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.