethal event is the modification at position 71 whereas molecules only containing the modification at position 2 are active in the aminoacylation reaction. Methoxyamine modification of cytidine residues has been used to show that the anticodon loops of bacterial and mammalian initiator tRNAs have similar tertiary structures2" and also that precursor tRNATyr adopts a clover-leaf configuration before maturation.'" Affinity chromatography has been used to isolate purified aminoacyl-tRNA synthetases (or ligases).Columns of Sepharose-phenylalaninezo3and Sepharose- methionine204 have been used to purify their cognate synthetases. In the reverse type of reaction the crude synthetases have been adsorbed on phosphocellulose columns205 and the individual synthetases have been eluted with a pure tRNA solution. 196 B. Roe M. Sirover. and B. Dudock Biochemistry 1973 12 4146. 19' B. Roe M. Michael and B. Dudock Nature New Biol. 1973,246 137. 19' L. P. Shershneva T. V. Venkstern and A. A. Bayer Nucleic Acids Res. 1974 1 235. 199 S. K. Dube Nature New Biol. 1973 243 103. 2oo L. H. Schulman Proc. Nut. Acad. Sci. U.S.A. 1972,69 3594. 201 P. W. Piper and B. F. €. Clark Nucleic Acids Res. 1974 1,45. '02 S. E. Chang and J. D. Smith Nature New Biol. 1973 246 165. '03 P.I. Forrester and R. L. Hancock Canad. J. Biochem. 1973 51 231. '04 M. Robert-Gero and J. P. Waller European J. Biochem. 1972 31 315. '05 F. von der Haar European J. Biochem. 1973 34 84; H. Yamada J. Biochem. 1973 74 187. Nucleic Acids 647 5 RNA Oneof the most interesting results in the viral RNA field is the report by Spiegelman and hisco-workers ofthe complete base sequence ofareplicating RNA molecule.206 It is probably worth describing the history of this RNA molecule which started in 1965 when a template-specific RNA replicase from E. cofi infected with the RNA phage QP was isolated2" and it was established that the enzyme preparation could mediate a virtually indefinite and catalytic synthesis of biologically com- petent and infectious RNA.This system was then used to investigate evolution in the test-tube that is conditions under which the QP-RNA molecules are liberated from many of the restrictions stemming from the requirements of a complete viral life cycle. It was argued that as replicase was provided and the RNA molecules did not have to infect cells for replication the RNA sequences coding for coat protein and replicase might be dispensable. A serial transfer experiment was devised in which the selective advantage depended upon rapid completion of synthesis. After 74 transfers a lower limit of 550 nucleotides had been reached corresponding to an 88 %rejection of the phage genetic information. The report at the end of last year2'* showed that further experiments had resulted in the isolation of a replicating molecule of only 218 nucleotides and this has now been sequenced.The length of this molecule is such that its sequence and that of mutants which it produces in response to external stimuli can be determined without too much effort. The sequence of the RNA is given in Figure 1. The RNA replicates by way of a two-stranded intermediate and it is argued that if a given variant is superior because of a particular sequence in its plus strand the advantage would be increased if the same sequence could occur in the minus strand. However the plus strand must then contain the antiparallel complement of the advantageous sequence and the formation of intra-strand helices should occur. As can be seen the sequence does contain several complementary runs of nucleotides capable of forming helical regions.Now experiments can be devised so that base changes which have occurred in the RNA mutating from one pheno- type to another can be determined. There is now a computer algorithm for generating all possible sequences of an RNA given the sequences of pancreatic and T1 RNase fragment^.^" Several sequences of R17 RNA have been determined.210 The sequence determination of QP RNA continues now that it has been possible to resynchronize RNA synthesis at an internal site of the RNA template.211 In MS2 phage the gene coding for the A-protein has been shown to start at nucleotide 130 from the '06 D. R. Mills F. R. Kramer and S. Spiegelman Science 1973 180 916. 20' I. Haruna and S. Spiegelman Proc.Nut. Acad. Sci. U.S.A. 1965 54 579. 208 D. L. Kacian D. R. Mills F. R. Kramer and S. Spiegelman Proc. Nut. Acad. Sci. U.S.A. 1972 69 3038. 209 L. L. King Math. Bioscience 1973 16 273. 210 U. F. E. Rensing and J. G. G. Schoenmakers European J. Biochem. 1973 33 8; U. F. E. Rensing Biochem. J. 1973 131 593; U. F. E. Rensing A. Coulson and E. 0.P. Thompson Biochem. J. ibid. p. 605. 211 D. Kalakofsky M. A. Billeter H. Weber and C. Weissmann J. Mol. Biol. 1973 76 271. G U/A A GA CG U UA uc CG CG CG GC GA GA GC UA AA GA CG CG CG GG CG AU AC GC CG CG GC GG CG CG CG UA UA AU CG CG GC GC CG CG CG CG GC CG CG CG CG AU GC AU pppGGGGA’ I/ACGGGAGUUCGA’ ‘GCU) {CUCC’ I{GAACCI \CCU\ /GGUGI \UCCCCOH AU AU UA UA CG GC C.G CG GC CG GC GC AU GC UA CG GC CG GC GC GC uc CG CG UA uu GC AU GC UA GC CG UG CG GG U C cc CG G Figure1 The complete sequence of the plus strand of MDV-1 RNA Nucleic Acids 649 5'-end and the initiating codon is GUG.2'2 Another fragment of the MS2 RNA genome 73 nucleotides long has been described and it shows a striking similarity to some ribosomal binding B.stearothermophilus ribosomes have been shown to protect a 38-nucleotide fragment of Qp RNA but the region contains no AUG or GUG initiator ~odon.~' The nucleotide sequence of a ribosome binding site of RNA synthesized in uitro from coliphage T7 a source evolutionally unrelated to sources from which previous sequences have been obtained is found to contain similar sequences to those found for R17 and QB sites.215 The probable initiator codon is in the sequence AACAUGAGG which also occurs in the R17 replicase cistron ini- tiation sequence.The pentanucleotide sequence GAGGU also occurs in the R17 A-protein ribosome binding site and the Qp A-protein site contains the sequence GAGG. It would appear that the primary sequence around the AUG codon does indeed have a major role in specifying the point of ribosome attachment for the initiation of protein synthesis. "he length of RNA fragments necessary for the formation of complexes with ribosomes has been investigated.216 Once again the report of a symposium on protein synthesis in reproductive tissue has been printed and issued in book form within lOOdays of the meeting2 "-at least some people can get their work printed quickly! Many interesting papers and discussions on eukaryotic mRNA are included.HnRNA or its constituent mRNA can be isolated using ordinary cellulose apparently without the need for the oligo dT which is usually at- tached to the cellulose. mRNA has also been isolated using poly(U) covalently linked to Sepharose" and mouse heavy-chain immunoglobulin mRNA has been purified by specifically binding it to complete myeloma protein and pre- cipitating the resulting RNA-protein complex with antiserum against the myeloma protein.220 The link between HnRNA and mRNA continues to be established. The poly(A) sequence in both RNAs has been shown to be the same,221 although HnRNA contains a poly(U) segment 30 nucleotides long which is absent in the mRNA ;this is possibly transcribed from the repeated regions of the DNA.222 DNA/RNA hybridization has been used to establish the identity of sequences of globin mRNA in giant nuclear precursor RNA of avian erythr~blasts.~' 212 G.Volckaert and W. Fiers F.E.B.S. Letters 1973 35 91. 'I3 G. Haegeman and W. Fiers European J. Biochem. 1973,36 135. 214 J. A. Steitz J. Mol. Biol. 1973 73 1. J. R. Arrand and J. Hindley Nature New Biol. 1973 244 10. A. G. Porter and J. Hindley F.E.B.S. Letters 1973 33 339. ' See Acta Endocrinologica 1973 Suppl. 180. 'I8 C. J. Larsen M. Marty R. Emanoil-Ravicovitch and M. Boiron F.E.B.S. Letters 1973 33 61. 219 U. Lindberg and T. Persson European J.Biochem. 1972 31 246. *" R. H. Stevens and A. R. Williamson Proc. Nut. Acad. Sci. U.S.A. 1973,70 1 127. ''I G. R. Molloy and J. E. Darnell Biochemistry 1973 12 2324. 222 G. R. Molloy W. L. Thomas and J. E. Darnell Proc. Nut. Acad. Sci. U.S.A. 1972 69 3684. 223 T. Imaizumi H. Diggelmann and K. Scherrer Proc. Nor. Acad. Sci. U.S.A. 1973.70 1122. 650 R.T. Walker More evidence is available which suggests that the poly(A) sequences in mammalian cell mRNA originate in the nucleus224 and that once in the cytoplasm they become smaller with age.225 A partial base sequence of an mRNA has been reported.226 The immuno- globulin light-chain mRNA of mouse myeloma cells contains a ‘poly(A)’ sequence composed entirely of A residues. The sequence of four oligonucleotides each about 20 residues long can be correlated with the known amino-acid sequence of t’he protein and a fifth oligonucleotide must be derived from a region of the mRNA which is not translated.The determination of some nucleotide sequences for HeLa cell HnRNA confirms previous observations that the GC doublet occurs very infrequently in the vertebrate genome.227 The Xenopus oocyte continues to be used for the micro-injection of eukaryotic mRNAZ2* and precursor mRNAZz9 in which it is translated very efficiently. However a word of caution has been given in the interpretation of some of the results obtained with precursor mRNA because of the sensitivity of the It is claimed that only 1% of an mRNA contaminating the high molecular weight RNA which it is desired to show contains mRNA sequences would account for some of the published results.It is the duty of people using this system to use controls which demonstrate that this is not the case. The fidelity of translation of some mRNAs has been checked under very critical eonditions such that the amino-acid sequence of the product has been compared with that of the in vim pr~duct.’~’ The translation of mRNA in heterologous in uitro systems has continued.232 One such system described consists of mouse liver ribosomes rabbit reticulocyte initiation factors and rat liver pH 5en~ymes.2~~ This directs the synthesis of all known duck globin chains from duck globin mRNA but if given a saturating mixture ofeach of rabbit and duck globin mRNAs only rabbit globin synthesis takes place.Rabbit globin mRNA has been translated on ribosomes from trout liver and kidney bean root tips.234 In the ribosomal RNA field major sequence heterogeneity has been observed between the 5s RNA from the kidneys and ovaries of Xenopus laeui~.~~~ The nucleotide sequence of a 5.8s rRNA from Saccharomyces cereuisiae has been 224 W. Jelinek M. Adesnik M. Salditt D. Sheiness R. Wall G. Molloy L. Philipson and J. E. Darnell J. Mol. Biol. 1973 75 515. 225 D. Sheiness and J. E. Darnell Nature New Biol. 1973 241 265. 226 G. G. Brownlee E. M. Cartwright N. J. Cowan J. M. Jarvis and C. Milstein Nature New Biol. 1973 244 236. 227 N. W. Frazer B. E. H. Maden and R. H. Burdon F.E.B.S. Letters 1973 36 257. 228 C.D. Lane and C. M. Gregory European J. Biochem. 1973 34 219. 229 R. Williamson C. E. Drewienkiewicz and J. Paul Nature New Biol. 1973 241 66. 230 C. D. Lane C. M. Gregory T. Iyazumi and K. Scherrer Nature New Biol. 1973 243 78. 231 N. J. Cowan and C. Milstein European J. Biochem. 1973,36 1; R. F. Jones and J. B. Lingrel J. Biol. Chem. 1972 247 7951. 232 A. G. Stewart E. S. Gander C. Morel B. Luppis and K. Scherrer European J. Biochem. 1973 34 205. 233 M. H. Schreier T. Staehelin A. Stewart E. Gander and K. Scherrer European J. Biochem. 1973 34 21 3. 234 C. Vaquero L. Reibel J. Delaunay and G. Shapira Biochem. Biophys. Res. Comm. 1973 54 1171. 235 P. J. Ford and E. M. Southern Nature New Biol. 1973 241 7. Nucleic Acids 651 determined236 and the deliberations of a Cold Spring Harbor Symposium on the ribosome have appeared under the title ‘Ribosome Model to Take Home to Ma.’237 While it undoubtedly provides an up-to-date summary of our present knowledge of ribosomal structure and function it is highly doubtful whether in the majority of cases ‘Ma’ would be either interested or impressed! 6 DNA An excellent review entitled ‘The Primary Structure of DNA’ has appeared.238 This deals with methods of sequencing DNA and in particular the interaction of restriction enzymes and other proteins with DNA and some of the literature covered is still in the press at the end of 1973.Bernardi and his co-workers have been investigating the specificity of the DNases :239 Helix aspersa DNase pancreatic DNase E.coli DNase I and spleen DNase have been studied. It is concluded that these enzymes are not as non- specific as has previously been assumed. The snail enzyme is thought to recognize a sequence at least two nucleotides long the pancreatic and E. coli enzymes recog- nize a sequence of at least three nucleotides and the spleen DNase one of at least four nucleotides. The specificity of the DNases remains constant throughout the course of digestion and these enzymes may not be too unlike therestriction enzymes except that the nucleotide sequences they recognize are much shorter. A method of using these enzymes in nucleotide sequence studies has been proposed.240 Neutron activation analysis has been used to measure the total and terminal phosphorus contents of oligonucleotide^,^^^ and thus their molecular weights can be calculated.The method is claimed to use less than a milligram of polymer of molecular weight lo7. Two satellite DNAs have been investigated. The original satellite the ‘poly- (dAT)’ from crabs has been shown to possess 89 % of the thymine residues (and hence also the adenine residues) as XpTpTpX and a further 7 %as XpTpTpTpX.242 This non-random base arrangement explains the anomalously low density of this satellite DNA. A satelIite DNA from kangaroo rat has been found to have the sequence (27),243each diploid cell containing 80 x lo6 repetitions. 5‘A C A C A G C G G G 3’ 3’T GT GT C GC C C “5’ ( 1 (27) 236 G. M. Rubin J. Biol. Chem. 1973 248 3860. 23’ See Nature New Biol.1973 246 129. 238 K. Murray and R. W. Old Progr. Nucleic Acid Res. Mol. Biol. 1973,14 to be published. 239 A. Devillers-Thiery S. D. Ehrlich and G. Bernardi European J. Biochem. 1973 38 416 and the following fouY papers; J. Laval J. P. Thiery S. D. Ehrlich C. Paoletti and G. Bernardi European J. Biochem. 1973,40 133 and the following three papers. 240 G. Bernardi S. D. Ehrlich and J. P. Thiery Nature New Biol. 1973 246 36; S. D. Ehrlich J. P. Thiery R. Devillers-Thiery and G. Bernardi Nucleic Acids Res. 1974 1 87. 241 L. Clerici E. Sabbioni F. Campagnari S. Spadari and F. Girardi Biochemistry 1973 12 2887. 242 S. D. Ehrlich J. P. Thiery and G. Bernardi Biochem. Biophys. Acta 1973 312 633. 243 K. Fry R. Poon P. Whitcome J. Idriss W. Salser J.Mazrimas and F. Hatch Proc. Nut. Acad. Sci. U.S.A. 1973,10 2642. 652 R. T. Walker Modern methods available for obtaining the primary sequence of DNA include:238 (i) the use of the repair reaction of DNA polymerase I for single- stranded DNA regions (the length of DNA repaired can be restricted by providing only two or three deoxynucleoside triphosphates and a ribonucleotide can also be incorporated in the presence of Mn2 +);(ii) the specific labelling of the 5‘- or the 3’-termini;(iii) the use of enzymes to produce double-strand breaks at specific sites ;(iv) the in nitro transcription reaction to analyse regions of DNA around the promoters; (v) the protection of a region of DNA by a protein or ribosomes followed by analysis of the protected fragment; and (vi) the use of partial endonuclease digests of uniformly labelled DNA to give large fragments which can subsequently be analysed by chemical and enzymatic degradative methods.DNA polymerase I has been used to show that the cohesive ends of phage $80 have identical sequences to those of phage A.244 DNA polymerase I has also been primed by a synthetic octadeoxynucleotide complementary to a sequence of phage f DNA and the adjacent DNA sequence of 50 nucleotides has been deter- mined.245 Despite the fact that the sequence of the octanucleotide was chosen to be complementary to a DNA sequence coding for the coat protein the sequence of the DNA obtained shows that it is probably an inter-cistronic region. The sequence is very T-rich and contains several short repeated sequences.The amino-acid sequence of the coat protein is now thought to be incorrect. Khorana has put his ability to synthesize oligodeoxynucleotides (22 units in length) to good use by determining the sequence of DNA in the phage 480,which contains the tRNATy‘ gene past the precursor tRNA sequence into the promoter and terminator regions of the phage genome.246 Using a restricted number of deoxyribonucleoside 5’-triphosphates and also the ribosubstitution technique a sequence of 23 nucleotides into the terminator region beyond the DNA coding for the CCA end has been determined. This sequence contains two palindromic sequences and also several elements of symmetry. The sequence of an octanucleo- tide of the promoter region beyond the 5’-end of the terminal pppG of the pre- cursor tRNA has been found to be ACGCGGGG.The properties required of primers used in the repair reaction of DNA poly- merase I have been investigated.247 Oligonucleotides with a high purine content (needless to say the most difficult to synthesize) are the best primers and usually a length of 8-12 nucleotides is required for specific initiation and primer activity. Some activity is detected with pieces as short as trimers and tetramers indicating that the enzyme must play a role in stabilizing the primer on the template. Polynucleotide kinase has been to label the 5’-termini of the DNAs from phage h and phage 424 and the sequences of the cohesive ends of these and 244 R. Bambara R. Padmanabhan and R.Wu J. Mol. Biol. 1973,75 741. 24s F. Sanger J. E. Donelson A. R. Coulson H. Kossel and D. Fischer Proc. Nar. Acad. Sci. U.S.A. 1973 70 1209. 246 P. C. Loewen and H. G. Khorana J. Biol. Chem. 1973 248 3489. 247 M. Goulian S. H. Goulian E. E. Codd and A. Z. Blumenfield Biochemistry 1973 12 2893; W. Oertel and H. Schaller European J. Biochem. 1973,35 106; G. G. Peters and R. S. Hayward ibid. 1973 31 360. 24a K. Murray Biochem. J. 1973 131 569. Nucleic Acids 653 that of several other lambdoid and non-lambdoid DNA phages249 have been determined. The sequences of all the lambdoid phages are identical and the sequence between the single-strand breaks has a two-fold rotational axis of sym-metry and is probably involved in the recognition of the site by the enzyme re- sponsible for the formation of the cohesive ends.The 3’-terminal nucleotide sequences of phage A have also been determined following the labelling of the 3’-end~~~’ and together with the known 5’-terminal sequences a sequence of 25 base pairs in the vicinity of the termini is now known. The cohesive ends of the non-lambdoid phages are quite long (19 bases) and they contain no apparent rotational axis of symmetry.249 Much more is now known about the restriction system used by many bacteria to recognize and destroy foreign DNA. Each system consists of two enzymes. One the restriction enzyme is an endonuclease which cleaves foreign but not host DNA at specific sites often by means of two single-strand breaks a short distance apart to create cohesive ends of characteristic sequence for each enzyme.The second enzyme is a methylase which methylates the host DNA to prevent its degradation. Many restriction enzymes each of which will be accompanied by a methylase enzyme have been discovered and a system of nomenclature has been proposed251 which it is hoped will be adopted by everyone in this field before the present chaos is further increased. The proposed nomenclature is given in the Table together with a list of the known sites of action of the restriction enzymes. The use of these enzymes in DNA sequence determination is already apparent and they have also been used to obtain a genetic map of the SV40,251,252 4X174,253 and A,254 genomes. A simple assay for restriction endonucleases has been proposed.255 The DNA sequences recognized by the restriction enzymes have so far all been shown to possess a high degree of symmetry238 and the one methylase enzyme which has been extensively studied has been shown very pro- bably to methylate that sequence in the host DNA which would have been cleaved by the endonuclease thus confirming the one substrate-two enzyme concept for this system.256 In rather an ominous development a biologically functional bacterial plasmid has been constructed in uitro by joining restriction endonuclease-generated fragments of separate plasm id^.^^' This hybrid plasmid DNA has been inserted 249 K.Murray and N. E. Murray Nature New Biol. 1973 243 134. P. H. Weigel P. T. Englund K. Murray and R. W. Old Proc.Nut. Acad. Sci. U.S.A. 1973 70 1151 ;G. S. Ghangas E. Jay R. Bambara and R. Wu Biochem. Biophys. Res. Comm. 1973 54 998. 2s’ K. J. Danna G. H. Sack jun. and D. Nathans J. Mol. Biol. 1973 78 363. 2s2 G. H. Sack and D. Nathans Virology 1973,51 517. 2s3 C. Y.Chen C. A. Hutchinson and M. H. Edgell Nature New Biol. 1973 243 233; M. Sclair M. E. Edgell and C. A. Hutchinson J. Virol. 1973 11 378. 2s4 B. Allet P. G. N. Jeppesen K. J. Katagiri and H. Delius Nature 1973 241 120. *” F. M. DeFilippes Analyt. Biochem. 1973 52 637. 2s6 H. W. Boyer L. T. Chow A. Dugaiczyk J. Hedgpeth and H. M. Goodman Nature New Biol. 1973 244 40. ” S. N. Cohen C. Y. Chang H. W. Boyer and R. B. Helling Proc. Nut. Acad. Sci. U.S. A. 1973,70 3240. 654 R. T. Walker Table Abbreviations and DNA sequences at sites of restriction for restriction enzymes Source of enzyme Abbreviat iona DNA sequence at restriction siteb Reference Haemophilus injluenzae R.Hin,I HinJI Unknown - strain Ra Haemophilus injluenzae R.HindII 45’ pG-T-YTR-A-C 260 strain Rd C-A-R~Y-T-~p 5’ Haemophilus injuenzae R.HindIII 5’ PA’A-G~C-T-T 238 strain Rd T-T-C~G-A-AP3.5’ Escherichia coli R.Eco, 5‘ PG~A-A~T-T-c 26 1 resistance transfer factor RI C-T-TLA-A-G~I f 5’ Escherichia coli R.Eco,, + I 5’ pC-C-A-G-G 262 resistance transfer factor RII G-G-T-C-CP5‘ I t Haemophilus aegyptius R.Hae C-CGG-G~ 4 5‘ PG-GTC-C 5’ 238 Haemophilus aphirophilus R.Hap 5‘ ~C~C~G-G 263 G-GIC-CP 5’ Haemophilus parainjuenzae R.Hpa1 HpaII t &known Restriction enzymes are designated R and modification enzymes M followed by the three-letter code describing the organism from which they were obtained.Subscripts describe the strain or a plasmid carried by the organism and where more than one enzyme is produced by a given strain these are distinguished by Roman numerals written in line with the code for the enzyme. The broken line drawn through the sequence around the sites of restriction represents an axis of two-fold rotational symmetry and the arrows show the position of hydrolysis of the phosphodiester bonds. Y is a pyrimidine and R a purine residue. into E. coli by transformation and has been shown to be biologically functional so that the bacterium possesses genetic properties and base sequences from both parent DNA molecules.This genetic engineering requires little skill as the restric- tion enzyme produces complementary cohesive ends from the two plasmids which can then be joined by ligase. It has already been suggested that it would be ‘interesting’ to incorporate a tetracycline-resistance gene from a plasmid into bacteria and no doubt the medical profession will find it most ‘interesting’ to be confronted with a whole new series of bacterial strains which possess specific drug resistance. Further implications of the technique are obvious and one can only hope that workers in this field will ‘restrict’ their own enthusiasm in design- ing experiments to see what happens when various DNA molecules are linked together particularly where the DNA from oncogenic viruses is concerned.Nucleic Acids 655 h I I dI-e U W c < u u < 0 8I-U c u u < u < < U % U u U v) I I 4 U c U U c (3 u c u U I-< 0 u c u I-I-e u V k-W c W W 3 U 3 V 0 d u < U U 0 u U u U u U u 3 3 *3 U u 4 U 3 4 0 3 u 3 3 U "< b, ou n d & E 656 R. T. Walker Finally more is now understood about the interaction of DNA operators with protein repressors. In the lactose operon of E. coli the DNA sequence protected by the repressor has been isolated and its sequence determined.The DNA was transcribed into RNA and a sequence of 24 base pairs258 was deter- mined. Using a mutant E. coli strain the 5'-end of the Zac mRNA has been transcribed in vitro and its initial sequence was found to match the sequence of the operator fragment which was followed by an AUG starting at residue 39 and continuing with an RNA sequence which codes for the amino-terminal sequence of B-galactosidase. This sequence is shown in Figure 2. The operator fragment has a symmetrical arrangement of bases and the method by which the repressor and operator interact is being investigated. However all repressor-operator interactions are not as simple as this system. In bacteriophage A,259 two lambda operators exist to which the lambda repressor protein binds to maintain the phage in an inactive state.More than one molecule of repressor binds per operator molecule and eventually two sequences of 100 base pairs each are covered. A model is suggested in which the operator consists of a sequence of some 35 base pairs which binds a dimeric repressor and four additional monomer units may then add to sequences ca. 15 base pairs long adjacent to the primary sequence. The two lambda operators are known to have different DNA sequences and the system is obviously very complicated. It is interesting that the operator sequences were obtained following the action of restriction endonucleases which act at symmetrical sequences and this suggests that the sequence of this promoter may also possess elements ofsymmetry.Thanks are due to Dr. R. J. H. Davies who collected much of the material for the section on Photochemistry and Physical Chemistry of Polynucleotides. 258 W. Gilbert N. Maizels and A. Maxam Cold Spring Harbor Symp. Quantitative Biol. 1973 38 845. 2s9 T. Maniatis and M. Ptashne Nature 1973 246 133; T. Maniatis M. Ptashne and R. Maurer Cold Spring Harbor Symp. Quantitative Biol. 1973 38 857. "O T. J. Kelly and H. 0.Smith J. Mol. Biol. 1970 51 393. 261 J. Hedgpeth H. M. Goodman and H. W. Boyer Proc. Nut. Acad. Sci. U.S.A. 1972 69 3448. 262 C. H. Bigger K. Murray and N. E. Murray Nature New Biol. 1973 244 7. 263 H. Sugisaki and M. Takenami Nature New Biol. 1973 246 140.

ISSN:0069-3030    

DOI:10.1039/OC9737000624

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

21 General Methods By W. B. MOTHERWELL and J. S. ROBERTS Chemistry Department University of Stirling Stirling 1 Alkanes The anion derived from lithium triethylborohydride is an exceptionally potent nucleophile for displacement reactions with organic halides.’ Although tertiary halides react slowly and tend to give elimination products the corresponding alkanes are generally formed in excellent yield even from secondary cycloalkyl bromides and neopentyl systems which are normally highly resistant to sub- stitution. Studies with the readily prepared deuteriated analogue reveal that reaction occurs with clean stereochemical inversion. Masamune and his co- workers2 have also prepared a new hydride reagent by treatment of lithium trimethoxyaluminium hydride with cuprous iodide.Primary secondary tertiary allyl aryl vinyl and neopentyl bromides are all smoothly reduced to the hydro- carbons in very high yield at room temperature and primary and secondary mesylates also react. An unusual stereochemical dependence on substrate structure has however been uncovered by use of the deuteriated reagent. Thus in the 2-substituted norbornane series bromides are reduced with complete retention of configuration whereas the corresponding mesylates react with exclusive inversion. An excellent alternative to the Clemmensen method for the reduction of aryl ketones involves reaction with a trialkylsilane in trifluoroacetic acid.3 Nitriles undergo a reductive elimination of the cyano-group on treatment with alkali metals in HMPA.4 Full details have now been described for the ‘tandem alky- lation’ sequence in which treatment of an aromatic aldehyde or ketone with an organolithium reagent followed by lithium-ammonia reduction in the same vessel leads to the alkylated aromatic hydrocarbon in excellent yield.5 Pursuing their studies on organocopper chemistry Posner and his co-workers6 have now developed an efficient sequence for the conversion of an aldehyde carbonyl group into a tertiary alkyl carbon atom in which each of the three H.C. Brown and S. Krishnamurthy J. Amer. Chem. SOC. 1973,95 1669. ’ S. Masamune P. A. Rossy and G. S. Bates J. Amer. Chem. SOC.,1973 95 6452. C. T. West S. J. Donnelly D. A. Kooistra and M. P. Doyle J. Org. Chem. 1973,38 2675. T. Cuvigny M.Larcheveque and H. Normant Bull. SOC.chim. France 1973. 1174. S. S. Hall and S. D. Lipsky J. Org. Chem. 1973 38 1735. G. H. Posner and D. J. Brunelle Tetrahedron Letters 1973 935; J. Org. Chem. 1973 38 2747 ;J.C.S. Chem. Comm. 1973,907. 657 W. B. Motherwell and J. S. Roberts alkyl groups may be different (Scheme 1). Certain ketones can also be success-fully transformed. 0 II Reagents i Li '[ArSO,CHP(OR),] -; ii RiCuLi H + ;iii Na-Hg scheme 1 Phenolic hydroxy-groups in the form of their sulphonic esters can be reductively removed by catalytic hydrogenation with palladium-charcoal catalyst at mod- erate temperature and atmospheric pressure.' The cross-coupling reaction of secondary racemic Grignard reagents with aryl or unsaturated halides takes place stereospecifically in the presence of a chiral nickel complex ;although some isomerization occurs this reaction can be used to prepare optically active hydrocarbons.* The reductive coupling of aralkyl halides by bivalent vanadium complexes is unique in giving only the dimeric Wurtz prod~ct.~ The preparation of isotopically labelled aromatic substrates continues to generate interest.Perdeuteriated hydrocarbons can be conveniently prepared on a large scale either by using high temperatures and dilute acid conditions" or by employing a platinized short-fibre asbestos catalyst.' Deuterium oxide acts as the isotope source in both cases. A cautionary note on the use of organo-aluminium dihalide catalysts has been sounded.I2 Two pathways for the specific introduction of one deuterium atom are the replacement of the thallium residue in arylthallium ditrifluoroacetates with sodium borohydride in deuteriated ethanol,13 and the reduction of aryl halides with sodium borodeuteride and palladium ch10ride.l~ 2 Alkenes The Wittig reaction remains as an unchallenged cornerstone of organic synthesis not only serving in its own right but also providing inspiration for mechanistically ' K.Clauss and H. Jensen Angew. Chem. Internat. Edn. 1973 12 918. * G. Consiglio and C. Botteghi Helv. Chirn. Acta 1973 56 460. T. A. Cooper J. Amer. Chem. SOC.,1973,95,4158. lo N. H. Werstiuk and T. Kadai Canad. J. Chem. 1973 51 1485. G. Fischer and M. Puza Synthesis 1973 218. 'I J. L. Garnett M. A. Long R.F. W. Vining and T. Mole Tetrahedron Letters 1973 4075. l3 R. B. Herbert Tetrahedron Letters 1973 1375. '' T. R. Bosin M. G. Raymond and A. R. Buckpitt Tetrahedron Letters 1973 4699. General Metho& related procedures. A generally applicable method for the synthesis of substituted con-jugated cyclohexadienes has been reported independently by two groups' (Scheme2) thus extending an isolated observation by Buchi and Wuest.16 More- over the American group have shown that the use of an alicyclic enone offers a quick and convenient entry to anti-Bredt 01efins.l~ R1,)$ + Ph,P=O R2 Scheme 2 An interesting observation by Whitesides and his co-workers' relates to the use of iron-moderated carbonium ions as reagents for organic synthesis.These undergo reaction with nucleophiles as shown in Scheme 3. This approach is claimed to be especially useful for the preparation of cis-allylphosphonium salts and in conjunction with the deuteriated iron complex as a source of specifically labelled isoprene units for biosynthetic studies. A second group have also des- cribed the addition of nucleophiles to metal-activated olefins as a synthetically useful process.' 1iii Fe(CO),' + Reagents i Fe,(CO),; ii CO-HBF,-CF,CO,H; iii Nu-Scheme 3 The scope and utility of silylated reagents for olefin synthesis have been extended by the discovery that silyl-substituted carbanions of the type [(Me,Si),CH -,I -Is (a)W. G. Dauben D. J. Hart J. Ipaktschi and A. P. Kozikowski Tetrahedron Letters 1973,4425; (b)F.Bohlmann and C. Zdero Chem. Ber. 1973 106 3779. l6 G. Buchi and H. Wiiest Helo. Chim. Acta 1971 54 1767. " W. G. Dauben and J. Ipaktschi J. Amer. Chem. SOC.,1973,95 5088. T. H. Whitesides R. W. Arhart and R. W. Slaven J. Amer. Chem. SOC.,1973,95 5792. l9 A. Rosan M. Rosenblum and J. Tancrede J. Amer. Chem. SOC.,1973,95 3062. W.B. Motherwell and J. S. Roberts can be prepared by cleavage of a trimethylsilyl group from the compound [(Me,Si) +lCH -,I using sodium methoxide in HMPA.20 A sulphur analogue of the Wittig reaction involves treatment of the carbonyl compound with the carbanion derived from a t-butyl alkyl sulphoxide and reaction of the resultant /I-hydroxy-sulphoxide with N-bromo or N-chloro-succinimide to give a thermally labile B-sultine which decomposes to the olefin.21 This method is especially suited to the formation of trisubstituted olefins.P-Hydroxy- sulphoximines readily prepared by the reaction of a carbonyl compound with N-methylphenylsulphonimidoylmethyl-lithium,are also useful precursors for olefin synthesis since they undergo reductive elimination on treatment with aluminium amalgam followed by acetic acid.22 Other aspects of the chemistry of this important sulphoximine group have been concisely reviewed.23 A facile method for the conversion of a carbonyl into an exomethylene group involves sequential treatment with 3-pyrroline perchlorate diazomethane and n-butyl- lithium. The intermediate aziridinium ylide thus formed breaks down immediately to the ~lefin.~~ The ability of the sulphonyl grouping to stabilize an adjacent carbanion has been exploited by Julia and Paris2' in a new synthesis of tri- and tetra-substituted alkenes (Scheme 4) A complementary approach via up-unsaturated phenyl sulphones has also been described.26 S02Ph R S0,PhI OHI R lARz R( I I R2 R3 1ii (R'= H) S02Ph OR5 PhOzS)4R3 +-tR4 R' R2 R3 R2 'R4 Reagents i RSX;ii POCl,; iii M-Hg R5 = Ac Ms or Ts M = Na or A1 Scheme 4 Reagents for the direct deoxygenation of organic compounds continue to find application in olefin synthesis.A French group have shown that the THF complex of titanium trichloride reacts with magnesium under argon to give a H. Sakurai K. 1. Nishiwaki and M. Kira Tetrahedron Letters 1973 4193.21 F. Jung N. K. Sharma and T. Durst J. Amer. Chem. SOC.,1973.95 3420. 22 C. R. Johnson J. R. Shanklin and R. A. Kirchhoff J. Amer. Chem. Soc. 1973 95 6462. 23 C. R. Johnson Accounts Chem. Res. 1973,6 341. 24 Y. Hata and M. Watanabe J. Amer. Chem. SOC.,1973 95 8450. 25 M. Julia and J.-M. Paris Tetrahedron Letters 1973 4833. 26 (a) V. Pascali N. Tangari and A. Umani-Ronchi J.C.S. Perkin I 1973 1166; (b) V. Pascali and A. Umani-Ronchi J.C.S. Chem. Comm. 1973 351. General Methods lower-valent titanium species which has proved to be an excellent reagent for the intermolecular deoxygenation of carbonyl compounds to 01efins.~’ Unlike the lower-valent tungsten halides reported last year high yields of olefins can be obtained from both aliphatic and aromatic aldehydes and ketones.Thus acetone gives tetramethylethylene in 98 % yield ! The year under review has also witnessed the emergence of synthetically useful organoselenium reagents. Sharpless and his co-workers28 report that alkyl phenyl selenoxides eliminate under very mild conditions and triphenylphosphine selenide in trifluoroacetic acid is the reagent of choice for the preparation of olefins from epoxides with retention of stereochemistry. Conversions of the cyclohexanone -+cyclohexene type are normally carried out via reduction of an enolic derivative. Barton and his colleagues30 recommend reaction of the carbonyl group with toluene-a-thiol and subsequent desulphuri- sation with nickel boride. Iron pentacarbonyl selectively transforms enol acetates vinyl chlorides and a/?-unsaturated aldehydes into the corresponding olefins in modest yie1d.j However the reaction of a carbonyl compound with chlorotri- methylsilane and zinc in ether solution offers a new one-step method for transfor- mations of this type in preparatively useful yield.32 Bis-cyclo-octa- 1,5-(diene)nickel reacts with the thionocarbonates of vicinal diols to produce alkenes in an efficient and stereospecific manner.33 Methyltriphenoxyphosphonium iodide in HMPA is a mild reagent for the selective dehydration of secondary alcohols in the presence of tertiary with a high predominance of the more stable Saytzeff alkene.34 Further details have been published on the useful P-2 nickel catalyst which is remarkably sensitive to the steric environment of a double bond and reduces dienes and acetylenes with high ~electivity.~ In an elegant synthesis of /?-acorenol use has been made of the retro-ene reaction to transform an enone into a rearranged olefin (Scheme 5).36 C0,Et &O Me Me Reagents i MeLi; ii CICH,OMe I OMe Scheme 5 2’ S.Tyrlik and 1. Wolochowicz Bull. SOC.chim. France 1973 2147. 20 K. B. Sharpless M. W. Young and R. F. Lauer Tetrahedron Letters 1973 1979. 29 D. L. J. Clive and C. V. Denyer J.C.S. Chem. Comm. 1973,253. 30 R. B. Boar D. W. Hawkins J. F. McGhie and D. H. R. Barton J.C.S. Perkin I 1973 654. 31 S. J. Nelson G. Detre and M. Tanabe Tetrahedron Letters 1973 447. 32 W. B. Motherwell J.C.S. Chem. Comm. 1973 935. 33 M.F. Semmelhack and R:D. Stauffer Tetrahedron Letters 1973 2667. 34 R. 0.Hutchins M. G. Hutchins and C. A. Milewski J. Org. Chem. 1972 37 4190. 35 C. A. Brown and V. K. Ahuja J.C.S. Chem. Comm. 1973 553; J. Org. Chem. 1973 38 2226. 36 W. Oppolzer. Helv. Chim. Acta 1973 56 1812. 662 W.B. Motherwell and J. S. Roberts Synthetic challenges in the terpene field continue to stimulate the development of new methods for the stereospecific construction of highly functionalized olefins. Corey and Chen37 have found that the addition of organocopper re- agents to A2s4-dienoic esters results in a highly stereoselective 1,6addition to yield tri- and tetra-substituted olefins. Sigmatropic rearrangements of sulphur- containing intermediates have claimed the attention of several groups.Thus a new version of the dithioester thio-Claisen rearrangement provides a highly stereoselective synthesis of (E)-trisubstituted double bonds,38 and the [2,3] sigmatropic shift of a-substituted methylallylsulphonium ylides affords an entry to trans-trisubstituted 01efins.~’ Readily prepared ally1 sulphones undergo thermal rearrangement involving the transfer of an alkyl group from sulphur to carbon with simultaneous extrusion of sulphur dioxide.40 Evans and his co-w~rkers~~ have now described a remarkably stereoselective synthesis of trisubstituted allylic alcohols involving alkylation of sulphoxide-stabilized allylic anions (vinyl anion equivalents) followed by [2,3] sigmatropic shift and subsequent desulphurization. This clever scheme is unfortunately plagued by non-regioselec- tivity in the alkylation step.Normant and his co-~orkers~~ have also extended their work on the reactions of vinylcopper reagents to include a synthesis of stereospecifically trisubstituted allylic alcohols. A novel method for the conversion of epoxides into allylic alcohols which avoids the use of strong base has been developed (Scheme 6).43 A particularly striking and apparently general feature of this sequence is that in the decomposition of the P-hydroxy-selenoxide elimination occurs away from the hydroxy-group. An adaptation of the Julia- Johnson olefin synthesis has been used to prepare stereoselectively trisubstituted allylic alcohols in good yield.44 eL+ 0 ‘E‘ SePh 1 ii OH r OH f 1 Reagents i PhSe -;ii H 202 Scheme 6 37 E.J. Corey and R. H. K. Chen Tetrahedron Letters 1973 161 1. 38 H. Takahashi K. Oshima H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973 95 5803. For further extensions of this approach consult refs. 181 182. 39 P. A. Grieco D. Boxler and K. Hiroi J. Org. Chem. 1973 38 2572. 40 J. B. Hendrickson and R. Bergeron Tetrahedron Letters 1973 3609. 41 D. A. Evans G. C. Andrews T. T. Fujimoto and D. Wells Tetrahedron Letters 1973 1385 1389. 42 J. F. Normant G. Cahiez C. Chuit and J. Villieras Tetrahedron Letters 1973 2407. 43 K. B. Sharpless and R. F. Lauer J. Amer. Chem. SOC.,1973 95 2697. 44 H. Nakamura H. Yamamoto and H. H. Nozaki Tetrahedron Letters 1973. 11 1. General Methods The allylic epoxide (1) can be selectively opened either to the (2)-or (&isomer of the trisubstituted allylic alcohol (2) or to the homoallylic alcohol (3) by a judi- cious choice of reducing medium.4s A practical method for the stereospecific inversion of an acyclic di- or tri- substituted double bond has been developed by Vedejs and F~chs.~~ Conversion into the epoxide with retention of stereochemistry followed by ring opening with lithium diphenylphosphide and subsequent treatment with methyl iodide generates a phosphorus betaine which fragments to the alkene with overall inversion of stereochemistry.Organoboranes are also important intermediates in two stereospecific diene syntheses. Monochloroborane diethyl etherate reacts with alkynes to give isolable dialkenylchloroboranes which are readily converted into cis-trans-dienes by reaction with sodium hydroxide and iodine or into cis-olefins by protonoly- s~s.~~ trans-trans-Dienes can be prepared through the intermediacy of the novel organoborane (4) (Scheme 7).48 CIFR' R'C=CCl 4 H K"h H RZ (4) RZ"i LR\ R' ttB R' OMe Reagents i,+BH, -25 "C;ii R2C-CH; iii NaOMe 25 "C;iv Pr'C0,H Scheme 7 a-Mercaptoketones react with vinyltriphenylphosphonium bromide and base to give dihydrothiophens in varying yield.Oxidation to the sulphone and cheletropic fragmentation provides a regiospecific and stereospecific diene ~ynthesis.~' " R. S. Lenox and J. A. Katzenellenbogen J. Amer. Chem. SOC.,1973 95 957. 46 E. Vedejs and P. L.Fuchs J. Amer. Chem. SOC.,1973,95 822. 4' H. C. Brown and N. Ravindran J. Org. Chem. 1973.38 1617. 48 E.-I. Negishi and T. Yoshida J.C.S. Chem. Comm. 1973 606. 49 J. M. Mclntosh and H. B. Goodbrand Tetrahedron Letters 1973 3157. W. B. Motherwell and J. S. Roberts Olefins can be regenerated from their dibromides by treatment with sodium thiosulphate in DMSO.” 3 Alkynes and Allenes Trialkylalkynylborate anions formed by treatment of lithio-acetylides with trialkylboranes show promise of impressive synthetic utility. In the presence of iodine5’ or methanesulphinyl chloride” a primary or secondary alkyl group is transferred from boron to carbon yielding alkylacetylenes. Triarylboranes can also be employed in this reaction to give arylalkynes which are unobtainable by the more conventional alkylation sequence.Cuprous chloride in pyridine is an extremely efficient catalyst system for the oxidation of dihydrazones to acetylenes by molecular oxygen under very mild condition^.^ The base-induced reaction of certain non-enolizable carbonyl compounds with trimethylsilyldiazomethane or dimethylphosphonodiazomethaneprovides a simple one-step procedure for the preparation of the homologous alk~ne.’~ Diarylacetylenes can be obtained by the direct reaction of a,a-dichlorodibenzyl sulphides with triphenylphosphine and potassium t-butoxide.’ Stereospecific methods for the construction of cis-and trans-enyne units have been outlined by Corey and R~den.~~ Metallic reduction of the dibromoacetal (5) can be controlled to give either the allene (6) or the cyclopropanone acetal (7) on a preparatively useful scale.” Propargyl esters e.g.(8) can be smoothly rearranged by silver-ion catalysis to allenic esters e.g. (9).’* R’ R’ R2+C=C-R3 MR3 0-0-~4 R2 OCOR~ (8) (9) ” K. M. Ibne-Rasa A. R. Tahir and A. Rahman Chem. and Ind. 1973 232. 51 H. C. Brown J. A. Sinclair M. M. Midland A. Suzuki N. Miyaura S. Abiko and M. Itoh J. Amer. Chem. SOC. 1973 95 3080. ’’ M. Naruse K. Utimoto and H. Nozaki Tetrahedron Letters 1973 1847. Further uses of trialkylalkynylborate anions are cited in refs. 132 157 175 and 176. 53 J. Tsuji H. Takahashi and T. Kajimoto Tetrahedron Letters 1973 4573. 54 E. W. Colvin and B. J. Hamill J.C.S. Chem. Comm. 1973 151. ” R.H. Mitchell J.C.S. Chem. Comm. 1973,955. 56 E. J. Corey and R. A. Ruden Tetrahedron Letters 1973 1495. ’’ G. Giusti and C. Morales Bull. SOC.chim. France 1973 382. H. Schlossarczyk W. Sieber M. Hesse H.-J. Hansen and H. Schmid Hefu. Chim. Acta 1973 56 875. General Methods 665 a-Acetylenic epoxides are readily prepared and can be converted into a- allenic alcohols either by reaction with a dialkylcopperlithium reagents9 or by treatment with an organoborane in the presence of a small amount of oxygen.60 4 Alkyl Halides The reaction of a secondary alcohol with N-halogenosuccinimide in the presence of triphenylphosphine gives the corresponding halide under mild conditions with complete inversion of stereochemistry.6 Dimethylbromosulphonium bromide is a convenient reagent for the conversion of alcohols into bromides through a mainly inversion process.62 Alkyl iodides are obtained in good yield from primary and secondary alcohols by treatment of the tosylate with magnesium i~dide.~ The successful preparation of cycloalkyl iodides without elimination is particularly noteworthy.Yields in the Kochi decarboxylation of acids to tertiary chlorides are markedly improved by using N-chlorosuccinimide as the halogen source and DMF-acetic acid as the solvent.64 Thus for example l-chlorobicyclo[2,2,2]octanewas ob- tained from the bridgehead acid in 95 % yield. Extremely facile ionic chlorination of saturated hydrocarbons can be achieved without rearrangement by treatment with sulphuryl chloride in ~ulpholane.~~ Ultraviolet irradiation provides a smooth and mild conversion of polyhalo- genomethyl groups into di- or mono-halogenomethyls.66 Dialkylaminosulphur trifluorides react readily with acids or aldehydes and ketones to give acyl fluorides and gem-difluoro-compounds re~pectively.~ The reaction of dibromodifluoromethane with tris(dimethy1amino)phosphine in glyme provides a reagent for the conversion of a carbonyl group into a difluoro- exomethylene group.68 Phenyltrifluoromethylmercury69 and bromodi-fluoromethylphosphonium salts7' represent two new and very useful sources of difluorocarbene.A very simple and stereospecific route to trans-alkenylboronic acids from terminal alkynes involves hydroboration with catecholborane and subsequent hydroly~is.~~ The potential of these reagents lies in their complementary be- haviour towards halogens.Reaction with iodine in the presence of sodium hydroxide yields the trans-alkenyl iodide whereas treatment with bromine 59 P. R. Ortiz de Montellano J.C.S. Chem. Comm. 1973 709. 6o A. Suzuki N. Miyaura M. Itoh H. C. Brown and P. Jacob Synthesis 1973 305. 61 A. K. Bose and B. Lal Tetrahedron Letters 1973 3937. 62 N. Furukawa T. Inoue T. Aida and S. Oae J.C.S. Chem. Comm. 1973 212. 63 J. Gore P. Place and M. L. Roumestant J.C.S. Chem. Comm. 1973 821. 64 K. B. Becker M. Geisel C. A. Grob and F. Kuhnen Synthesis 1973 493. " I. Tabushi Z. Yoshida and Y. Tamaru Tetrahedron 1973 29 81. 66 N. Mitsuo T. Kunieda and T. Takizawa J. Org. Chem.1973 38 2255. 6' L. N. Markovskij V. E. Pashinnik and A. V. Kirsanov Synthesis 1973 787. 68 D. G. Naae and D. J. Burton Synthetic Comm. 1973,3 197. 69 D. Seyferth and S. P. Hopper J. Org. Chem. 1972 37 4070. 70 D. J. Burton and D. G. Naae J. Amer. Chem. SOC.,1973,95 8467. 71 H. C. Brown T. Hamaoka and N. Ravindran J. Amer. Chem. SOC.,1973 95 5786 6456. 666 W. B. Motherwell and J. S. Roberts involves inversion of configuration to give the cis-alkenyl bromide thus paving a way for the preparation of vinylorganometallics of known stereochemistry. Although many mechanistic questions remain to be settled Grob and Becker7* have defined experimental conditions which consistently lead to the predominant cis-or trans-addition of hydrogen chloride to olefins.5 Alcohols Polymethylhydrosiloxane in combination with bis(dibuty1acetoxy)tin oxide or palladium on charcoal has been introduced for the selective reduction of aldehydes and ketones under neutral condition^.^^ Potassium tri-isopropoxy- borohydride is a highly stereoselective reagent for the rapid reduction of ketones to the thermodynamically less stable epimer of the corresponding Halides esters amides nitriles and epoxides are inert. In HMPA at 25”C tetrabutylammonium cyanoborohydride is an exceptionally mild reagent which reduces only alkyl iodides and to a lesser extent bromides to the alkane. How- ever the addition of acid to the medium drastically alters the reducing ability and permits the selective reduction of aldehydes even in the presence of ketonic and iodo-group~.~’ Hydroboration-oxidation of alkenes with monochloroborane diethyletherate is claimed to give the anti-Markownikoff alcohols in 299.5 % isomeric purity thus exhibiting a stronger regiospecificity than borane itself.76 Aliphatic and aromatic carboxylic acids are rapidly and quantitatively reduced to the primary alcohols by borane in THF.77 Ester nitro- halogen nitrile and keto-groups are unaffected.An improved synthesis of secondary alcohols from terminal alkynes has been published (Scheme 8).78 B13 / RI-CECH J-B R’-CH,-CH \ lii B~ R~CH,-CH-R~ * R~CH,-CH-R~ I I OH H Reagents i ,2 moles; ii MeLi R’Br; iii NaOH-H,O 0 Me Me Scheme 8 ” K. B. Becker and C. A. Grob Synthesis 1973,789.73 J. Lipowitz and S. A. Bowman J. Org. Chem. 1973 38 162. 74 C. A. Brown S. Krishnamurthy and S. C. Kim J.C.S. Chem. Comm. 1973 391. ’’ R. 0.Hutchins and D. Kandasamy J. Amer. Chem. SOC.,1973,95,6131. ’‘ H. C. Brown and N. Ravindran J. Org. Chem. 1973 38 182. ’’ N. M. Yoon C. S. Pak H. C. Brown S. Krishnamurthy and T. P. Stocky J. Org. Chem. 1973,38 2786. 78 G. Zweifel. R. P. Fisher and A. Horng Synthesis. 1973 37. General Methods 667 The lithium-triethylcarboxide-inducedreaction of a,a-dichloromethyl methyl ether with a representative series of trialkylboranes is reported to give tertiary carbinols in very high yield at low temperat~re.~’ Improved procedures have been presented for the Prkvost reaction. Treatment of an alkene with a thallium carboxylate and iodine gives the trans-a-iodo- carboxylate in high yield which can be elaborated to the diol in standard fashion.” A second report claims that silver acetate is unnecessary and may be replaced by cupric or potassium acetate or even by acetic acid.81 A potentially more simple procedure is the oxidation of alkenes by iodine tristrifluoroacetate which gives the cis-esters of vicinal diols.82 A useful synthesis of 1,6diols involves ring opening of an epoxide with the anion derived from the reaction of a trialkylborane with a vinyl-lithium com- pound followed by oxidative work-~p.~~ The ortho-nitrobenzoate grouping is useful for the protection of alcohols and Regeneration by intramolecular displacement of the alcohol occurs on treatment with zinc dust and ammonium chloride.Corey and Suggs8’ have recommended the use of the allyloxycarbonyl group for the protection of hydroxy- and amino-functions. 6 Ethers The transition-metal-catalysed epoxidation of allylic and homoallylic alcohols by tertiary butyl hypochlorite is a highly regio- and stereo-selective process.86 An improved method for the preparation of epoxides from highly hindered ketones involves formation of a P-hydroxy-sulphide with phenylthiomethyl- lithium followed by alkylation at sulphur and subsequent base treatment.87 (NN-dialky1amino)dimethyloxosulphoniumfluoroborate has been recommended as a nucleophilic methylene-transfer reagent.88 A stereospecific method for the formation of cis- and trans-epoxides from the benzylidene acetal of the same diol has been outlined (Scheme 9).89 The photolysis of $-unsaturated nitrite esters provides a useful method for the preparation of functionalized tetrahydrofuran system^.'^ A new furan 79 (a) H.C. Brown and B. A. Carlson J. Org. Chem. 1973 38 2422; (6) H. C. Brown J.-J. Katz and B. A. Carlson ibid. p. 3968. R. C. Cambie R. C. Hayward J. L. Roberts and P. S. Rutledge J.C.S. Chem. Comm. 1973 359. ” L. Mangoni M. Adinolfi G. Barone and M. Parrilli Tetrahedron Letters 1973 4485. ” J. Buddrus. Angew. Chem. Internat. Edn. 1973 12 163. 83 K. Utimoto K. Uchida and H. Nozaki Tetrahedron Letters 1973 4527. 84 D. H. R. Barton I. H. Coates and P. G. Sammes J.C.S. Perkin I 1973 599. E. J. Corey and J. W. Suggs J. Org. Chem.1973 38 3223 3224. 86 K. B. Sharpless and R. C. Michaelson J. Amer. Chem. SOC.,1973 95 6136. 87 J. R. Shanklin C. R. Johnson J. Ollinger and R. M. Coates J. Amer. Chem. SOC. 1973.95 3428. 88 C. R. Johnson and P. E. Rogers J. Org. Chem. 1973,38 1793. 89 D. A. Seeley and J. McElwee J. Org. ChPm. 1973 38 1691. 90 (a) M. P. Bertrand and J. M. Surzur Bull. SOC.chim. France 1973,2393; (6)R. Nouguier and J. M. Surzur ibid. p. 2399. W. B. Motherwell and J. S. Roberts OTs " i. ii iii Me -+ Me$Me Me Me H Mex'i('h Br Ph meso OY Ph 1ivO \ 1 O 0Y iv1 Me\? Reagents i NBS-H,O; ii TsCl; iii NBS-CCI,; iv base; v H,O; vi Br- Scheme 9 synthesis involves the oxa-analogue of the well-known vinylcyclopropane rearrangement (Scheme Q-H R' R2 R' R2 Reagents i Me,i-CH,; ii HgSO Scheme 10 Sodium hydride in THF at room temperature has been described as a reagent for the methylation of even highly hindered phenols.92 A convenient new route to alkyl hydroperoxides in excellent yield utilizes treatment of an alkyldichloroborane with oxygen and subsequent hydroly~is.~~ Cyclic disulphides can be prepared in high yield by sulphur treatment of lead dithiolates which are obtained by the almost instantaneous reaction of an a,o-dithiol and lead acetate in aqueous solution.94 91 M.E. Garst and T. A. Spencer J. Amer. Chem. SOC.,1973,95 250. 92 B. A. Stoochnoff and N. L. Benoiton Tetrahedron Letters 1973 21. 93 M. M. Midland and H. C. Brown J. Amer. Chem. SOC.,1973,95 4069.94 R. H. Cragg and A. F. Weston. Tetrahedron Letters 1973 655. General Methods 669 Additional reagents for the deoxygenation of sulphoxides to sulphides include acetyl chloride,g5 titanium tri~hloride,~~ and dichl~roborane.~' Di-isobutyl- aluminium hydride may prove to be a most efficacious reagent for the preparation of sulphides from sulph~nes.~~ 7 Amines Alkyldichloroboranes are even more reactive than their monohalogeno counter- parts and react with azides to give secondary amines in virtually quantitative yield with retention of stereo~hemistry.~~ Full details have been published of the rapid and quantitative reduction of primary secondary and tertiary amides of both aliphatic and aromatic carboxylic acids to the corresponding amine by excess diborane."' No products arising from cleavage of the amide linkage were detected.Secondary amides can be selectively cleaved in the presence of tertiary by using a diphenyldialkoxysulphurane followed by reduction of the sulphilimine to the free amine.'" The copper or palladium salts of aromatic acids react with ammonia under pressure to give aniline derivatives by exclusive ortho-attack and decarboxylation.' O2 Another modification of the Clarke-Eschweiler method for the methylation of primary and secondary amines involves reaction in methanol solution with a large excess of formaldehyde and subsequent borohydride reduction.' O3 A very good method for the monomethylation of aromatic amines in the presence of ester amide or nitrile functions involves prior formation of the N-aryl- aminomethylsuccinimide and then cleavage with sodium borohydride in DMS0.'04 Further studies on the use of triflamides for the monoalkylation and protection of amines have been detailed."' The addition of chlorosulphonyl isocyanate to a hexane solution of a tertiary alcohol provides an exceptionally simple route to the chlorosulphonyl amine and hence to the amine itself.'06 The procedure is also successful for other alcohols which can form moderately stable carbonium ions.The ene-reaction of protected diallylamines e.g. (lo),is a very useful method for the preparation of functionalized pyrrolidines e.g.(11) O7 Corey and Snider'08 have also used an aza-ene reaction of 4-phenyl- 1,2,4-triazoline-3,5-dione in the elaboration of the cyclohexene (12) to the prostanoid precursor (13).'' T. Numata and S. Oae Chem. and Ind. 1973 277. 96 T. L. Ho and C. M. Wong Synthesis 1973 206; S.vnthetic Comm. 1973 3 37. 97 H. C. Brown and N. Ravindran Synthesis 1973 42. 98 J. N. Gardner S. Kaiser A. Krubiner and H. Lucas Canad. J. Chem. 1973 51 1419. 99 H. C. Brown M. M. Midland and A. B. Levy J. Amer. Chem. Sor. 1973,95 2394. loo H. C. Brown and P. Heim J. Org. Chem. 1973,38 912. lo' J. A. Franz and J. C. Martin J. Amer. Chem. SOC. 1973 95 2017. Io2 G. G. Arzoumanidis and F. C. Rauch J.C.S. Chem. Comm. 1973 666. Io3 B. L. Sondengam J. H. Hemo and G. Charles Tetrahedron Letters 1973 261. Io4 S. B. Kadin J. Org. Chem. 1973,38. 1348. I"' (a)J. B. Hendrickson and R.Bergeron Tetrahedron Letters 1973 3839 4607 (b).I.B. Hendrickson R. Bergeron A. Giga and D. Sternbach J. Amer. Chem. Sor. 1973,95 3412. Io6 J. B. Hendrickson and I. Joffee J. Amer. Chem. Sor. 1973,95 4083. Io7 W. Oppolzer E. Pfenninger and K. Keller ffelu. Chim. Acta 1973 56 1807. lo* E. J. Corey and B. B. Snider Tetrahedron Letters 1973 3091. W.B. Motherwell and J. S. Roberts (13) Very good yields are obtained for the reduction of aromatic nitro-compounds to amines by using sodium borohydride dihalogenobis(tripheny1phosphine)-nickel(rr).'O9 Tri-iron dodecacarbonyl and methanol shows promise as a syn- thetically useful reagent for the reduction of the carbon-nitrogen double bond.' ' The Friedel-Crafts alkylation of anilines is often beset with experimental difficulty.In an extended investigation Gassmann and his colleagues" ' have shown that the azasulphonium salt (14) gives rise to an ylide which undergoes intramolecular ortho-alkylation to afford the thioether (15). Subsequent de- sulphurization yields the alkyl derivative. Two distinct routes are now available to these important salt precursors and simple modifications have led to the development of new indole and oxindole syntheses. Several additional methods are now available for the dequaternization of ammonium salts.' ' In particular the exceptional nucleophilic displacement ability of lithium n-propyl mercaptide in HMPA provides a mild and rapid method for the dealkylation of aromatic and aliphatic quaternary ammonium salts.Moreover this reagent displays a superior selectivity for the removal of methyl groups and hence paves the way for a general synthesis of tertiary amines.' ' On the other side of thecoin ethylene oxide has been found to facilitate the quater- nization of sterically hindered amines.' l4 Io9 K. Hanaya N. Fujita and H. Kudo Chem. and Ind. 1973 794. lo H. Alper J. Org. Chem. 1972 37 3972. 'I' P. G. Gassmann and T. J. van Bergen J. Amer. Chem. Soc. 1973 95 590 591 2718; P. G. Gassmann T. J. van Bergen and G. Gruetzmacher ibid.,p. 6508. 'Iz (a)T. L. Ho Synthetic Comm. 1973 3 99; (b) S. Gerszberg R. T. Gaona H. Lopez and J. Comin Tetrahedron Letters 1973 1269; (c) D. Aumann and L. W. Deady J.C.S. Chem. Comm. 1973 32. 'I3 R. 0.Hutchins and F.J. Dux J. Org. Chem. 1973 38 1961. A. Donetti and E. Bellora Tetrahedron Letters 1973 3573. General Methods 671 The vast array of new methods for protection of the amino-function have been the subject of a useful review.'15 Two reports describe the use of the iso- bornyloxycarbonyl group,' l6 and the ortho-nitrobenzoyl group is also useful for peptide synthesis.' ' An interesting example of tertiary amine protection during phenolic oxidative coupling involved use of the borane complex.' '' 8 Aldehydes and Ketones The specific oxidation of primary alcohols can be achieved in high yield with the commercially available chromium trioxide intercalated in graphite.' Dimethyl sulphide can be replaced by dirnethyl sulphoxide in the Corey-Kim oxidation of alcohols;'20 the only drawback to this modification is that chlorination of double bonds is a competing process.The same disadvantage is experienced in the use of the iodobenzene dichloride-pyridine oxidant.I2' The interesting observation has been made' 22 that sterically hindered secondary alcohols can be oxidized in the presence of DDQ ;unhindered alcohols e.g. cyclohexanol and cyclopentanol are recovered unchanged. High-yield oxidations of primary and secondary alcohols can be achieved with the chromium trioxide-3,Sdirnethyl- pyrazole complex.'23 Trityl ethers can be converted into aldehydes or ketones by disproportionation in the presence of catalytic quantities of salts of the tri- phenylmethyl cation.' 24 Dehalogenation of a-halogeno-ketones can be readily accomplished with titanium trichloride.' 25 Mild hydrolytic conditions using titanium tetrachloride have also been found for the conversion of vinyl chlorides' 26 and vinyl sulphides' into ketones.Grignard reagents react cleanly with S-(2-pyridyl)thioates (16) to give ketones in high yield.'28 The absence of tertiary alcohols can be rationa- lized in terms of the slow reaction of the Grignard reagent with the co-ordinated 'Is L. A. Carpino Accounts Chem. Res. 1973,6 191. I' (a)G. Jager and R. Geiger Annafen 1973 1535; (bJM. Fujino T. Fukuda S. Kobayashi and M. Obayashi Chem. and Pharm. Bull. (Japan) 1973,21 87. 'I7 A. K. Koul J. M. Bachhawat B. Prashad N. S. Ramegowda A. K. Mathur and N. K. Mathur Tetrahedron 1973 29 625. I M.A. Schwartz B. F. Rose and B. Vishnuvajjala J. Amer. Chem. Soc. 1973,95 612. I19 J.-M. Lalancette G. Rollin. and P. Dumas Canad. J. Chem. 1972 50 3058. 120 E. J. Corey and C. U.Kim Tetrahedron Letters 1973 919. J. Wicha A. Zarecki and M. Kocor Tetrahedron Letters 1973 3635. 122 J. Iwamura and N. Hirao Tetrahedron Letters 1973 2447. 123 E. J. Corey and G. W. J. Fleet Tetrahedron Letters 1973 4499. M. P. Doyle D. J. DeBruyn and D. J. Scholten J. Org. Chem. 1973 38 625. 125 T.-L. Ho and C. M. Wong Synthetic Comm. 1973,3 237. 126 T. Mukaiyama T. Imamoto and S. Kobayashi Chem. Letters 1973 715. T. Mukaiyama K. Kamio S.Kobayashi and H. Takei Bull. Chem. SOC.Japan; 1972 45 3723. 12* T. Mukaiyama. M. Araki and H. Takei J. Amer. Chem. SOC.,1973 95 4763.672 W. B. Motherwell and J. S. Roberts Yamamoto et ~1.'~~ have found that s-butyl-lithium in HMPA-THF is an efficient base for the generation of 1-(alky1thio)vinyl-lithium (18) which as was reported earlier by Corey and Seebach is an acyl anion synthon of considerable importance. A good method for converting a ketone into its methyl ketone analogue which is superior to the Wittig reaction involving a-methoxyethyli- denetriphenylphosphorane has been reported (Scheme 1l).' 30 Li OH .CO,H 0-c //O I II II MeCC0,Li R'C-COMe R'C-COMe I II II OMe R2 Me R2 Me 111 1 R' R' \ No lv \ /OMe CH-C + c=c / /\ R2 'Me R2 Me Reagents i R'R2CO; ii PhS0,Cl-py; iii heat K,CO,; iv H,O' Scheme 11 Both methyl-and phenyl-methoxycarbenepentacarbonyltungsten(o) react with diazoalkanes to form enol ethers in high ~ie1d.l~' A useful route to substituted ketones involves the alkylation or protonation of trialkylalkynylborate salts (19) followed by oxidation (Scheme 12)' 32 Over the past four years Meyers and his co-workers have amply demonstrated the tremendous versatility of 5,6-dihydro-l,3-oxazinesin the syntheses of a large array of aldehydes and ketones and functionalized derivatives thereof.Much of this elegant research has now been reported in and reviewed.'34 R' -I R:B + LiCECR2 + RiBCrCR' Li' RiBC=CRZR3 1 R C -CHR2 R3 II 0 Reagents i R3X (R3 = alkyl allyl or H); ii H,02-OH Scheme I2 K. Oshima K. Shimoji H. Takahashi H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973 95 2694.I3O G. Caron and J. Lessard Canad. J. Chem. 1973.51 981. 131 C. P. Casey S. H. Bertz and T. J. Burkhardt. Tetrahedron Letters 1973 1421. 13' A. Pelter C. R.Harrison and D. Kirkpatrick J.C.S.Chem. Comm. 1973 544. 33 A. I. Meyers and E. M. Smith J. Org. Chem. 1972,37,4289; A. I. Meyers A. Nabeya H. W. Adickes I. R. Politzer G. R. Malone A. C. Kovelesky R. L. Nolen and R.C. Portnoy ibid. 1973 38 36; A. I. Meyers E. M. Smith and M. S. Ao ibid. p. 2129; A. I. Meyers A. C. Kovelesky and A. F. Jurjevich ibid. p. 2 136. 134 E. W. Collington Chem. andhi. 1973 987. General Methods A new synthesis of ketones from olefins involves the reaction of dialkyl- borinates (available from dialkylchloroboranes) with a,a-dichloromethyl methyl ether in the presence of lithium triethylcarboxide followed by basic oxidation of the intermediate (20) (Scheme 13).13' B-Alkyl-3,5-dimethylborinans(21) react with aa-unsaturated enones by conjugate transfer of the alkyl group to give substituted ketones.'36 R:BOR2 + C1,CHOMe + LiOCEt -+ RiCB,OMe R:C=O I\ C1 OR2 Reagents i H,O,-OH (20) ~ Scheme 13 Acid chlorides can be converted into ketones with alkylrhodium(1) complexes (22)(Scheme 14).137The benefits of this route are that the initial chlororhodium(1) complex is recycled in the synthesis and the complex (22) is unreactive towards aldehydes esters and nitriles.Further synthetic interest in bis(methy1thio)- cyclopropanes is witnessed by their conversion into ketones with aqueous trifluoroacetic acid e.g.the obtention ofcycloheptanone in 90%yield from(23).' " Rh'CI(CO)(Ph,P) + RIM -+ MCI + [Rh'R'(CO)(Ph,P),] (22) '1 Rh'CI(CO)(Ph,P) + R'CR2 + [Rhll'R'(CI)(RZCO)(CO)(Ph,P)z] II 0 Reagents i R'COCI M = Li or MgX Scheme 14 cis-1,2-Diols and conformationally mobile trans-1 ,Zdiols can be cleanly cleaved into dicarbonyl compounds by activated manganese dioxide.' 39 B.A. Carlson and H. C. Brown J. Amer. Chem. SOC.,1973,95 6876. 13' E. Negishi and H. C. Brown J. Amer. Chem. Soc. 1973 95 6757. 137 L. S. Hegedus S. M. Lo and D. E. Bloss J. Amer. Chem. SOC.,1973. 95 3040. 138 D. Seebach M. Braun and N. Du Preez Tetrahedron Letters 1973 3509. G. Ohloff and W. Giersch Angew. Chem. Internat. Edn. 1973 12 401. W.B. Motherwell and J.S. Roberts Useful experimental modifications for acetal formation and hydrolysis are contained in a paper by Andersen and Uh.14' New carbonyl-protecting groups include mono- and di-2,2,2-trichloroethyl acetals (24 ;X = OEt or OCH2CC13)141 and bromomethylmethylene acetals (29.' 42 Regeneration of the carbonyl compound from these two derivatives involves reductive cleavage with activated zinc in ethyl acetate (or THF) and methanol respectively. Ketones can also be protected against a range of hydrolytic reductive and oxidative reagents via the oxime (26) from which the parent carbonyl compound can be regenerated by suitable hydrolysis condition^.'^^ In addition to the numerous reports last year concerning the dethioacetalization of 1,3-dithiolans and 1,3-dithians further work reveals that sulphuric acid,' 44 0-mesitylenesulphonylhydroxylamine,'45 and cupric chloride-cupric oxide'46 are also effective reagents.In a series of papers Evans et ~1.'~'have described the useful technique of cyanosilylation of aldehydes and ketones with trimethylsilyl cyanide. According to the substrate this reaction is efficiently catalysed either by cyanide ion or a Lewis acid. In addition to its protective property (removal with silver fluoride) the silyloxynitrile group of an aromatic aldehyde can function as a useful acyl anion equivalent (Scheme 15).14* Relevant to the above results is the fact that aromatic aldehydes undergo conjugate addition to aB-unsaturated carbonyl systems with cyanide ion catalysis probably via the corresponding cyanohydrin anion.'49 OSiMe OSiMe, I ArCH 2ArLR + ArCR I I II CN CN 0 Reagents i LiNPr',; ii RX Scheme 15 I4O N.H. Andersen and H. Uh Synthetic Comm. 1973 3 125. 14' J. L. Isidor and R. M. Carlson J. Org. Chem. 1973 38 554. 14' E. J. Corey and R. A. Ruden J. Org. Chem. 1973,38,834. 143 I. Vlattas L. Della Vecchia and J. J. Fitt J. Org. Chem. 1973 38 3749. 144 T.-L. Ho H. C. Ho and C. M. Wong Canad. J. Chem. 1973,51 153. 14' Y. Tamura K. Sumoto S. Fujii H. Satoh and M. Ikeda Synthesis 1973 312. 14' K. Narasaka T. Sakashita and T. Mukaiyama Bull. Chem. SOC.Japan 1972,453124. 147 D. A. Evans L. K. Truesdale and G. L. Carroll J.C.S. Chem. Comm. 1973,55; D. A. Evans. J. M. Hoffman and L. K. Truesdale J. Amer.Chem. Soc. 1973 95 5822; D. A. Evans and L. K. Truesdale Tetrahedron Letters 1973 4929; see also W. Lidy and W. Sundermeyer Chem. Ber. 1973 106 587. 14* K. Deuchert U. Hertenstein and S. Hunig Synthesis 1973 777; c$ G. Stork and L. Maldonado J. Amer. Chem. SOC.,1971 93 5286. 149 H. Stetter and M. Schreckenberg Angew. Chem. Internat. Edn. 1973 12 81; Tetru-hedron Letters 1973 1461. General Methods Functionalized Aldehydes and Ketones.-Addition of chromyl chloride to di- and tri-substituted olefins using acetone as solvent produces a-chloro-ketones in good yield -a reductive work-up with zinc and acetic acid yields the correspond- ing ketone.' "The reaction of organocuprates with a-chloro-acid chlorides also produces a-chloro-ketones in moderate yields.' '' Many synthetic schemes depend at some point or other on the use of ap-unsaturated ketones (and esters) as building blocks.In the year under review a number of new or modified ways of generating these intermediates have been reported. Three groups,' 52 working independently have utilized the fact that selenoxides readily undergo syn-elimination to form olefins. Thus an efficient de- hydrogenation can be achieved by introducing the phenylseleno-moiety a to a carbonyl function (ketone aldehyde ester) and subsequently oxidizing the product (Scheme 16). In the case of aldehydes and ketones the simplest procedure R q 9 0 -R q O PI[R~] 0; + -R T O X X (X = H alkyl Ar or alkoxy) Scheme 16 for the first step is the direct addition of benzeneselenenyl chloride to the carbonyl compound.' 52c For esters three methods of introducing the a-phenylseleno- group are available (Scheme 17).lS2' Sulphur can replace selenium in this Br R -CO,Et RdCO,E~ PhSeCH,CO,Et Reagents i R,NLi; ii PhSeCl; iii RCH,X; iv PhSe-Na+ Scheme 17 process as evidenced by the work of Trost and Sal~mann.''~ In this case the carbonyl enolate is quenched by dimethyl disulphide (selective for esters) or 150 K.B. Sharpless and A. Y. Teranishi J. Org. Chem. 1973 38 185. N. T. L. Thi H. Riviere and A. Spassky Bull. SOC.chim. France 1973 2102. lS2 (a) H. J. Reich I. L. Reich and J. M. Renga J. Amer. Chem. SOC. 1973 95 5813; (b)D. L. J. Clive J.C.S. Chem. Comm. 1973 695; (c) K. B. Sharpless R. F. Lauer and A.Y. Teranishi J. Amer. Chem. SOC. 1973 95 6137. 153 B. M. Trost and T. N. Salzmann J. Amer. Chern. SOC.,1973 95 6840; see also D. Seebach and M. Teschner Tetrahedron Letters 1973 51 13; J. L. Herrmann M. H. Berger and R. H.Schlessinger J. Amer. Chem. SOC.,1973 95 7923. W.B. Motherwell and J. S. Roberts diphenyl disulphide followed by oxidation to the sulphoxide and subsequent pyrolysis. Hooz and Brids~n'~~ have found a neat solution to the problem associated with the regiospecificity of the Mannich condensation when an unsymmetrical ketone is used. The success of this new method hinges upon the reaction of di-methyl(methy1ene)ammonium iodide (in DMSO) with an enol borinate as the latent carbonyl function (Scheme 18). Since it has already been shown that enol R2 CH2NMe2 I R:BOC=CHRi R2c-LHR1 II 0 + Reagent i Me,N=CH I-Scheme 18 borinates can be obtained either by the reaction of trialkylboranes with a-diazo- ketones or by conjugate addition of organoboranes to a&unsaturated ketones this method is highly versatile.An alternative approach'55 t0 this problem involves the Mannich reaction (followed by quaternization) of an a-substituted /I-keto-ester. Heating the intermediate salt in DMF effects the conversion into the a-methylene ketone. One of the classical methods of introducing ap-unsaturation into a ketone involves an a-halogenation-dehydrohalogenationsequence. Like the Mannich reaction this route usually suffers from the lack of regiospecificity in the formation of the a-halogeno-ketone from an unsymmetrical ketone.Stotter and Hill156 have explored this problem with the result that the necessary control can be achieved under the correct experimental conditions using position-specific lithio-enolates (Scheme 19). OSiMe 0 111. IV ___) vi. iv OBr Reagents i LiNPr',; ii CISiMe,; iii MeLi (1 equiv.); iv Br, -78 "C;V AcZO-HCIO,; vi MeLi (2 equiv.) THF Scheme 19 154 J. Hooz and J. N. Bridson J. Amer. Chem. SOC., 1973 95 602. 155 R. B. Miller and B. F. Smith Tetrahedron Letters 1973 5037; Synthetic Comm. 1973 3 359. ISh P. L. Stotter and K. A. Hill J. Org. Chem. 1973. 38 2576. General Methods 677 Trialkylalkynylborates (19) appear under several headings in this chapter and are proving to be extremely versatile synthetic intermediates.Their reaction with acyl chlorides yields A4-1,2-oxaborolens (27) which can be oxidized to ap-unsaturated ketones (Scheme 2O).' Enol acetates of P-diketones (and R' R' (27) Reagents i AcCl; ii Cr0,-H + Scheme 20 /I-keto-esters) react with one molar equivalent of a lithium dialkylcuprate to give P-substituted enones (and ap-unsaturated esters).' 58 Ketenthioacetals' 59 featured strongly last year as valuable intermediates. In extending the scope of their versatility Seebach et ~1.'~'have shown that the conjugated derivatives undergo nucleophilic attack by alkyl-lithiums to give a carbanion which can be quenched by an alkyl halide i.e. addition at C(4)of a masked ap-unsaturated ketone (Scheme 21).Another useful synthesis of ap-unsaturated ketones (and Reagents i Bu"Li; ii MeI iii hydrolysis Scheme 21 R' R' R'CECCH,OMe 2 \ \ /H /c=c=c \ -/c=c\ RZ H R2 /c=o R3 Reagents i Bu"Li-TMEDA; ii R'X; iii Bu"Li; iv R3X; v H,O+ Scheme 22 aldehydes) involves the metallation of propargyl and allenic ethers (Scheme 22).I6l Acid chlorides can be homologated to aP-unsaturated aldehydes in good overall yield by a four-step sequence (Scheme 23).' 62 Addition of dichloromethyl-lithium to a ketone followed by rearrangement to an a-chloro-aldehyde and 15' M. Naruse T. Tomita K. Utimoto and H. Nozaki Tetrahedron Letters 1973 795. 158 C. P. Casey D. F. Marten and R. A. Boggs Tetrahedron Letters 1973 2071; see also G. H. Posner and D.J. Brunelle J.C.S. Chem. Comm. 1973 907. D. Seebach M. Kolb and B.-T. Grobel Chem. Ber. 1973 106 2277. I6O D. Seebach M. Kolb and B.-T. Grobel Angew. Chem. Internat. Edn. 1973 12 69. 16' Y.Leroux and C. Roman Tetrahedron Letters 1973 2585. H. Newman J. Org. Chem. 1973 38 2254. W.B. Motherwell and J. S. Roberts subsequent dehydrochlorination serves as a route to aP-unsaturated aldehydes (Scheme 24).' OH RCOCl A RCOCECSiMe '* RAHCH,CH(OMe) % RCH=CHCHO Reagents i Me,SiCECSiMe, AlCl,; ii OMe- MeOH; iii NaBH,; iv H,O+ Scheme 23 R2 R2 I HCI R'CH2CRZ R'CH,&OLi 5 R'CH,CCl -P R'CH=C I1 I I \ 0 CHCI CHO CHO Reagent i C1,CHLi Scheme 24 Further work on the thermal cyclization of unsaturated ketones has revealed a method of preparing alkylidene-cyclopentanones and -cyclohexanones.' 64 Cyclic 1,3-diketones can be converted into the corresponding @-unsaturated enones either by reduction of the derived P-halogeno-afi-unsaturated enones with zinc-silver couple'65 or by mild base treatment of the mono-tosylhydra- zones.'66 Stork and Danhei~er'~~ have described a beautiful method for the synthesis of 4-alkylcyclohexenones.The success of this route lies in the regio- specific monoalkylation of P-diketone enol ethers followed by hydride reduction and acid hydrolysis (Scheme 25). This methodology has permitted a short and Reagents i LiNPr',; ii RX; iii LiAIH,; iv H,O* Scheme 25 efficient synthesis of ( & )-P-vetivone.' 68 Like P-keto-phosphonium salts P-keto- phosphonate~"~ also form dianions which can be alkylated at the y-carbon.' 70 Using this procedure Grieco et have generated the 1,Sdiketone (28) by alkylation with 1,3-dichlorobut-2-ene followed by acid hydrolysis.An intra- 163 H. Taguchi S.Tanaka H. Yamamoto and H. Nozaki Tetrahedron Lerrers 1973 2465. 164 M. Bortolussi R. Bloch and J. M.Conia Tetrahedron Letters 1973 2499. 165 R. D. ClarkandC. H. Heathcock J. Org. Chem. 1973 38 3658. 166 G. A. Hiegel and P. Burk J. Org Chem. 1973 38 3637. 167 G. Stork and R.L. Danheiser J. Org. Chem. 1973 38 1775. 168 G. Stork R. L. Danheiser and B. Ganem J. Amer. Chem. SOC.,1973,95 3414. 169 M.S. Chattha and A. M. Aguiar J. Org. Chem. 1973 38 2908. P.A. Grieco and C. S. Pogonowski J. Amer. Chem. SOC., 1973,95 3071.P. A. Grieco and C. S. Pogonowski Synthesis 1973 425. General Methods molecular Horner-Wittig reaction of (28) produces the substituted cyclic enone (29). 00 0 I1 II I1 (MeO),PCH ,CCH(CH,),CMe I R Buchi and Vederas172 have described an alternative method to the Wharton reaction for the transposition of a keto-group and a double bond in conjugated ketones (Scheme 26). Recently a new oxidative procedure for the cyclization of ketoximes to isoxazoles has been reported.' 73 Reagents i 12-KI NaHCO,; ii Na-NH,-Bu'OH Scheme 26 Enol borinates react with ketones and aldehydes to produce /3-hydroxy- ketones and appropriate modifications in the enol borinate structure permit the formation of /I-hydroxy-esters and -thi~esters.'~~ Further examples of the versatility of trialkylalkynylborates are illustrated by the important conversions shown in Scheme 27.'75*'76 by-Unsaturated ketones can be obtained by the reaction of allylic Grignard reagents with 2-substituted 4,4-dimethyloxazolines followed by hydrolysis.' 77 Another synthesis of @-unsaturated aldehydes,' 78 based on a [2,3] sigmatropic rearrangement has been recorded (Scheme 28). In polar solvents (e.g. sulphur dioxide) the silver-ion-induced dechlorination of a-chloro-aldonitrones in the presence of certain olefins can give substituted nitrones predominantly G. Buchi and J. C. Vederas J. Amer. Chem. SOC. 1972,94 9128. "' K. Maeda T. Hosokawa S. Murahashi and I. Moritani Tetrahedron Letters 1973 5075. 174 T.Mukaiyama K. Inomata and M. Muraki J. Amer. Chem. SOC. 1973 95 967; Bull. Chem. SOC. Japan 1973,46 1807. 175 M. Naruse K. Utimoto and H. Nozaki Tetrahedron Letters 1973 2741. 176 A. Pelter C. R. Harrison and D. Kirkpatrick Tetrahedron Letters 1973 4491. 177 C. Lion and J.-E. Dubois Bull. SOC. chim. France 1973 2673. 17' L. Mander and J. V. Turner J. Org. Chem. 1973,38 2915. W.B. Motherwell and J. S. Roberts f iv R' R2 R' R2 R:BC=CR~Li + LRiB2 ii iii H? Ref. 175 \ Ref. 17ivi R3 HO R3 R' R2 1iii v H RiB CH,COX R' RZ R'MR2 x HO R3 H CH2COX 0 CH,COX (X = alkyi aryl or alkoxy) Reagents I y R 3 ;ii AcOH; iii NaOH; iv H,O,-OH-; v I,; vi BrCH,COX Scheme 27 CN Reagent i H,O ' Scheme 28 which on hydrolysis lead to By-unsaturated aldehydes (Scheme 29).'79 In effect this means that a-chloro-aldonitrones are a-acyl carbonium ion equivalents.This substitution process also occurs in high yield with a number of aromatic systems affording P-aryl aldehydes. With acetylenes conjugated nitrosonium ions give cycloaddition products (30) which after base treatment (e.g. basic alumina) undergo a retro-Diels-Alder reaction to yield aP-unsaturated enone systems (Scheme 30).I8O S. Shatzmiller P. Gygax D. Hall and A. Eschenmoser Helv. Chim.Acru 1973 56 2961. S. Shatzmiller and A. Eschenmoser Helv. Chim. Am 1973 56. 2975. General Methods 681 I Me Me 0-Reagents i AgBF, SO,; ii H,O+ Me Scheme 29 A general route to trans-76-unsaturated aldehydes involves alkylation of (1-vinylthio)allyl-lithium followed by a thio-Claisen rearrangement and sub- sequent hydrolysis (Scheme 3 l).I8' Substitution of an ethoxy-group at C(2) in the sulphide precursor results in a new route to y-keto-aldehydes.'82 An aza- Claisen rearrangement of N-allyl N-vinyl quaternary ammonium salts also provides an interesting route to $-unsaturated aldehydes.' 83 Scheme 31 Schlessinger and his co-workers have had a fruitful year in the area of carbonyl anion equivalents and new Michael receptors which in many cases provide efficient routes to various 1,4-dicarbonyl systems.Of particular interest is the generation of the carbanions (31),184 (32),'85 and (33).186 Both (31) and (32) I81 K. Oshima H. Takahashi H. Yamamoto and H.Nozaki J. Amer. Chem. SOC.,1973 95 2693. 182 K. Oshima H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973,95 4446. 183 P. M. McCurry,jun. and R. K. Singh Tetrahedron Letters 1973 3325. I84 R. J. Cregge J. L. Herrmann J. E. Richman R. F. Romanet and R. H. Schlessinger Tetrahedron Letters 1973 2595. 185 J. L. Herrmann J. E. Richman and R. H. Schlessinger Tetrahedron Letters 1973 2599. I86 J. E. Richman J. L. Herrmann and R. H. Schlessinger Tetrahedron Letters 1973 3267 3271 3275; J. L. Herrmann J. E. Richman P. J. Wepplo and R. H. Schlessinger ;bid. p. 4707. W.B. Motherwell and J. S. Roberts P 0 0 MeS SMe "+JMe MeS Xplt-fytR SMe R SMe (35) (36) (37) have been used for conjugate addition to ap-unsaturated carbonyl compounds while the more versatile anion (33) can be mono-alkylated (leading to aldehydes) di-alkylated (leading to ketones) acylated (leading to a-functionalized carbonyl compounds) and undergo Michael addition to electron-deficient olefins (leading to a variety of 1,4-dicarbonyl systems).The same synthetic goal can be achieved by using the opposite strategy whereby the thioacrylate (34)lg7 functions as a Michael receptor for such nucleophilic species as enamines and lithio-enolates of esters and lactones. In a similar vein the keten thioacetal monoxides (35; R = H or alkyl)' can be used as Michael receptors for a wide variety of nucleo-philic species. With lithio-enolates the resultant anion (36)' 89 can either be quenched (leading to substituted aldehydes) alkylated (leading to substituted ketones) or in the case where R = vinyl or a carbonyl function alkylated via the stabilized anion (37).9 Acids and Anhydrides Further work on disodium tetracarbonylferrate( -11) has extended the utility of this reagent by the demonstration that the intermediate anionic complexes (38) and (39) can be oxidized in high yield in the presence of water an alcohol and a secondary amine to give the corresponding acid ester and amide re- spectively.'g' Trimethylsilyl enol ethers of cyclic ketones react with arenesulphonyl azides to give unstable A2-triazolines e.g. (a), which lose nitrogen easily and rearrange to imidate esters e.g. (41) which in turn are hydrolysed to the corresponding acid^.'^' The Lansbury chloro-olefin annelation method has been adapted for an interesting cycloalkanecarboxylic acid synthesis.' 92 This is achieved by R.J. Cregge J. L. Herrmann and R. H. Schlessinger Tetrahedron Letters 1973 2603. "'J. L. Herrmann G. R. Kieczykowski R. F. Romanet P. J. Wepplo and R. H. Schles- singer Tetrahedron Letters 1973 47 11. J. L. Herrmann G. R. Kieczykowski R. F. Romanet and R. H. Schlessinger Tetra-hedron Letters 1973 47 15. I9O J. P. Collman S. R. Winter and R. G. Komoto J. Amer. Chem. SOC.,1973 95 249; see also S. N. Anderson C. W. Fong and M. D. Johnson J.C.S. Chem. Comm. 1973 163; K. M. Nicholas and M. Rosenblum J. Amer. Chem. SOC. 1973,95,4449. R. A. Wohl Helv. Chim. Acta 1973 56 1826; Tetrahedron Letters 1973 31 11. 192 P. T. Lansbury and R.C. Stewart Tetrahedron Letters 1973 1569. General Methods co Na,Fe(CO) + RX * [RFe(CO),]--+ [RCFe(CO),]-II 0 SO,Ar OSiMe C=N-S0,Ar (41) (40) introduction of a 1,l-dichloromethylene grouping in the correct juxtaposition with respect to an incipient cationic centre (Scheme 32). n = 3or4 Reagent i HC0,H Scheme 32 Fetizon et ut.193have described a method for the stepwise degradation of a carboxylic acid (viaits ester) by either one two or three carbon atoms. The first sequence is the familiar Barbier-Wieland degradation. Further developments in the use of photosensitive carboxy-pr'otecting groups have been reported (Scheme 33).194*195 In the case of the nitroanilide~,'~' the reaction only works if R2 # H (e.g. R2 = Me CH2Ph or Ph).The methyl- thiomethyl ester function can also be used as an acid-protecting group.196 Trifluoroacetic acid or methyl iodide regenerates the free acid ; alternatively alcoholysis and aminolysis conditions permit the conversion into esters and amides respectively.' 97 Reagents i EtOH; ii EtOH-H,O NO Scheme 33 A new method ofsynthesizing disubstituted maleic anhydrides involves the pyrolysis of the esters (42; R' = Me or Ph R2 = alkyl) which are derived from lg3 M. Fetizon F. J. Kakis and V. Ignatiadou-Ragoussis J. Org. Chem. 1973 38 1732. Ig4 J. C. Sheehan and K. Umezawa J. Org. Chem. 1973,38 3771. Ig5 B. Amit and A. Patchornik Tetrahedron Letters 1973 2205. 196 T. L. Hoand C. M. Wong J.C.S. Chem. Comm. 1973 224. 19' T. L. Ho and C.M. Wong Synthetic Comm. 1973 3 145. 684 W.B. Motherwell and J. S. Roberts an a-keto-acid and an ethoxyacetylene (Scheme 34).19*Acids can be dehydrated in good yield with cyanogen bromide in the presence of pyridine to give an- hydride~.~~~ A short-cut to the mono-homologation of a dicarboxylic acid has been reported.200 In this method the corresponding anhydride is allowed to react with excess diazomethane and the resultant ring-opened diazo-ketone methyl ester is subjected to the normal Arndt-Eistert conditions. //O 1 0 (42) Scheme 34 Functionalized Acids.-Malonic acid half-esters react with diphenylphosphoryl azide in the presence of triethylamine with transfer of the azido-group and the derived isocyanates (after Curtius rearrangement) react further with an alcohol to give urethane esters which can be readily converted into a-amino-acids.201 An interesting new synthesis of 8-hydroxy-acids has been reported,202 (Scheme 35) involving initial addition of a t-hexylmonoalkylborane to ethyl propiolate R' R' R' H c=c H /\ C02Et H iii ivl R 'CHCH2C02H I OH Reagents i HC=CCO,Et; ii NaOR'; iii HOR'; iv H,O,-OH- Scheme 35 followed by base-induced alkyl migration.Rathke and Sullivan203 have per- fected a technique permitting the isolation of the remarkably stable enolate 19* M. S. Newman and W. M. Stalick J. Org. Chem. 1973 38 3386. 199 T. L. Ho and C. M. Wong Synthetic Comm. 1973,3 63. 'OD E. W. Della and M. Kendall J.C.S. Perkin I 1973 2729. 201 S. Yamada K.Ninomiya and T. Shioiri Tetrahedron Letters 1973 2343. 202 E. Negishi and T. Yoshida J. Amer. Chem. SOC. 1973,95 6837. ,03 M. W. Rathke and D. F. Sullivan J. Amer. Chem. SOC. 1973,95 3050. General Methods 685 lithio t-butyl acetate which in toluene solution reacts rapidly with ketones to give P-hydroxy-t-butyl esters. Following on from last year's report on the [3,3] sigmatropic rearrangement of lithio-enolates of allylic esters Baldwin and Walker204 have shown that zinc enolates (43) also undergo the same type of reaction leading to $-unsaturated acids (Scheme 36). The same basic principle lies behind the report by Yamamoto Reagents i 'ko ;ii Zn Br Scheme 36 et that ally1 keten thioacetals undergo a thio-Claisen rearrangement to give stereoselectively the (E)-isomer acid derivative (Scheme 37).Reagents i BuSLi (2 equiv.); ii RX; iii MeI; iv CuC1,-CuO Scheme 37 Moderate yields of (E)-ap-unsaturated acids can be obtained by dehydrogena- tion of their a-lithiated salts with DDQ.205The direct conversion of an ester into an acid halide can be achieved with such reagents as Ph3PX (X = C1 or Br)206*207 and PhiPC1 BF3Cl-.206 10 Esters Methyl esters can be obtained in high yield by heating the corresponding tri- methylanilinium carboxylate salts.208 Trimethyl phosphate can be substituted for dimethyl sulphate in the formation of methyl esters even for hindered acids.209 204 J. E. Baldwin and J. A. Walker J.C.S. Chem. Comm. 1973 117. 205 G. Cainelli G. Cardillo and A.Umani-Ronchi J.C.S. Chem. Comm. 1973 94. 20h D. J. Burton and W. M. Koppes J.C.S. Chem. Comm. 1973 425. 207 A. G. Anderson jun. and D. H. Kono Tetrahedron Lerters 1973 5121. *08 I. Gan J. Korth and B. Halpern Synthesis 1973 494. *09 M M Harris and P. K. Patel. Chem. and Ind.. 1973 1002. W.B. Motherwell and J. S. Roberts Functionalid Esters-cr-Keto-esters can be prepared in moderate yield by ozonolysis of l-bromoacetylenes.2 Some new and interesting reactions leading to P-keto-esters have been reported (Scheme 38).21 '-'14 R I MeSC=CC H( 0Et),R*l MeSC=C=C(0Et) MeSC=C=C(0Et) R2 RCOCH,CO,Et I v Vl R1COCH,R2 R$2 R'COC=C(SMe) 4R'COCHR2C02R3 OSi(Me),Bu' / CH,=C + RCH,COCI \ OEt OSi(Me),Bu' OSi(Me),Bu' I I RCH=C-CH,CO,Et + RCH,C=CHCO,Et viill RCH ,COCH,CO,Et R2 I R'COCC0,Et 5R1COCHR2C0,Et fNH3 cl-Ref.214 I Reagents i LiNEt,; ii RX; iii H,O Hg2+; iv NaH-CS, 2MeI; v R30H-H +;vi H,O; vii Et,N; viii H,O + Scheme 38 The work of Hooz and Smith2" serves as a caveat to those carrying out alkylations of P-keto-esters (and P-diketones) via thallium enolates. Contrary to earlier reports exclusive mono-C-alkylation could not be achieved. The decarboxylation of P-keto-esters (and geminal diesters) can be carried out in wet dimethyl sulphoxide in the presence of catalytic quantities of sodium chloride.21 Alternatively for P-keto methyl esters lower temperatures can be used if lithium chloride or sodium cyanide in HMPA are the reagents.217 Boric acid treatment of an acylated succinic acid diester followed by hydrolysis of the intermediate enol borinate yields y-keto-esters directly.218 In addition to their ability to under- go alkylation keten N,O-acetals (44)can also be used for Michael addition to 'lo S.Cacchi L. Caglioti and P. Zappelli J. Org. Chem. 1973 38 3653. R. M. Carlson and J. L. Isidor Tetrahedron Letters 1973 4819. 'I2 I. Shahak and Y. Sasson Tetrahedron Letters 1973 4207. M. W. Rathke and D. F. Sullivan Tetrahedron Letters 1973 1297. 2 I4 K. Matsumoto M. Suzuki T. Iwasaki and M. Miyoshi J. Org. Chem. 1973,38 2731. 'Is J. Hooz and J. Smith J. Org. Chem. 1972,37,4200. 'I6 A. P. Krapcho and A. J. Lovey Tetrahedron Letters 1973 957. "' P. Miiller and B. Siegfried Tetrahedron Letters 1973 3565.'I8 P. A. Wehrli and V. Chu J. Org. Chem. 1973 38 3436. General Methods 687 electron-deficient olefins.’ Thus addition of (44)to cyclohexenone followed by hydrolysis and transesterification yields (45). (44) (45) An improved experimental procedure for ester alkylation has been noted’” -the main modifications are the use of lithium di-isopropylamide as base in THF to generate the enolate and carrying out the alkylation at -78 “C. This alkylation technique can also be applied to hydracrylates thus affording a-substituted acrylates on subsequent dehydration.221 The simple expedient of adding one molar equivalent of HMPA to the above base permits deconjugative a-mono- and di-alkylation of for example ethyl crotonate.”’ Pichat and Beau~ourt’’~ have reported good yields in the syntheses of the important annelating agents (46; R’ = Me R2 = H and R’ = H R2 = Me); 3-ethoxypropionyl chloride is used for the synthesis of (46 ;R‘ = R2 = H) (Scheme 39).R‘ COCl \/ + LiCH/CozSiMe3 \ R2 C0,EtH /c=c\ -4 /C02SiMe3COCH \C02Et ] ‘1 R’ COCH,CO,Et\/)c=c’\H R’ Reagent i H 2O Scheme 39 Lactone.-The cr-methylenation of y-and &lactones has again been actively pursued.224 The report by Grieco and Hir~i’’~~ of their new technique has ’I9 A. 1. Meyers and N. Nazarenko J. Org. Chem. 1973,38 175. ”O R. J. Cregge J. L. Herrmann C. S. Lee J. E. Richman and R. H. Schlessinger Tetra-hedron Letters 1973 2425. ”’ J. L. Herrmann and R. H. Schlessinger Tetrahedron Letters 1973 2429. 222 J. L. Herrmann G.R. Kieczykowski and R. H. Schlessinger Tetrahedron Letters 1973 2433. ’” L. Pichat and J.-P. Beaucourt. Synthesis 1973 537. 224 ((1) A. D. Harmon and C. R. Hutchinson Tetrahedron Letters. 1973 1293; (6) K. Yamada M. Kato and Y. Hirata. ibid. p. 2745; (c) R. C. Ronald ibid. p. 3831 (d) P. A. Grieco and K. Hiroi J.C.S. Chem. Comm. 1973. 500. 688 W. B. Motherwell and J. S. Roberts the advantages of better overall yield and simplicity with respect to the other methods. Achieving the same result but conceptually different are the methods of Hudrlik et and Eschenmoser et ~11.~~~ The first depends upon the cyclo- propylcarbinyl-homoallyl rearrangement of e.g. (47) in the presence of excess zinc bromide in 48% hydrobromic acid to give (48).The second method is an WH20H C0,Et (47) extension of Eschenmoser’s recently developed work on a-chloro-aldonitrones (Scheme 40). N H H CH, CH,Cl Reagents i AgBF,; ii KCN; iii KOBu’; iv aq. H,SO Scheme 40 Two papers by Trost et ~11.~~’ report on the formation of spiro-lactones the latter of which is a follow-up to the secoalkylation process reported last year (Scheme 41). Many important natural products incorporate a lactone ring and thus in order to facilitate the syntheses of such compounds an efficient lactone- protecting group has become increasingly desirable. The synthetic organic chemist now has the means to achieve this in the light of the work by Corey and 225 P. F. Hudrlik L. R. Rudnick and S. H. Korzeniowski J.Amer. Chem. Soc. 1973,95 6848. 226 M. Petrzilka D. Felix and A. Eschenmoser Heh. Chim. Acra 1973 56 2950. ”’ (a)B. M. Trost and H. C. Arndt J. Org. Chem. 1973,38 3140; (b)M. J. Bogdanowicz, T. Ambelang and B. M. Trost Tetrahedron Letters 1973 923. General Methods 0 0 Ref 2270) CN CN Reagents i Ph,S 4; ii H + ; iii NaOBr Scheme 41 Beames.228 This involves the addition of bis(dimethyla1uminium) ethane- 1,2-dithiolate (49) to e.g. y-butyrolactone to give the intermediate hydroxy-keten thioacetal (50) which rapidly cyclizes in the presence of toluene-p-sulphonic acid to yield the dithio-ortho-lactone (51). Such compounds are reasonably stable to aqueous acetic acid methanolic potassium hydroxide LiAlH, and MeLi and are reconverted into the parent lactone by treatment with mercuric oxide and boron trifluoride etherate.This same protective sequence can be applied to esters (except those which do not possess an or-hydrogen) to give keten thioacetals whose synthetic value has been of increasing interest recently. I1 Amides and Nitriles Last year it was reported that diphenylphosphoryl azide was very effective in promoting formation of the amide linkage with little or no racemization; a similar efficiency has now been noted with diethylphosphoryl cyanide in the presence of trieth~lamine.~~~ As an alternative to the Ritter reaction Barton et ~1.~~" have found that treatment of an alcohol with chlorodiphenylmethylium hexachloroantimonate in the presence of nitrile solvents gives the corresponding amide.The synthesis .of amides by the reaction of isocyanates with organolithium reagents has been shown to be quite general.231 Some new or modified nitrile 228 E. J. Corey and D. J. Beames J. Amer. Chem. Soc. 1973 95 5829. 229 S. Yamada Y. Kasai and T. Shioiri Tetrahedron Letters 1973 1595. 230 D. H. R. Barton P. D. Magnus and R. N. Young J.C.S. Chem. Comm. 1973 331 13' N. A. LeBel R. M. Cherluck and E. A. Curtis Synthesis 1973 678. 690 W.B. Motherwell and J. S. Roberts syntheses have been noted (Scheme 42).232-235For aryl aldoximes trichloro- a~etonitrile~~~ can be used as the dehydrating and dicyclohexylcarbodi-imide237 agents. RCOX Ref 233' (Re[ 235) RCONH,,RCSNH,,RCH=NOHR-&4 RCNo,:,i:r ,,,,RCH=NOH Reagents i (PNCI,),; ii CHCI, aq.NaOH PhCH,N'Et C1-; iii 1,1 -dicarbonylbi-imidazole CH ,CI Scheme 42 A general method of converting ketones and aldehydes into nitriles involves the reaction of the carbonyl compound with tosylmethylisocyanide in the presence of base.238*239 Tetra-alkylammonium cyanides are reported to be more powerful nucleophiles than sodium cyanide for displacement reactions.240 B-Keto-nitriles are readily accessible by the reaction of the ketone with chlorosulphonyl iso- cyanate followed by treatment with DMF.241 12 Alkylation and Coupling Reactions Several annelation sequences of wide-ranging practical utility have been developed. These are discussed in Chapter 18. A useful compendium of articles on the topic of alkylation has been The synthetic merits of potassium hydride over sodium hydride for the rapid formation of anions include the formation of highly hindered alkoxides and boro- hydrides the preparation of dimsyl anion at room temperature and the acces- sibility of new and powerful proton-specific bases which catalyse the aromatization of limonene to para-cymene in five minutes at room temperature.243 Much attention has been devoted this year to the development of practical methods for the monoalkylation of ketones.Conia and his co-worker~~~~ recommend stereoselective conversion into the silyl enol ether followed by their modified Simmons-Smith cyclopropanation and ring opening with sodium hydroxide in aqueous methanol. In a conceptually identical approach use has 232 G.Rosini. G. Baccolini and S. Cacchi J. Org. Chem.. 1973 38 1060. 23J J. C. Graham Tetrahedron Letters 1973 3825. 234 T. Saraie T. Ishiguro K. Kawashima and K. Morita Tetrahedron Letters 1973,2121. 235 H. G. Foley and D. R. Dalton J.C.S. Chem. Comm. 1973 628. 236 T. L. Ho and C. M. Wong J. Org. Chem. 1973,38 2241. T. L. Ho Syntheric Comm. 1973 3 101. 0. H. Oldenziel and A. M. van Leusen Tetrahedron Letters 1973 1357. 239 U. Schollkopf and R. Schr(ider Angew. Chem. Internat. Edn. 1973 12,407. 240 D. A. White and M. M. Baizer J.C.S. Perkin I 1973 2230. *'I J. K. Rasmussen and A. Hassner Synthesis 1973 682. 2'2 D. Burns Chem. and Ind. 1973 870; R. 0.C. Norman ibid. p. 874; R. Baker ibid. p. 877 T. L. Gilchrist ibid. p. 881 ; W. Carruthers ibid.p. 931 ; D. C. Ayres. ibid. p. 937; R. W. Alder ibid. p. 983. ''j C. A. Brown J. Amer. Chern. SOC.,1973,95 982,4100. 2J4 J. M. Conia and C. Girard Tetrahedron Letters 1973 2767. General Methods 69 1 been made of the enamine derivatives followed by thermal opening of the cyclo- propane with aqueous methanol.245 The introduction of a tertiary alkyl group adjacent to a ketonic functionality can be accomplished by the reaction of the a,a'-dibromoketone with the mixed organocopper reagent [Bu'OBU'CUL~].~~~ This procedure is however clearly limited to symmetrical ketones. In an alter- native approach which is also the method of choice for the introduction of a secondary alkylidene group Corey and Chen247 have employed a-dithiomethyl- ene ketones as versatile intermediates (Scheme 43).0 Li+ A/ 0 SMe WSMe 0 Me O+Li' Reagents i. '"PBu', CS,; ii MeI; iii Me,CuLi -78 "C,20 min iv Me,CuLi 0°C. 1 hour Scheme 43 Improvements in classical condensation reactions continue to be made. Dimethyl malonate reacts with ketones in the presence of titanium tetrachloride and pyridine to give good yields of +unsaturated compounds even in previously cited unsuccessful cases.248 The reaction of morpholinocyclohexene with malonic acid derivatives in DMF or ethanol or without solvents leads to the correspond- ing cyclohexylidenes in a process which is more effective than the Knoevenagel 14' M. E. Kuehne and J. C. King J. Org. Chem. 1973. 38 304. 246 G. H. Posner and J.J. Sterling J. Amer. Chem. Soc. 1973. 95. 30-6 247 E. J. Corey and R. H. K. Chen Tetrrrhedron Letters 1973. 3817. 248 W. Lehnert Tetrahedron 1973. 29 635. W. B. Motherwell and J. S. Roberts condensation and more convenient than the Reformatsky reaction.249 The direct alkylation of aldehydes possessing an a-hydrogen atom with an alkyl halide can be conveniently carried out wing phase-transfer catalytic techniques.250 House and his co-~orkers~~ have controlled thecrossed aldol reaction by treating a pre-formed lithium enolate with an aldehyde in the presence of magnesium bromide or zinc chloride when the product is presumably trapped as the metal chelate. Treatment of an a-diketone with two equivalents of lithium di-isopropyl- amide generates a dianion which can undergo C-alkylation in' good yield.252 Lithium secondary amide bases also provide an effective method for the irrever- sible generation of the conjugated bases of ap-unsaturated ketone^.^ Sub-sequent methylation then gives the a' product.The reductive methylation of enolizable aldehydes or ketones can be achieved using formaldehyde and an alkali-metal iron ~arboxylate.~~~ An efficient and generally applicable method for the stepwise a-alkylation of esters ketones and nitriles via their cr-t-butylthio- derivatives has been described (Scheme 44).255 R' R' R' I I R'R'CHY * C R3-C-Y I xs/ I 'y R2 R2 X = halide; Y = C02Me CN or COMe Reagents i base R'X; ii Raney Ni; iii base R'X; iv 2Li H'; v 2Li R3X Scheme 44 Me Me 14' F.S. Prout J. Org. Chem. 1973 38 399. 150 H. K. Diet1 and K. C. Brannock Tetrahedron Letters 1973 1273. H. 0.House D. S. Crumrine and A. Y.Teranishi J. Amer. Chem. Soc. 1973,95,3310. 2sz A. S. Kende and R. G. Eilerman Tetrahedron Letters 1973 697. 253 R. A. Lee C. McAndrews K. M. Patel and W. Reusch Tetrahedron Letters 1973,965. 254 G. Cainelli M. Panunzio and A. Umani-Ronchi Tetrahedron Letters 1973 2491. lS5 S. Kamata S. Uyeo. N. Haga and W. Nagata Synthetic Comm. 1973 3 265. General Methods 693 A new general method for the alkylation of enamino-ketones at the y-position e.g. (52; R = H) to (52; R = alkyl) has been The conjugate addition reaction of trans-alkenyl-alanes to enone systems occurs in a stereo- specifically trans manner to give y6-unsaturated ketone^.^ s ' Olah and his co-~orkers~~ have described methoxycarbenium hexafluoro- antimonate as a new methylating agent and also claim that the hexafluoro- phosphate gegenion gives the most convenient stable and soluble Meerwein sah2s9 Organocopper chemistry maintains its rapid pace of development.In addition to the various aspects already cited three groups have described unsymmetrical organocuprates RR'CuLi which operate with selective transfer of R'.260 Normant and his colleagues26 have reported further studies on vinylcopper reagents culminating in a stereospecific synthesis of ap-unsaturated acids. Lithium dialkylcuprates react more rapidly in ether solution with tosylates than with halides.262 The cross-coupling reaction between alkylthioallylcopper and allylic halides proceeds regiospecifically in excellent yield.263 Further information is now available on the selective cross-coupling reaction which utilizes an allylic mesitoate The metallation of limonene with the complex of n-butyl-lithium and tetramethylethylenediamine was described last year.A second group have now reported the generation of allyl-lithium and methallyl-%thium from propene and isobutene by this method.26s These reagents couple with organic halides in very good yield. Trost and his co-workers266 continue to develop new and elegant synthetic methods. In their allylic alkylation sequence the interaction of a nucleophile with a readily prepared n-allylpalladium complex is used to construct a new carbon-carbon bond (Scheme 45).Further- more in the presence of a chiral phosphine ligand exceptionally high optical yields of 12-24 %.have been obtained ;this degree of asymmetric induction is exceeded only by the Wilke oligomerization process.267 Tertiary-butyl trifluoroacetate in trifluoroacetic acid is an effective reagent for the rapid alkylation of activated aromatic compounds.268 Thallium trifluoroacetate is not only useful for the oxidation of phenols to quinones but also acts as a highly efficient two-electron oxidant for intra- 256 M. Yoshimoto N. Ishida and T. Hiraoka Tetrahedron Letters 1973 39. 257 J. Hooz and R. B. Layton Canad. J. Chem. 1973,51 2098. 258 G. A. Olah and J. J. Svoboda Synthesis 1973 52. 259 G.A. Olah J. A. Olah and J. J. Svoboda Synthesis 19j3 490. 260 (a) H. 0. House and M. J. Umen J. Org. Chem. 1973 38 3893; (6) J.-P. Gorlier L. Hamon J. Levisalles and J. Wagnon J.C.S. Chem. Comm. 1973 88; (c) G. H. Posner and C. E. Whitten Tetrahedron Letters 1973 1815. 261 J. F. Normant G. Cahiez C. Chuit and J. Villieras J. Organometallic Chem. 1973 54. C53. 262 C. R. Johnson and G. A. Dutra J. Amer. Chem. SOC.,1973 95 777 7783. 263 K. Oshima H. Yamamoto and H. Nozaki J. Amer. Chem. SOC.,1973,95 7926. 264 J. A. Katzenellenbogen and R. S. Lenox J. Org. Chem. 1973 38 326. 265 S. Akiyama and J. Hooz Tetrahedron Letters 1973 41 15. 266 B. M. Trost and T. J. Fullerton J. Amer. Chem. SOC.,1973 95 292. "' B. M. Trost and T. J. Dietsche J. Amer. Chem.SOC.,1973,95 8200. 268 U. Svanholm and V. D. Parker J.C.S. Perkin I 1973 562. W. B. Motherwell and J. S. Roberts R Reagents i PdCI,; ii Na' (CO,Et),C- 4Ph,P Scheme 45 molecular phenolic oxidative coupling.' ' Vanadium oxytrifluoride is the reagent of choice for the smooth inter- and intra-molecular coupling of non-phenolic benzylis~quinolines.~~~ Facile coupling of sterically hindered 2,6-dialkylphenols has been realized with periodic acid.270 13 Miscellaneous Neckers et al. have been carrying out some interesting research on the use of polymer-protected reagents. One such reagent is the water-stable polystyrene- aluminium chloride complex which in appropriate swelling solvents e.g. benzene can be used as a catalyst for ether27' and ester272 syntheses.Another is the Rose Bengal-chloromethylated polystyrene complex which functions as an insoluble sensitizer for photo-o~idations.~~~ A similar heterogeneous system can be realized with Rose Bengal and Methylene Blue attached to basic anion- exchange and acidic cation-exchange resins respectively.274 Further work by Rieke et al. has led to the discovery of methods for preparing highly activated metals e.g. and magnesium.276 A method of preparing aluminium hydride which is soluble in diethyl ether has been reported.277 Kwart and C~nley~~~ have described modified Birch reduction conditions which may prove useful in certain cases ; conjugation of 1-methoxycyclohexa- 1,4-dienes can be achieved with a number of catalyst^.^^" The use of lithium 2,2,6,6-tetra- methylpiperidide as a potent and relatively cheap base for effecting a number of 269 S.M. Kupchan A. J. Liepa V. Kameswaran and R. F. Bryan J. Amer. Chem. SOC. 1973,95 6861. 270 A. J. Fatiadi Synthesis 1973 357. 271 D. C. Neckers. D. A. Kooistra and G. W. Green J. Amer. Chem. Suc. 1972,94,9284. 272 E. C. Blossey L. M. Turner and D. C. Neckers Tetrahedron Letters 1973 1823. 273 E. C. Blossey D. C. Neckers A. L. Thayer and A. P. Schaap J. Amer. Chem. SOC. 1973,95 5820. 274 J. R. Williams G. Orton and L. R. Unger Tetrahedron Letters 1973 4603. 27s R. D. Rieke S. J. Uhm and P. M. Hudnall J.C.S. Chem. Comm. 1973 269. 276 R. D. Rieke and S. E. Bales J.C.S. Chem. Comm. 1973 879. 277 E. C. Ashby J. R. Sanders P. Claudy and R.Schwartz J. Amer. Chem. SOC.,1973 95 6485. "* H. Kwart and R. A. Conley J. Org. Chem. 1973 38 201 1. 279 A. J. Birch and K. P. Dastur J.C.S. Perkin I 1973 1650. General Methods chemical transformations e.g. carbene benzyne and enolate formation has been advocated.280 Enamines can be prepared in high yield by condensation of the carbonyl compound with trimethylsilyl derivatives of secondary amines.28 For aldehyde enamines the reaction of Grignard reagents with NN-dialkylformamides has been found to be In Diels-Alder reactions the dienophiles 2-phenyl- and 2-thiono-A4- 1,3-dioxolen can act as acetylene equivalents283 while a-bromoacrolein functions as an allene R. A. Olofson and C. M. Dougherty J. Amer. Chem. SOC.,1973,95 582. R.Comi R. W. Franck M. Reitano and S. M. Weinreb Tetrahedron Letters 1973 3107. 282 C. Hansson and B. Wickberg J. Org. Chem. 1973 38 3074. 283 W. K. Anderson and R. H. Dewey J. Amer. Chem. SOC.,1973,95 7161. 284 B. B. Snider J. Org. Chem. 1973 38 3961.

ISSN:0069-3030    

DOI:10.1039/OC9737000657

出版商:RSC    

年代:1973

数据来源: RSC

摘要:

Author Index Aaron H. S. 271 Abad G. A. 147 Abdul H. S. M. 193 Abe N. 420,428 Abe T. 68,419 Abegg V. P. 222 Abeles R. H. 99 102 105,115 Abelson J. 644 Aberhart D. J. 482 615 Abiko S. 348 404 Abis L. 90 Abott G. G. 496 Abou Donia S. A. 597 Abraham E. P. 482,616 Abramovitch R. A. 227 505 Abronin I. A. 179 Absar I. 269 Abskharoun G. A. 196 Abu-Isa I. A. 327 Ackerman P. 518 Acton E. M. 448 Adair W. L. 111 Adam W. 24 25 240 369,399 Adams B. L. 208 219 57 1 Adams J. T. 393 Adams M. J. 107 Adamson J. 435 455 456 Adamyants K. S. 455 Adesnik M. 650 Adger B. M. 177 478 Adickes H. W. 672 Adinolfi M. 667 Adlam B. 514 Adler B. 245 Adler E. 400 Adlercreutz H.20 Adlkofer J. 244 Afzal M. 240 Agarwal K. L. 284,637 Agdeppa D. A. 371 Agner G. 257 A osta W. C. 87 201 313,318,378,575 Agranat I. 50 68 413 425,525 Agris P. F.,645 Aguiar A. M. 678 Ahern P. 478 Ahlbor U. C. 16 Ahmad Y.,505 Ahond A. 544 Ahuja V. K. 258 348 366,661 Aida T. 665 Aiyar L. 72 Ajisaka K. 43 Akagi K. 535 Akeson A. 109 Akhrem A. A. 454 Akhtar M. 98 109 118 619 Akhtar M. H. 229,486 Akhtar 2. M. 13 Akima T. 66 Akitt J. W. 45 Akiyama M. S. 362 Akiyama S. 693 Akiyami T. 420 Akopyan M. E. 12 Aksenov V. S. 361 Aksnes G. 278 Albagli A. 72 Albano E. L. 455 Alberts A. H. 369 571 Alder R. W. 356 Alderfer J. L. 635 Alewood P.F. 96 185 Alexander R. G. 14 Alfredsson G. 283 Al-Jobore A. A. H. 436 Allan G. G. 341 Allen F. H. 56 Allen J. 560 Allen L. B. 636 Allen L. C. 268 Allen R. B. 24 Allenmark S. 294 Allerhand A. 35,39,40 434 Allet B. 653 Allinger N. L. 50,409 Allison W. S. 107 Allum K.G. 340 Almy J. 213 Alonso J. H. 213 Alper H. 169 252,499 670 Al-Radhi A. K. 442,467 Alston P.V. 583 Altenbach H.-J. 90,391 474,589 Altman S.,644 Alvarez M. A. 561 Alwair K. 164 289 Alzerreca A. 415 575 Amann W. 416 Ambelang T. 572 688 Ambler R. P.,19 Amit B. 683 Amiya S. 88 587 Ammon H. L. 47,48,50 53,413,417,478 Amos D. W. 64 394 Ananchenko S. N. 564 Anastassiou A.G. 96 233,516 519 Andersen K. K. 384 Andersen N. H. 553 674 Anderson A. G. jun., 190,428,685 Anderson B. 179 Anderson B. F. 53 225 499 Anderson B. R. 179 Anderson D. J. 190 191,471 Anderson E. 132 Anderson H. W. 359 Anderson J. E. 386 Anderson J. R. 243 Anderson K.K. 43 Anderson L. A. 388 Anderson L. B. 286 Anderson N. H. 586 Anderson R. L. 247 Anderson S. N. 682 Anderson W. K. 350 499,695 Ando W. 198 202,205 208,223,416 Andrade J. E. 346 Andrae S. 225 390 Andreetti G. D. 512 Andrews G. 211 Andrews G. C. 283,662 Andrews G. D. 229 Andrews J. P. 346 Andrews P. S. 254 Andrieux C. P.,286,288 Andrieux J. 508 Andrist A. H. 76 Anet,F. A. L. 38,39,357 Angadiyvar C.S. 311 Angyal S. J. 43 431 432,435,436,438,448 Anh N. T. 89 374 376 583,596 Ankel H. 110 Ansari H. R. 550 696 Author Index Ansell H. V. 392 Aue D. H. 190 213 Anselmi C. 141 218,474 Adteunis M. 43 515 Auerbach R. A. 376 Antonucci F. R. 319 Aulich H. A. 309 495 Aumann D. 670 Ao M. S. 672 Aurnann G. 638 Aoki K. 553 Aumann R. 230 Appel R.,282 Aurich H. G. 174 Applequist D. E. 159 Ausrnann A. 82 Appleton T. G. 257 Avaca L. A. 296 Aprahamian N. S. 68 Avnir D. 68 425 Apsimon J. W. 43 Avrutskaya I. A. 293 Aragozzini F. 610 Axen U. 17 Arai H. 507 Ayer W. A. 556,558 Arai K. 625 Ayers 0.E. 341 Arakawa S. 407 Ayres D. C. 690 Araki M. 671 Ayscough P. B. 153 Araki Y.453 459 Ayyar K. S. 583 Arce de Sanabia J. 240 Azarnia N. 432 Archie W. C. jun. 273 Azizullah O. 292 Arditti J. 563 Azuma K. 256 Ardrey R. E. 19 Azuni T. 314 Arfin S. M. 615 Arhart R. W. 139 659 Baba H. 68 Arigoni D. 87,212,379 Baba Y. 88,587 560,605 Babad H. 385 Armarego W. L. F. 607 Babadjamian A. 73 Armenakian A. 436 Babievskii K. K. 293 Armitage I. 434 Babson J. 115 Armitage I. M. 43 Babson R. D. 628 Armour E. A. 134 Baccolini G. 690 Arndt H. C. 688 Bachhawat J. M. 671 Arnett E. M. 147 Bacon R. G. R. 396 Arnold B. J. 404 Baczynskyj L. 17 Arnold D. R. 200 224 Bade T. R. 159 Arnold J. C. 404 Badelay R. J. 119 Arnott S. 642 Bader R. F. 119 Arora S. 575 Baechler R. D. 276 Arotsky J. 68 Backvall J.-E.489 Arrand J. R. 649 Baehler B. 437 Arrick R.E. 439 Bahr W. 641 Arzoumanidis G. G. Baenziger N. C. 47 395,669 Baer E. 327 Asao T. 419,474 Baer H. H.,433 468 Ashby E. C. 374 596 469 694 Baungartel H. 492 Ashley-Smith J. 246 Bagal T. L. 67 Ashworth P. 155 165 Baggett N. 437 407 Bahl C. P. 637 Askani R. 90 Bailar J. C. jun. 266 Ast T. 12 340 Ast W. 267 Bailey P.S.223 Atherton F. R. 191,522 Baily D. S. 144 Atkins P. W. 176 Baines D. A. 64 394 Atkins R. C. 412 Baird N. C. 184 Atlani P. 372,439 Baizer M. M. 690 Atlas D. 116 Bakeev N. F. 339 Atmeh R. F. 510 Baker A. D. 10 Attig T. G. 257 Baker B. A. 261 Attridge C. J. 253 Baker C. 10 Au T. Y. 538 Baker D. A. 437,462 Baker D. C. 439 Baker P. B. 239 Baker R.130,243 255 690 Bakuzis P. 173 Balanson R. D. 552 Balasingham K.,346 Balch A. L. 247,264 Baldwin J. E. 76 94 191 228 229 234 475 482 484 615, 616,685 Baldwin M. A. 14 15 Baldwin R. M. 61 1 Baldwin S. W. 84 378 Bales S. E. 694 Ball D. H. 441 Ballard D. G. H.,256 332 Baltenas R. 333 Balteniene J. 333 Bambach G. 465 Bambara R.,652 653 Barnford C. H. 256,328 Banaszak L. 110 Bandlish B. K. 516 Banger J. 69 Bgnhidai B. 193 Banks R. E. 186 192 Banthorpe D. V. 241 265 Baranowska E. 559 Barbalat-Rey F. 434 Barbarella G. 516 Bard A. J. 287 296 Bard M. 51 1 Bardos T. J. 636 Barents R. A. 159 Barfield M. 45 Barford A. D. 455 Bargon J.22 154 Barker R. 437,444 Barltrop J. A. 313 316 509 Barner R. 94 Barnes A. C. 51 1 Barnett B. L.,246 Barnett R. E. 149 385 Barnett R. W. 257 Barnett W. E. 232 Barnier J. P. 218 573 Baron W. J. 197 202 397 Barone. G. 667 Barr R. F. 184 Barrans J. 274 Barrell B G. 644 Barrio J. R. 630 631 Barrow K.D. 555,603 Barrow M. J. 48 Barry J. E. 301 698 Bartak D. E. 289 Bartczak. T. J. 53 225 499 Bartlett E. H. 68 Bartlett P. A. 565 584 585 Bartlett P. D. 275 481 Bartling G. J. 503 Bartman B. 73 Barton D. H. R. 132 450 483 555 560 563 564 567 603 607,66 1,667 Bartsch R. A. 145 Bashir N. 319 478 Basketter N. S. 508 Basom G. L. 632 Bassi I.W. 327 Basters J. 248 Bastide J. 85 348 Basus J. T. 38 Basus V. J. 357 Bates G. S. 657 Bates R. B. 147 Batich C. 571 592 Battersby A. R. 619 620,62 1,623 Battioni J. P. 508 Battiste M. A. 412 471 Baty J. D. 19 Batz H. G. 346 Bau R. 267 Bauer G. 346 Bauer H. 436 Bauer R. J. 636 Bauld N. L.,. 88 164 418 Baum A. A. 499 Baum J. 510 Baumann F. 450 Baumgartner F. 256 Baumstark A. L. 275 481 Baxt W. G. 626 Bayer A. A. 646 Bayer E. 436,460,638 Bayerl B. 248 Beach D. L. 257 Beak P. 393 510 Beall H. 45 Beames D. J. 689 Bear C. A. 48 Beard J. 88 180 Beaucourt J.-P. 687 Beaudoin G. J. 565 Bebbington G. H. 346 Bechet J. J. 114 Beck J.F. 619 Becker H. 400 Becker H. G. C. 393 Becker. J. Y.. 356 Becker K. B. 665,666 Becker V. 626 Beckey H. D. 13 14 Beckwith A. L. J. 161 28 1 Beeby J. 429 Beeby P. J. 525 Beeman C. P. 386 Beger J. 253 255 Begland R. W. 373 Begley M. 57 Behbud A. 554 Behre H. 440 Behret H. 305 Beierbeck H. 43 Beilin S. I. 255 256 Beilis Y. I. 301 Belgordskaya 0. I. 256 Belikov V. M. 293 Belitskaya Z. V. 67 Bell A. M. 568 Bell B. 248 Bell R. A. 37 44 596 Bellamy A. J. 44 80 Belletire J. L. 399 Bellora E. 670 Belluco U. 252 Bellus D. 89 362 Beltrame P. 71 142 Beltrame P.L. 142 BeMiller J. N. 448 450 459 Benaim J. 263 Benezra S. 7 Benfield F. W. S. 246 Benjamin B.M. 85 367 Bennett G. N. 639 Bennett M. A. 264 Bennett R. L. 245 Beiio A. 73 Benoit F. 11 Benoiton N. L. 668 Benschop H. P. 277 28 1 Ben-Shoshan R. 406 Bente P. F. 20 Bentley T. J. 546 Bentley T. W. 8 12 Benton J. L. 329 Bentrude W. G. 282 Berdick T. E. 201 223 Berens A. R. 328 Beretta M. G. 610 Berger A. 116 Berger J. G. 592 Berger M. H. 675 Btrger R. 139,416,592 Bergeron R. 88 231 662,669 Berget B. J. 599 Bergman J. 489 Author Index Bergman R. G. 125 178 200 216 224 232 402 416 497 498,586 Bergot B. J. 554 Bergstrom R. G. 396 Berkenkotter P. 303 Berkowitz P. T. 636 Berlin Y. A. 637 Berliner E. 67 Berlot J. 503 Berman H.M. 624 Bernal I. 50 Bernard D. 274 Bernardi F. 394 Bernardi G. 65 1 Bernasconi C. F. 395 396 Bernath G. 515 Bernath T. 395 Bernhard H. O. 548 Bernhard S. A. 110 Bernstein L. L. 627 Berson J. A. 76,91,219 228 232 Bert M. 328 Berthier G. 174 Bertini F. 176 Bertolini M. 438 Bertoniere N. R. 197 Bertram J. 299 Bertrand M. P. 667 Bertz S. H. 247 672 Bessell E. M. 14 455 Bethell D. 22 26 28 154 186,237 Bethell G. S. 45 1 Betoux J. M. 399 B6ttolo G. B. M. 563 Beveridge D. L. 9 Bewick A. 296 Beylis P. 440 Beynon J. H. 12,20 Beynon P. 610 Bezman S. A. 254 Bhacca N. S.,35,84,227 228,316,503,561 Bhatti A. K. 515 Bianchi G. 69 86 Bickelhaupt F.24 501 571 Biddlecom W. G. 21 1 Biddles I. 152 Biedermann H.-G. 34 1 Biefeld C. G. 49 Biehl R. 174 Bielmann J. F. 208 Bielski B. H. J. 172 Bienvenue A. 375 Bier D. M. 16 Bigeleisen J. 122 Bigelow W.B. 147 593 Author Index Bigger C. H. 656 Biggi G. 395 596 Bigley D. B. 14 Bilevitch K. A. 27 28 Bilik V. 456 460 Biller F. 379 Billeter M. A. 647 Billets S. 19 Billingsley F. P. 185 Billups W. E. 229 261 414,549 Billy G. 404 Binger P. 575 Bingham R. C. 92 124 133,389 595 Binkley R. W. 432 Binkley W. W. 432 Binsch G. 384 Birch A. J. 265 694 Birch P. L. 118 Birchall J. M. 194 Bird C. W. 243 Bird P. H. 254 Birdsall. B. 35 40 Birladeanu L.91 228 Birley A. W. 330 Birnbaum G. I. 57 566 Birnberg G. H. 52 Bisceglia R. H. 213 378 Bischof E. 461 Bishop J. O. 626 Bishop K. C. 237 Bistritskaya E. V. 335 Bixler H. J. 333 Bjorndal H. 450 Blackborow J. R. 64 Blackburne I. D. 513 Blackmore T. 258 Blackwell L. F. 144 Blais P. 333 Blank B. 26 Blank G. M. 309 Blattman P. 624 Blatz P. E. 137 Blenkinsopp J. 212 Blickenstaff R. T. 564 Bloch K. 115 Bloch R. 87 579 678 Block A. 636 Block E. 212 Blomberg C. 24 571 Bloomfield J. J. 303 Bloor J. E. 9 Bloss D. E. 251 673 Blossey E. C. 347 565 694 Blout E. R. 116 117 Bloxham D. P. 115 Blucher W. G. 394 Blume E. 495 Blume G. 196 Blumenfield A.Z. 652 Boar R. B. 560,661 Bocek P. 15 Bocelli G. 512 Bochkov A. F. 440 Bock H. 571 Bock K. 434 453 457 458 Bode D. 641 Bodewitz H. W. H. J. 24 Bodkin C. L. 272 Bodor N. 193 197 Bodrikov I. V. 68 Boeckman R. K. jun., 552,579,581 Boekelheide V. 409 410,430 Boelema E. 219 Bonnemann H. 243 Boerboom A. J. M. 13 Bossler H. M. 324 Bottcher H. 393 Bogdanov A. A. 638 Bogdanovic B. 243,259 57 1 Bogdanowicz M. J. 213 217. 218 572 573 574,688 ' Boggs R. A. 246 247 677 BognAr R. 453 Bohlmann. F. 348 608 659 Bohm H. 376 Boicello A. 516 Boie I. 279 Boiron M. 649 Boisdon M. T. 274 Boiwe T. 109 Bol'shedvorskaya R. L. 348 Bolton R. 401 Bonazza B.R. 383 Bond A. 258,260 Bond P. J. 642 Bonds W. D. jun. 340 Bonn R. 452 Bonnafous J. C. 551 Bonnemann H. 571 Boon P. J. 452 Boone J. R. 596 Booth H. 432 515 Borcic S. 126 Borden W. T. 76 228 595 Borders D. B. 391 Bordwell F. G. 213 377 Borer P. N. 642 Borgulya J. 24 1 Borgulya R. 94 Bortolussi M. 87 579 678 Bory S. 516 Boschi R. 410 Boschi T. 264 Bose A. K. 283,665 Bosin T. R. 658 Boss C. R. 335 Botteghi C. 259 367 658 Bottini A. T. 179 Boucher E. A. 323 Bouchet P. 494 Boudjouk P. 167 Boudreau J. 541 Bouis P. A. 368 Bourbien M. S.,285 Bourgeois J.-M. 437 462 Bover W. J. 72 Bowden K. 131 Bower J. D. 480 Bowes C. M.360,404 Bowlus S. B. 245 549 553 Bowman S. A. 666 Bowman W. R. 614 Boxler D. 662 Boyd D. R. 88 Boyer H. W. 653 654 656 Boyle F. T. 493 Boyle L. W. 578 Boyle P. J. R. 20 Brace N. O. 161 Braceman J. I. 565 Brackeleire M. D. 428 Brackman D. S. 330 Braden R. 501 Bradley C. H. 482 616 Bradshaw J. S. 494 Bradsher C. K. 52 89 583 Brady R. F. jun. 436 BrandCn C. I. 109 Brake P. F. 3 18 Bramblett J. D. 96 272 Brame E. G. jun. 327 Bramley R. K. 94 Branca J. 213 Brandsma L. 212 Brandstetter F. 638 Branfman A. R. 60 Brannock K. C. 692 Braterman P. S. 244 Brauer D. J. 246 Brauman J. I. 83 229 585 Braun D. 326 Braun M. 673 Brazeau P.. 18 Brazier J.F. 269 271 700 Breen D. L. 9 Breitmaier E. 37 433 Bremholt T. 400 Bremser W. 38 422 Brennan M. P. J. 301 305 Brennan M. R. 436 Brenner S. 147 Breslow R. 83 139,230 286 321 386 416 427,592 Brettle R. 301 Brewer R. 125 Brice M. D. 247 Bridson J. N. 676 Briggs J. M. 41 Bright D. 386 Bright G. M. 426 Bright H. J. 99 104 Brighton C. A. 329 Brightwell N. E. 239 424,476 Brimacombe J. S. 442 443 450 455 460 467,468 Brink A. J. 462 Brinker U. H. 37 233 386,388 Brinkman M. R. 22 26 28 154 186 237 Brion C. E. 13 Britt W. J. 508 Britton A. 627 Britton W. E. 292 Broadhurst M. J. 286 388,389 Brocard J. 579 Brock D. J. H. 115 Brockman H.407 Brodie J. D. 623 Bromilow R. H. 277 Brook P. R. 84 Brooke P. K.; 189 Brookes A. 418 Brookes I. R. 256 Brookhart M. 80 261 Brookhart M. S. 497 Brooks C. J. W. 19 380 Brooks J. J. 47 Broom A. D. 635 Broquist H. P. 529 Brown C. 29,230 Brown C. A. 258 348 366,66 1,666 690 Brown C. E. 623 Brown D. J. 243 Brown H. C. 124 125 141 348 350 473 571 576 657 663 664 665 666 667 668,669,673 Brown J. M. 94 232 260 Brown J. N. 5 16 Brown J. P. 464 Brown L. E. 98 Brown M. P. 245 251 Brown 0.R. 202,305 Brown P. 12 Brown P. M. 563 Brown R. F. C. 227 Brown R. T. 538 541 545 Browne D. T. 40 Browne J. W. 568 Browning J. 258 Brownlee G. G.650 Brownlee R. T. C. 73 Brownridge J. R. 379 Brubaker C. H. jun. 340 Bruce M. I. 245 258 Bruch M. 427 Bruntrup G. 522 Brufain M.. 610 Bruhin J. 409 Bruice P. Y. 239 391 474 Bruice T. C. 239 391 474 Bruins Slot J. H. W. 436 Brundle C. R. 10 Brunelle D. J. 246 657 677 Bruner F. 16 Bruner H. 266 340 Bruneton J. 544 Brunner H. 258 Brunse A. J. 627 Bruton C J. 645 Bryan C. J. 68 Bryan R. F. 401 532 694 Bryce G. F. 118 Bryce-Smith D. 3 1 1 318,401 Brzechffa M. 41 1 Buckpitt A. R. 658 Buchi G. 659 Burton D. J. 665 Bubnov N. N. 27,28 Buchachenko A. L. 23 29 Buchanan J. G. 451 Buchardt O. 507 508 520 Buchecker C. 225 492 499 Buchner W.244 Buck,K.T.,427,519,531 Buckley A. 72 Buckley P. D. 144 Buddnis J. 667 Author Index Budnik R. A. 261 Budzikiewicz H. 2 3 9 Biichi G. 58 679 Biichi H. 284 Buehner M. 107 110 Biirgi H. B. 60 Bugianesi R. 440 Buhner D. 426 Buhr G. 227 Bui A. M. 544 Bujnoch W. 203 Bull J. R. 561 Bullock A. T. 341 Bullock C. 443 Bunce N. J. 399 Buncel E. 149,242,395 Bundy C. H. 192 Bunnett J. F. 71 144 148,181,537 Bunton C. A. 278 Bunzli J. C. 595 Burchfield H. P. 13 Burdett K. A. 229 230 Burdon R. H. 650 Burgada R. 274 Burgdorfer G. 178 521 Burger K. 86 273 477 49 1 Burgess E. M. 512 Burgus R. 18 Burk P. 678 Burkhardt T. 348 Burkhardt T.J. 247,672 Burlingame A.L. 563 Burnett M. G. 248 Burns D. 690 Burns P. A. 475 Burr J. G. 629 Burri P. 67 393 Bursey J. T. 387 Bursey M. M. 7 9 387 Burton D. J. 47 685 Burton R. 434 Busch A. 366 499 Buschek J. M. 513 Bushweller C. H. 45 Buswell R. L. 145 Butchard C. G. 455 Butcher M. 18 Buter R. 325 Butler W. M. 264 Butterworth R. F. 434 436 Buttiglieri M. W. 627 Button A. C. 60 Buxton P. C. 403 Bystrov V.F. 450 Cabell-Whiting P. W. 214 Cabiddu S. 71 Author Index Cacace F. 69 Cacchi S. 686 690 Cadogan J. 1. G. 29,176 188,278,279 Caglioti L. 686 Cahiez G. 245,361,662 693 Cahill R. 51 Caine D. 318 Caine lli G. 685 692 Cairncross A. 373 Cairns M.A. 260 Calabrese J. C. 52 144 257,571 Caldeira P. P. 566 Calder G. U. 178 319 369,402,479 Caldwell J. 94 Caldwell R. A. 31 1,480 Calf G. E. 250 Call L. 319 Cama L. D. 484 Camaggi C. M. 172 Camaioni D. M. 374 Cambie R.C. 667 Carnerman A. 59 Camerman N. 59 Cameron G. C. 341 Camp R. L. 222 Campagnan F. 65 1 Campbell I. D. 32 Campbell M.-T. 276 Canet D. 181 Canonica L. 568 599 Cantrell T. S. 426 480 Capek K.,468 Capka M. 266,340 Capon B. 449 Capuano L. 477 Carassiti V. 252 Carbon J. 643 645 Cardillo G. 685 Cardin C. J. 245 Cardin D. J. 234 243 245 Carenza M. 328 Carey F. A. 187 278 Cargioli,J. D. 39 41 42 Carhart R. E. 36 Carless H.A. J. 479 Carlson B. A. 667 673 Carlson D. J. 333 Carlson R. E. 552 Carlson R. G. 317 318 586 588 Carlson R. M. 674 686 Carman C. J. 36 Carman R. M. 380 Carnahan E. 83 Carniti P. 71. Caron G. 672 Carpenter A. K.,289 Carpino L. A. 67 1 Carrie R.,86 Carroll D. I. 13 Carroll F. A. 240 Carroll F. I. 380 Carroll G. L. 674 Carruthers W. 690 Carstens L. L. 558 Carter T. P. 223 Cartwright E. M. 650 Carty A. J. 5 19 Caruthers M. H. 284 Cary L. W. 38 611 Casadevall A. 68 Casale A. 327 Casey C. P. 246 247 672 677 Casey M. L. 74 Cashen M. J. 238 391 Cashion P. J. 637 Casnati G. 69 Caspi E. 564,603 Cassar L. 243 251 263 Castedo L. 534 Castenson R. L.128 Castro B. 454 Catlin J. C. 639 Cattania M. G. 142 Caubere P. 181 Caughlan C. N. 269 Cauquis G. 305 Cava M. P. 427 519 53 1 Cavi A. 544 Ceasar G. P. 233 388 Ceder O. 504 Celis J. E. 645 Cense J. M. 218 Ceraso J. M. 527 Cerfontain H. 42 Cerimele B. J. 11 Certi G. 141 Cerutti P. A. 640 Cervinka O. 513 Cesari M. 252 Cessna A. J. 136 Cetinkaya B. 234 243 Chaabouni R. 471 Chadwick D. 8 Chadwick,,M. 8 Chain Sir E. 555 603 Chakhmakhcheva 0.G. 637 Chakraborti P. C. 557 Chalet J. M. 437 462 Chalk A. J. 341 Chalk R. C. 441 Challa G. 325 Challand S. R. 193 508 Challis B. C. 66 67 Chamberlain K. B. 265 Chamberlin M. J. 640 Chambers R. D. 504 Chambers V.E. M. 568 Chan A. S. K. 252,499 Chan C. Y.,248 Chan H. T. J. 399 Chan P. C. 172 Chan S. I. 625 Chan T. H. 283 Chandrasekaran S. 272 Chandrasekhar K. 107 Chandross E. A. 428 Chang B. C. 274 275 Chang C. S. 164 Chang C. Y. 654 Chang F.C. 563 Chang P.L.,481 Chang S. 641 Chang S.E. 646 Chang S.-H. 343 626 Chanon M. 73 Chao P. 96 501 Chapleur Y.,454 Chapman 0. L.; 81 178 319 369 402 414, 479,575 Chapman T. M. 638 Chapman V. A. 627 Charalambides A. A. 538,541 Charles G. 562 669 Charles J. J. 338 Charpentier C. 19 Charrier C. 263 Charton B. I. 140 Charton M. 140 Chastrette F. 526 Chastrette M. 526 Chatt J. 248 264 Chattha M. S. 678 Chauhan M.S. 404 Chaves 0.G. 442 Cheer C. J. 213 378 Chekrii P. S. 253 Chelhot N. C. 489 Chelton E. T. J. 628 Chen C. Y. 653 Chen F. M. F. 495 Chen H. E. C. 26 Chen K.-N. 252 Chen K. S. 153 159 176,382 Chen R. H. K. 245,662 691 Chen T.-K. 504 Cheng P.T. 417 Chenier J. H. B. 334 Cherkin A. 627 Cherluck R. M. 689 Chernenko G. M. 255 Cherry W. 595 Clark D. B. 299,300 Chesick J. P. 90 Clark D. G. 94 Cheung H. T. 538 Clark H. C. 139 244 Cheung L. D. 52 251,256,257 Chia L. L. S. Y. 637 Clark I. M. 568 Chiang J. F. 591 Clark M. 504 Chibikjian J. G. 641 Clark M. G. 115 Chickos S. S. 303 Clark R. A. 591 Chidester C. C. 461 Clark R. D. 678 Chien Y.-H. 630 Clark S. D.359 Chihal D.' M. 84 227 Clarke M. T. 31 1 228,316 Claudy P. 694 Childers R. F. 35 39 Clause A. O. 35 Chin H. B. 267 Clauss K. 658 Chin N. W. K. 79 Clay R. M. 514 Ching 0.A. 442 Clayton C. J. 451 Ching S.-H. L. 468 Clegg A. S. 568 Chinh T. M. 70 Clemens J. 258 Chikamatsu H. 534 Clernenti S. 69 Chiprnan D. M. 630 Clernetson K. J. 445 Chippendale K. E. 189 Clennan E. L. 313 509 Chisholm M. H. 139 Cleophax J. 464 244,257 Clerbois N. 41 1 Chittenden G. J. F. 440 Clerici A. 396 452 Clerici L. 651 Chiusoli G. P. 243 257 Clerici M. G. 252 Chizhov 0.S. 19 Clesse F. 51 1 Cho I. 344 Cliff G. R. 190 498 Choay P. 465 Clive D. L. J. 283 661 Chock P. B. 630 675 Chow L. T. 653 Clouse A. O. 32 Chow W. Y. 414 Coates D.A. 167 Christensen B. G. 484 Coates I. H. 483 667 485 Coates R. M. 127 667 Christensen H. C. 154 Coburn T. T. 200 203 Christensen L. F. 635 224,429 Christian W. 98 Cochran D. W. 34 35 Christiansen J. K. 458 544 Christie R. M. 67 Cocivera M. 26 45 395 Christl M. 522 Cooker D. 448 Christoph G. G. 408 Cockerill A. F. 42 Chu A. K. C. 404 Codd E. E. 652 Chu V. 686 Codding P. W. 58 Chu W. 286 Codrington R. 42 Chuche J. 79 Cody V. 59 Chuit C. 245 361 662 CoSlho J. S. de B. 563 693 Coetzer J. 58 462 Chvalovsk9 V. 67 Coffin R. L. 318 552 Ciabattoni J. 199 225 586 Cicchetti O. 333 Coggins L. W. 627 Ciccioli P. 16 Cohen L. A. 74 Cignarella G. 498 Cohen S. N. 654 Cimino G. 559 Colburn R. W. 14 Ciufferini E.120 Colby B. N. 13 Clar E. 425 Cok C. M. 147 Clar F. 425 Cole P. E. 641 Clardy J. 52,58,59,544 Coleman J. P. 299 551,554 558 559 Collette J. W. 254 Claridge D. V. 264 Colli H. N. 37 Clark B. F. C. 643 644 Collier M. R. 244 645,646 Collin J. 263 Author Index Collin P. J. 425 Collington E. W. 546 672 Collins C. J. 85,215,367 Collins J. H. 11 Collins P. M. 431 437 438,453,459 Collman J. P. 262 263 340,682 Colombo G. 89 Colonna S. 384 Colvin E. W. 664 Cornbret J.-C. 282 Combriato G. 643 Corni R. 695 Comin J. 670 Cornmeyras A. 68 Conant R. 451 Concannon P. W. 199 225 Concepcion J. G. 148 Congdon W. I. 342 Conia J. M. 87,204,213 218,573,579,678,690 Conley R.A. 694 Conlin R. T. 198 223 57 1 Conn J. 45 1 Connolly J. D. 561 562 Connor J. A. 247 Conover J. H. 626 Conover,W. W. 218,474 Conrad W. E. 275 Consiglio G. 259 367 658 Conti F. 255 260 Conway B. E. 296 Cook A. H. 255 Cook D. M.,145 Cook I. F. 606 Cook J. S. 640 Cook M. J. 5 15 Cook M. M. 513 Cook R. D. 271 Cooke M. P. 340 54Y Cooks R. G. 12,20 128 Cookson R. C. 583 Coornbs R. V. 566 Coon C. L. 394 Cooper C. M. 483 Cooper D. J. 461 463 464 Cooper D. R. 344 Cooper J. 152 167 382 Cooper R. D. G. 484 Cooper T. A. 658 Copocasale D. 4 17 Coppola J. 57 Coquelet C. 494 Corain B. 260 Corbella A. 600 Author Index Corcoran J. W. 450 Cordella G.498 Cordes E. H. 40 Corey E. J. 89 145,212 245 260 282 365 552 557 576 583 662 664 667 669 671,674,689,691 Corfield P. W. R. 453 Cormier R. A. 575 Cornelisse J. 311 314 398 Corneo G. 626 Cornford A. B. 184 Cornforth J. W. 597 Corrie J. E. T. 607 Corriu R. J. P. 250 Costa D. J. 269 Coton G. 399 Cotton F. A. 247 Cotton W. D. 194 246 Coulson A. 647 Coulson A. R. 652 664 Coulson D. R. 357 Courchene W. L. 11 Courtois J.-E. 450 Couse N. L. 627 Coussemant F. 72 Cowan N. J. 650 Cowley A. H. 270 Cox B. G. 376 Cox J. R. 241 Cox P. A, 8 Cox P. J. 55 Cox R. A-. 242 376 Cox R. E. 563 Cox W. W. 318 552 586 Coyle J. D. 316 Crabb T. A. 51 Cragg R.H. 668 Cram D. J. 384 387 410 51 1,527 Cramer F. 638 639 643,645 Crarner G. M. 146 206 420,591,593 Cramer R. E. 43 Cramers. C. A. 15 Crampton M. R. 70,395 Crandall J. K. 218 474 Cranor P. T. 128 Crawford R. J. 79 Creary X. 129 Creasey S. E. 441 Cree G. M. 440 Creed D. 507 Cregge R. J. 681 687 Cremer S. E. 40 Cresp T. M. 394 524 Cress J. P. 504 Cresson P. 230 D’Amore M. B. 83,229 Crews P. 88 180 da Mota M. M. M. 247 Cribley,.K. 36 Damps K. 560 Criegee R. 390 Dan E.,.331 Crilly W.,44 80 Dana G. 68 Crivello J. V. 418 Danby C. J. 10 Croatto U. 264 Danen W. C. 153 159 Crochet R.A. 400 169 Crociani B. 264 Danforth J. D. 329 Crombie L. 57,94 Dang T.-P. 259 Cross J.H. 549 Danheiser R. L. 553 Cross R. J. 244 557,577,583,678 Crothers D. M. 640 Daniel S. H. 96 64 1,642 Danieli B. 568 Crow W. D. 197 200 Daniels P. J. L. 87 396 Danna K. J. 653 Crowe E. W. 147 388 Danna R. 566 592 Dannenberg J. J. 128 Cruickshank D. W. J. Dannhardt G. 521 423 Daoust V. 463 Cruikshank B. I. 260 Darbre A. 19 Crump D. R. 567 Darby A. C. 68 Crumrine D. S. 692 Darias J. 554 560 561 Cryberg R. L. 143 Darnell J. E. 649 650 Csizmadia I. G. 198,225 Darwish D. 120 Cue B. W. 227 505 Dashevsky V.G. 513 Cullison D. A. 592 da Silva R. R.,194 Cumrnings D. J. 627 Dastur K. P. 553 694 Cundall R. L. 312 Dau M.-E. T. H. 374 Cundy C. S. 243 245 376 Cunico R. F. 205 Dauben W. G. 90 236 Curson D.A. 333 582,583,659 Curtis E. A. 689 Davalt M. 229 Cusachs L. C. 268 Dave V.,488 Cusack N. J. 632,639 David C. W. 215 Cushley R. J. 38 614 David M. P. 177 402 623 479 Cuthbertson E. 51 David S. 595 Cutler T. P. 227 315 Davidson D. L. 338 Cuvigny T. 657 Davidson E. A. 441 Cyr N. 434 Davidson E. W. 147 Czajlik I. 256 Davidson P. J. 244 247 Czapski G. 157 Davies A. G. 167 173 281 Davies D. H. 328 Da’Aboul I. 450 Davies G. L. O. 42 da Costa R. L. 41 1 Davies J. V. 449 Dahlberg D. B. 148 Davies M. E. 625 Dahn H. 371 Davies N. R. 260 Dai S. -H. 78 Davies R. C. 619 621 d’Alberquerque I. L. Davies R. J. H. 642 563 Davies R. M. 141 Dale J. 50 Davis D. D.. 40,147.593 Dall’Asta G. 327 Davis F. A. 242 Dalling D.K. 36 Davis L. 110 Dallocchio F. 112 Davis R. E. 43,258,551 Dalton D. R. 141 690 Davis T. L. 200 Dalton J. C. 317 480 Davison A. 246 Daly J. W. 237 Davy J. R. 410 Daly W. H. 347 Dawes K. 313 509 Damji S. W. H. 45 395 Dawkins J. V. 256 332 Dawson J. B. 318 Day A. C. 53 225 313 499,509 Day A. R. 493 Day F. H. 52 89 583 Day M. 333 Day R. O. 61,624 Dayal S. K. 73 Deadman W. D. 49 Deady L. W. 670 Dean D. 79,473 Dean E. M, 404 Deane M. 252 De’ath N. J. 270 275 276,499 De Bardeleben J. F. 318 De Bernardi M. 551 de Bie D. A. 71 DeBie M. J. A. 435 De Boer A. 457 de Boer J. 386 de Boer Th. J. 41 1 De Brackeleire M. 311 De Bruin K. E. 272,276 De Bruyn D. J. 671 De Bruyne C.K. 448 De Camp M. R. 197,397 Decock-Le-RCvCrend B. 227,571 Dedieu A. 119 Deem M. L. 82 Deeming A. J. 256 Defaye J. 43 1 466 De Filippes F. M. 653 De Franco R. J. 72 591 Degani C. 444 de Graaf H. G. 501 Degtyareva T. G. 334 de Gunst G. P. 314 Dehmlow E. V. 576 Dejter-Juszynski M. 446,460 Dekkers A. W. J. D. 518 De Klein W. J. 308 De Koning A. J. 83 Delac J. 630 De La Cruz D. 319,414 479 De La Higuera N. 482 615 de la Mare P. B. D. 141 Delange R. J 118 Delaunay J. 650 Delay F. 575 Delbaere L. T. J. 49 de Lima 0.G. 563 Delius H.,653 Della E. W. 684 Della Vecchia L. 674 Delong S. S. 627 Delpiero G. 252 De Luca P. 567 Demain A. L.58 de Mayo P. 320 321 481,516 de Meijere A. 90 135 230,589,591,595 de Member J. R. 136 357 Demian B. 67 De Micheli C. 86 Demidovich G. V. 260 Dengler B. 642 Denhardt D. T. 640 den Heijer J. 314 den Hertog H. J. 502 de Nijs H. 564 Denis J. M. 218 573 Denisov E. T. 334 Denisov L. N. 334 Denney D. B. 270,274 275 Denney D. Z. 270,275 Dennis N. 182 508 Dennis R. W. 281 Denny W. A. 568 Deno N. C. 375 Denyer C. V. 283,661 DePasquale R. J. 251 de Pava 0.V. 86 De Puy C. H. 159 de Reinach-Hirtzbach F. 560 de Ridder J. J. 436 Derocque J. L. 216 De Rosa M. 567 De Rossi R. H. 395 Dervan P. B. 228,232 de Sanabia J. A. 24,399 De Schryver F. C. 311 312,428 De Selms R.C. 575 Deshpande P. D. 556 Desiderio D. M. 17 De Simone R. 333 Desimoni G. 89 Deslongchamps P. 372 439 de Stefano S. 559 Detre G. 249 362 661 Deuchert K. 674 Deutsch C. J. 379 Dev S. 558 Dev V. 179 de Valk J. 71 Devillers-Thiery A. 651 de Vos D. 68 de Vries L. 196 Dewar M. J. S. 8 9 75 92 94 133 139 193 197 199 220 225, 231,389,471,595 Author Index Dewey R. H. 350 499 695 Dextraze P.,462 Deyrup J. A. 191 522 Dhanraj J. 330 Dharan M. 471 Dhillon B. S. 183 Diaper D. G. M. 223 Dickinson R. 374 Dickinson R. J. 18 Dickstein J. I. 270 Diebert C. E. 271 Diebler H. 148 Diehl D. R. 432 Diehl H. W. 450 Dierdorf D. S. 270 Dieterich D.501 Dieth H. K. 692 di Fate V. G. 129 Diggelman H. 649 Di Giorgio J. B. 87 Dijong I. 452 Dill K. 128 Di Mari S. J. 529 Dimmel D. R. 215 Dinse K. P. 174 Di Nunno L. 417 Dinya Z. 453 Dirheimer G. 644 Dittmar W. 200 224 Dittmer D. C. 481 Dittrich B. 204 Diversi P. 357 DiviS J. 67 Dixon W. T. 155 165 166,407 Djerassi C. 36,513,561 566,567,568 Doak G. O. 270 Dobashi T. S. 207 Dobbs A. J. 176 D’Obrenan P. 644 Dobretsov S. L. 327 Dobson C. M. 32 Dodd D. 243 Dodd J. R. 421 Doddrell D. 35,434 Doel M. T. 639 Doering W. von E. 91 95 119,228,230 Doherty C. F. 597 Dolbier W. R. 213 Dolce D. 213 Dolce D. L. 589 Dolcetti G. 248 340 Dolgoplosk B.A. 255 256,259,267 Dolling U.-H. 201 Domin E. 641 Donahue J. 277 Donahue J. A. 372 Author Index Donelson J. E. 652 Duncan J. L. 168 Doner L. W. 460 Duncan W. G. 84 Donetti A. 670 Dunham L. L. 554 Donges R. 417,589 Dunitz J. D.; 50 60 Donnelly S. J. 657 Dunkin I. R. 131 Dorman D. E. 434 Dunlap R. P.,376 Dorschel C. 540 Dunlop I. 156 Dossena A. 69 Dunn M. F. 241 Dou H. J. M. 153 Dunne K. 135 Dougherty C. M. 194 Dunnill P. 346 Dupaix A. 114 695 Douglas A. G. 554 Dupeyre R. M.,518 Dounchis H. 192 Du Preez N. 673 Doutheau A. 195 Durette P. L. 432 433 Dowd W. 124 126 453 Doyle E. R. 448 Durr H. 398 589 Doyle M. J. 234 243 Durst T. 211 212 482 Doyle M. P. 159 657 660 67 1 Duschek C.253,255 Draganit I. 373 Duteil M. 251 Draganit Z. 373 Dutra G. A. 123 245 Drakesmith A. J. 262 693 Draper R. W. 546 Dutton G. G. S. 431 Dreeskamp H. 248 Du Vernet R.,430 Dreissig W. 59 Dux F. J. 670 Drenth W. 256 Duynstee E. F. J. 381 Drewes H. R. 208 Dwek R. A. 435 Drewienkiewicz C. E. Dyatkin B. L. 196 650 Dybvig D. H. 142 Drinkard W. C. 255 Dye J. L. 527 Drury A. F. 159 Dzidic I. 13 Drury R. F. 383 Duax W. L. 57 59,596 Dubac J. 204 Eaborn C. 68 260 Dubbeldam J. 501 Eakers C. W. 184 Dube S. K. 646 Earl R. A. 445 Dubois J. E. 140 145 Eastlick D. T. 278 679 Eaton P. E. 589 Dubois R. 43 Ebel J. P. 643 644 Dubrovina N. I. 450 Eber J. 557 Duchamp D. J. 17 60 Eberbach W. 316 46 1 Eberhart M. K.157 Dudley A. R. 34 Ebersole R. C. 563,603 Dudock B. 643 645 Eberson L. 285 302 646 392,395 Dueber T. E. 216 Ebine S. 90 418 Durr H. 203 Eck C. R. 215 Duffy M. J. 453 Eck D. L. 144 Dugaiczyk A. 653 Ecker A. 279 Dugas V. B. 117 Ecker H. 279 Duhamel L. 486 Edelman I. 537 Duhamel P. 486 Edelmann R. 275 Duke A. J. 119 Eder H. 437 Duke R. E. jun. 85,317 Edgar A. R. 451 Duke R. P. 513 Edge D. J. 158 159 Dukek U. 518 167 Dumas P.,671 Edgell M. H. 653 Dumitriu S. 337 Edmond J. 560 Dumont W. 259 Edmonds A. C. F. 212 Dunathan H. C. 586 Effenberger F. 64 182 Dunbar R. C. 387 393 240,394,399 Efimov V. A. 637 Efraty A. 244 Egan R. S.,450 Eggert H. 36 Eglinton G. 563 Egorora V.V.,564 Eguchi S. 518 550 Ehntholt D.J. 419 Ehrenson S. 73 Ehrlich A. 67 Ehrlich S. D. 651 Eichelberger J. L. 279 Eick H. A. 49 Eidenschink R. 499 Eilby J. E. 223 Eilerman R. G. 692 Eilert J. H. 164 Einhellig K. 273 491 Einspahr E. 386 Einstein F. W. B. 454 Eisch J. J. 207 Eisenhut M. 269 Eisenstein O. 89 374 583,595,596 Eisler W. J. 16 Eisner T. 553 Eizenberg L. 317 571 Eklund H. 109 El-Anani A. 69 Eland J. H. D. 10 Elder R. C. 318,408 Elgavi A. 84 Elguero J. 494 Eliel E. L. 516 Elix J. A. 394 399 El Khadem H. 431 El-Kholy I. El-S. 510 Elkin K. 16 Ellestad G. A. 556 Ellinger Y.,174 Elliott P. L. 36 Elliott R. L. 519 Ellis D. E. 125 Ellis K.,276 Ellis P.D. 42 Ellis S. R. 15 Ellison R. A. 576 Ellwood D. C. 460 El-Obeid H. A. 118 Elson I. H. 153,382,395 El Taliawi G. M. 157 Emanoil-Ravicovitch R. 649 Emgler E. M. 133 Emoto S. 436 466 Empsall H. D. 258 Emsley J. W. 35 Enemark J. H. 264 Engel Ch. R. 565 Engelmann A. 213,355 377 706 Author Index Engler E. M. 218 389 595 Englert G. 548 Englund P. T. 653 Entwistle N. 560 Enwall C. 629 Epiotis N. D. 75 81 206,583,595 Epling G. A. 92 Erdmann V. A. 645 Eremenko 0.N. 253 Erickson R. J. 630 Erker G. 27 229 359 Ermer O. 50 571 Ernst R. 563 Ernst R. R. 31 Ershov V. V. 29 Ertel W. 504 Ervast H.-S. 20 Eschermoser A. 95,680 688 Eshdat Y.,114 Eto M.444 Evans A. G. 164 Evans B. 445 Evans C. A. 13 Evans C. H. 627,628 Evans D. A. 211 283 407 549 553 619 662,674 Evans D. F. 43 Evans J. 264 Evans J. A. 252 Evans J. M. 568 Evans M. E. 438 441 448 Evans R. 598,602 Evans S. 8 Evans T. E. 383 Evelyn L. 437 Everett D. H. 328 Everitt G. F. 252 Everling B. W. 215 Everse J. 107 630 Excoffier G. 447 Exner J. H. 383 Exner O. 74 Ezaki N. 460 Ezekiel A. D. 437 Faerber P. 641 Fagerburg D. R. 190 Fahey D. H. 248 Fahey D. R. 248 Fahmy M. A. 278 Fahrni P. 94 241 Fajkos J. 569 Falbe J. 262 Falck J. R. 305 533 Falco E. A. 465 Faler G. R. 82 Fales H. M. 14 17 Falk J. C. 326 Faller J.W. 44 Fallis A. G. 550 Falshaw C. P. 94 230 Fantazier R. M. 493 Faraone F. 257 Farbman S. 17 Fgrcasiu D. 198 223 571 Fgrcasiu M. 198 218 223,571 Farkas I. 453 Farmer J. H. 387 Farnden K. J. F. 612 Farnell L. 78 Farnell L. F. 41 Farneth W. E. 83 229 Farnham W. B. 277 Farnum D. G. 137 Farona M. F. 261 Farooqi M. A. 505 Farrell N. 260 Farsang G. 305 Fasiska E. J. 432 Fatiadi A. J. 694 Faulkner D. 123 Faulkner D. J. 551,554 559 Fava A. 120,516 Favre B. 371 Fawcett J. K. 59 Fawcett P. 482 616 Fayat C. 184 Fayos F. 544 Fayos J. 58 551 554 559 Featherman S. I. 515 Fedarko M. C. 40 Fedorchenko V. I. 301 Fedorynski M. 196 Feeney J. 32.35,40,464 Feeney R.E. 322 Fehn J. 86,477 Feldblium V. Sh. 253 Felden R. 319 Felix D. 688 Feller C. 503 Felzenstein A. 88 Fenical W. 56 554 558 Fenselau. C. 19 Fentiman A. F. 14 Fenton D. F. 328 Fenwick J. 198 225 Ferekh J. 269 Ferguson G. 562 Ferguson L. N. 571 Ferrari G. 568 Ferrier R. J. 431 446 451,458,459 Ferris J. P. 59,319,373 495 Fessenden R. W. 155 163 Fktizon M. 376 683 Fiato R. A. 591 Fickes G. N. 68 Field F. H. 14 138 Fielder R. J. 445 Fields E. K. 177 Fields R. 194 Fierman A. H. 271 Fiers W. 649 Fife T. H. 132 Figuera J. M. 193 197 Fike S. A. 73 Filby W. G. 449 Fild M. 269 Filippini G. 48 423 Filkenstein M. 301 Filler R. 488 Fink T.R. 642 Finkelhar R. 245 Finkenbine J. R.,283 Finzi P. V. 86 Fioshin M. Ya 285 293 Firestone R. A. 85 Fisch M. H. 563 Fischer A. 65 238 394 395 Fischer D. 652 Fischer D. E. 237 Fischer E. O. 247 Fischer F. 243 Fischer G. 658 Fischer H. 24 25 26 182,237,240,399 Fischer J. P. 337 Fischer K. 246 571 Fischer N. H. 35 Fischer P. 64 394 Fischer S. 486 Fischler I. 248 FiSera L. 73 Fishbein R. 375 Fisher C. M. 223 Fisher R. D. 124 Fisher R. P. 666 Fissekis. J. D. 627 Fitt J. J. 674 Fitton H. 265 Flaherty B. 437 Flammang. R. 41 1 Flammang-Barbieux M. 411 Fleet G. W. J. 576 671 Fleischmann R. 260 285,299,300 Fleming F. A. 142 Fleming I.419 Fleming M. 234 Author Index Fleming R. H. 91 228 Franke R.,244 Flesch G. D. 11 Franz J. A. 150 669 Fletcher H. G. jun. 450 Franzen G. R. 384 452,453 Franzmann G. 346 Fletcher R. 451 Fraser A. R. 254 Fleury M. B. 295 Fraser A. W. 530 Flewett G. W. 64 394 Fraser J. G. 568 Flick B. H. 563 Fraser R. R.,42 Flippen J. L. 252 Fraser S. B. 541 Flitsch W. 422 519 Fraser-Reid B. 460 Flood T. C. 257 Frater G. 198 225 Florey J. B. 268 Frazer N. W. 650 Florio S. 417 Frazer T. H. 643 Flowers H. M. 446 460 Frazier J. 641 Flynn C. R. 404 Frkchet J. M.,345 445 Foa M. 263 447 Fohlisch B. 518 Freeburger M. E. 279 Foley H. G. 690 Freeman P. K. 133 Foltz R. L. 14 Frthel D. 372 439 Fondy T. P. 455 Fresco J.R. 626 639 Fong C. W. 682 640,641 FOOS,J. S. 589 Fretz E. R. 242 Foote C. S. 475 Freudenthal A. F. 488 Forcellese M. L. 555 Fridkin M. 637 Forchioni A. 464 Friedrich E. C. 129 Ford G. C. 107 110 Friedrich K. 396 416 Ford P. J. 650 504 Ford W. T. 78 146 Friedrich L. E. 480 Forder R. A. 246 Frimm R. 73 Foreman M. I. 44 Fritsch W. 567 Forkey D. M. 504 Fritz H. 391 589 Foroughi K. 274 Frayen P. 278 Forrest T. P. 495 Frohlich J. C. 17 Forrester A. R. 168 Frost D. C. 8 184 595 318,408 Frost K. A. 179 Forrester P. F. 448 Fruchier A. 43 Forrester P.I. 646 Fry A. J. 292 Forster H. 174 Fry F. S. 510 Forsyth D. A. 63 Fry J. F. 124 Forsythe G. D. 147 Fry K. 652 Foster A. B. 14 435 Fryber M. 607 455,456 Frydman B.619 Foster A. M. 87 201 Frydman R. B. 619 Foster E. L. 564 Fryer R. I. 523 Foster H. E. 492 Fu E. W. 387 Foster S. A. 502 Fu W. Y. 215 Foster W. E. J. 166 Fuchs P. L. 282 663 Foti F. 196 397 Fueno T. 68,73 142 Foucaud A. 184 Furst A. 567 Fourrey J. L. 556 Fuganti C. 613 Fowler F. W. 87 522 Fuhr H. 381 Fox J. J. 465 628 633 Fuji K. 58 544 Fox M. A. 396 Fujii H. 202 Fraenkel H. A. 179 Fujii S. 674 Franck R. W. 310 390 Fujii T. 627 695 Fujimoto H. 76 78 Franck-Neumann M. Fujimoto T. T. 283 662 225,492,499 Fujino M. 671 Frank G. 524 Fujisawa Y. 635 Frank G. W. 50 Fujita E. 602 Frank J. K. 53 312 Fujita K. 214 Fujita N. 670 Fujita T. 73 602 Fujiwara Y. 244 254 361 Fukuda T. 671 Fukui K.76 82 179 Fukui T. 641 642 Fukumoto K. 183 188 530,533,535,541 Fukunaga K. 64 Fukuto T. R. 278 Fukuyama Y. 560 Fukuzumi K. 251 Fulke J. W. B. 562 Fullbier H. 255 Fuller W. 625 Fullerton T. J. 693 Funabiki T. 248 Funfschilling P. 230 Furimsky E. 172 Fume M. 389 Furst G. T. 84 Furtsch T. A. 270 Furue M. 310 Furukawa F. 253 Furukawa H. 55 Furukawa J. 253 255 265 Furukawa N. 665 Fyfe C. A. 45 395 Gabelman N. 626 Gabriel O. 11 1 Gaddy H. R. 192 Gaffney J. S.,381 Gagnaire D. 431 432 440,447 Gagosian R. B. 317 Gaibel Z. L. F. 314 Gajewski R. P. 480 Gal A. 125 216 Galantay E. 566 Galbraith M. N. 551 606 Gall J. G. 627 Gall M. 376 Gallagher M.J. 279 Gallagher P. E. 552,582 Gallagher P. G. 326 Gallo G. G. 610 Gallo R. 73 Gallup G. A. 386 Gambino S. 296 Games D. E. 14 Gan I. 685 Gandhi S. S. 183 Gandolfi R. 86 Gander E. S. 650 Ganem B. 553 577 581,678 Ganguly A. K. 461 708 Author Index Gano J. E. 317,571 Gansow 0.A. 30,43 Ganter C. 518 Gaona R. T. 670 Gaoni Y. 362 499 Garbesi A. 516 Gardner E. J. 3 18,408 Gardner J. N. 669 Gardner J. O. 579 Gardner P. D. 290,224 Gardner R. C. F. 245 Gardner S.A. 254 Garegg P. J. 283,451 Gariboldi P. 600 Garner B. 218 Garnett J. L. 250 658 Garnier B. 213 573 Garratt P. J. 37 386 429 Garst J. F.,207 Garst M. E. 496,668 Gassen H.G. 642 Gassman P. G. 127,129 131 134 143 184 208 222 236 261 381,399,486,503,670 Gateau-Olesker A. 461 Gatti G. 384 Gaudry M. 376 Gaviraghi I. G. 512 Gaylord N. G. 337 338 Gebert P. H. 200 224 422 Gefter M. L. 645 Gehriger C. L. 395 Geiger R. 671 Geisel M. 665 Gelan J. 43 GellCri A. 494 Gemilev U. M. 439 Gennaro G. P. 96 Gennaro U. 327 Gent P. A. 451 George J. K. 85 Georgiev V. St. 545 Gerasimov V. I. 339 Gerdil R. 295 Gerlach H. 42 379 Germain A. 68 Germeraad P. 189 Gero S. D. 434 461 462,464 Gerry M.C. L. 374 Gerszberg S. 670 Gesson J. P. 564 Geurrieri F. 243 Geurtsen G. 71 Gewald K.,497 Ghangas G. S.,455,653 Ghatak U. R. 557 Ghiringhelli D.613 Ghosez L.,363 583 Ghosh B.C. 449 Giacomello P. 69 Giannini D. D. 596 Giannotti C. 257 Gibb W. H. 329 Gibbons C. 340 Gibbons W. A. 41 Gibbs J. J. 555 Gibby M.G. 39 Gibney K. B. 431 Gibson D. H. 369 Gibson H. H.,192 Gibson K. H. 619 Giege R. 643 Gieren A. 491 Giersch W. 673 Giezynski R. 253 Giga A. 669 Gigg R. 451 Gilbert,A.,311,318,401 Gilbert B. C. 157 169 172,281 Gilbert J. C. 229 Gilbert J. D. 19 380 Gilbert M. T. 19 Gilbert W. 656 Gilchrist T. L.,177 190 199 205 226 319 471,478,504,690 Gileadi E. 287 Gilgen P. 237 354 Gilham P. T. 637 639 Gill J. C. 522 Gill P. L. 443 Gillespie J. P. 164 425 Gillespie P. 268 284 Gillespie R.J. 72 133 Gillon H. M. 67 Gilman N. W. 399 Ginelli E. 626 Giordano C.,90 Giordano F. 567 Girard C. 204,218,573 690 Girardi F. 651 Giraud M. 508 Girault J. P. 68 Girling R. L. 433 Gitis S. S. 70 Giusti G. 664 Given R. M. 248 Givens R. S. 318 552 586 Giziewicz J. 635 Glaser L. 110 Glaser R. 345 638 Glaser S. 284 Glass R. S.,508 Glaudemans G. P. J. 438,453 Glazer E. A. 222 Gleason W. B. 437 Gleicher G. J. 404 Gleiter R. 591 594 Glinsukon,T. 58 Glockling F.,252 Glukhovtsev V. G. 26 Gnanapragasam,N. S.,68 Go K. T. 55 Goad L. J. 607 Godel M.,72 Goeckner N. A. 427 Goedecke E. 417,589 Goedken V. L. 408 Gondos Gy. 5 15 Goh S. H.,424 474 Gokel G.W. 122. 527 Gold V. 37 Goldberg B. J. 128 Goldborn P. 260 Goldenberg V. I. 335 Gol’dfarb Ya L. 179 Golding B. T. 232 623 Goldschmitt E. 94 232 Gol’dshleger N. F.,250 Goldstein J. H. 36 Goldstein M. J. 78 133 221,592,593 Goldstein S.L. 239 Golemba F.J. 330 Golling R.,630 Gollnick K. 82 Gol’teuzen E. E. 70 Gomez-Gonzales L. 395 Gonipper R. 358 360 415,479,511 Gonzdlez A. G. 554 560,561 Gonzalez E. R. 292 Gonzalez-Porque V. P. 111 Goodbrand H. B. 663 Goodman H. M. 653 656 Goodman L. 448 Goodman M. M. 242 Goodman N. C. 626 Goodman R. A. 40 Goodwin,T. W. 606,607 Goon D. J. W. 399 Gopal R. 182 Gorchen A. 619 Gordon E. M. 482 Gordon M.137 Gordon S. L. 44 Gore J. 195 665 Gorenstein D. G. 278 Goricnic B.,126 Gorina N. V. 258 Gorlier J.-P. 246 693 Gorzynski J. D. 251 Author Index Gosavi R.K. 198,225 Gosfeld H. 637 Goshaev M. 401 Gosney I. 188 Gosser L. W. 247 Gotfredsen W. O. 603 Goto K.,44 596 Goto T. 465 609 Gotschi E. 95 Gotthardt H. 320,481 Gottlieb D. 61 1 Gottschalk E. M. 641 Goudmand P. 227,571 Goulding B. T. 94 Goulian M. 652 Goulian S.H. 652 Goutarel R. 450 465 547 Govindachari T. R. 563 Goyanes-Villaescursa, V. 627 Grace D. S.B. 279 Graefe J. 248 Graessle I. 518 Gratzel M. 324 Graf G. 437 Graf R. 462 Gragerov I. P. 23 24 Graham J. C. 690 Graham W.D. 218 Grahn W. 592 Gralla J. 642 Grandjean J. 40 Granger M. R. 147 Grant D. M. 36 Grant J. L. 150 368 Grant R.W. 207 Grantham P. J. 554 Graovac A. 424 Grard C. 251 Grasselli P. 613 Grassi G. 196 397 Grassie N. 327 Gratani F. 333 Gravestock M. B. 565 585 Gray G. A. 40 Gray G. R. 444 Grayson M. A. 15 Graziani M. 252 Greco F. 253 Gree D. 86 Gree R. 86 Green B. S. 84 Green C. L.,549 Green G. W. 694 Green J. 38 233 388 419 Green M. 258 264 265 Green M. L. H. 246,264 Greene F. D. 222 Greenberg A. 78 Greenberg S. 633 Greenhalgh R. 277 Greenstock C. C. 156 Greenwald R.B. 191 Greenwood G. 138,587 Gregorio G. 255 Gregory B. J. 121 Gregory C.M. 650 Greibrokk T. 196,481 Greig C. C. 238 395 Gretton W. R. 614 Greuter H. 238 Greve W. 444 Grey R. A. 415 Gribble G. W. 302 Grieco P. A. 145 249 552,662,678,687 Grieg C. C. 65 Griessl E. 341 Griffin G. W. 84 197 227 228 239 315 316,424,476 Griffith R.C. 233 Griffiths D. V. 515 Griffiths J. 314,427 Grigg R. 75 76 82 87 94,495 Griller D. 170 281 Grimme W. 94,95,229 230,233,360,476 Grimshaw J. 164 289 292,294 Grimsrud E. P. 122 Grisebach H. 461 Grivas J. C. 393 Grob C. A. 73,665,666 Grobel B.-T. 677 Groen A. 26 Groen M. B. 65 238 3 94 Groenenboom C. J. 248 Groenewege M. P. 55 387 Groger D. 548 Gronowitz S.,42 Grootveld H. H. 571 Gross B.454 Gross H. J. 645 Grossman N. R. 131 Grotch G. L. 17 Grotewold J. 316 Groth P. 50 Grovenstein E. 68 Grubbs E. J. 207,381 Grubbs R.,427 Grubbs R. H. 266 340 415 Grube P. L.,341 Gruber W. 214 Grudtsyn Yu D. 70 Gruentzmacher R. R. 125 Gruetzmacher G. 208 399,486,670 Grunanger P. 86 Grunberger D. 639 Grundke H. 348 Grutzner J. B. 146,482 592,616 Gschwend H. W. 363 411 Guerino A. M. 18 Guergerich F. P. 529 Gunther H. 36 280 379,386,422 Guest I. G. 553 564 Gusten H. 8 Guggenberger L. J. 244 Guilford H. 107 Guillet J. E. 330 331 Guillaumet G. 181 Guillemin R. 18 Gullo V. P. 563 Gunavan J. 239 Gund T. M. 218 Gundermann K. D. 525 Gunn B.C. 399 Gunn P. A. 562 Gunning H. E. 198 225 Gunther H. 37 38 Gupta N. K. 284 Gupta P. 437 438 Gupta R. N. 617 Gupta S. K. 243 Gurny R. 462 Gurst J. E. 567 Guschlbauer W. 642 Gutfreund H. 109 Guthrie C. 644 Guthrie R. D. 345 436 441,447,461,464 Gutman I. 424 Gutsche D. 399 Gutschke D. 189 222 Guttormson R. J. 49 Guyot A. 328 Guyot M. 182,403 Guzzi R. A. 338 Gwinner P. A. 417 Gygax P. 680 Gymer G. E. 177 190 199,226,471 504 Haak W. J. 610 Haake P. 271 277 Hass C. K. 196 Haas M. A, 265 Haats W. J. 38 Haber J. H.-A. 317 Haber S. B. 482 Habersaat K. 366 499 710 Habib M. S. 505 Habrarken C.L. 493 Hachiro H. 67 Hackert M. L. 107 Haddadin M.J. 477,489 Hadden R. C. 139,220 Haddon W. F. 20 Haede W. 567 Haegeman G. 649 Hafner E. W. 99 Hafner K. 417,418,491 589 Haga K. 454 Haga N. 692 Hagaman E. W. 34 38 218,233,386,544 Hagan E. L. 214 Hagen E. L. 136 571 Hagen K.,371 Hagenberg L. 642 Hagiwara T. 198 223 Hahn B. S. 629 Hahn E. F. 353 Hahn R. C. 65,238,394 Hai S. M. A. 190 Haigh F. C. 441 Haimova M. A. 568 Haines A. H. 442 460 635 Hajos Z. G. 578 Halberstadt I. 203 Halevi E. A. 126 Haley J. F. 41 1 Hall C. D. 96 272 Hall D. 680 Hall H. K. 576 Hall L. D. 13 43 434 435,437,455 Hall M. S. 554 599 Hall R. E. 121 124 Hall S. S. 554 657 Hall T. W. 406 Hallensleben M.L. 341 Halpala J. 145 Halpern B. 685 Halpern J. 248 Halpern Y. 136 357 Halton B. 414 Halton M. P. 414 Ham P. J. 57 Hamaoka T. 350,665 Hamasaki T. 609 Hamelin J. 85 86 348 Hamer N. K. 237 Hamersma J. W. 129 Hamill B. J. 664 Hamilton E. J. 237 Hamilton G. A. 98 166 401 Hamilton J. B. A. 68 Hamilton W. C. 54 432 Hammen R. F. 2 11 Hammer F. T. 369 Hammerich O. 297 298 Hammond G. S. 9 240 314 Hammond S. J. 153 Hamon L. 246,693 Hamori E. 324 Hanack M. 216 Hanaya K. 670 Hancock K.G. 91,229 Hancock R. D. 340 Hancock R. L. 646 Hancock W. S. 557 Hanessian S. 434 436 451 453 454 459 460,462,637 Hanfland P. 19 Hansen E. R. 282 Hansen H.-J. 25 94 234 235 236 238 239 240 241 353 399,664 Hansen M.35 Hansen R. H. 326 Hanson J. R. 598 601 602 Hansson C. 695 Hantala R. R. 83 Harada F. 643 Harada N. 551 Harana K. 488 Harden R. C. 42 Harding K. E. 361 586 Hardy A. D. U. 51 Hargreaves N. G. 251 Harger M. J. P. 280 Hargis,J. H. 23 153,382 Hariharan P. C. 78 139 Harimoto T. 266 Harlow R. L. 481 Harminer Y. 125 Harmon A. D. 552,687 Harmon C. W. 626 Harmon R. E. 243 Harness J. 443 Harnisch J. 96 191 Harrington R. M. 241 Harris J. M. 124 Harris L. E. 481 Harris M. M. 685 Harris R. K. 41 Harris R. O. 257 Harris T. M. 424 Harrison A. G. 7 Harrison C. R. 349,672 679 Harrison I. R. 327 Harrison J.F. 184 Harrison J. M. 84 Harrison R. 455 Author Index Harrison R. G. 567 Harrit N. 507 Hart D. J. 583 659 Hart D. W. 259 Hart E. J. 154 Hart H. 49 133 219 221,227 Hartless R. L. 346 Hartley B. S. 116 Hartley F. R. 244 Hartley G. H. 330 331 Hartman G. D. 184,222 381 Hartmann W. 200 224 Hartrnann A. 280 Hartter D. R. 373 Hartzler H. D. 196 Haruna I. 647 Harvey R. G. 424,474 Hasegawa A. 452 Hasegawa H. 164 Hasegawa M. 332 Hashida Y. 67 Hashimoto H. 196 397 Hashimoto M. 283 483 Hass J. R. 9 Hassaneen H. M. 241 49 1 Hasselmann D. 229 Hassner A. 191 471 477,512,690 Hasty N M. 82 Haszeldine R. N. 194 195 Hata G. 253 Hata Y. 660 Hatch F.652 Hattaway J. H. 314 Hattori M. 641 Haufman J. R. 16 Hauminer Y. 132 Hauptmann H. 498 Havel J. J. 223 Havlicek S. C. 436 Hawkes G. E. 43,302 Hawkins C. 3 14 427 Hawkins D. W. 560,661 Hawkins E. 626 Hawkins E. G. E. 222 Hawley M. D. 289 Hawthorne M. F. 252 Hay A. S. 341 Hay R. W. 446 Hayaishi O. 106 Hayakawa K. 428 Hayakawa Y. 85 265 553,578 Hayami J. 120 Hayashi N. 254 Hayashi S.,182 554 Hayashi T. 259 603 Author Index Hayashi Y. 185 Hayasi Y. 508 Hayatsu H. 628 629 Hayes F. N. 640 Hayes J. 28 154 186 237 Hayes L. J. 185 187 Hayes R. 495 Hayes T. 26 Hayez E. 205 258 Haylock C. R. 454 Hayon E. 157 172 Hayward R. C. 667 Hayward R.S. 652 Hazama M. A16 Hazard R. 293 Heaney H. 403 Hearn M. J. 222 Heathcock C. H. 678 Heathcock S. 265 Hecht S. M. 633 Hecht S. S. 372 Heckrnan J. 637,645 Hedberg K. 371 Hedgpeth J. 653 656 Heesing A. 189 222 242,399 Hefelfinger D. T. 50 Hegarty A. F. 169 241 Hegedus L. S. 251 340 673 Hehlmann R. 626 Hehre W. J. 139 219 220,388,394,595 Heiber M. 27 359 Heidmann W. 638 Heilbronner E. 384,571 591 592,594,595 Heim P. 669 Heimbach P. 97 243 262,571 Heimberger S. I. 542 Heimgartner H.. 25 240 Heindel N. D. 404 Heinecke M. 641 Heitzer H. 495 Hekman M. 594 HelgCe B. 294 Helgeson R. C. 384,527 Helle T. L. 388 592 Heller S. R. 17 Hellerrnan L.98 Helling R. B. 654 Hellwinkel D. 592 Helrnick L. S. 502 Helmkarnp G. K. 522 Helmkarnp G. M. 115 Helrny E.,212 Helquist P. J. 251 Helton D. O. 372 Helwig G. S. 218 474 HCrno J. H. 669 Hems J. M. 121 Hems R. 435,455 Henc B. 259 Henderson M. S. 562 Henderson R. 561 Henderson R. E. L. 633 Henderson R. W. 153 Hendrick M. E. 197 202,205 Hendrickson J. R. 88 139,231,662,669 Henglein A. 324 Henrichs P. M. 383 Henrici-Olive G. 254 Henry P. M. 244 Hentchoya J. 562 Henton D. E. 317 588 Henzel K. A. 128 Hepinstall J. T. jun. 153 Herbach J. 205 Herbert J. A. L. 492 Herbert R. B. 189 658 Herde J. L. 252 Herewaldt L. A. 427 Herold C.-P. 463 Herr R.W. 218 Herring F. G. 184 Herrmann J. L. 675 68 1,682,687 Hersh L. B. 106 Hershfield R. 372 Hertenstein U. 674 Hervens F. 492 Herz W. 55 Heskins M. 331 Hess R. W. 257 Hesse J. 213 355 377 Hesse M. 94 234 353 548,664 Hesse R.H. 567 Hester N. E. 522 Hetflejs J. 250,253,266 340,361 Heu B. 203 Heusler K. 518 Hevey R. C. 115 Heweh,.J. E. 493 Hewson M. J. C. 269 Heyes G. 226 Hezemans A. M. F. 55 387 Hickmott P. W. 582 Hidai M. 251 252 Hiegel G. A. 678 Higa T. 498 Higara N. 340 Higashi F. 283 Higgins J. 279 Higgins R.J. 66 Higley D. P. 229 Higuchi H. 202 Hihara N. 120 Hiiragi M. 183 Hikino H. 558 Hilbers C. W. 640 641 Hildesheirn,J. 465 Hildick B.J. 632 Hill A. E. 138 587 Hill C. W. 643 Hill D. T. 504 Hill E. 110 Hill H. D. W. 31 Hill J. R. 34 Hill K. A. 676 Hill M. E. 394 Hill N. J. 244 Hill R. K. 234,592,615 Hiller J. M. 537 Hilliard T. A. 316 Hills T. L. 147 Hindley J. 649 Hine J. 73 Hines J. N. 351 Hintz P. J. 513 Hinze A. G. 248 Hirai Y. 535 Hirano S. 444 Hirao N. 67,67 1 Hiraoka T. 693 Hirata Y. 552 553,547 607,687 Hiroi K.,552 662 687 Hirose A. 64 394 Hirose T. 395 Hirota S. 412 Hirschfeld D. R 56 558 Hirschhorn K. 626 Hirschmann F. B. 564 Hirschmann H. 564 Hisada R. 393 Hixson S. S. 194 227 315 Hiyarna T. 191 Hjortas J. 48 HlavatL J. 73 Ho H. C. 674 Ho L.L. 213 Ho N. W. Y. 637 Ho R. I.-F. 493 Ho T. L. 406 669 670 671,674,683,684,690 Hobbs P. D. 240 Hobson J. D. 241 Hobson R. F. 519 Hocking W. H. 374 Hocks L. 266 Hodder 0.J. R. 53,225 499 Hodgernan D. K. C. 172 Hodges R. J. 250 712 Author Index Hodgkinson A. J. 561 Hopf P. D. 608 Huber J. H. 588 Hodgson G. L. 552,621 Hopkinson A. C. 199 Huber R.,390 Hodgson P. 374 225,384 Hubert A. J. 205 258 Hoefnagel A. J. 73 Hopkinson J. A. 12 266 Hogberg H. E. 407 Hoppe B. 414 Huche M. 230 Hoel E. L. 252 Hopper S. P. 196 665 Huckstep L. L. 482,615 Hofer O. 516 Horan H. 560 605 Hudnall P. M. 694 Hoff S. 212 Horgan S. W. 424 Hudrlik P. F. 552 688 Hoffman J. 438 Horii S. 464 Hudson A. 152 167 Hoffman J.M. 139,407 Horn D. H. S. 551. 606 382 416,592,674 Horner C. J. 242 Hudson C. E. 88,418 Hoffman L. 412 Horner L. 287 Hudson R. F. 29 76 Hoffman N. W. 263 Horner M. W. 443 120,230,277,384,392 Hoffman P. 268 Hornfeldt A.-B. 42 Hubner W. 347 Hoffman A. K. 309 Horng A. 666 Hiinig S. 415 674 Hoffman H. M. R. 88 Horning E. C. 13 Huffman J. H. 636 138 361 375 514 Horning M. G. 13 Huffman J. W. 551,555 579,587 Horsington A. 466 Hughes A. N. 276 Hoffmann M. K. 387 Horspool W. M. 319 Hughes C. R. 553 Hoffmann M. Z. 172 507 Hughes N. A. 433 443 Hoffmann R. 75 78,96 Horton D. 431 432 451,456 202,268,595 433 434 439 440 Hughes R. P. 257 Hoffmann R. W. 204 449,453,457,466 Hui B. C. 260 Hoffmann W. A. 283 Hoshi A. 636 Hui B. C. Y.,248 Hofman H. 523 Hoshi T.118 Huie B. T. 252 Hogeveen H. 97 214 Hoshino M. 90 418 Hultman D. P. 441 22 1,236,388,593 Hosokawa T. 495 496 Hume E. L. 399 Hogeveen M. 261 679 Humer P. W. 193 Hogg J. W. 554 Hota N. K. 257 Humffray A. A. 285 Hohner G. 526 Hough L. 443 308 Holbrook J. J. 109 Houk K. N. 85 89 317 Hummel K. 267 Holden J. L. 259 366,367,417,583 Hummel K. F. 205 Holder R. W. 91,228 Houminer Y . 216 562 Humski K. 126 Holland J. M. 404 592 Houng-Min Shih 204 Hung H.-K. 557 Holland P. C. 115 House H. O. 246 376 Hunneman D. H. 20 Holland V. R. 239 692,693 Hunt E. 620 Hol1and;W. H. 16 Houser K. H. 289 Hunt K. 84 Hollenstein R. 407 Housmans J. G. H. M. Hunt N. 58 Holliman F. G. 189 381 Hunter D. H. 145 Hollings D. 264 Howard A. S. 440 Huntsman W. D. 348 Hollins R.A. 410 Howard F. B. 641 Hupe D. J. 148 Hollitzer O. 502 Howard J. 4 18 Hurst J. 492 Hollstein K. 61 1 Howard J. A. 172 269 Hursthouse M. B. 57 Holm S. 496 334 Husson H.-P. 544 Holmes W. F. 16 Howe D. V. 264 Hutchins J. E. C. 132 Holmquist G. 626 Howe I. 20 Hutchins M. G. 661 Holmstadt B. 16 Howell J. M. 96 Hutchins R. O.,66 1,666 Holness N. J. 120 Howells D. 91,214,268 670 Holsboer F. 415 280 Hutchinson C. A. 653 Holt G. 226 Howells M. A. 47 Hutchinson C. R. 552 Holtby-Brown R. D. 72 Howells R. D. 47 687 Holtom A. M. 598 Howley P. M. 205 Hutchinson S. A. 424 Hol9 A. 440 Hoyashi Jt 3 18 Huth A. 425 Homer J. 34 Hsiung V. 461 Hutson G. V. 334 Honda K. 298 Hsu C. M. 412 Huttner G. 247 Honda S. 457 Huang C. T. 208,503 Hutton R. S.139 416 Honda T. 533 Huang C. Y. 630 592 Hong Mee Lee 205 Huang H. C. 55 Hutzenlaub W. 635 Hooper M. L. 645 Huang H. H. 386 Huxtable R. J. 610 Hooz J. 362 676 686 Huang L. 134,215 Huyn C. 399 693 Hub L. 513 Hwang J.-T. 278 Author Index Ibarbia P. A. 162 Isagulyants V. G. 196 Ibne-Rasa K. M. 664 Ish-Horowicz D. 643 Ibrahim B. 182 508 Ishibashi H. 488 Ibusuki T. 367 Ishibe N. 509 Ichihara A. 610 Ishida N. 693 Ichikawa M. 328 Ishido Y. 453 459 631 Ichino M. 636 Ishigami T. 254 420 Ichino T. 249 Ishiguro T. 690 Idaka E. 609 Ishikawa F. 641 Iddon B. 189 Ishikawa M. 567 Ido T. 628 Ishikawa N. 182 Idriss J. 652 Ishikura H. 643 Igeta H. 505 507 Ishimi K. 251 Ignatenko A. V. 26 Ishiyama H. 4 18 Ignatiadou-Ragoussis V.Ishizo H. 277 683 Ishizu K. 164 Iguchi M. 552 Isidor J. L. 497,674,686 Ihara M. 533 621 623 Isobe M. 488 Iio M. 444 Israel S. C. 342 Ikeda M. 488 511 674 Itagaki N. 256 Ikeda S. 256 266 Itagaki T. 395 Ikegami S. 568 Itakura K. 637 Ikegawa S. 568 Itatani H. 401 Ikehara M. 633 636 Ito S. 88 418 583 587 639,641,642 Ito T. 460 Ikeler T. J. 230 Ito Y. 203,254,445,499 Imagawa K. 89 Itoh K. 401 Imaizumi T. 648 Itoh M. 308 348 428 Imamoto T. 671 664,665 Imanishi T. 204 Itoh T. 473 Imberger H. E. 308 Ivanov V. L. 393 Imoto. M. 337 Iversen P. E. 293 Inaba J. 642 Iwahashi H. 190,474 Inaba S. 249 250 Iwakura C. 303 Inagaki M. 185 186 Iwamura H. 387 Inagaki S. 82 179 Iwamura J. 67 1 Inaki Y. 256 Iwanami M.481 Inamoto N. 187 279 Iwane H. 258 Inch T.D. 277,43 1,437 Iwasa T. 464 444,461,516 Iwasaki M. 326 Ingold C. K. 124 Iwasaki T.,294,295,686 Ingold K. U. 169 334 Iwase J. 251 Ingram A. S. 67 Iwata R. 248 Inomata K. 88 679 Iwata S. 185 Inoue S. 265 51 1 Iwataki I. 466 Inoue T. 665 Iyazumi T. 650 Inoue Y. 68 Iyer R. 69,438 Inouye Y. 207 Iyoda J. 263 Inubushi Y. 499 Iyoda M. 422 Ioffe B. V. 188,192,227 Izawa K. 73 142 Ioffe S. L. 196 Izumi K. 457 Ionescu L. G. 278 Izumi Y. 258 Ipaktschi J. 582 583 659 Jabloner H. 335 Irie H. 535 538 Jackson A. H. 14,69 hie T. 417 Jackson J. L. 495 Irngartinger H.,50 Jackson R. 253 Irvine F. 227 Jackson R. A. 152 167 Irving P. 19 382 Isaacs N. S. 83 144 Jacob P.665 Isaacs N. W. 57 Jacobson B. M. 583 Jacobson S. E. 257 Jacqmin G. 404 Jacques J. 596 Jacquesy J.-C. 564 Jacquesy R. 564 Jager G. 671 Jaenicke L. 549 Jaffe A. 416 592 Jaffe H. H. 242,399 Jahelka J. 66 Jain T. C. 634 Jakobsen H. J. 35 Jakowski J. 20 Jalonen J. 11 James B. R. 243 248 260 James K. 438,445 James M. N. G. 49,58 Janata J. 72 Janiga E. R. 217 Janik B. 630 Jankowska I. 541 Jankowski K. 541 Jankowski W. C. 601 Janousek Z. 358 Janssen J. W. A. M. 493 Jaquier R. 494 Jaret R. S. 464 Jarman M. 14 Jarreau F.-X., 547 Jarrell H. C. 441 Jarvis J. A. J. 244 Jarvis J. M. 650 Jary J. 442 Jasor Y. 376 Jay E. 637,653 Jeffrey G. A. 432,433 Jeffries M.453 Jeffs P. W. 576 Jelinek W. 650 Jencks W. P. 74 Jenkins A. D. 345 447 Jenkins I. D. 279 456 Jenkins J. A. 219 Jenkins J. K. 546 Jennings K. R. 20 Jenny E. F. 5 18 Jenny W. 409 Jensen B. S. 297 Jensen F. R. 257 Jensen H. 658 Jensen H. P. 87 212 379 Jeppesen P. G. N. 653 Jeremik D. 554 Jerina D. M. 237 239 387,391,424,474 Jerome B. 164 Jersak U. 479 Jesson J. P. 30 45 Jewell J. S. 451 714 Author Index Jhong Kook Kim 181 Jikeli G. 36 Jindal S. P. 147 Joffe A. 139 Joffe Z. 324 Joffee I. 139 669 Joh T. 248 Johne S. 548 Johns S. R. 43 Johnson A. W. 464 Johnson B. F. G. 246 256,264 Johnson C. D. 69 74 392 Johnson C.R. 123 217 218 245 574 660 667,693 Johnson D. C. 441 Johnson D. H. 514 Johnson I. 42 Johnson J. W. 328 Johnson L. F. 609 Johnson M. D. 243 682 Johnson M. G. 318 Johnson P. L. 61 Johnson R. N. 435,455 Johnson R. W. 317 Johnson W M. 387 Johnson W. S. 565,584 585,586 Johnston J. P. 556 Johnston M. D. 45 Johnstone R. A. W. 7,8 9 10 12 19 Joines R. C. 200 JokiC A. 441 554 Jolles C. 536 Jolley J. W. 144 Jommi. G. 600 Jonas K. 243 246 571 Jonassen H. B. 260 Jondahl T. P. 80 Jones A. J. 37 221 386 Jones A. S. 627 628 639 Jones D. N. 212 Jones D. W. 89 186 398,404,583 592 Jones Sir. E. R. H. 563 568 Jones G. 190 498 Jones G. H. 630 Jones H.L. 159 Jones J. B. 564 Jones J. G. L. L. 565 Jones J. K. N. 437 439 44 1,460 Jones K. W. 626 Jones M. 197 198 201 202,205,409,571 Jones M. jun. 223 224 Jones N. J. 49 Jones R. A. 461,634 Jones R.A.Y.,493,513 515 Jones R. F. 650 Jones W. D. 381 Jones W. M. 200 203 204 224 230 422 429 Jonkman H. T.,221,386 388 Jordaan A, 462 Jordaan J. H. 437 Jordan J. W. 314 Jordan P. M. 619 Jorgensen W. L. 595 Jornvall H. 109 Jose F. L. 484 Joseph J. T. 369 Joshi B. S. 55 Joshi G. S. 182 183 Joska J. 569 Josh T. 300 Joucha M. 86 Jovanivich A. P. 129 Joyeux M. 546 Jubault M. 288 Judy K. J. 554,599 Ju-ichi M. 534 Julia M. 251 560 586 660 Julia S.205 399 Julian J. F. 327 Juliano P. C. 41 Jung F. 482 660 Jung G. 37,433 Jurjevich A. F. 672 Jussiaume A. 72 Kabalka G. W. 407 Kablitz H.-J. 259 Kabore I. 450 465 Kabuto C. 474 Kacian D. L. 647 Kaczmar U. 347 Kadaba P. K. 85 Kadai T. 658 Kadin S. B. 669 Kaesz H. D. 252 Kagan H. B. 259 Kagan J. 371 Kagi D. A. 583 Kagramanov V. N. 638 Kainosho M. 43 Kaiser E. M. 503 Kaiser R. 417 589 Kaiser S. 669 KajfeZ F. 523 Kaji A. 120 Kaji Y. 342 Kajimoto T. 664 Kajiwara M. 541 Kakehi K. 457 Kakimuna K. 610 Kakis F. J. 683 Kakisawa H. 603 Kakizaki H. 70 Kakurai T. 341 Kalakofsky D. 647 Kalckar H. M. 11 1 Kalechits I. V. 253 Kalinicheva N. A.255 256 Kalinin V. N. 339 Kalvoda J. 86 Kalwyck K. C. 123 Kamano Y. 566 Kamata S. 692 Kameda N. 256 Kameda Y. 464 Kamego A. 278 Kamerling J. P. 435 436 Kameswaran V. 401 532,694 Karnetani T. 183 188 530,533,535,541 Kamigata N. 393 Kaminskii A. Ya. 70 Kamio K. 671 Kamiya K. 464 Kamiya T. 483 Kamiya Y. 568 Kamkha M. A. 176 Kamm K. S. 321 Kan C. 34,544 Kanai T. 636 Kanaoka Y. 317,401 Kanda Y. 504 Kandasamy D. 666 Kane M. J. 510 Kane V. V. 201 224 409 Kaneda T. 90 Kaneko C. 567 Kaneko T. 586 Kanematsu K. 428 Kannellias L. 129 Kannen N. 410 Kano S. 183 Kanzawa F. 636 Kaplan H. 117 Kaplan L. 159 383 Kaplan L. J. 145 Kaplan M.L. 28 334 346,514 Kaplan N. O. 107 Kapoor S. K. 551,555 Kaptein R. 23 Karaev S. F. 521 Karim A. 396 Kariv E. 287 Karle I. L. 54 58 Karle J. 252 Author Index Karle J. M. 54 Karlsson B. 56 Karnischty L. A. 499 Karplus M.,76 Karsch H. H. 244 Kartashov V. R. 68 Kartha G. 55 Kartsova L. A. 192,227 Karyakina G. I. 253 Kasai Y. 283 689 Kasal A. 568 Kashimura N. 436 Kashiwagi M. 185. Kashutina M. V. 196 Kasida Y. 628 Kasler F. 45 Kasperek G. J. 239,391 474 Kastening B. 295 Katagiri K. J. 653 Katagiri N. 637 Katayama C. 54 387 Katchalski E. 347 Katner A. S. 34 544 Kato A. C. 640 Kato H. 421 Kato K. 564 Kato M. 552 576,687 Kato S. 64,76 191,394 Kato T.420,454 Katritzky A. R. 69 182 508,513,515 Katsuhara Y. 240 399 Katz J. J. 623 667 Katz S. 589 Katz T. J. 83 389 589 Katzenellenbogen J. A. 245 549 553 663 693 Kaufman D. C. 347 Kauffmann T. 182 366 499 Kaufmann D. 90 Kaufmann G. 637 Kaupp G. 82,427 Kavilek J. 70 Kaverzneva E. D. 450 Kawabata S.,466 Kawakita M. 625 Kawamoto M.,339 Kawanisi M.,89 Kawasaki K. 307 Kawashima K. 690 Kawazoe Y. 628 Kaye H. 343 Kaziro Y. 625 Kazmaier P.M. 96 185 Kazuya M. 133 Kearney J. A. 169,241 Kearns D. R. 82 334 625,641 Keating M. 177 478 Kebarle P. 368 380 Keehn P.M.,411 Keeley D. 218 574 Keith G. 644 KeIleher P. G. 334 346 Keller A.332 Keller H. 332 Keller K. 364 669 Keller-Schierlein W. 385 Kelley R. C. 540 Kellie G. M. 514 Kellner M. 379 Kellog M. S. 90 Kellog R. M. 96 Kelly D. R. 135 Kelly R. B. 557 Kelly T. J. 656 Kelsey D. R. 125 216 Kemmitt R. D. W. 252 Kemp D. S. 74 Kemp K.C. 68 Kemp-Jones A. V. 38 221,386,419,594 Kempmeier J. A. 153 Kendall M. 684 Kendall M. C. R. 148 Kendall N. T. 194 Kende A. S. 399 546 692 Kenkyusho R. 557 Kennard C. H.L. 48 Kennard O. 56 57 Kennedy J. P. 328 338 Kennewell P. D. 511 Kenney M. E. 44 Kensler T. T. 169 Kent P. W. 435,455 Kenyon G. L. 40 Keogh M. J. 89,583 Keough T. 20 Kerber R. C. 412,419 Kershaw J. R. 319 507 Kershner L. D.383 Kerur D. R. 223 Kessar S. V. 182 183 Kessonikh A. V. 26 29 Kessler H. 418 Ketley J. N. 11 1 Kevill D. N. 123 Key J. M.,256 Khalaf A. A, 68 Khali F. Y. 278 Khan H. A. 70,395 Khan W. A. 282 Khare G. P. 636 Khasaninah A. 278 Khattak I. 564 Khidekel M. L. 250 253 Khorana H. G. 637.652 Khorapd H. G. 284 Khorlin A. Ya. 450 Khouw V. T. 496 Khuong-Huu Q. 450 465 Kice J. L. 149 384 Kieczykowski G. R. 682 687 Kiefer H. C. 342 Kielbania A. J. 236 Kigasawa K. 183 Kiguchi T. 81 540 Kihata T. 298 Kiji J. 253,255,265 Kikuchi M. 341 Kikuchi S. 338 Kikuchi T. 561 Kilbourn B. T. 244 Kilby D. C. 68 Kilian R.J. 215 Killian M. T. 20 Kim C. B. 123 Kim C.S. 491 Kim C. U. 671 Kim J. H. 404 Kim J. J. 624 Kim J. J. P. 61 Kim S.C. 666 Kim S. H. 624,625 Kimber B. J. 41 Kimura B. Y. 252 Kimura K. 303 Kimura M. 64 70 564 King J. C. 691 King J. M. 157 369 King L. L. 347 King R. B. 260 King R. W. 200 224 422,464 King T. J. 318,408,495 563 Kingsley W. G. 146 206,420,591 Kingston B. M. 243 Kingston D. G. I. 387 Kinnier W. 630 Kinoshita M. 347 627 Kinson P.L. 226 Kiprianova L. A. 23 Kka M. 165,660 Kirby A. J. 277 Kirby G. W. 370 374 612,614 Kirchhoff R. A. 660 Kiriyama T. 5 18 Kirk D. N. 564 Kirk G. R. A. 460 Kirkegaard L. H. 633 Kirkpatrick D. 349,672 679 Kirmse W. 213 214 355,377 716 Author Index Kirsanov A.V. 665 Kirsch J. F. 372 Kishi Y. 609 Kishimoto S. 67 Kishimoto T. 157 Kiskis R. C. 257 Kiso Y. 249 250 259 Kispert L. D. 155 Kita Y. 191 Kitaev Y. P. 24 Kitahara Y. 90 418 419,474 Kitaigorodsky A. I. 513 Kitamura N. 629 Kitamura T. 248 Kitaura Y. 58 Kitchin J. 95 482 Kiuchi K. 504 Klabunde K. J. 245 Klabunde U. 251 Klabunovskii E. I. 258 Klaebe A. 271 Klarner F.-G. 239 392 476 Klasinc L. 8 Kleid D. G. 638 Klein H. 233,476 Klein H.-F. 257 Klein J. 78 356 516 596 Klein P. D. 16 393 Klemer A. 455 Klenk H. 240 399 Klepikova V. I. 255,257 Kleppe K. 284 Kletz I. M. 342 Kleveland K. 97 Kline S. A. 133 22i 593 Klinga K.548 Kloosterziel H. 80 Kloster-Jensen E. 352 Kluender A. 482 616 Kluepfel D. 610 Klump G. 347 Klunklin G. 311 Klusacek H. 268 Knaus G. N. 496 Kneen G. 89,583 Kneidl F. 501 Kneubiihler W. 409 Knipe A. C. 376 Knist J. 214 Knittel D. 295 Knobler C. B. 252 Knoll W. M. J. 610 Knoth W. H. 247 Knothe L. 419 Knox S. A. R. 418 Knudsen T. P. 318 Knunyants L. T. 196 KO E. C. F. 136 Kobayashi M. 393 Kobayashi S. 64 395 671 Kober H. 203,398 Kobisch G. 143 Kobrich G. 229 571 Koch D. 300 Koch E. 192 226 Koch H. F. 148 Koch M. 34,544 Koch V. R. 299,300 Kochetkov N. K. 19 440,455,629 Kochetkova M. N. 638 Kochi J. K. 152 153 158 159 167 173 176 203 245 251 314,321,382,395 Koch-Pomeranz U.94 236 Kock D. 486 Kokor M. 562,671 Kodaira K. 68 Kodera Y. 536 Kobrich G. 367 Kohler E. 245 Koehler R. E. 485 Kolbl H. 412 Koeners H. J. 493 Koenig F. R. 129 Koenig K. E. 522 Konig W. A. 436 Konigshofen H. 386 Koppelmann E. 499 Koeppl G. W. 74 Koerner von Gustorf E. 248 Kossel H. 639 652 Koster H. 638 Koga K. 384 387 496 527 Kogure T. 249,250,259 Koh H. 645 Kohnstam G. 121 Koide H. 191 Koide T. 642 Kokura M. 252 Kolb B. 367 Kolb M. 677 Kolbah D. 523 Kolc J. 178 429 Kolesnikov S. P. 195 Koletar J. 566 Kollman P. A. 596 Kollman T. M. 323 Kollmar H. 139 220 Kolomnikov I.S. 252 Kolosov M. N. 637 Komissarov F. Ya 196 Komiya S. 257 Komoroski R. A. 40 Komoto R. G. 262 682 Kompis I. 548 Konaka R. 169 Kondo E. 568 Kondo K. 89 Kondo T. 465 Kondratenkov G. P. 257 Konigshofen H. 37 Konishi H. 412 Kono D. H. 685 Kono H. 250 Konoike T. 203 Kooistra D. A. 657,694 Koonsviteky B. P. 68 Kopecky K. R. 223 Kopecky W. J. jun. 53 478 Kopolov S. 325 Kopp E. 641 Koppel G. A. 485 Koppes W. M. 685 Korcek S. 334 Koreeda M. 551 Koriyama S. 558 Kormer V. A. 255,256 257 Kornfeld R.,20 Korobko V. G. 637 Koroleva E. V. 188 Korshak Yu U. 255 256 Korth J. 685 Kory D. R. 317 Korzeniowski S. H. 552 688 Koser G. F. 184 236 261,381 Kost A.A. 629 Koster R.,575 Kosuka M. 85 Kotani E. 306 533 538 Kotik M. P. 630 Kotowycz G. 45 Koudijs A. 71 Koul A. K.,671 Koull I. S.,261 KouwenhovenpC. G. 522 Kovacic P. 208 219 395,400,571 KOV~CS, K. 515 Kovalenko L. I. 196 Kovif J. 433,468 Kovelesky A. C. 672 Kowalski S. 626 Kowar T. 415 Koyama G. 466 Koyama K. 317 Kozarich J. W. 633 Kozikowski A. P. 583 659 Author Index Kramer F. R. 647 Kramer J. D. 91 229 Krantz A. 225,319,414 479,575 Krapcho A. P. 686 Krapp W. 592 Kraus M. 340 Krebs A. 178 521 Kreevoy M. 74 Kreis G. 247 Kreissl F. R. 247 Kreiter C. G. 247 Krepinsky J. 568 Kresge A. J. 74 Kretzschmar H.-J. 347 Kricka L.J. 68 Krishna N. R. 44 Krishnamoorthy V. 563 Krishnamurthy S. 657 666 Kristinsson H. 315 Krodel E. 102 Krohnke F. 508 Krojka K. E. 200 Kroll L. C. 266 340 Krommer H. 492 Kronzer F. J. 445 Kropacheva E. N. 267 Kropp P. J. 314 Krubiner A. 669 Krubsack A. J. 498 Kruger C. 246 Kruger G. 566 Kruger T. L. 147 Kruk C. 42 Krul L. P. 339 Kruse C. G. 493 Krusic P. J. 173 KrutoSikovl A. 73 Kubias J. 70 Kubo I. 546 Kubo M. 421 524 Kubo Y. 256 Kucherov V.F.,486 Kucinski P. 565 Kuck V. J. 139 185 416,592 Kudo H. 670 Kuehne M. E. 691 Kiisters W. 321 481 Kufe D. 626 Kuhar M. J. 587 Kuhne H. 444 Kuhnen F. 665 Kukolja S. 484 Kulczycki A. 205 Kuljaeva V. V. 461 Kum S. G. 128 Kumada M.249 250 259 Kumadaki S. 504 Kumai S. 214 Kumar A. 284 Kumari G. V. 459 Kumber P. L. 507 Kume H. 236,429 Kumler P. 240 Kunde K. 424 Kundu K. K. 72 Kunesch N. 34,544,545 Kunieda T. 665 Kunitomo J. 534 Kunstmann M. P. 556 Kuntz E.,251 Kuo S. 626 Kupchan S.M. 401,531 532,534,694 Kurapova A. E. 253 Kuretani K. 636 Kurhajec G. A. 142 Kurilenko A. I. 339 Kuritani M. 387 Kuroda S. 419 Kurosaki T. 346 Kurosawa H. 256 Kurras E. 244 Kurreck H. 174 Kursawa W. 233,476 Kurtz D. W. 229 Kurtz W. 64 182 394 Kurz M. E. 395 Kushida K. 459 Kusmierek J. T. 635 Kusmin M. G. 393 Kuszmann J. 443 Kutney J. P. 58 544 Kuwakani J. H. 141 Kuzuhara H. 436,466 Kuzuya M.,219,221 Kwant P.W. 221 388 593 Kwart H. 231 694 Kwok H. S. 18 Kwong J. 313 509 Kyba E. P. 387,527 Laatsch H. 407 La Bar R. A. 200 204 224,422 Labat J. 450 Labaw C. S. 491 Labler L. 567 Lach D. 358 360 Ladanyi L. 305 Laemmle J. 374 596 Lai Y.Z. 449 Laird T. 93 209 Lake J. R. 482 Lal B. 283 665 Lalancette J.-M. 67 1 Lallem J. Y. 560 Lallemand J. Y.,586 Lalor F. J. 252 Lam L. K. M.,124 La Mar G. N.,44 Lambert J. B. 87 126 129,514,586 Lambert R. W. 191,522 Lamfrom H. 644 Lammers J. G. 426 Lammert S. R. 484 Lamy E. 286 Lancaster J. E. 391 Lancaster L. A. 149 Lancelot C. J. 124 Lancini G. 610 Lancini G. C. 610 Lande S. 19 Landis M. E. 275 481 Landis R. T. jun. 169 286 Landry L.C. 640 Lane C. D. 650 Lane S. A. 94 230 Lang U. 492 Langer E. 411 Langlois N. 259 Langova J. 253,361 Lankin D. C. 84 228 316 Lansbury P. T. 552,582 587,682 Lantsera L. T. 196 Lappert M. F. 234 243 244,245,247,250,25 1 Larcheveque M. 657 Larkin J. P. 172 281 Larkins J. T. 12 Laroff G. P.,26 155 Larsen C. J. 649 Larsen J. W. 120 368 Larsen S. 508 Last A. M. 72 131 Laszlo P. 40 Latham D. W. S. 492 Lauer R.F. 87,88 212 661,662,675 Laurenco C. 274 Laurent A. 471 Laval J. 651 Lavallee P. 451 454 Laver R. F. 379 Lavie D. 56 Lavielle G. 282 Law A. M. G. 344 Law J. H. 598 Lawesson S.-O.,63 Lawler R. G. 24,26,426 Lawrence A. H. 321 Lawrence B. M. 554 Lawson A. J. 29,67,230 Lawson J.430 Layton R. B. 693 Leavell K. H. 229,414 Leaver D. 496 Le Bel N. A. 689 Le Belle M. J. 21 1 Leboul J. 464 Lebreux C. 372 Lechtken P. 82 83 321 Lednor P.W. 251 Ledon H. 205 Ledwith A. 68 161 Lee A. G. 40 Lee A. O. 363 Lee C. C. 136 Lee C. H. 630 Lee C. S. 687 Lee C.-Y. 630 Lee D. G. 379 Lee E. 195,623 Lee G. C. Y. 625 Lee J. 504 Lee K. H.,55 Lee K. W. 346 Lee R. A. 692 Lee R. C. T. 18 Lee S. T. 184 Leenders L. H. 312 Leete E. 536 Leffek K. T. 70 Lefour J.-M. 374 596 Lefur R. 431,432 Legan E. 149,384 LeGoff E. 49 178,403 415 Le Guen J. 392 Lehmann J. 432,458 Lehmann W. D. 13 Lehmkuhl H. 244,285 Lehn J.-M. 527 Lehner H. 411 Lehnert W. 691 Le-Hong N.434,437 Lehr M. H. 333 Lehrach H. 630 Leigh G. J. 248 Leigh J. S. 33 Leistner E. 617 618 Leitich J. 192 226,248 610 Leloir L. L. 431 Lemal D. M. 96 396 501 Lemieux R. 49 Lemieux R. U. 45 431 432,434,445 Lemke P.A. 482,616 Lemonnier A. 19 Lenarda M. 252 Leng M.,642 Lenoir D. 123 Lenox R. S. 663,693 Lenskinski R. E. 43 Author Index Lenz G. R. 81 Liang G. 133 137 389 Lenz R. W. 326 426,595 Leonard D. R. A. 65 Liav A. 465 395 Liberles A. 78 Leonard N. J. 312 630 Libman J. 398,428 631,633 Lichtenthaler F. W. 636 Lepage Y. 406 462,465 Lepley A. R. 206 Lidy W. 674 Lepper H. 255 Lie R. 498 510 Lerdal D. 475 Liebman J. F. 77 Leresche J.-P. 37 1 Liepa A. J. 401 531 Le Reverend B.571 532,694 Lerner L. M. 442 456 Lietman P.S. 19 Leroux Y. 677 Lietzke M.H. 215 Leshina T. V.,176 Lightfoot D. R.,641 Lesk A. 78 Lightner D. A. 50 Lessard J. 672 Ligon R. C. 586 Lester G. R. 12 Liljas A. 107 Letsinger R. L. 629 Liljegren D. R. 612 Lett R. 516 Lilly M. D. 346 Leuderwald A. 329 Lim P. K. K.,279 Leusink A. J. 244 Limburg K. 645 Levek R. P. 89,583 Lin A. J. 405 Lever 0.W. 475 Lin C. 232 Leverenz K. 496 Lin C. Y. 319,414,479 Levi A. 384 575 Levin C. C. 202 595 Lin F. F. S. 96 272 Levin R. H. 37 197 Lin G. H. Y. 56 558 201,223,224,386,409 Lin H. C. 394 Levine M. D. 642 Lin K.T. 141 Levine S. P. 20 Lin L. J. 482 615 Levine Y. K. 40 Lin L. P. 261 Levisalles J. 246 693 Lin Y.,145 Levit A. F. 23 24 Lindberg B. 438,450 Levit S.116 Lindberg U. 649 Levita G. 120 Lindgren J.-E. 16 Levitan P. 399 Lindon J. C. 35 Levitt M.,625 Ling N. 18 Levsen K. 20 387 Lingrel J. B. 650 Levy A. B. 473 477 Link S. 553 669 Linstrumelle G. 205 Levy G. C. 34 39 40 Lion C. 679 41,42 Lipowitz J. 666 Levy R. L. 15 Lippmaa E. 28 29 Lew G. 350 Lippman N. M. 261 Lewin A. H. 396 Lipsky S. D. 657 Lewis B. 258 Lipsky S. R. 19 38 614 Lewis D. C. 153 382 Liott M. 481 Lewis D. J. 627 Litt M. H. 324 Lewis E. S. 229,414 Littauer U. Z. 637 Lewis F. D. 3 16 3 17 Littlecott G. W. 250, Lewis G. J. 277 437 252 444,516 Littlefield. L. B.. 270 Lewis J. 256 264 265 Litzow M. R.,244 Lewis J. R. 530 Liu H. 155 Ley A. N. 644 Liu. H. J. 578 Leyendecker F. 579 Liu; J.-C.; 369 Leyshon LT.J. 502 Liu R.-R. 148 Lezius A. G. 641 Liu R. S. H. 42 Leznoff C. C. 345 Liu T. H. 153 Li T. 348 Livingston C. M. 517 Author Index Livingstone D. B. 492 Llaguno E. C. 51 Llewellyn J. W. 467 Lloyd P. F. 445,448 Lloyd R. V. 152 Lloyd W.J. 455 Lloyd-Jones J. G. 606 Lo S. M. 251 673 Lobach M. I. 255 257 Lockridge O. 105 Lockwood P. A. 223 Loeffler P. A. 43 Loliger J. 482 615 Loev B. 504 Loew G. 8 Loewen P. C. 652 Loewengart G. V. 274 Logue M. W. 312 Lok M. T. 527 Lomant A. J. 640 Lomas J. S. 145 Long L. jun. 441 Long M. A. 658 Long R. A. 636 Longevialle P. 14 Longi P. 253 Lont P.J. 71 Loomis G. L. 552 Lopez H. 670 Lopez L. 274 Lopez M. I. 204 Lorand J.P. 207 Lorber F. 267 Lorenc Lj. 86 Lorens R. B. 218,474 Lorenz H. 247 Lorne R. 399 Losey E. N. 178,403 Loskot S. 258 Lossing F. P. 11 Lotz A. 174 Louie M. L. S. 237 Lourens G. J. 462 Lore C. J. 248 Lo Vecchio G. 196 397 Lovey A. J. 686 Lovins R. E. 15 Low J. Y.F. 245 Lowe G. 199,485 Lowe R. W. 437 Lown J. W. 229 473 486 Lowy D. R. 639 Lucacs G. 544 Lucas H. 669 Lucchini V. 384 Luckenbach R. 276 Luetzow A. E. 449 Luger P. 59 Lugovsky A. A. 513 Lugtenburg J. 426 Luhan P. A. 55 Lukacs G. 461,462 Lunasin A. 630 Lunazzi L. 172 Lund H. 288 Lundberg R. D. 338 Lundeen J. W. 251 Lundt I. 434,457 Luongo J. P. 326 Luppis B. 650 Luskus L. J. 85,417 Lustig R.S. 316 Lutlringer J.P. 520 Lutskii A. E. 301 Luyten J. A. 15 Lwowski W. 185 190 Lyle R. E. 510 Lynn L. 437 Lyons A. 83 Lyons A. R. 281 Lyons J. E. 249,260 Lythgoe B. 567 McAlpine J. B. 450 McAndrews C. 692 McArdle P. 264 265 McBee E. T. 89 203 583 McBlewett F. 278 McBrady J. J. 142 McBride J. M. 139,416 592 McBride T. 252 McCabe P. H. 517,518 MacCallum J. R. 329 McCamey D. A. 611 McCannish M. 19 McCarry B. B. 565 584 McCarthy J. R. 461 McCaskie J. E. 481 Macchia B. 141 Macchia F. 141 McClain W. H. 644 McClean A. 488 McClelland R. A. 72 McCleverty J. A. 247 McClure D. E. 87 McCollum G. J. 213 McCombs D. A. 147 McConnachie G. 168 MacConnell J. G. 549 McCorkindale N. J. 424 McCormack J.H. 627 McCormick J. P. 560 605 MacCoss M. 639 McCredie R. S. 312 McCrindle R. 561 562 McCurry P. M. jun. 553 681 McDermott J. X. 245 719 McDonald A. A. 428 McDonald A. L. 406 McDonald A. N. 53 225,499 McDonald B. 488 McDonald E. 597 619 620,62 1,623 McDonald G. G. 33 McDonald J. J. 633 McDonald P. D. 166 40 1 McDonald R. N. 128 McDonald S. 404 McDowell C. A. 184 McElwee J. 667 McEntire E. E. 232 McEwan R. S. 55 McFarlane W. 45 McGhie J. F. 560 661 McGibbon A. K. H.,144 McGlinchey M. J. 223 McGuchan R. 327 Mach K. 153 Machacek Z. 325 Macharcia B. W. 550 Machat R. 635 Machiguchi T. 90 418 Machora J. 153 Maciel G. E. 36 42 McIntosh C. L. 81 178 319 369 402 414 479,575 McIntosh J.M. 663 McIntyre A. L. 145 McIver R. T. 380 McKee R. L. 497 McKeever L. D. 137 Mackellar F. A. 540 McKelvey J. M. 68 McKelvy J. F. 114 Mackenzie R. E. 246 McKenzie S. 340 McKeough D. 498 McKervey M. A. 123 Mackey J. K. 639 Mackie A. M. 567 Mackie D. M. 439 McKillop A. 234 399 McKinley J. F. 122 McKinley S. V. 347 McKinney C. R. 15 McKinney R. J. 252 McKnight W. J. 326 McLafferty F. W. 14,15 18 19 20 387 McLauchlan K. A. 176 MacLean D. B. 535 McManus J. P. 341 McMaster B. N. 12 McMillan J. G. 131 MacMillan J. H. 510 720 McMurray W. J. 19 McNelis E. 239 MacNicol D. D. 51 McOmie J. F. W. 177 402,404,415,479 McPhail A. T. 52,55,89 583 McPherson A.624 McQuillin F. J. 248,250 McRitchie A. 424 MacSweeney D. F. 552 McWhinnie W. R.,34 Madan P. B. 190 Maddock S. J. 253 Madeja R. 94 241 Maden B. E. H. 650 Maeda K. 249,466,495 496,679 Maeda S. 453 Maeda T. 554 Magi M. 28 Maerker G. 505 Markl G. 237 361,498 501,521 Maezawa T. 339 Magennis S. A. 245,25 1 Mageswaran S. 92 93 209,210,401,516 Magnus P. D. 240 450 563,689 Magoon E. F. 262 Magrath I. T. 626 Mah H. 566 Mahmood M. 436 Maier G. 78 414 415 57 5 Mairanovskii S. G. 285 Maitra H. S. 110 Maizels N. 656 Majerski Z. 126 Makarenkova L. M. 196 Makino S. 88 587 Makosza M. 196 Makovetskii K. L. 259 Makovetsky K. L. 256 Maksimovic Z. 86 Malament D. S. 205 Malatesta V.169 Malaval A. 372 Maldonado L. 674 Malhotra 0.P. 110 Mallams A. K. 464 Mallikarjuna Rao V. N. 310 Mallinson P. D. 168 Mallon C. B. 202 Malone G. R. 672 Maly N. A. 261 Malysheva N. N. 19 Manabe O. 67 Manchand P. S. 558 Mandell N. 277 Mandella W. L. 310 390 Mander L. 679 Mander L. N. 211 557 619 Mandville G. 579 Manecke G. 347 Maness D. D. 125 Mango F. D. 97 Mangoni L. 667 Manhas M. S. 283 Mani J. C. 551 Maniatis J. 656 Mann V. 508 Manning C. 311 Mannschreck A. 367 ManojloviC-Muir L. 54 Manske R. H.F. 535 Mansuy D. 560,586 Manzer L. E. 251 Maples P. K. 258 Maquestian A. 41 1 Maradufu A. 440 Marcil M. J. V. 212 Marcinkiewicz S. 94 Marcu K. 643 645 Marcus D. M.455 Margaretha P. 192 226 Margolin Z. 72 591 Margrave J. L. 414 Mariano P. S. 227 3 15 Marigliano H. M. 464 Marino G. 19 Marino J. P. 533 586 Markaryan S. A. 29 Markey S. P. 20 Markezich R. L. 565 584 Markham L. D. 260 Markovskij L. N. 665 Marks G. C. 329 Marks T. J. 43 247 Marmer R. S. 280 Marmer W. N. 505 Maron L. 451 Marples B. A. 564 565 Marquarding D. 122 268 Marquardt D. N. 340 Marquet A. 376 516 Marr G. 122 Marraccini A. 257 Marsh R. E. 386 Marsh W. C. 562 Marshal A. G. 43 Marshalkin M. F. 488 Marshall J. L. 131 Marshall P. J. 607 Marsman J. W. 244 Marten D. F. 246 677 Author Index Marten T. 601 Martin A. R. 515 Martin C. 498 Martin F. H. 642 Martin G. J. 361 Martin H.-D.384 594 Martin J. 492 Martin J. C. 119 145 669 Martin J. D. 554 560 561,563 Martin M. L. 361 Martin M. M. 157 369 Martin R. 399 644 Martin R. A. 503 Martinelli E. 610 Marty M. 649 Maruya K. 254 Maruyama H. 240 399 Maruyama K. 89 407 583 Marvell E. N. 232 234 348 Marx J. N. 553 Marzin C. 43 Masada G. M. 428 Masamune S. 38 220 221 263 386 415 419,575,594,657 Maskasky J. E. 44 Maslakiewicz J. R. 504 Mason J. F. 55 387 Masse R. 462 Massey V. 102 105 Massey-Westropp R. A. 557 Masters C. 250 Masui J. 509 Masui M. 305 Mateescu G. D. 133,425 Mathey F. 276 498 Mathias R.,’196 Mathieu J. 76 227 571 Mathis F. 271 Mathur A. K. 671 Mathur N. K. 671 Matkin D.404 Matlin S. A. 199 266 Matreyek W. 336 Matrka M. 67 Matsuda K. 434 Matsuda Y. 303 Matsugashita S. 488 Matsui K. 64 67 394 395 Matsumoto J. 466 Matsumoto K. 294,295 686 Matsumoto M. 89 Matsumura H. 123 Matsuo A. 554 Author Index Matsuoka M. 294 Matsuura K. 453,459 Matsuyama Y. 307 Matsuzaki E. 208 Mattes K. 178,319,402 Matthaei H. 642 Maujean A. 79 Maume B. F. 15 Maurer R. 656 Mavel G. 45 Mavrov M. V. 486 Maxam A. 656 Maxwell I. E. 386 Maxwell J. R. 563 Maycock A. L. 115 Mayeda E. A. 296 Mayenhofer H. 324 Maynes G. G. 159 Maye B. C. 42 Mazerolles P. 204 Mazhar-ul-Haque 269 Mazrirnas J. 652 Mazur S. 286 475 592 Mazzarella L. 567 Mazzocchi P. H. 53,316 478 Mazzu A.79,473 Meakin P. 30 45 268 Meakins G. D. 568 Means G. E. 322 Medem H. 213 Medlik A. 356 Medvedev B. Y. 27 Meek D. W. 245 Mehri H. 544 Mehri M. 34 Mehrotra A. K. 208,550 Mehta G. 551 555 Meier H. 226 Meier H. P. 363 Meier W. 567 Meinwald J. 553 Meisel D. 157 Meisinger R. H. 92 Meissner B. 422 Meissner U. 422 Meister B. 259 Melby E. 393 Melby E. G. 138 393 Mellon F. A. 7 8 9 10 Mellor D. 334 Mellows S. M. 404 Meloche H. P. 114 Meltin S. 248 Melton L. D. 454 Menapace H. 261 Mendenhall G. D. 169 Meneghini P. 327 Menendez V. 193 197 Mengel R. 461,634 Menger F. M. 372 Mennenga H. 244 Menzelaar H. L. C. 13 Menzies I. D. 563 Meot-Ner M. 14 Meridith R. S. 427 Merour J.Y.,263 Merrifield R. B. 344 Merritt V. Y. 311 398 Mersmann G. 455 Mertis K.,260 Merz A. 361 Mesentsev A. S. 461 610 Meshishnek M. J. 213 474 Mesh J. C. 511 Messer R. R. 119 Messmer A. 494 Metcalf J. C. 40 Meth-Cohn O. 319,492 Metzger J. 73 153 Meyer L. U. 230 589 Meyer R. B. 637 Meyers A. I. 496 546 672,687 Meyers C. Y. 213 Meyerson S. 177 Meyer zu Reckendorf W. 461 Mez H. C. 518 Michael M. 646 Michaels A. S. 333 Michaelson R. C. 259 667 Michaud H. 492 Michelot D. 399 Michl J. 404 429 Michl R. J. 396 Middleditch B. S. 17 Middleton E. J. 606 Midgley I. 566 Midland M. M. 348,664 668,669 Mighaed M. D. 14 Migita T. 198 202 208 223,416 Migita Y. 317 Mignery R.645 Michailovic M. Lj. 86 Mikan V. 70 Mikhailopulo I. A. 454 Miki S. 412 Milavetz B. 38 610 Miles D. L. 257 Miles H. T. 641 Milewski C. A. 661 Milinchuk V. K. 323 MiljkoviC M. 441 Miller B. 405 Miller C. H. 553 Miller D. L. 625 Miller F. 125 Miller J. A. 241 407 499 Miller J. H. 20 Miller L. L. 299 300 305,533 Miller N. R. 626 Miller R. B. 552 676 Miller R. D. 213 589 Miller R. J. 536 Miller S. I. 148 494 Miller S. L. 373 Miller W. N. 508 Millington D. S. 14 Mills D. R. 647 Mills N. S. 314 Mills 0.S. 48 423 Mills R. W. 215 552 Milne G. W. A. 14 17 18 Milstein C. 650 Mirnura T. 428 Min T. B. 282 Minale L. 559 567 Minasso B. 260 Minata H. 393 Minato S.640 Minchniewicz J. 637 Minisci F. 392 396 Minshall J. 443 468 Mirkind L. A. 285 Mirvish S. S. 374 Misbach P. 243 571 Mishrikey M. M. 510 Mislow K. 268 276 277,411 Mison P. 471 Misra R. A. 367 Misumi S. 90 410 526 Mitani S. 253 Mitchard L. C. 264 Mitchell G. N. 380 Mitchell H. L. 269 Mitchell R. H. 213 664 Mitchell R. W. 248 Mitchell T. D. 41 Mitra A. K. 406 557 Mitsch R.A. 142 Mitscher C. A. 14 Mitsudo T. 249 258 Mitsugi T. 568 Mitsuhashi T. 200 203 Mitsurnura K. 67 Mitsunobu O. 283 635 Mitsuo N. 665 Mittal R. K. 256 Miura I. 563 Miura Y. 347 Mixan C. E. 514 722 Miyake A. 253 Miyakoshi T. 254 Miyamoto T. 427 511 Miyano S. 196,397 Miyashita A. 257 Miyaura N.348 664 665 Miyoshi M. 294 295 473,686 Mizogami S. 410 Mizoguchi T. 3 17 Mizoroki T. 254 Mizuno K. 425 Mizuta E. 464 Mizuta K. 56 Mo F. 57 Mo Y. K. 133 135 136 137 138 150 357 368,393,425 Modena G. 384 Mobius K. 174 Moerck R. E. 412,471 Moffatt J. G. 454 456 630,633,634 Mofti A. M. 450 455 Mohn-Wehner A. 72 Mohri M. 248 Moinet G. 365 579 Moir A. 334 Moir M. 563 Moiroux J. 295 Moiseev I. I. 250 Moiseev Yu.-V. 328 Moitu J. C. 150 Mokren J. D. 453 Mole T. 658 Molho D. 182 403 508 Molin M. 97 262 Molin Yu. N. 176 Molina G. 576 Mollere P. D. 595 Molloy G. R. 649 650 Monache F. D. 563 Moncur M. V. 146,592 Money T. 215 549 552 Moniz W. B. 32 Monneret C. 450 465 Monshouwer J.C. 73 Montana A. F. 428 Montando G. 73 Montecalvo D. F. 360 404 Monti L. 141 Moody D. C. 32 Moon S. 376 Moore H. W. 84 189 Moore J. S. 449 Moore R. E. 543 Moore W. M. 159 Moore W. R. 359 Moorhouse S. 244 Author Index Moppett C. E. 522 Muller D. G. 549 Morales C. 664 Miiller E. 425 477 Moralioghi E. 453 Muller P. 195 396 414 Morand P. 565 Miiller W. E. 568 Moras D. 110 Muenchow H. L. 450 Morchat R. 200 224 Muesser M. 43 1 Moreau B. 516 Muter B. 519 Moreau C. 372,439 Muetterties E. L. 96 Moreau J. J. E. 250 268 Moreau S. 564 Muglia P. M. 336 Morel C. 650 Muir K. W. 245 Moreland C. G.. 270 Mukai T. 520 Mores F. 147 Mukaiyama T. 88 283 Morgan A. R. 642 671,674,679 Morgan D. D. 424 Mukam L.562 Morgan R. E. 31 Mukherjee D. 565 Morgan T. D. B. 399 Mulheirn L. J. 602 Morgenlie S. 440 Muller E. 80 86 226 Mori A. 418 236 Mori K. 551 Muller H. J. 636 Mori T. 81 203 Muller J. 244 247 Moriarty R. M. 233,252 Muller K. 233 Moriarty T. C. 147 Muller P. 232 Moriconi E. J. 84 Mullik S. U. 256 Morimoto M. 344 Mulliken R. S. 9 Morin R. B. 482 Mulvey D. M. 628 Morioka S. 639 Mumada M. 250 Morisaki M. 115 Mumma R. O. 444 Morisawa Y. 568 Munday K. A. 109 Morishima I. 596 Munoz A. 269 Morita K. 690 Murahashi S. 427 679 Morita T. 420 428 Murahashi S.-I. 204 Moritani I. 204 244 258,266,495,582 266 361 495 496 Murai A. 459 582,679 Murai S. 263 Moritani J. 258 Murakami Y. 277 Moroe M. 249 Muraki M. 88 679 Morokuma K'. 184 Murase I.203 254 Moron J. 619,620 Murata I. 204,236,429 Morris D. E. 262 519 Morris H. R. 18 19 Murata N. 342 Morrison H. 3 16 Murata T. 20 Morrison J. D. 11 Murata Y.,417 Morrison R. J. 248 Murayama D. R. 427 Morton D. R. 565 585 Murphy D. 166,436 Morton G. O. 556 Murphy D. P. H. 394 Morton J. R. 172 Murphy G. J. 196 Mosbach K. 107 Murray A. W. 319 507 Mosbo J. A. 516 Murray K. 637 651 Moser G. A. 341 653,656 Moses B. C. 334 Murray N. E. 653 656 Mosher H. S. 379 Murray N. G. 399 Moss R. A. 201 202 Murray N. L. 642 595 Murray R. K. 277 Motherwell W. B. 661 Murray W. P. 491 Mourad M. S. 181 Murrell J. N. 63 Mousseron-Canet M. Murthy D. V. K. 630 551 Musgrave W. K. R.,504 Mowat W. 244 Myers J. A. 200 Moyer C. E. 71 Myers M.E. jun. 327 Miillen K. 388 Myhre P. C.,136 Author Index Naae D. G. 665 Nabeta K. 610 Nabeya A. 672 Nachtkamp K. 37 233 386,388 Nadjo L. 286 287 Nadtochii M. A. 26 Naf F. 232 Nagabhushan T. L. 434 445 Nagai Y. 249 250 259 538 Nagakura S. 185 Nagase H. 553 Nagasse S. 68 Nagata W. 580 692 Nagel D. L. 374 Nahar S. 437 Naidoo B. 69 Nair M. K. V. 165 Naito T. 81 387 534 539,540 Nakadaira Y. 318 Nakagawa M. 54 387 422 Nakagawa T. 326,468 Nakaguchi O. 483 Nakai H. 317 465 Nakai K. 347 Nakai M. 254 Nakai T. 505 Nakajima M. 73 Nakamara A. 248 Nakamura H. 508,662 Nakamura N. 415 575 Nakamura T. 466 Nakanishi K. 318 551 563 Nakano J. 183 Nakashima T. 221 594 Nakasuji K.236 429 Nakata J. 557 Nakayama M. 554 Nakayama S. 187,279 Nakazaki N. 164 Nakazawa T. 204 Nakimoto A. 249 Nakoro T. 183 Nalliah B. 535 Nambara T. 568 Napoli J. J. 87 588 Nappier T. E. jun. 245 Naran ,S. A. 637 Naraska K. 674 Narayanaswami S. 612 Naruse M. 664,677,679 Narwid T. A. 546 Naser-ud-Din 477 Nash C. H. 482,616 Nash D. R. 503 Nash R. D. 552 Nasielski J. 404 Nasipuri D. 406 557 Naso F. 417 Nathans D. 653 Natowsky S. 592 Natsume M. 240 488 504 Natterstad J. J. 42 Navangal H. V.,137 Nauratil T. 478 Nayak U. R. 558 Nayler J. H. C. 483,484 Nazarenko N. 687 Neckers D. C. 82 347 694 Nefedov 0.M. 195' Negishi E. 350,673,684 Negishi E.-I. 663 Neidle S.57 Neilson G. W. 281 382 Neims A. H. 98 Nelsen S. F. 164 169 425 Nelson G. L. 34 Nelson R. F. 289 303 Nelson S. F. 286 513 Nelson S. J. 249 362 661 Nkmec J. 465 Neogi A. N. 341 Neta P. 154 156 157 163 Neu U. 203 Neuberger A. 619 621 Neuenschwander M. 4 19,480 Neumann P. 409 Neuss N. 34 482 544 615,616 Neuvar E. W. 142 Newcomb M. 78,'146 Newkirk D. D. 404 Newkome G. R. 503 526 Newman A. R. 247 Newman H. 677 Newman M. S. 195,363 684 Newmark R. A. 34 Newton M. D. 179,3 19 414,479,575,624 Newton M. G. 50,409 Ng H. Y. 320 Ng Ying Kin N. M. K. 466,467 Nicholas H. B. 61 624 Nicholas K. M. 263,682 Nicholls W. C. 396 Nichols S. B. 503 Nickon A. 87 Nicoletti R. 555 Niederhauser A.480 Niemayer H. M. 147 Nierlich D. P. 644 Nieuwpoort W. C. 221 Nieuwcnhuis T. 195,396 Niewport W. C. 386,388 Nihonyanagi. M. 249 250 Niida T. 460 Nijdam K. 71 Nikiforov G. A. 29 335 NikoliC A. 373 Nilsson A. 301 Nilsson S. 395 Nimmich W. 450 Nimoto F. 164 Ning R. Y. 190 Ninomiya I. 81 534 539,540 Ninomiya K. 226 283 684 Nishida S. 409 Nishiguchi T. 25 1 Nishijima Y. 329 Nishikawa K. 412 Nishikawa M. 464 Nishikimi M. 104 Nishimura J. 64 395 Nishimura S. 249 255 625,643 Nishimura T. 191 Nishioka I. 536 Nishiwaki K. I. 660 Nishiyama K. 4 12 Niwa H. 547,607 Niwa M.,552,561 Nixon J. F. 260 Nixon L. 619 Njimi Th. 562 Noguchi L. 531 Nolte R. J. M. 256 Noltes J.G. 244 Nolen R. L. 546 672 Nonaka G. 536 Nonaka Y. 340 Norbeck J. M. 386 Nordlander J. E. 125 Nordstrom B. 109 Norelle J. R. 399 Norin T. 554 Norman L. R. 553 Norman R. 0. C. 157 172,281,401,690 Normant H. 657 Normant J. F. 245 361 662,693 Norris R. D. 384 Northmore B. R. 329 Norton J. R. 340 Nouguier R. 667 Novik P. 442 Novotny B. 518 Nowak A. V. 17 Noyce D. S. 73 128 Noyori R. 85 88 236 254,261,265,578,587 Nozaki H. 123 191 234 508 662 664 667 672 677 678 679,681,693 Nozoe T. 38.419 Numata T. 169 Nunn M. J. 499 Nusse B. J. 261 Nuttall S. J. 313 509 Nyberg K. 285 297 392,401 Nyberg S. C. 4 17 Nystrom R. F. 61 1 Oae S. 665 669 Oates J. A. 17 Obayashi M.67 1 Obi N. 70 O’Brien P. F. 534 Occolowitz J. L. 11 O’Connell E. L. 113 O’Connell E. M. 207 O’Connor J. 212 Oda J. 207 Oda M. 230,419 Odaira Y. 240,399,427 Odani M. 509 Odum R. A. 186 Oeckl S. 396 Oehlmann L. 495 Oehlschlager,A. C. 607 Oehme G. 244 Oertel W. 652 Ogasawara K. 188 533 535 Ogasawara T. 466 Ogata I. 248 Ogawa H. 421,524 Ogawa T. 90 Ogden J. S. 246 Ogi K. 198 225 Ogilvy M. M. 318 Ogilvy M. O. 408 Ogino T. 578 Ogliaruso M. A. 237 Ogoshi H. 252,412 Oguchi N. 436 Ogura F. 387 Ogura H. 54 Oh S. 74 Ohara S. 557 Ohashi M. 310,311,398 Ohashi Y. 258 554 Ohgo Y. 258 Ohishi N. 104 Ohkawa H. 444 Ohki M. 468 Ohloff G. 232 55 1 673 Ohlsson I. 109 Ohlsson R.107 Ohmori H.,305 Ohno M. 466 Ohnsorge U. F. W. 555 Ohrt D. W. 248 Ohrui H. 436 466 633 Ohta T. 253 Ohtake T. 196 Ohtani H. 88 Ohtani M. 587 Ohtsuka E. 284 633 639 Oie T. 549 Ojima I. 249 250 259 Oka H.,633 Okabe H. 536 Okada A. 165 Okada K. 596 Okada S. 607 Okamoto K. 488 Okarnoto T. 357 395 428 Okamoto Y. 344 520 Okawara M. 326,346 Okazaki R. 187 279 Okazaki S. 326 Okazaki Y. 464 Okhlobystin 0. Yu. 27 28 Oki M. 41 1 Okinoshima H. 250 Oku T. 483 Okuda K. 258 Okuda S. 547 Okuma K. 418 Okuyama T. 73 142 150 Olah G. A. 45 64 124 133 135 136 137 138 150 214 357 368 383 389 392 393 394 395 425 426,595,693 Olah J. A. 136,357,693 Old R. W. 651 653 Oldenziel 0.H.690 Oldfield E. 35 39,40 OlivC J.-L. 551 OlivC S. 254 Oliver J. P. 596 Oliver S. S. 129 Olivson A. 28 Ollinger J. 667 Ollis W. D. 29 92 93 94 209 210,211,230 401,516 Olofson R. A. 194,695 Olsen K. W. 110 Author Index Olson P. E. 502 Omiti H. 254 Omura T. 252 Ona H. 220 221 263 415,575,594 O’Neill J. 139 416 592 O’Neill W. P.,61 1 Ong K. S. 459 Ono N. 473 OnOdera K. 436 Onoue H. 582 Oparaeche N. N. 453 Opheim K. 553 Oppolzer W. 364 553 661,669 Oram R. K. 270 Orchard A. F.,.8 Orchin M. 424 Orr G. 178 319 369 402,479 Ortiz de Montellano P. R. 665 Orton C. 82 321 694 Orvedal A. W. 420,593 Osawa T. 554 Osborn J. A. 254 Osborne M. R. 67 Oshima K.123 234 662,672,681,693 Ossip P. S. 277 Ostrovskaya I. Ya. 259 O’Sullivan M. 241 Oth J. F. M.,421 524 Otocka E. P. 336 Otroshchenko,0.S. 401 Otsu T. 337 Otshbo T. 410 526 Otsuka S. 248 253 Otsuki T. 407 Otto E. 551 Ottenbrite R. M. 583 Ourisson G. 129 560 561,562 Overberger C. G. 73 342,344 Overend W. G. 437 Overton K. H. 556,561 598 Owens P. H. 147 Oyama K. 503 Ozainne M. 550 Ozaki A. 254 Ozaki S. 385 Pac C. 425 Pacansky J. 81 178 319 342 369 402 414,479,575 Pachler K. G. R. 32 Packer E. L. 40 Padden F. J. jun. 326 Author Index Paddock G. 644 Paddon-Row M. N. 82 121 197 200 396 583,595 Padilla A. G. 276 Padmanabhan R. 652 Padwa A. 79,471,473 Paetzold P.I. 348 Pagani G. 512 Page E. H. 84 378 Page R. P. 17 Pagni R. M. 429 Paige J. N. 131 Pais M. 547 Pak C. S. 666 Paknikar S. K. 552 PaleEek J. 73 Palma G. 328 Palyi G. 256 Panchenkov G. M. 260 Paukstelis J. V. 550 Panunzio M. 692 Paoletti C. 651 Pappas P. R. 236 261 Paquette L. A. 38 52 92 128 131 233 236 261 262 286 386 388,389 Parham W. E. 502 Paris J.-M. 660 Park Y. J. 432 Parker A. J. 119 Parker C. E. 9 Parker D. R. 381 Parker K. A. 579 Parker V. D. 297 298 301 394,693 Parkinson B. 52 Parkinson C. 195 Park Kim J. J. 624 Parks J. E. 247 264 Parrilli M. 667 Parrish D. R. 578 Parrish F. W. 441 Parry R. J. 565 585 Parshall G. W. 247,248 251 Partington P. 32,40 Parton S.K. 182 Pasanen P. 11 Pascali V. 660 Pascoe J. M. 127 Pascual C. 11 560 Pashinnik V. E. 665 Pass G. 453 Pasternak G. 537 Pasynkiewin S. 253 Pat J. 312 Patchornik A. 345 347 447,683 Pate C. T. 381 Patel G. N. 332 Patel H. A. 519 Patel K. M. 692 Patel P. K. 685 Patil V. D. 558 Patoiseau J.-F. 564 Paton R. M. 29 Patrick T. B. 188 Patrushin Y. A. 267 Pattenden G. 597 Patton D. S. 137 Paudler W. W. 242 504 Paul B. 434 Paul D. 253 Paul E. G. 36 Paul I.C.,51,53,56,312 Paul J. 650 Pauling H. 259 Paulissen R. 205 258 Paulsen H. 440 444 461,463 Pavan M. 551 Pavlik J. W. 313 509 Pavlis R. P. 153 382 Peach C. M. 564 Peagram M. J. 35 1 Peake S. C. 269 Pearce B. W. 196 Pearce R.,244 245 Pearl N.J. 79 593 Pearson H. 386 Pearson J. E. 37 Pearson M. J. 483,484 Pearson R. G. 76 Pechet M. M. 567 Pedersen C. 453 457 458 Pedersen C. L. 508 520 Pedersen J. A. 165 Pederson L. G. 9 Peel R. P. 437 Peel T. E. 72 133 Peet W. P. 376 Peeters H. 422 519 Pegel K. H. 556 Pehk T. 28,29 Pelc B. 567 Peles P. 142 Pelster D. R. 17 Pelter A. 349 672 679 Peltier D. 288 Pendersen E. B. 63 Pendlebury A. 568 Penman A. 450 Penzer G. R. 630 Perchonock C. 139,4 16 5 92 Perego G. 252 PerjCssy A. 73 Perkins M.J. 381 Perlberger J. C. 232 Perlin A. S. 434 439 440 Perl’mutter B. L. 195 Pernet A. G. 434,451 Perold G. W. 440 Perret F. 437 Perreten J. 227 Perrotti E.252 Perry D. H. 404,415 Perry M. B. 463 Person H. 184 Person T. 649 Pert C. B. 537 Peters C. S. 42 Peters E. N. 124 125 Peters G. G. 652 Petersen T. E. 63 Peterson J. L. 245 Peterson P. E. 383 PetkoviC Lj. 373 Petrissant G. 644 Petrovskii P. V. 29 Petrushanskaya N. V. 253 Petrzilka M. 688 Pettit G. R. 566 Petty H. E. 128 Peverada P. 38,614 Peyrot M. 406 Pfannemuller B. 324 Pfau M. 404 Pfenninger E. 364 669 Pfleiderer W. 635 Pfluger C. E. 481 Pfoertner K. H. 567 Pfohl S. 268 Philips K. D. 466 Philipson L. 650 Phillips G. O. 449,453 Phillips G. T. 610 Phillips L. 435,452,556 Piancenza L. P. L. 556 Picaud F. 644 Pichat L. 687 Pick M. R. 413 Pickenhagen W. 232 Pickering M.43 Pickles V.A. 435 436 Pidcock A. 260 Pieroni J. 84 Pierrou L. 16 Pierson G. O. 222 Pietra F. 395 596 Pietropaolo R. 257 Pigram W. J. 625 Pihlaja K. 11 Pilkington J. W. 239 Pillai P. M. 440 Pilot J. F. 54 269 Pilotte J. 207 Pilotti A. M. 56 726 Pincock J. A. 200 224 315 Pincock R.E. 122 387 Pines A. 39 Pines S. H. 306 Pinhey J. T. 568 Pinkerton T. C. 644 Pino P. 259 367 Pinschmidt R. K. 76 Piper J. U. 576 Piper P. W. 644 646 Pitha J. 639 Pitha P. M. 639 Pitkethly R. C. 340 Pittman C. U. jun. 155 341 Pitts J. N. 381 Place P. 665 Placucci G. 172 Plakidina M. V. 67 Plat M. 34 544 Platenburg D. J. H. M. 277,281 Plato M. 174 Plekhanova I. G. 29 Pletcher D.285 299 300 Pletcher T. C. 150 Plinke G. 421 Plorde D. E. 576 Plunkett A. O. 508 Pochini A. 69 Podder S. K. 642 Poe M. 623 Porschke D. 640 642 643 Pogonowski C. S. 678 Poisson J. 34 544 545 Polakova-Paquet A. 565 Polan H. L. 19 Polanc S. 493 Poland J. S. 246 Polansky 0.E. 192,226 Polhl L. 37 Politzer I. R. 672 Poljakova L. A. 27,28 Pollack R. M. 77 Pollak A. 141 Pollard Y. 34 Pollman T. G. 257 Pollock R. J. 106 Pollock R. J. I. 252 Polonsky J. 555 556 Polyakova V. P. 258 Pomerantz M.,198 223 Ponchet J. 437 Pong R. G. S. 81,479 Ponpipom M. M. 454 458,460 Poon R. 652 Popjdk G. 560 Author Index Pople J. A. 9 78 79 Puckett R. T. 41 1 137 139,432 Puddephatt R. J. 245 Popp G.285 25 1 Porta O. 396 Putter H. 415 Porter A. G. 649 Puglisi V. J. 287 Porter D. J. T. 99 104 Puliti R. 567 Porter H. K. 392 Puosi G. 260 Porter R. 43 Purdie N. 368 Porter R. S. 327 Putz G. H. 126 Portmann R. E. 518 Puza M. 658 Portnoy R. C. 672 Pyrek J. St. 559 562 Posner B. 229 Posner G. H. 123 245 Quast H. 229,472 246 361 552 657 Queen A. 121 677,691,693 Quigley G. 624 Possagno E. 69 Quin L. D. 515 Potapov V. K. 638 Quiniou H. 5 11 Potier P. 34 544 Quinkert G. 227 Potter S. E. 409 Quinn C. B. 52 144 Potter W. 328 516,571 Potts K. T. 498 510 Quirk R. P. 147 Poulin J.-C. 259 Qureshi A. A. 545 Pousset J.-L. 19 Qureshi M. I. 505 Poutsma M. L. 162 Povall T. J. 19 Raba M. 645 Powell J. 257 Rabek J. F. 324 Powell R.L. 274 275 Rabenstein D. L. 38 Powers J. L. 117 419 Pradere J. P. 51 1 Raber D. J. 121 124 Pragnell J. 568 Rabi J. A. 628 Prakash A. 192 Rabin €3. R.,118 Prange U. 421 Rackham D. M. 42 Prashad B. 671 Radatus B. 460 Pratt A. D. 560 Radlick P. 56 554 Pratt D. W. 374 558 Preckel M. 263 573 Radom L. 78 79 139 Pregaglia G. F. 255,260 432 Pregosin P. S. 41 Radscheit K. 567 Prelog V. 610 Raghavan N. V. 258 Prensky W. 626 Ragozzino L. 551 Prestegard J. H. 625 Rahimtula A. D. 109 Preston C. M. 435 Rahman A. 664 Previtali C. M. 316 Rahn R.O. 640 Price P. 564 Raia D. 342 Price P. M. 626 Rainoldi G. 568 Price R. 40,433 Raj Bhandary U. L. 284 Prietzel H. 492 637,644,645 Prins W. L. 96 Rajeswan K. 85 183 Prinzbach H.90 391 217 419 Rakhys J. W. jun. 347 Prior A. M. 461 Ramage R. 553 Prochkka z. 569 Rameau J.-J. 285 Proctor G. R. 488 Ramegowda N. S. 671 Prokofiev M. A. 638 Ramey K. C. 233 Prosser J. 626 Ramirez F. 54,268,269 Prout F. S. 692 274,284 Prout K. 246 Rarnirez R. 346 390 Prusiner P. 636. Ramsay J. N. 65 394 Pruss G. M. 145 Ramsden C. A. 199 Pryor W. A. 153 225,. 47 1 Ptashne M. 656 Ramsey B. G. 571 Author Index RQnby,B. 324 Randall E. W. 4 1 Randerath K. 637 Randhawa R. 183 RandiC M. 424 Rando R.R. 115 Ranganathan D. 208 550 Ranganathan S. 208 550 Ranganayakulu K. 134 215 Rangarajan M. 19 Rank A. 96 Rank W. 468,469 Ransford G. H. 465 Ranu B. C. 557 Ranzi B. M. 599 Rao D. R. 456 Rao J.M. 80 Rao M. N. M. 389 Rao V. S. R. 432 Raoult A. 149 Raoult E. 288 Rapoport H. 536 543 611 Rapp M. W. 126 Rappoport Z. 125 142 2 16 Rasmussen J. K. 512 690 Rasmussen P. 453 Rassat A. 174 381 518 Rastetter W. 482 615 Ratcliffe A. H. 543 Ratcliffe R. W. 485 Rathke M. W.,684 686 Ratliff R. L. 640 Rau H. 244 Rauch F. C. 395,669 Rauk A. 185,268 Rausch M. D. 254 341 Rautenstrauch V. 207 551 Ravetch. J. 642 Ravindran N. 350 663 665,666,669 Rawlinson D. J. 392 Rawson D. I. 386 Raymond K.N. 236 Raymond M. G. 658 Raymond-Hamet 548 Raynolds R. W. 159 Read G. 407 Reardon E. J. 80 261 314 Rebafka W. 411 Recker K. 37 386 Record K. A. F. 513 Reddy T. B. 309 Redlich H.461 Rich A. 61 624 625 Reed C. A. 340 643 Reed L. L. 61 Richards C. M. 437 Reed R. I. 17 Richards E. E. 568 Rees C. W. 86,177,190 Richards R. L. 264 199 226 471 478 Richards W. G. 78 504,508 Richardson A. C. 443 Rees D. A. 450 Richardson N. V. 8 Rees H. H. 606 Richman J. E. 681 687 Rees N. H. 164 Richmond G. D. 183 Reese C. B. 639 403 Reetz M. 193 Richter D. 645 Reetz M. T. 77,227 Ridd J. H. 67 Regitz M. 280 Riddell F. G. 514 Rehder-Stirnweiss W. Riddle D. L. 643 645 260 Ridley D. D. 199 485 Reibel L. 650 Rieff L. P. 27 1 Reibstein D. 598 Riegl J. 477 Reich C. J. 379 Rieke R. D. 694 Reich H. J. 88 675 Riess J. G. 245 269 Reich I. L.,88,675 Righetti P. P. 89 Reich L. 333 Rigo A. 328 Reichmanis E. 516 519 Rihs G. 518 Reich-Rohrwig P.257 Rijks J. 15 Reid A. A. 79 Rinck R. 191,226 Reid B. R. 641 Rindone B. 599 Reid D. H. 67 Rinehart K. L. jun. 38 Reid R. W. 223 60,610,611 Reid W. 213 Ringsdorf H. 329 346 Reiff H. 501 Rippa M. 112 Reimann H. 464 Risitano F. 196 397 Reimlinger H. 205 258 Risler W. 229 472 Reingold I. D. 409 Ristagno C. V. 426 Reinhoudt D. N. 522 Ritchie R. G. S. 441 kinitz E. R. 645 Riveros J. M. 380 Reiss J. A. 410 Rivier J. 18 Reitano M. 695 Riviere H. 675 Reiter P. L. 240 399 Rizzardo E. 567 Reitz R. R. 32,236,261 Robbins H. M. 120 RemeS M. 67 Robert D. U. 269 Rempel G. L. 248 260 Robert J. B. 386 Remy M. 404 Robert J. C. 114 Renaud R. N. 302 Robert-Gero M. 646 Renault J. 503 Roberts B. P. 170 173 Renga J. M. 88,675 28 1 Rensing U.F. E. 647 Roberts D. W. 194 195 Restivo R. 562 Roberts F. M. 598 Reszelbach R. 645 Roberts G. A. F. 447 Reuben J. 43 Roberts G. C. K. 40 Reusch W. 692 Roberts J. D. 37 43 Rewicki D. 427 386,434 Rey P. 381 Roberts J. L. 667 Reyes-Zamora C. 449 Roberts J. S. 55 Reynolds F. 639 Roberts P. J. 8 57 Reynolds-Warnhoff P. Roberts R. M. 68 387 Robertson B. E. 49 Rhine W. 47 Robertson D. H. 17 Rhodes Y. E. 129 Robins M. J. 461 632 Ribas I. 534 634 Ricca G. S. 610 Robins R. K. 455 636 Rice K. C. 521 637 Robinson D. H. 632 Robinson J. D. 40 Robinson J. J. 65 Robinson J. L. 630 Robinson J. M. 503,526 Robinson M. L. 404 Robinson N. 450 Robinson P. J. 195 R&k J. 379 Rockett B. W. 122 RodC-Gowal H.371 Rodionov A. P. 486 Rodrigo R. 535 Rodriguez B. 558 Rodriguez M. L. 560 Rodtiguez O. 369 Roe B. 643,645,646 Roeder S. B. W. 38 Roderer R. 486 Roker K.-D. 525 Rollgen F. W. 14 Roffia P. 255 Roger G. P. 346 Rogers M. T. 152 Rogers P. E. 282 667 Rogerson,T. D. 396,537 Rogovin Z. A. 337 Rolfe R. E. 169 Roling P. V. 374 596 Rolland Y. 544 Rollin G. 671 Rollins A. J. 460 Rollmann L. D. 341 Rolls J. P. 38 610 Roman C. 677 Romanet R. F. 681,682 Ronald R. C. 552,687 Ronchetti F. 605 Ronlan A. 298 301 Roobeek C. F. 97 Roof A. A. M. 42 Ros P. 119 Ros R. 252 Rosan A. 264,659 Rose B. F.,401,53 1,67 1 Rose D. 255 Rose I. A. 113 Rose K. A. 153 Rose P.D. 247 Rose P.G. 328 Roseberry T. 32 RosCn K. 504 Rosen M. A. 612 Rosenberg J. M. 61,624 Rosenblum M. 263,264 659,682 Rosenfeld J. 136 214 57 1 Rosenfeld S. M. 26 Rosenstein R. D. 59 Rosenstock H. M. 12 Rosenthal A. 437 459 462 Rosenthal I. 507 Rosenthal U. 244 Rosini G. 690 Ross F. K. 54 Ross J. 20 Ross S. D. 301 Rossi R. 357 Rossi R. A. 148 537 Rossi U. 253 Rossman M.%.,107,110 Rossy P. A. 657 Roth A. S. 147 Roth H. D. 28 Roth R. 319 414 479 Roth W. R. 27 229 359 Rothberg I. 561 Rothenberg S. 596 Rother H. J. 229 360 Rothman E. S. 372 Rouette H. K. 72 Roumestant M. L. 665 Rouse R. A. 303 Roustan J. L. 263 Routledge W. 518 Royston G. M. D. 264 Rozhdestvenskaya N. N. 196 Ruasse M.-F.140 Rubenstein P. 440 Rubin G. M. 651 Rubottom G. M. 204 Rucktaschel R. 369 Rudd E. J. 301 Ruden R. A. 664,674 Rudnick L. R. 552 688 Rudolph J. P. 147 Ruge B. 203 589 Rugg P. W. 632 Ruiz V. M. 407 Ruo T. 603 Rupert C. S. 640 Ruprecht R. M. 626 Rusan V. 338 Rushworth A. 122 Russel R. K. 38 Russell A. F. 633 634 Russell D. R. 252 269 Russell G. B. 568 Russell P. J. 161 Russell R. K. 233 386 388 Russo G. 605 Rustenburg J. 20 Ruta M. 42 Rutledge P. S. 667 Ryan K. J. 448 Ryan T. J. 373 Ryang M. 263 Author Index Rycklik I. 465 Ryde-Petterson G. 302 Ryder M. A. 628 Ryhage R. 15 Rykov S. V. 29 Ryono L. 25 1 396 SBa J. 534 Saba S. 515 Sabbioni E. 651 Saber T.M. H. 305 Sack G. H. jun. 653 Sadavoy L. 257 Sadeh S. 362,499 Sadler I. H. 34 35 229 Sadykov A. S. 401 Saegusa T. 203,254,499 Saenger W. 60 61 Sagatys D. S. 145 Sagdeev R. Z. 176 Sahn D. J. 150 Saiki Y. 202,416 Saito I. 418 Saito K. 265 Saito S. 183 254 Saito Y. 367,483 Sakai F. 212 Sakai I. 20 Sakai M. 220 221 253 263,386,594 Sakakibara Y. 253 Sakamoto M. 41 I Sakamoto N. 248 Sakamura S. 610 Sakan K. 418 Sakashita T. 674 Sakata Y. 387,410 526 Sakharovsky V. G. 450 Sakito Y. 518 Saksena A. K. 461 Sakumi H. 165 Sakuragi M. 332 Sakurai H. 425 660 Sakurai S. 627 Salamone J. C. 342. 344 Salaun J. 213 573 Salaun J. R. 218 Salditt M. 650 Salem L. 76 228 384 595 Sales K.D. 169 Salikhov K. V. 176 Salomon C. 259 Salomon R. G. 203,3 14 321 Salovey R. 332 Salser W. 652 Salsky R. L. 148 Salter J. C. 130 Saltiel J. 314 428 Saluvere T. 28 29 Author Index Salzmann T. N. 675 Samanen J. M. 533 Sammes P. G. 181 199 266 403 404 483 583,667 Sams J. 374 Samsonova L. V. 335 Samuel P. A. 207 Samuni A.,,156 157 Sanchez M. 269 Sandall J. P.B. 401 Sander E. G. 628 Sanders D. C. 389 Sanders J. R. 694 Sanderson B. R. 173 Sandy J. D, 619 Sanger F. 652 Sano H. 263 Sanstead J. K.,302 Santarelli C. 555 Santhanaan K. S. V. 165 Santini-Scampuca C. 245 Santopietro- Amisano A. 613 Sanui K. 326 Sanyal B. 557 Sarabhai A. 644 Saraie T. 690 Sarcevic N.354 399 Sarel S. 88 181 406 Sarfati R. 547 Sargent M. V. 394,524 Sarhan A. 384 Sartorelli A. C. 405 Sarver E. W. 404 Sasada Y.,258,413,554 Sasaki E. 339 Sasaki F. 466 Sasaki K. 418 Sasaki M. 444 Sasaki S. 567 Sasaki T. 428 518 550 Sasakowa E. 265 Sass R. L. 414 Sasse W. H. F. 425 Sasson Y. 686 Sato H. 318 Sato K. 265 Sato M. 603 Sato T. 44 66 203 412 Sato Y. 317 332 Satoh F. 535 Satoh H. 674 Sattar A. 553 Saunders B. C. 239 Saunders D. G. 153,502 Saunders J. 621 Saunders J. K. 43 44 Saunders M. 133 136 139,214,416,571,592 Saunders W. H. 144 Schlierf C. 412 Sauter H. 89 Schlittler E. 548 SavCant J. M. 286 287 Schlosberg R. H. 136 288 Schlossarczyk H. 94 Savignac P. 274 234,353,664 Savin V.I. 24 Schmickler H. 36 37 Sawada S. 234 38,386,422 Sawara K. 254 Schmid H. 25 94 234 Sawyer C. B. 372 235 236 237 238 Sayer B. 37 596 239 240 241 353 Sayo H. 305 354,399,548,664 Scaiano J. C. 167 316 Schmid M. 94 241 399 Scala A. 599 Schmid R. 461 Scannon P. J. 147 Schmidbauer E. 90,39 1 Scarpa I. S. 342 474,589 Schaap A. P. 82 347 Schmidbaur H. 244 694 Schmidt A. H. 83 213 Schade G. 82 321 Schadt F. L. 127 Schmidt B. R. 635 Schafer H. 300 486 Schmidt E. A. 375 Schaefer J. 40 Schmidt E. K. G. 415 Schafer W. 498 Schmidt F. 417 491 Schaeffer R. 32 Schmidt G. M. J. 84 Schael F. C. 321 Schmidt R. R. 82 Schaller H. 652 Schmidt U. 279 Schallner O. 135 595 Schmidt W. 63,76,410 Scharpen L. H. 250 415 Schechter H.389 Schmir G. L. 372 Schechter I. 116 Schmir G. S. 150 Scheerer B. 366,499 Schmitt D. L. 260 Schemer M. 324 Schmitt J. L. 208 Scheinmann F. 260 Schmitz H. 589 Scheit K. H. 630 641 Schmook F. P. 610 643,645 Schmutzler R. 269 Schell F. M. 544 Schnabl G. 207 Schellenberg K. A. 111 Schneider G. 508 Scheller O. 90 Schneider H. W. 419 Schen K. 152 Schneider M. 589 Schenk W. K. 419 Schneider R. 287 Scheppers G. 203 Schoch J. P. 399 Scherer H. 280 Schoder G. 524 Scherer 0.J., 207 Schollkopf U. 193,690 Schernau U. 641 Schonleber D. ,390 Schemer K. 649,650 Schoenmakers J. G. G., Scheuer P. J. 436 647 Scheurer H. 399 Schoukopf U. 495 Schiavelli M. D. 125 Schofield K. 74 392 Schiebel A. H. 428 Scholten D. J. 671 Schield J. A.188 Scholz U. 635 Schiess P. 230 Schonbrunn A. 99 Schinke U. 242 Schonhorn H. 326 Schittenhelm W. 30 Schooley D. A. 554,599 Schlegel J. M. 65 Schott H. 638 639 Schlesinger G. 373 Schouteden E. 312 Schlessinger R. H. 675 Schrader L. 200 224 68 1,682,687 Schray K. J. 113 Schletter I. 540 Schreckenberg M. 674 Schleyer P. von R. 78 Schreiber W. L. 575 79 121 123 124 127 Schreier M. H. 650 133 139 198 218 Schroder G. 421 220,223,389,571,595 Schroeder L. R. 441 730 Schroder R. 495,690 Schrofer E. 458 Schroff L. G. 41 1 Schuddemage H. D. R. 20 Schuerch C. 345 445 446,447 Schuler R. H. 154 155 Schulman L. H. 646 Schulten H. R. 13 14 Schultz A G. 545 Schultze K. W. 440 Schulz R. C. 324 325 347 Schupp E.518 Schuster D. I. 318 Schuttenberg H. 347 Schwaiger G. 518 Schwalbe C. H. 60.61 Schwartz A. W. 452 Schwartz J. 259 Schwartz J. A. 236,434 Schwartz M. A. 401 531,671 Schwartz R. 694 Schwarzenbach D. 437 Schweickhardt C. 390 SchweCg,'A. 498 592 Schweizer E. E. 491 Schwesinger R. 391,589 Sclair M. 635 Scolastico C. 588 610 Scorrano G. 384 Scott A. I. 58 542 544 545,610,623 Scott F. L. 169 241 Scott G. 328 334 Scott J. A. 380 Scott L. T. 194 246 420,587 Scott M. 107 Scott W. B. 122 Scribe P. 68 Scrimgeour C. M. 241 407 Scriven E. F. V. 192 Scully F. 316 Sealy R. C. 157 Sears B. 40 Seccombe R. C. 48 Secrist J. A. 630 Sedlmayer P. 250 Sedor F. A. 628 Seebach D. 673 675 677 Seel K.94 233 476 Seeley D. A. 667 Seeliger A. 283 Seeman J. I. 228 Seeman N. C. 61,624 Segal J. A. 246 Segal R.,559 Seguchi K. 89 583 Sehested K. 154 Seidman J. G. 644 Seifert W. K. 563 Seigert K. G. 154 Seiki T. 323 Sekera M. H. 586 Sekiguchi S. 64 67 70 384,395 Sekine K. 395 Sekiya M. 631 Sekizaki H. 51 1 Seliger H. 638 Selve C. 454 Semmelhack M. F. 72 251 351 396 537 589,591,592,661 Semmingsen D. 4 15 Sen G. 5 16 Senatore L. 120 Sendijarivic V. 126 SenkIer C. A. 123 Senning A. 496 Seno T. 645 Senoff C. V. 252 Sensi P. 610 Seo E. T. 289 Seo S. 605 Septe B. 257 Sepulchre A. M. 434 46 1,462 Sepulveda L. 278 Sequin U. 345 638 Sera A. 89 583 Sergeev N.M. 45 Sergeev Yu. 12 Sergi S. 257 Serota S. 505 Serratosa F. 18 1 403 Serres B. 204 Serve D. 305 Seshadri T. R. 563 Setlow J. K. 640 Seto H. 38 61 1 Seto S. 434 Sevin A. 2 18 Seybold G. 133 415 479 Seyden-Penne J. 89 Seyferth D. 196 204 280,665 Sgarabotto P. 5 12 Sgaramella V. 284 Shabarova Z. A. 638 Shahak I. 686 Shahak Y. 630 Shamma M. 533,545 Shanklin J. R.,660 667 Shannon P. V. R. 69 Shapira C. 650 Author Index Shapiro M. 18 Shapley J. R. 254 Sharma N. K. 482,660 Sharma R. P. 555,603 Sharon N. 114 465 Sharp J. T. 79 Sharpless K. B. 87 88 212 259 379 661 662,667,675 Shatzmiller S. 680 Shavel J. jun. 51 1 Shavit N. 630 Shaw B. L. 252 Shaw C. F. 251 Shaw C.K. 38,614 Shaw D. 35 Shaw G. 632 Shaw M. A. 348 Shawali A. S. 241 491 Shea K. J. 153 159 382 Shearing D. J. 145 Sheehan J. C. 683 Shefter E. 60 Sheikh Y. M. 567 568 Sheiness D. 650 Sheldrick W. S. 269 Shellhamer D. F. 190 213,474 Shemin D. 623 Shen C. M. 347 Shen J. 136 357 393 Shen K.-W. 76 Shen M. S. 432 Shen T. Y. 440 Sheppard W. A. 373 492 Sherkin P. B. 153 Sherlock M. 264 Sherman W. R. 16 Sherrod S. A. 4 1 1 Shershneva L. P. 646 Shevlin P. B. 23 382 Shibaev N. N. 629 Shlbasaki M. 550 Shibuya S. 183 Shieh J. J. 414 Shiga T. 157 Shigemitsu Y. 240 399 Shillody D. D. 351 383 Shima M. 583 Shimado Y. 633 Shimagaki M. 557 Shimamura T. 266 Shimanouchi H. 413 Shimizu Y.387 Shimoji K. 672 Shiner V. J. 124 126 Shingaki T. 185 186 Shingu T. 561 Author Index Shinoda J. 203 Shinohara H. 326 Shioiri T. 226 283,684 689 Shiojima T. 70 395 Shiono R. 59 Shirk J. S. 81,479 Shirrell C. D. 52 Shlyapintokh V. Ya. 335 Shmonina V. L. 255,259 Shold D. M. 123 Shono T. 214 Shore B. L. 16 Shortland A. J. 244 Shotton D. M. 116 Showalter H. D. 14 Shriver D. F. 43 245 Shteinman A. A. 250 Shu P. 391 Shudo K. 143,395,437 488 Shugar D. 635 Shulman R. G. 640,641 Shuman D. A. 637 Siddall J. B. 554 599 Sidhu R. S. 208 Sidwell R. W. 636 Sieber W. 94 234 353 664 Siefken U. 191 226 Siegel M. G. 387 527 Siegel S. 248 Siegfried B. 686 Sienkowski K.J.203 Sigman D. S. 117 Signorini M. 112 Sih C. J. 482 616 Silva M. E. F. 17 Silver S. M. 552 Silverman G. 486 523 Silverman R. S. 65 394 Silverstein R. M. 549 Silverthorn W. E. 264 Silvestri G. 296 Silvestro L. 257 Sim G. A. 55 Simeral L. 36 Simic M. 157 Sirnionescu C. I. 337 338 Simm I. G. 10 Simon E. J. 537 Simon H. 379 Simon H. E. 30 Simon J. 527 Simon L. N. 636 Simon W. 73 Simonet J. 288 Simonetta M. 142 Simons S. S. 499 Simpson D. A. 383 Simpson G. E. F. 405 Smith P. J. 144 Simpson P. 272 Smith P. M.,341 Sims C.L. 553 Smith R. J. 227 Sims J. 85 367 Smith R. M. 464 Sims J. J. 56 554 558 Smith R. R. 338 Simsek M. 637,644,645 Smith S. G. 119 393 Sinclair J. A. 348 664 Smith W.K. 147 Singh M. 182 Smithers D. A. 545 Singh R. K.,553 681 Smolanoff J. 47 1 Singh S. P. 371 Snatzke F. 573 Sinnema A. 83 Snatzke G. 424 513, Sinner G. T. 148 55 1 Sinnott M.L. 448 Sneden D. 624,625 Sinnwell V. 46 1 Sneen R. A. 120 Sirnov V. A. 285 Snider B. 342 Sirover M. 645 646 Snider B. B. 669,695 Sisido K.,89 Snieckus V. 5 19 Skattebd L. 97 196 Snoble K. A. J. 278,482 477 Snorn E. C. G. 73 Skein S. M. 176 Snyder C. D. 611 Skell P. S. 153,159,193 Snyder E. I. 282 201,223,226,382 Snyder H. R. 427 Skinner S. J. M. 109 Snyder S. H. 537 Skorobogatova E. V. 68 Soad H. R. 79 Slaugh L. H. 262 Sodano G. 567 Slaven R. W. 139 659 Soderlund G. 109 Slessor K.N. 454 Sodini G. C. 19 Slichter W. P. 40 So11 D. 638 645 Sloan K.B.186 Sldrensen S. 35 Slocum D. W. 68 Sogah G. D. Y. 387,527 Slomp G. 147 388 592 Sop,J. A. 41 Slopiarka M. 566 Sohar P. 443 515 Slutsky J. 218,231 Sohn M. B. 197 Small L. E. 147 Sojka S. A. 32 Smart J. C. 246 Sokolova N. P. 258 Smedley S. 437 Sol& P.,181 403 Smid J. 325 Solar S. 192 226 Smiley I. E. 107 Solch M. A. 129 Smirnov V. D. 638 Solomon I. 44 Smith B. F. 676 Solomon J. J. 138 Smith C. D. 207 576 Soman R. 234 Smith C. J. 644 Somanathan R. 93 210 Smith C. P. 269 Somei M. 240 488 Smith C. V. 549 Sommer R. G. 630 Smith D. 8 Sondengam B. L. 669 Smith D. J. 440 Sondheimer F. 360,404 Smith D. J. H. 276 421,423,525 Smith D. M. 421 Sonnichsen G. 147 Smith D. S. H. 567 Sono M. 629 Smith E. L. 118 Sonoda N. 263 Smith E.M. 672 Sonveaux E. 363,583 Smith G. F. 543 545 Sood V. K. 552 Smith G. N. 543 Sotia D. 316 Smith H. O. 139 220 Sorensen T. S. 79 85 656 133 134,215,217 Smith J. 686 Sorm F. 569 Smith J. D. 644 645 Sosnovsky G. 392 646 SouZek M. 440 Smith J. G. 405 Souma Y. 263 Smith M. 639 Sousa L. R. 387 527 Smith P. A. S. 192 Southern E. M. 650 732 Southgate R. 483 484 Stehlicek J. 345,447 Sovocool G. W. 480 Steinbach K. 204 Sowa W. 440,452 Steiner P. R. 434 437 Spadari S. 651 Steiner R. F. 630 Spalding T. R. 244 Steinhart W. 643 Spangler B. 80 Steinmetz W. E. 371 Spangler C. W. 80 Steitle R. B. 227 315 Spangler R. J. 404 Steitz J. A. 649 Sparkes G. R. 186 Stephany R. W. 256 Spassky A. 675 Stephens R. D. 410 Speckamp W.N. 518 Stephenson G. P. 627 564 Stephenson G. V. 334 Spee T. 314 Stephenson J. R. 623 Spencer A. 248 Stephenson L. M. 87 Spencer T. A. 496,668 Stephenson R. W. 86 Spendel W. 183,403 St6rba V. 66 70 Spenser I. D. 617 618 Sterenzat D. E. 267 Spenser T. A. 148 Sterling J. J. 123 245 Spichtig A. M. 450 246,691 Spiegelman S. 626 647 Stermitz F. R. 305 533 Spierenburg J. 68 Stern P. 284 Spitaler U. 548 Sternbach D. 669 Springer I. S. 43 Sternbach H. 643 Sprinzl M. 437,643,645 Sternbach L. H. 190 Squire R. H. 242 318 399 399,408 Sternhell S. 538 Srinivasan R. 31 1 398 Sternlicht H. 40 Srivanavit C. 276 Stetter H. 674 Srivastava R. M. 514 Stetter J. 51 1 Staab H. A. 411,422 Stevens C. G. 425 Staalman D. J. H. 41 1 Stevens C. L. 440,465 Stabba R.243 571 Stevens I. D. R. 119 Stache U. 567 Stevens M. F. G. 399 Stackhouse J. F. 242 Stevens R. H. 649 Stadler P. 461 Stevens R. V. 232 Stadtman E. R. 630 Stevens T. S. 206 Staehelin T. 650 Stevenson B. K. 133 Stahl S. 644 Stevenson G. M. 319 Stainbank R. E. 252 507 Staley S. W. 79 146 Stevenson G. R. 148 206,420,591,593 Stevenson J. R. 200,224 Stalick W. M. 684 Stewart A. G. 650 Stallard M. O. 551 Stewart J. A. G. 229 Stanbury P. 83 Stewart R. 72 503 Stanforth R. R. 417 Stewart R. C. 582 682 Stang P.J. 215 216 Steyn P. S. 58 Stanley J. P. 153 Stille J. K. 279 Stannett V. 337 Stillwell R. N. 13 Stanovnik B. 493 494 Stirling C. J. M. 384 Stathakos D. 11 1 Stivala S. S. 333 Staub A. P. A. 459 Stock J. 72 591 Stauffer R.D. 351 396 Stocky T. P. 666 537,661 Stoddart J. F. 431 452 Steele E.S. 395 Stoffel W. 19 Stefani A. 367 Stofko J. J. 94 232 StefanoviC D. 8 Stokes D. H. 437 Stefanovic M. 554 Stollar H. 516 Stefanovskaya N. N. Stone F. G. A. 258,418 255,259 Stonemark F. E. 68 Steglich W. 502 Stoochnoff B. A. 668 Stehelin L. 129 Stoodley R. J. 95 Author Index Storer R. 597 Storey P. M. 281 Stork G. 553 577 579 581,674,678 Storr R. C. 86,177,478 508 Storrs E. E. 13 Stothers J. B. 34 42 215,488 Stotter P. L. 676 Stoute V. 222 Stowe G. T. 73 Stoyanovich F. M. 179 Strand J. W. 395 Strathdee G. G. 248 Strating J. 219,369,571 Straub H. 80 425 Straube F. A. 38 422 Strauss D. B. 639 Strauss M. J. 396 Strausz 0.P.198 225 Streckert G. 450 Streeper R. D. 200,,224 Streeter D. G. 636 Streith J. 520 Streitweiser A. 147 Strettmatter P. 98 Strich A. 268 Strickland R. C. 546 Strickler S. J. 425 Strohmeier W. 260 Stromar M. 523 Strominger J. L. 111 440 Strong J. G. 377 Strope D. 245 Strozier R. W. 85 89 366,583 Strugnell C. J. 248 Stubbs M. E. 237 Stuckwisch C. G. 85 Stucky G. D. 47 Stusche D. 90 Su A. C. L. 254 Su Y. Y. 96 Subra R. 174 Sucrow W. 566 Suda M. 263,415,575 Suda T. 567 Suddath F. L. 61 624 Sudoh R. 468 Suss G. 491 Suss H. U. 418 Suggs J. W. 260,667 Sugihara Y. 519 Sugimori A. 420 Sugimoto A. 567 Sugimoto H. 508 Sugimoto T. 508 Suginome H. 564 Sugioka T. 425 Author Index Sugisaki H.656 Sugiyama H. 434 Sugowdz G. 425 Suhara Y. 466 Sukawa H. 520 Sukihara M. 298 Sullivan D. E. 302 Sullivan D. F. 684 686 Sullivan G. R. 379 Sullivan J. W. 302 Sullivan R. J. 68 Sumitani K. 249 250 Summers A. J. H. 313 509 Summers J. W. 324 Summers,-W. A. 629 Sumoto K. 51 1,674 Sunami M. 509 Sunamoto J. 277 Sundaralingam M. 636 Sundararajan P. R. 432 Sundararaman P. 55 Sundberg R. J. 186 Sunderman F. B. 216 Sundermeyer W. 674 Sundin S. 554 Sunjie V. 523 Sunko D. E. 126 Surzur J. M. 667 Suschitzky H. 189 192 319,492,582 Suss M. U. 589 Sustmann R.,82 Susuki S. 183 Sutcliffe L. H. 161 251 Sutherland B. M. 640 Sutherland D. R. 494 Sutherland I.O. 29 92 93 209 210 21 1,401 409,5 16 Sutherland J. C. 640 Sutherland J. K. 578 Sutton W. B. 105 106 Suzuki A. 308,348,554 664,665 Suzuki E. 51 1 Suzuki J. 416 Suzuki K. T. 547 601 607 Suzuki M. 295,686 Suzuki Y. 609 Svanholm U. 394,693 Svec H. J. 11 Svensson S. 438 Sviridov B. D. 29 Svoboda J. J. 137 383 392,393,693 Svoboda M. 145 Svoboda P. 250 252 266,340 Swahn C.-G. 451 Swain C. G. 376 Swank D. D. 269 Swann B. P. 399 Sweeny J. G. 370,374 Sweet E. M. 266,340 Sweet F. 627,628 Sweetman B. J. 17 Swenson J. R. 78 Swenton J. S. 229 230 Swern D. 185 Swoboda J. J. 586 Sykes R. J. 38,614 Symonds V. B. 117 Symons E. A. 395 Symons M. C. R. 281 3 82 Sysak P. K. 87 Szabb I.F. 453 Szafraniec L. J. 27 1 Szarek W. A. 437 439 441,451,460 Szcimies G. 96 Szczeparik P. A. 393 Szeimies G. 19 1,474 Szeto K. S. 638 Szeimes G. 226 Tabase K. 38 Tabrizi F. M. 19 Tabushi I. 42 1,524,665 Tacconi G. 89 Tachi K. 251 Tanzer C. 433 Taft R. W. 73 137 Tagano T. 253 Tagegami Y. 249 Taguchi H. 678 Taguchi T. 308,488 Tahara A. 557 Tahir A. R. 664 Taillefer R. 37,372,596 Tait B. S. 279 Tait G. H. 619 Takagi S. 59 Takahashi A. 338 Takahashi H. 234 332 662,664,672,681 Takahashi H. 183 188 253,481,533 Takahashi S. 20 74 250 340 Takahashi T. 535 Takai A. 104 Takai H. 457 Takaki U. 325 Takaku H. 633 Takamoto T. 468 Takao N. 536 Takao S. 602 Takase K.419,420,428 Takasugi H. 539 Takaya H. 88,254,587 Takayama C. 73 Takayama K. 488 Takayama M. 561 Takebayashi M. 185 186 Takeda A. 212,377 Takeda K. 596 Takegami Y. 258 Takei H. 67'1 Takemoto K. 256 337 Takemoto T. 558 Takenami M.,656 Takeshita H. 583 Takeuchi N. 306,538 Takeuchi S. 258 Takeuchi T. 202,329 Takeuchi Y. 182 283 508 Takiura K. 457 Takizawa T. 665 Takuwa A. 407 Talamini. G. 328 Talanov Yu. M. 258 Tallec A. 293 Tamaki A. 245,251 Tamao K. 249,250 Tamaru Y. 665 Tamburin H. J. 53 478 Tamm C. 345,638 Tamoto K. 538 Tamura H. 303 Tamura S. 554 568 Tamura Y. 191 488 51 1,674 Tan C. T. 42 Tan Y. Y. 325 Tanabe M. 38,212,249 362,601,609,611,661 Tanabe T. 258 Tanaka E.251 Tanaka H. 325 332 538,549,631 Tanaka J. 54 387 Tanaka M. 258,342 Tanaka N. 120 Tanaka S. 427,678 Tanaka Y. 494 Tancrede J. 264,659 Tang R. T. 395 Tang Y.-N. 96 Tangari N. 660 Tani K. 253 Tani S. 535 Tanida H. 123,417,596 Taniguchi H. 51 1 Taniguchi Y. 42 1 Tanny S. R. 43 87 522 Tarama K. 248 Taravel F. R. 440 Tarelli J. M. 457 Tarpley A. R. 36 Thayer A. L. 82 347 Tartakovskii V. A. 196 694 Tasaka K. 274 Thebtaranoth. Y. 29,92, Tashiro Y. 258 209,211,401,516 Tatara M.,628 Thenn W. 86,477 Tatemitsu H. 54 387 Thi N. T. L. 675 Tatsuoka T. 519 Thiele D. 642 Taube A. 559 Thiele K.-H. 244 245 Taurins A. 496 Thiery J. P. 651 Tawara Y. 412 Thio J. 236 Taylor D. J. 328 Thomas A.F. 550 Taylor E. C. 234 399 Thomas C. B. 161,401 Taylor G. N. 514 Thomas E. J. 351 Taylor J. B. 51 1 Thomas H. T. 550 Taylor J. W. 122 Thomas R. 60 Taylor N. F. 435 Thomas W. L. 649 Taylor P. 342 Thomas W. R. 503 Taylor P. J. 630 Thompson D. J. 265 Taylor R. 63 69 392 Thompson D. T. 253 Taylor R. J. K. 212 Thompson E. 0.P. 647 Taylor R. P. 71 Thompson J. A. 223 Taylor S. H. 258 Thompson J. C. 324 Taylor S. P. B. 396 Thompson P. J. 251 Taylor S. S. 107 Thompson R. C. 116 Tazawa I. 635 117 Tazawa S. 635 Thomson I. C. 29 Tchir M.F. 404 Thomson J. A. 606 Tebbe F. N. 246 Thomson J. K. 434 Tebby J. C. 278 Thomson K. S. 627 Tedder J. M.,167 Thomson R. H. 318 Tegg D. 630 408,563 Teh H.-S. 644 Thorneley R. N. F. 148 Tehan F.J. 527 Thorogood P. B. 79 Teich N. M. 639 Thorpe J. W. 376 Temme G. H. 589 Thrierr J. 642 Temyachev I. D. 24 Thyagarajan B. S. 516 Tennant G. 492,494 Tidwell T. J. 147 Teo K. E. 376 Tighe B. J. 344 Teo W. K. 248 Timberlake J. W. 516 Terabe S. 169 Timko J. M.,384 527 Teraji T. 483 Timmons R. B. 630 Teranishi A. Y. 88,675 Timpanaro P. L. 125 692 Tin K. C. 212 Teranishi S. 254 Ting K.-L.-H. 18 Terao T. 284 Tinker H. B. 262 Terashima S. 145 550 Tinoco I. 642 Terashima T. 609 Tinyakova E. I. 255 Terayama H. 436 256,259 Terenius L.,537 Tipson R.S. 436 Teresawa T. 580 TiSler M.,493 494 Terhune S. J. 554 Titlestad K. 50 Terni H. A. 287 Tjan P.W. H. L. 266 Teschner M.,675 Tobias R. S. 251 Teterina M.P. 255 Tobinaga S. 306 533 Teufel H.518 538 Tewson T. J. 69 Tonko P. G. 148 Texjer F. 85 348 Toda M.,547,607 Teyssie Ph. 205 258 Todd J. F. J. 14 266 Todozhokova A. S. 253 Tezuka T. 641 Tohma M.,564 Thame N. G. 338 Tokoroyama T. 560 Thanel G. L. 457 Tokumasu H. 196 Author Index Tokunaga M.,79 Tolbert G. D. 15 Tolbert L. M.,229 Tollefsen D. M.,427 Tolman C. A. 250 Tolman R. L. 455 Tolstikov G. A. 439 Tomalia D. A. 131 Tomao K. 259 Tomer K. B. 507 Tomilov A. P. 285 Tornita E. 157 Tomita S. 203,499 Tomita T. 564 677 Tomita Y. 605 607 Tomlinson B. L. 31 Tomson M.B. 368 Tonge A. P. 515 Tonnard F. 86 184 Toppet S. 311 428 Topsom R. D. 73 Tori K.,43,417 Torii S. 307 549 Torimoto N. 186 Torsell K. 63 Toscano V. G. 194 Townsend C.A. 623 Townsend D. E. 428 Toyoda Y . 263 Tracey A. S. 454 Trahanovsky W. S. 237 575 Tran Hun Dau. M.-E. 596 Traubel T. 464 Traverso O. 252 Treasurywala A. M.,58 544 Treffert D. 73 Trefonas L. M.,52 516 Treichel P. M. 257 Tremaine P. H. 70 Tremont S. J. 480 Trenwith M.,169 Trepanier. D. L. 522 Tresca J. P. 556 Trimitsis G. B. 147,388 592 Trimmer R. W. 319 495 TrinajstiC N. 424 Trindle C. 185,278,381 Trippett S. 269,270,276 Trocha-Grimshaw J. 294 Troilo G. G. 264 Tronchet J. M.J. 434 437,462 Trost B. M.,211 213 217 218 226 263 412 426 572 573 574,675,688,693 Author Index Trotter J. 56,406 Uchida K. 667 Trozzolo A. M. 331 Uchida Y. 251 252 Truesdale E.A. 410 Uchino N. 253 Truesdale L. K. 407,674 Ud Din Z. 195 Trummlitz G. 465 Uebel J. J. 43 Tsai A. 481 Ueda T. 520 Tsai C. S. 449 Uehara K.,342 Tsai M. R. 207 Uematsu T. 627 Tsai S. C. 20 Uesugi S. 633 636 Tsay Y.-H. 246 Ugi I. 268,284 Tschesche R. 563 Ugi I. K. 122 Tseng C. 586 Ugo R. 255,260 Tseng S. S. 319 Uh H. 586 674 Tsernoglou D. 110 Uh H.-S. 553 Ts’o,P. 0.P. 635 Uhlenbeck 0.C. 642 Tsolis E. A. 268 274 Uhm S. J. 694 Tsuboi S. 212 377 Ujiie A. 183 Tsuchiya T. 464 505 Ullman E. F. 319 507 Ullmann E. 346 Tsuge S. 329 Ullrey D. 11 1 Tsui S. K. 144 Umani-Ronchi A. 660 Tsuji J. 244 254 361 685,692 664 Umeda I. 254 Tsuji K. 323 333 Umemoto T. 410 526 Tsuji T. 409 Umen M. J. 246 693 Tsujimura S. 326 Umeno M.249 Tsukada H. 413 Umezaki A. 254 Tsuneda K. 249 Umezawa H. 466 Tsuruki S. 255 Umezawa K. 683 Tsuruoka T. 460 Umezawa S. 464 Tsutsumi S. 263 Umino H. 165 Tuchscherer C. 427 Underwood G. R. 65 Tucker L. C. N. 442 318,394 443,445,450,467 Undheim K. 498,510 Tuddenham R. M. 583 Uneyano K. 307 Tuhy P. M. 117 Unger L. R. 82 321 Tunggal B. D. 280 694 Turley P. C. 271 Uno K. 66 Turner A. B. 200 567 Unrau A. M. 607 Turner D. W. 10 Uomori A. 607 Turner J. V. 21 1,679 Uonezawa T. 596 Turner L. M. 694 Upton C. E. E. 245 Turner R. B. 43 351 25 1 Turner R. M. 247 Urban F. J. 484 Turner S. R. 347 Urbani R. 582 Turnquist C. R. 122 Usieli V. 88 181 Turrentini L. D. 125 Usov A. I. 455 Turro N. J. 82 83 317 Usselman M. C. 516 32 1 Usui H.428 Tursch B. M. 561 Usui T. 434 Tuttle M. 409 Utille J. P. 447 Tuxford A. M. 296 Utimoto K. 664 667 Tuzimura K. 434 677,679 Twine C. E. 9 Utley J. H. P. 68 169 Twitchett P. J. 401 293,302 Twu J. 115 Uyeo S. 692 Tyler J. K. 374 Tyman J. H. P. 259 Vahrenholt F. 82 Tyrlik S. 248 661 Vaish S. P. 26 Tyurin Y. M. 285 Valasinas A. 619 Vale W. 18 Ubasawa M. 639 Valente L. 19 Valenty S. J. 193 201 226 Valnot J.-Y. 486 Vatter K. 66 Valverde S. 558 van Bekkum H. 83 248 Van Bergen T. J. 208 486,670 van Boom J. H. 639 Vandenberg E. J. 335 Van den Berg G. R. 277 281 Van Den Elzen R. 21 1 van der Gen A. 68 586 Van Der Groen G. 448 Vanderhoek J. Y. 640 van der Lans H. N. M. 502 Van der Lingt W.T. A. M.,119 van der Plas H. C. 71 Vanderpool S. 229 Vanderwalde A. 65,394 van der Weerdt A. J. A. 41 1 Vander Zwan M. C. 363 van de Sande J. H. 284 van Drunen J. A. A. 80 Vangedal S. 603 Van Gennep H. E. 495 Van Howerbeke Y. 41 1 van Koten G. 244 Van Leusen A. M. 495 690 van Lienden P. W. 256 van Rautwijk F. 83 Van Schoor M. 311,428 van Tamelen E. E. 540 van Veldhuizen A. 7 1 van Wageningen A. 42 Van Wazer J. R. 269 van Wijk A. M. 83 Vaquero C. 650 Vardanyan L. M. 255 Varech D. 596 Varghese A. J. 629 640 Varsella A. 87,2 12,379 450 Vasiliev V. A. 255 256 257 Vass G. 461 462 Vass V. 305 Vassie S. 136 Vatz J. B. 71 Vaughan K. 478 Vaughan W. R. 215 VEelhk J. 67 Vecchio R.L. 395 VeEeia M. 70 Vedejs E. 278,482,663 736 Vederyapin A. A. 258 Vederas J. C. 679 Vega E. 79,473 Vehoeven J. W. 4 1 1 Veillard A. 119 268 Velen S. R. 494 Venkataraghavan R. 18 19 Venkataraman B. 165 Venkstern T. V. 646 Venot A. 594 VerEek B. 493 Vereshchagin L. I. 348 Verheyden J. P. H. 454 456 Verhoevon J. W. 518 Verine A. 406 Verkruijsse M. D. 212 Verkade J. G. 5 16 Verlangieri A. J. 444 Vermeer H. 501 Vernin G. 153 Vernot A. 221 Vethaviyasar N. 446 459 Vetter W. 548 Vevers R. J. S. 494 Victor R. 406 Vidari G. 551 Viehe H. G. 358,492 Vignon M. 447 Vijayalakshmi K. S. 432 Vikha G. V. 450 Vilesov G. I. 12 Vilkas M. 114 Villieras J. 245 282 361,662,693 Vincze A.633 Vining R. F. W. 658 Vink J. 436 Vinter J. G. 514 Virgilio J. A. 73 Vishnuvajjala B. 401 531,671 Visser L. 117 Viswanathan N. 563 Vitullo V. P. 131 238 391 Vlattas I. 674 Vleugels J. 381 Vliegenthart J. F. G. 435,436 Vogtle F. 94 232 409 526 Voelter W. 37,433,436 460,461 Voet J. G. 99 104 Vogel E. 37,38,90,233 239 386 388 391 392,422,474,476,589 Vogel P. 133 136 214 571 Vogt J. 11 Volckaert G. 649 Vold R. L. 30 Vold R. R. 30 Volger H. C.,97 Volkmann R. A. 565 585 Vollhardt K. P. C. 37 178 232 386 416 497,498 Vollman J. P. 333 Volpi E. 596 Vol’pin M. E. 252 von Bredow K. 89 von der Haar F. 643,646 von Philipsborn W. 407 Voorhees K. J.527 Vo Quang Y. 85 348 Voskuil W. 381 Vukov V. 79 Waali E. E. 200 204 230 Wachsman M. A. 84 Wada M. 283 Wada Y. 464 Wade L. E. 94 231 Wadsworth W. S. jun., 277 Waespe H.-R. 25 240 Wagner H.-U. 479 Wagner J. 527 Wagner K. 495 Wagner K. P. 257 Wagnon J. 246,693 Wahren M. 248 Wai H. 72 Waight E. S. 556 Wakatsuki Y. 350 501 Wakisaka K. 183 Wakselman M. 114 Walvisky S. W. 89 212 576 Walker A. J. 12 Walker D. C.,296 Walker J. A. 94 234 685 Walker R. T. 627 628 629,639 Wall R. 650 Wallace J. C.,287 Wallace R. W. 201 Wallace T. W. 181,403 583 Wallenfels K. 504 Waller J. P. 646 Walling C. 157 Walser A. 486 523 Author Index Walsh C. 105 Walsh C.T. 99,102,115 Walsh H.C. 42 Walter A. 418 Walter H. F. 374 Walter T. J. 50 409 Walton D. R. M. 68 Wan C.-C.,78 Wander J. D. 431 434 457 Wang A. H. J. 56 Wang C. M. 674 Wang I. S. Y. 76 Wang S. 522 Wang S. Y. 629 Warburg O. 98 Warburton D. 346 Ward D. J. 439 Ward H. R. 24 26 Ward J. S. 262 Ward R. S. 237 348 Ware P. 381 Waring A. J. 239 Warkentin J. 376 Warner P. 389 Warnhoff E. W. 376 387,488 Warning K. 282 Warren C. R. 303 Warren S. 91 214 280 374 Warrener R. N. 82,417 583 Washburne S. S. 5 10 Wassen J. 37 233 386 388 Wasserman E. 139 185 416 592 Wasserman H. H. 38 222 576,614 Wasson J. S. 193 Watanabe H. 420 Watanabe K. 326 Watanabe K. A. 465 Watanabe M. 660 Watanabe Y.249 258 Wataya Y. 628 Waters J. M. 48 Waters T. N. 48 Watkins S. F. 46 Watkinson I. A. 109 Watson C. R. 429 Watson J. T. 17 Watson K. J. 508 Watson P. L. 82 417 583 Watts C. R. 85 Watts P. 278 Watts P. H. 53,417,478 Watts P. H. jun. 47 Watts W. E. 206 Author Index Waugh J. S. 39 Waxman S. 626 Webb L. 110 Webber J. M. 437,450 Weber D. 608 Weber E. 526 Weber H. 284,647 Weber N. 548 Weber W. P. 522 Weber W. W. jun. 444 Webster D. E. 250 Webster 0.W. 373,492 Webster R. G. 67 Weckerle W. 432 Weeks C. M. 57 Wehrli. F. W. 35,36,610 Wehrli P. A. 686 Wei C. C. 58 544 Weidemiiller W. 417 Weidner U. 592 Weigel P. H. 653 Weigert F. J. 255 Weil T. A. 248 Weiler L. 8 595 Weinberg N.L. 309 Weiner H. 120 Weinreb S. M. 695 Weinshenker N. M. 347 Weinwurzel D. H. 128 Weinzierl J. 624 Weis C. D. 89 362 Weiss F. 326 Weiss G. 551 Weiss K. 247 Weiss R. 225 390 412 Weiss R. G. 194 Weiss S. 492 Weiss U. 521 Weiss W. 174 Weissenbach J. 644 Weissman B. 586 Weissmann C. 647 Weitmeyer C. 135 Welch G. 72 Wellner. D. 98 99 Wells D. 283 662 Wells P. B. 250 Wells R. D. 436 Weltin E. E. 78 Wempen I. M. 465 Wender I. 248 Wendschuh P. H. 381 Wenkert E. 34 35 38 218 232 233 386 544,556 Wentrup C. 195 396 Wepplo P. J. 681 682 Wepster B. M. 73 Werbelow L. G. 43 Werbin H. 640 Weringa W. D. 464 Werness P. G. 414 Wickberg B. 695 Werstiuk N. H. 37 596 Widdowson D.A. 607 658 Widmann E. 518 Werthemann D. P. 321 Widmer U. 94,235,239 Wertzler R. 17 Wieber M. 274 Wessel E. P. 89 Wiebers J. L. 637,639 Wessler E. P. 583 Wiedhaup K.,586 Wessels P. L. 32 Wiegers K. E. 145 West A. C. 446 Wiehager A. C. 56 West B. F. 436 Wieringa J. H. 219 West C. T. 159,169,657 Wiersum U. E. 195,386 West R. 167 310 389 Wife R. L. 89 583 Westerman P.,133,426 Wiffen J. T. 152 Westerman P. W. 137 Wilcox C. F. 591 368 Wilcox W. S. 334 Westheimer F. 273 Wiles D. M. 333 Westoal J. H. 14 Wiley P. F. 461 Weston A. F. 668 Wilke G. 243 246 259 Westwood J. H. 435 571 455,456 Wilkes C. E. 333 Wetmore S. I. 471 Wilkins B. 260 Wetmur J. G. 630 Wilkins S. W. 259 Wewerka D. 267 Wilkinson A. L. 65 Weyerstahl P. 196 Wilkinson G.244 248 Weyler W. 84 Willcott M. R. 43 551 Wheeler G. L. 47 50 Williams D. E. 46 52 417 Williams D. H. 18 19 Whipple E. B. 42 464,567 Whistler R. L. 459 Williams D. J. 60 Whitcome P. 652 Williams D. L.,640 White,.A. I. 41 Williams D. L. H. 399 White A. M. 124 Williams E. 40 White D. A. 690 Williams E. H. 460 White D. W. 274 375 Williams G. H. 153 White J. D. 558 559 Williams G. J. 464 White J. F. 245 Williams J. M. 466 467 White J. G. 84 Williams J. R. 82 321 White R. 254 694 White R. F. M. 45 Williams L. F. 163 White R. J. 610 Williams N. E. 437 Whitehead M. A. 434 Williams N. R. 437 451 Whitehouse N. R. 437 Williams R. C. 122 Whitesides G. M. 245 Williams R. E. 345 269 Williams R. J. P. 32 Whitesides T.H. 139 Williams T. R. 51 1 659 Williams W. J. 195 Whitesides T. M. 261 Williams W. M. 512 Whitham G. H. 351 Williamson A. R. 649 Whiting D. A. 51,57,94 Williamson R. 650 Whitkar D. R. 117 Williard K. F. 314 Whitlock L. R. 327 Willig B. 520 Whitten C. E. 123 246 Willson J. S. 401 693 Willy W. E. 565,584 Whittle P. J. 270 Wilson D. M. 40,563 Whitton B. R. 459 Wilson D. P. 630 Whyman R. 262 Wilson G. A. 457 Whyte J. N. C. 19 Wilson G. L. 20 Wiberg K. B. 133 237 Wilson G. S. 508 Wiberg K. W. 379 Wilson H. L. 369 Wicha J. 564 671 Wilson I. F. 278 Wichmann K. 341 Wilson 3. A. 399 738 Wilson K.R. 387 Wilson M. A. 141 564 Wilson R. M. 318,408 Wilson S. E. 236 Wilson S. R. 43,351 Wilton D. C. 98 109 Wing R.M. 43 56,554 558 Wingard R. E. 38 92 233,386,388 Winkler H. U. 13 Winkler J. 387 Winnick M. A. 222 Winslow F. H. 331 336 Winstein S. 119 120 129 Winston A. E. 516 Winter S. R.,262 682 Winters R. E. 11 Wipf H. K. 19 Win J. 352 Wiseman J. R.,52 144 516,571 Witherup T. H. 198 Witherup T. W.,22-3 Witkop B. 237 Witkowski J. T. 636 Wittek P. J. 424 Witten T. A. 20 Wittig G. 486 Wogan G. N. 58 Wohl R. A. 682 Wojcicki A. 243 257 262 Wold F. 115 Wold S. 74 Wolf A. D. 198 201 223,224,409,571 Wolf C. J. 15 Wolf G. 186 Wolf G. C. 564 Wold H. 626 Wolf R. 269 271 390 Wolf R. A. 147 Wolf U. 519 Wolfe N. L. 128 Wolff G. 561 Wolff M. E. 57,596 Wolff S. 213 318,378 Wolfhugel J.79 Wolfsberg M. 122 126 Wolschowicz I. 661 Wolters J. 68 Wong C. M. 406 669 671,683,684,690 Wong C. S. 248 Wong J. L. 372 Wong J. Y. 345 Wong K. L. 625 641 Wong P. 583 Wong P. S. 52 89 Author Index Wong S.M. 560 Yamaizumi K. 643 Wong W. 46 Yamakawa K. 249 Wong Y. P. 625,641 Yamamoto A. 245,256 Woo E. P. 421 257 Wood D. C. 265 Yamamoto H. 96 123 Wood D. E. 163 234 662 672 678 Wood G. 514 681,693 Wood G. W. 323 Yamamoto K.,250 253 Wood J. L. 414 259,265,423 Woods S. M. 488 Yamamoto M. 329 Woodward P. 418 Yamamoto S. 596 Woodward R. B. 529 Yamamoto T. 245,256 530 Yamamoto Y. 204,207 Woollard J. M. 498 257,329,418 576 Woollard J. McK. 190 Yamamura S. 547 552 Workulich P. M. 552 607 Worthington D.J. 317 Yamane H. 535 Worthy T. E. 640 Yamane T. 626,641 Wouters-Leysen J. 448 Yamaoka N. 434 Woukulich P. M. 582 Yamaoka T. 185 Wray V. 435,452 Yamasaki K. 3 11 Wreland T. 283 Yamataka H. 128 Wright C. D. 142 Yamauchi K. 627 Wright H. 59 558 Yamauchi S. 314 Wright H. E. 58 Yamazaki H. 350,501 Wright P. W. 567 Yamazaki K. 398 Wu R. 652,653 Yamazaki N. 253,263 Wu T. 586 Yamdagni. R. 368,380 Wubbels G. G. 314,427 Yamunoto K. 164 Wiiest H. 659 Yan S. 615 Wulff G. 384 563 Yanashita M. 249 Wulfman D. S. 196 Yang C. S. C. 42 Wunderli A. 94 241 Yang N. C. 240 398 Wuonola M. A. 529,530 428 Wyatt M. 43 Yang P. P. 44 Wyatt P. A. H. 72 Yang S. 645 Wynberg H. 219 369 Yang S. K. 641 386,571 Yang S. S. 240 Yano K. 127 Xavier A.V. 32 Yano M. 329 Yaroslavsky C. 347 Yabusaki K. 535 Yasuda S. 466 Yager W. A. 185 Yasunami M. 38,419 Yagi H. 239 391 424 Yates D. H. 229 4 74 Yates G. B. 68 302 Yagi K. 98 104 Yates K. 72 Yagihara M. 474 Yates P. 417 Yakhontov L. N. 488 Yathindra N. 432 Yalpani M. 610 Yato. T.. 416 Yamabe S. 76 Yeboah,’S. O. 293 Yamada H. 550,646 Yeh C. L.. 233. 252 Yamada K. 552 553 Yeh; E. L.; 233-687 Yekta A. 82 Yamada M. 208 Yin M. B. 163 Yamada S. 283 550 Ying Ming Cheng 204 567,684,689 Yokoi T. 561 Yamada S. I. 226 Yokoyama K. 85 265 Yamada T. 284 578 Yamada Y. 643 Yon J. 114 Yamagata T. 253 Yoneda S. 412 416 Yamaguchi T. 339 417,508 Author Index 739 Yonezawa K. 203 Yonezawa T. 3 1 1 398 Yoon N. M. 666 York E.J. 200,224 Yoshida H. 516 Yoshida K. 68 Yoshida K. J. 436 Yoshida M. 157 636 644 Yoshida T. 254 350 663,684 Yoshida Z. 252 412 416,417,508,665 Yoshifuji M. 187 279 Yoshikawa K. 596 Yoshikawa M.,454 Yoshikawa S. 253 255 Yoshikawa Y. 534 Yoshima Y. 43 Yoshimoto H. 401 Yoshimoto M. 693 Yoshimura J. 288 Yoshimura N. 258 266 Yoshimura Y. 191 Yoshino A. 311 398 Yoshino J. 418 Yoshino T. 631 Yoshioka M. 580 Young D. 246 Young D. W. 361 Young M. W. 661 Young R. C. 455 Young R. N. 689 Youssef A. K. 237 Youssif N. 216 Yovell J. 88 Yu S. M. 236 261 Yuan S. S. 58 Yudis M. D. 461,464 Yuen J. M.C. 257 Yukawa Y. 128 Yunker M. 460 Yurjev V. P. 439 Zabel D. E. 237 Zabrocki K.384 Zador E. 369 Zagalak B. 42 379 Zaitseva G. V. 454 Zakharychev A. 564 Zalkow L. H. 551 Zaman T. 619 Zamir L. 610 Zander R. 477 Zanella R. 252 Zanlungo A. 459 Zaporozhets E. V.,293 Zappelli P. 686 Zarecki A. 671 Zaro J. 207 Zavada J. 145 Zawoiski S. 628 Zdero C. 348,659 Zdunneck P. 244 Zeck 0.F. 96 Zehavi U. 345 447 465 Zeiler A. G.,.242 385 hiss H. H. 119 Zeller K. P. 226 Zelli S 16 Zelnik R. 56 Zembayashi M. 259 Zenbayashi M. 499 Zeplichal G. 267 Zeppezauer E. 109 Zhidomirov G. M.,179 Zhorov Y. M. 260 Ziegenmeyer J. 637 Ziegler G. R. 147 Ziegler J. L. 626 Ziehn K. D. 282 Ziemann H. 501 Zieserl J. F.,17 Ziffer H. 228 Zimmerman H. E. 92 227,229,315,316,321 Zinke H.462 Zinnes H. 511 Zipper P.,641 Zollinger H. 67,72,392 393 Zollinger J. L. 142 Zoltewicz J. A. 502 Zon G. 236,261 Zsindely J. 94,235,237 241,354,399 Zubareva N. D. 258 Zuman P. 72 Zumwald J. B. 437 Zundel J. L. 561 Zupan M. 141 Zurabyan S E. 450 zur Haussen H. 626 Zurr D. 450 Zvagulis M. 145 Zvdfina V. 67 Zvezdina V. V. 638 Zweifel G. 666

ISSN:0069-3030    

DOI:10.1039/OC9737000696

出版商:RSC    

年代:1973

数据来源: RSC