摘要:

13 Heterocyclic Chemistry ~~~ ~ By I. D. BLACKBURNE M. J. COOK and C. D. JOHNSON School of Chemical Sciences University of East Anglia Norwich NOR 88C The papers discussed (about one in ten of all those surveyed) have been classified according to ring size. We have made no deliberate attempt to slant the article in any particular direction but hope. that the space devoted to individual topics gives a realistic measure of the attention they have received in the chemical literature of 1972. 1 Small-ring Compounds The pursuit of potentially aromatic and antiaromatic three- or four-membered ring structures has led to the preparation of the novel phosphacycle (1)' and the 1,2-diazetine (2).2 The former is fairly stable but yields diphenylacetylene on pyrolysis at 120°C whereas the latter which in spite of a formal 671-electron system does not appear to sustain a diamagnetic ring current slowly decomposes to the di-imine (3) even at room temperature.Radical-cations of the 1,2-dithiet ring system the sulphur analogue of (2) arise when a-hydroxy-ketones or diketones are treated with acidic sodium ~ulphide,~ and renewed interest in the neutral ring (4)shows that it is cleaved by phosphorus compounds to give sulphur-containing phosphoranes e.g. (4)+ (5)-+ (6).4 Ph ,CO,Me P 1%Ph 0 (1 1 \C0,Me (2) %"02Me Me02C.N (3) Me Me cF3bs .Ph ' E. W. Koos J. P. Vander Kooi E. E. Green and J. K. Stille J.C.S. Chem. Comm. 1972 1085. E. E. Nunn and R. N. Warrener J.C.S. Chem. Comm. 1972,818. G. A. Russell R.Tanikaga and E. R. Talaty J. Amer. Chem. SOC.,1972 94 6125. N. J. De'Ath and D. B. Denney J.C.S. Chem. Comm. 1972 395. 425 I. D. Blackburne M. J. Cook and C. D. Johnson SCFMO calculations suggest that the thiirenium ion (7a) is substantially more stable than the open-chain carbonium ion (7b).' An attempt to stabilize the corresponding uncharged and an tiaromatic thiiren and seleniren ring systems by forming their tricarbonyliron complexes led only to the isolation of the corresponding carbene complexes although there was some evidence for the transient existence of the desired ring compound^.^ In the oxygen series further evidence in favour of the oxocarbene *oxiren equilibrium has been presented,' and in the nitrogen series attention has been drawn to the particularly stable anion (8) which declines to follow the elimination route to the antiaromatic 2-azirine.* H Ph In the realm of saturated three-membered-ring compounds the various preparations of the interesting syn-dioxide (9)9 and the syn-".' and anti-10*12 trioxides (10) and (11) seem timely in the light of the reportI3 of the naturally occurring benzene dioxide within the antibiotic (12).The valence isomerizations of (9),(lo),and the related systems (13a) and (13b)" have been examined (see also (9) 0 C0,Me 0 (13) a; X= 0 b; X = NTs A. S. Denes 1. G. Csizmadia and G. Modena J.C.S.Chem. Comm. 1972 8. P. G. Mente and C. W. Rees J.C.S. Chem. Comm. 1972 418; T. L. Gilchrist p. G. Mente and C. W. Rees J.C.S. Perkin I 1972 2165.S. A. Math and P. G. Sammes J.C.S. Chem. Comm. 1972 11. * G. M. Rubottom G. R. Stevenson J. C. Chabala and V. L. Pascucci Tetrahedron Letters 1972 3591. H.-J. Altenbach and E. Vogel Angew. Chem. Internat. Edn. 1972,1I 937. lo E. Vogel H.-J. Altenbach and C.-D. Sommerfeld Angew. Chem. Internat. Edn. 1972 11,939. " R. Schwesinger and H. Prinzbach Angew. Chem. Internat. Edn. 1972 11 942. l2 C. H. Foster and G. A. Berchtold J. Amer. Chern. SOC. 1972,94 7939. l3 D. B. Borders P. Shu and J. E. Lancaster J. Amer. Chem. Soc. 1972,94 2540. l4 D. Stusche M. Breuninger and H. Prinzbach Helc. Chim. Acta 1972,55 2359. Heterocyclic Chemistry Section 3). The mechanism of the interconversion of the more familiar arene monoxides into phenolic compounds has been studied in some depth and appears to involve both an acid-catalysed and a spontaneous aromatization route.' A range of oxaspiropentanes has been prepared by treating ketones with diphenylsulphonium cyclopropylide,' and two new routes to thiirans are reported.17 The products of the reaction of formaldehyde with primary amines in the presence of an aminating agent which were originally assigned the 2-alkyl- 2,4-diazabicyclo[ l,l,O]butane structure (see last year's Report") have now been identified as N-alkylgly~inonitriles.'~1-Azabicyclo[ l,l,O]butanes (14) obtained from the corresponding 1-azirines (1 5) and dimethylsulphonium methide are ring-opened by acid to azetidinols (16):20 the mechanism for the cleavage has Ph Ph OH ,R1 Ph 2-32 N R2 R2 'H been discussed in the light of kinetic isotope effect data.21 Details of a simple synthesis of the diaziridine (17) have appeared in which benzaldehyde and methylhydrazine are condensed in the presence of diborane.22 No diaziridines were obtained however from the reaction of dichlorocarbene with (1 8) instead the open-chain compounds (19) were formed and (19a) was shown to react further with dichlorocarbene to form the aziridine (20).23 PhCH2-N-N-Me Y Ph RO C-N =N*CO 2R (RO,C),h-N=CCI2 (EtO,C),N-N T2 \ (18) R = Me or Et (19) a; R = Et CCl b;R = Me (20) 15 G.J. Kasperek and T. C. Bruice J. Amer. Chem. SOC.,1972 94 198; G. J. Kasperek T. C. Bruice H. Yagi and D. M. Jerina J.C.S. Chem. Comm. 1972 784. 16 M.J. Bogdanowicz and B. M. Trost Tetrahedron Letters 1972 887. 17 T. H. Chan and J. R. Finkenbine J. Amer. Chem. SOC.,1972,94,2880;J. C. Hinshaw Tetrahedron Letters 1972 3567. 18 Ann. Reports (B) 1971 68 551. 19 A. H. Lawrence D. R. Arnold J. B. Stothers and P. Lapouyade Tetrahedron Letters 1972,2025. 20 A. G. Hortmann and D. A. Robertson J. Amer. Chem. SOC.,1972,94 2758. 21 B. K. Gillard and J. L. Kurz J. Amer. Chem. SOC.,1972 94 7199. 22 J. A. Blair and R. J. Gardner J.C.S. Perkin I 1972 485. 23 D. Seyferth and H.-m. Shih J. Amer. Chem. SOC.,1972,94 2508. I. D. Blackburne M. J. Cook and C. D. Johnson Appropriately substituted azomethine ylides arising from the cleavage of aziridines react with nitro so phenol^^^ to give 3,5-dihydro-2H-pyrrolo[3,4-d]- oxazoles e.g.(21) 4(22) in a remarkable one-step reaction and with keten~,~~ preferentially across the C=O bond to give oxazolidines e.g. (23)-+ (24). In the 1-azirine series an impressive number of papers have dealt with the Ph IY I Ph (24) photocleavage of the ring to the corresponding nitrile ylides. The ylides have been trapped by a wide range of dipolarophiles including keten,26a carbon dioxide,26b~cstyrene,26d di thioes ters 6d isocyanates,26c isothiocyanates,26c and ethyl cyanoformate26e and the enormous synthetic possibilities have been under- lined further by a comprehensive survey of the reactions of ylides prepared by ground-state routes2' (cf the synthetic uses of nitrile oxides reported in Section 2).In the absence of an added dipolarophile the photocher,ically produced ylides react2' with a further molecule of the parent 1-azirine as is exemplified by the conversion (25)-+(26).28aThe product (261 which had previously been assigned the structure (27) is an example of a class of compounds whose photodecom- position via azomethine ylides and enedi-imines is in itself a subject of current interest.28,2 I4 J. W. Lown and M. H. Akhtar J.C.S. Perkin I 1972 1459. 25 F. Texier R. Carrie and J. Jaz J.C.S. Chem. Comm. 1972 199. 26 (a) H. Heimgartner P. Gilgen U. Schmid H.-J. Hansen H. Schmid K. Pfoertner and K. Bernauer Chimia (Swirl.) 1972 26 424; (b) H. Giezendanner M. Marky B. Jackson H.-J. Jansen and H. Schmid Hefv. Chim. Acta 1972 55 745; (c) B. Jackson N.Gakis M. Marky H.-J. Jansen W. von Philipsborn and H. Schmid ibid. p. 916; (d)A.Padwa D. Dean and J. Smolanoff Tetrahedron Letters 1972,4087; (e) B. Jackson M. Marky H.-J. Jansen and H. Schmid Helv. Chim. Acta 1972 55 919. 27 R. Huisgen H. Stangl H. J. Sturm R. Raab and K. Bunge Chem. Ber. 1972 105 1258; K. Bunge R. Huisgen R. Raab and H. Stangl ibid. p. 1279; K. Bunge R. Huisgen R. Raab and H. J. Sturm ibid. p. 1307; R. Huisgen R. Sustmann and K. Bunge ibid. p. 1324. (a) N. Gakis M. Marky H.-J. Jansen and H. Schmid Helc. Chim. Acta 1972 55 748 ;A. Padwa S. Clough M. Dharan J. Smolanoff and S. I. Wetmore J.Amer. Chem. Soc. 1972 94 1395; (b) A. Padwa J. Smolanoff and S. 1. Wetmore J.C.S. Chem. Comm. 1972 409; A. Padwa and S. I. Wetmore ibid.p. 11 16. 29 A. Padwa and L. Gehrlein J. Amer. Chem. Soc. 1972 94 4933; A. Padwa and E. Glazer ibid. p. 7788; T. DoMinh and A. M. Trozzolo ibid. p. 4046. 429 Heterocyclic Chemistry Details of non-photochemical reactions of 1-azirines are also reported and include the reaction with diphenylcyclopropenone30 to give pyridones e.g. (28a)-(29) and with di~henylketen~' to give products such as (30) from (25) and (31) from (28b). The mechanism of their reactions with cyclopentadienones which lead to azepines is also discussed,32 and in another field evidence is presented which is purported to favour the existence of the l-azirine6 vinyl- nitrene equilibri~m.~ (28) a; R = Et H b;R = Me (29) The addition of copper(1) phenylacetylide to nitrones provides what seems a useful synthesis of cis-p-lactams e.g.(32).34 A new route to the trans-isomer of (32)is also described in which either cis-or trans-stilbene is irradiated in the pre- sence of phenyl isocyanate; the reaction contrasts with the reported failure of ground-state stilbene to add to the more reactive N-chlorosulphonyl i~ocyanate.~~ Interest36 in the mechanism and mode of reaction of the latter reagent with various alkenes has led to the identification at low temperatures of a number of thermally labile p-la~tams.~~' Details of the addition of various N-sulphonyl- amines to alkenes have also been described;37 thus styrene reacts with the complex (33) to give (34),together with some (35).37u 'O A. Hassner and A. Kascheres J. Org.Chem. 1972,37,2328. '' A. Hassner A. S. Miller and M. J. Haddadin Tetrahedron Letters 1972 1353. 32 V. Nair J. Org. Chem. 1972,37 802; A. Hassner and D. J. Anderson J. Amer. Chem. SOC.,1972 94 8255. 33 T. Nishiwaki J.C.S. Chem. Comm. 1972 565. '' M. Kinugasa and S. Hashi,moto J.C.S. Chem. Comm. 1972 466. 35 T. Kubota and H. Sakurai J.C.S. Chem. Comm. 1972 362. 36 (a)T. J. Barton and R. J. Rogido Tetrahedron Letters 1972,3901 ;J. R. Malpass ibid. p. 4951 ;T. J. Barton and R. J. Rogido J.C.S. Chem. Comm. 1972 878; J. R. Malpass and N. J. Tweddle ibid. pp. 1244 1247; (b) E. Dunkelblum Tetrahedron Letters 1972 1551. 37 1972,94,4386; (b)G. M. (a)E. M. Burgess and W. M. Williams J. Amer. Chem. SOC. Atkins and E. M. Burgess ibid. p. 6135. 1.D. Blackburne M. J. Cook,and C.D. Johnson P-Lactones react with acidic hydrogen peroxide to provide a convenient route to P-peroxy-la~tones,~~ one of a number of oxygen-rich systems which have attracted attention this year. Perhaps more significant than the above are the syntheses and spectral analyses of the smaller and less stable a-peroxy-lactones (36),39systems which are implicated in bioluminescence. It has been calculated using a theoretical treatment of thermochemical parameters that (36a) should have a half-life of 2500 s which is in fair agreement with that found experiment-ally.40 The same theoretical treatment predicts a half-life of only 0.34 s for the peroxy-dione (37) the substantiation of which should prove a formidable challenge !The photolysis of the five-membered-ringanalogues (38) which was reported last year41 to yield a-lactones has now been reinvestigated at 77 K and has allowed a spectral study to be made of the series (39).42 The lactones show the carbonyl stretching frequency in the range 1895-1935 cm-' which demon-strates that the compounds exist as such rather than as the zwitterions (40).The mechanism for ozonolysis also continues to attract attention :43 a dioxetan intermediate has now been isolated43"and further results have been presented43b which are consistent with the peroxy-epoxide intermediate proposed last year.44 Ow0 0-0 0-0 (36) a R =But (37) b; R =adamantyl 060 0-0 R R' R R =Me or Bunor R +R =(CH,), (n =2,3 or 4) 38 W. Adam and C. 1.Rojas Synthesis 1972 616. 39 W. Adam and J.-C. Liu J. Amer. Chem. Soc. 1972 94 2894; W. Adam and H.-C. Steinmetzer Angew. Chem. Internat. Edn. 1972 11 540. 40 W. H. Richardson and H. E. O'Neal J. Amer. Chem. SOC.,1972,94,8665. JI Ann. Reports (B) 1971,68 554. 42 0. L. Chapman P. w. Wojtkowski W. Adam 0. Rodriquez and R. Rucktiischel J. Amer. Chem. SOC.,1972 94 1365. 43 (a)P. R. Story E. A. Whited and J. A. Alford J. Amer. Chem. Soc. 1972 94 2143; (6) P. G. Gassman and X. Creary Tetrahedron Letters 1972 4411; (c) L. A. Hull I. C. Hisatsune and J. Heicklen J. Amer. Chem. Soc. 1972 94 4856; C. W. Gillies and R. L. Kuczkowski ibid. p. 7609. 44 Ann. Reports (B) 1971 68 553. Heterocyclic Chemistry 431 2 Five- and Six-membered-ring Compounds (4n + 2)-and 4n-n-Electron Structures.-The announcement4' in 1971 of the synthesis of isobenzofuran has stimulated activity in the field of fused hetero- cycles this year.Multiple reports on a further member of the series isoindole (41; X = NH) have now appeared which describe its preparation via pyrolysis of (42)46 and by retro-Diels-Alder reaction of either (43; X = NH)47 or the unstable adduct (44),"* the latter route parallelling the original isobenzofuran synthesis. [Decomposition of (43; X = 0)affords an alternative route to iso-ben~ofuran.~'] Spectral studies of isoindole indicate a predominance of the NH-tautomer and in line with its oxygen and sulphur analogues (41 ;X = 0or S) a degree of aromaticity. Structures of the type (41) readily react with dienophiles and this year further examples are reported viz.reaction of isobenzofurans with l-azirinesS0 and oxidation with singlet oxygen the rate being related to the ionization p~tential.~' However unusual behaviour in this context is shown by the reaction of the isoindole derivatives (45) with acetylenic esters where re- arranged 1 2 adducts result.52 PY dipyridyltelrazine+ PY (44) 45 Ann. Reports (B) 1971 68 575. 46 R. Bonnett and R. F. C. Brown J.C.S. Chem. Comm. 1972 393. 47 J. Bornstein D. E. Remy and J. E. Shields J.C.S. Chem. Comm. 1972 1 149. 48 G. M. Priestley and R. N. Warrener Tetrahedron Letters 1972 4295. 49 U. E. Wiersum and W. J. Mijs J.C.S. Chem. Comm. 1972 347. 50 V. Nair J. Org. Chem.1972 37 2508. 51 R. H. Young and D. T. Feriozi J.C.S. Chem. Comm. 1972 841. 52 L. J. Kricka and J. M. Vernon J.C.S. Perkin I 1972 904. I. D. Blackburne M. J. Cook and C. D. Johnson NR -+ 1 (45) R = Et or Bun Electronic stabilization of (41) is expected to follow from the introduction of aza-groups at points of high electron density. Derivatives of this type (46)and (47) have been reported for X = NMe53 and X = S;54they are aromatic by ring-current criteria and protonate on N-4 and N-5.53 Other l0n-electron systems of interest are the non-classical compounds (48)55and (49),56 in which the only uncharged resonance contributors possess quadri-covalent sulphur. The stability order for the series (48) is X = S > NMe > 0. Ph Ph Ph (47) Ph Ph Ph (48) (491 The relative aromatic character of fused heterocyclic-cyclobutadienes is a matter of some uncertainty.Though formally an 8.nn-system (50 ;X = 0,R = H) has been prepared and found to possess reasonable stability (‘schizoanti- aromatic’).’’ Ring-current criteria were not sufficiently definitive of its non- or anti-aromaticity. Sulphur analogues (50; X = S R = Ph)58 and previously R2 (50) RZ (52) described (51)59are however regarded as sustaining paramagnetic currents by comparison with dihydro-derivatives (52; R‘ = R2 = H60 or halogen61). Two other stable 8.n-systems have been prepared which display unusual reactivity ; 4-benzyl-1-alkyl-1,4-dihydr0-2,6-diphenylpyrazine(e.g. 53) is rapidly oxidized in 53 W. L.F. Armarego B. A. Milloy and S. C. Sharma J.C.S. Perkin I 1972 2485. 54 L. H. Klemm W. 0.Johnson and D. V. White J. Hererocyclic Chem. 1972 9 843. 55 M. P. Cava and M. A. Sprecker J. Amer. Chem. Soc. 1972 94 6214. 56 K. T. Potts and D. McKeough J. Amer. Chem. Soc. 1972 94 6215. 57 K. P. C. Vollhardt and R. G. Bergman J. Amer. Chem. SOC., 1972 94 8950. 58 P. J. Garratt and K. P. C. Vollhardt J. Amer. Chem. SOC.,1972. 94. 1023. 59 P. J. Garratt and K. P. C. Vollhardt J. Amer. Chem. SOC.,1972 94 7087. 6o P. J. Garratt and D. N. Nicolaides J.C.S. Chem. Comm. 1972 1014. 61 S. W. Longworth and J. F. W. McOmie J.C.S. Chem. Comm. 1972 623. Heterocyclic Chemistry solution by air to yield the 7.n-electron free-radical cation (54):2 and the analogous system (55)methylates on the sp3-rather than the usually more nucleophilic sp2-nitrogen,63 presumably to yield the homoaromatic ion (56).A diamagnetic ring current in the diazanaphthaquinone (57) is apparent from its n.m.r. spectrum and the absence of the tautomer (58),as demonstrated by the temperature-invariance of the spectrum also points to aromatic stability of the bicyclic form.64 CH,Ph CH,Ph Me I I I (56) A number of other fused-ring systems whose aromatic character is of interest have been studied this year. Approaches to the novel non-benzenoid hetero- aromatic 1,2-diaza-azulene have employed pyrazole-3(5),4-dialdehyde which gave 1,2-diaza-azulenones (59),a novel ring system which sustains a ring current and in which the keto-tautomer predominate^.^^ The parent deoxy-system (60) R I R (60) (61) H (59) R = H or Me was obtained from the partially saturated analogue by mild dehydrogenation a route successfully applied also to the novel 1,Zdiazapentalene (61).66 (62) is a previously described aromatic compound whose diaza-derivative (63) is now rep~rted.~’ The additional nitrogen atoms occupy sites of electron enrichment 62 J.W. Lown and M. H. Akhtar J.C.S. Chem. Comm. 1972 829. 63 H. Kohn and R. A. Olofson J. Org. Chem. 1972 37 3504. 64 T. Sasaki K. Kanematsu and S. Ochiai Tetrahedron Letters 1972 1885. 65 C. V. Greco and M. Pesce J. Org. Chem. 1972,37 676; C. V. Greco F. C. Pellegrini and M. A. Pesce J.C.S. Perkin I 1972 1623. 66 W. Treibs Chimia (Swirz.) 1972 26 627.6’ W. W. Paudler R. A. van Dahm and Y. N. Park J. Heterocyclic Chem. 1972 9 81. I. D.Blackburne M. J. Cook and C. D.Johnson and this compound is likewise aromatic. n-Homologues of the system (64) have also been prepared.68 The heterocirculene (65)is a member of a new class of polycyclic compounds of which only two other carbocyclic members are so far known.69 The authors69 suggest that the series should be of interest in terms of conformation optical activity and electronic charge distribution (as a function of the n-character of the central ring). (64) R = H Pr” or Ph (65) The use of HMO calc~lations,~~ n.m.r. signal shifts in the ring-current probe molecule 4-methyl-2,6,7-trioxabicyclo[2,2,2]octane,71 and pseudobase tauto-meric and protonation equilibria determinations7 have been discussed as general methods for assessment of heteroaromaticity and the application of tautomeric equilibria data to the 2-pyridone and related systems has been de~cribed.’~ The smooth conversion of (66) into (67)’4and the deprotona- tion of (68) to (69)75both point to aromatic stability of the 1-aza-4-phospha- benzene nucleus in part confirmed by ‘H and 31Pn.m.r.measurements on (67) + I H (66) 68 J. T. Shaw W. M. Westler and B. D. Stefanko J.C.S. Chern. Cornrn. 1972 1070. 69 J. H. Dopper and H. Wynberg Tetrahedron Letters 1972 763. ’O B. A. Hess L. J. Schaad and C. W. Holyoke Tetrahedron 1972 28 3657. ” T. J. Barton R. W. Roth and J. G. Verkade J.C.S. Chem. Comm. 1972 1101. l2 M.J. Cook A. R. Katritzky P. Linda and R. D. Tack Tetrahedron Letters 1972 5019. 73 M. J. Cook A. R. Katritzky P. Linda and R. D. Tack J.C.S. Perkin II 1972 1295. 74 G. Mark1 and D. Matthes Angew. Chern. Internaf. Edn. 1972 11 1019. 75 M. H. Mebazaa and M. Simalty Tetrahedron Letters 1972. 4363. 435 Heterocyclic Chemistry and (69). The geometry of the arsabenzene ring revealed by an X-ray structure analysis of 2,3$-triphenylarsabenzene is consistent with a delocalized 6n-electron system.’6 Photoelectron spectroscopy on phospha- and arsa-benzenes7 con-firms calculations which predict an unusual sequence of their n HOMOS the MO with the non-zero coefficient at the heteroatom being higher in energy than the MO with a node at the heteroatom in contrast to pyridine.A report of the trapping of bismabenzene as the bismabarralene (70) confirms the last member of the Group VB pyridine analogues.78 The facility of the heterocycle for cyclo- addition compared with previous members of the series (e.g. ar~abenzenes’~) suggests decreased resonance energy. A comprehensive study of tellurophen (71) reveals spectral similarities with furan (u.v.) and with thiophen and selenophen (i.r.).*’ It undergoes classical substitution reactions (at the 2-position) but tellurium has a strong n.m.r. deshielding effect distinguishing this compound from its analogues. Evidence for aromaticity in five-membered P-and As-containing rings has been presented. The lower barrier (AG:, = 35.2 kcal mol-’) to pyramidal inversion in the arsindole (72) than in a comparable acycylic arsine (AG2fl8 = 43.1 kcal mol- I) points to aromaticity which is maximal in the planar transition state,81 a con- clusion which compares with that reached previously for phospholes.82 The 3C n.m.r.spectrum of 1-phenylphosphole and particularly carbon-phosphorus coupling constants is regarded as being consistent with the relatively low barrier to phosphorus pyramidal inversion.83 The extreme rapidity of the retrocyano- ethylation of (73) to yield (74) may lend support in favour of a degree of aromatic 76 F. Sanz and J. J. Daly Angew. Chem. Internat. Edn. 1972 11 630. ’’ A. Schweig W. Schafer and K. Dimroth Angew. Chem. Internat. Edn. 1972 11 631; W. Schafer A. Schweig F. Bickelhaupt and H.Vermeer ibid. p. 924. 78 A. J. Ashe and M. D. Gordon J. Amer. Chem. SOC.,1972,94,7596. l9 G. Markl J. Advena and H. Hauptmann Tetrahedron Letters 1972 3961. 8o F. Fringuelli and A. Taticchi J.C.S. Perkin I 1972 199. R. H. Bowman and K. Mislow J. Amer. Chem. SOC.,1972,94,2861. 82 AHn. Reports (B),1971 68 574. 83 T. Bundgaard and H. J. Jakobsen Tetrahedron Letters 1972 3353. I. D. Blackburne M. J. Cook,and C. D. Johnson I (71) CD,CH(OMe)Ph (72) /\ I Ph CH,CH,CN Ph (73) (74) character in the non-planar ground state of phosphole although it may also reflect antiaromatic destabilization of (73).84 6a-Thiathiophthens and related compounds continue to arouse great interest and the numerous papers include an authoritative review of structural effects in these ~ysterns.’~ The effect of phenyl and methyl groups on S-S bonding are rationalizable by CND0/2 calculations.86 The synthesis of (75) and the correspondence of its U.V.spectrum with that of isoelectronic dibenzo[aj]- coronene is reported,” and X-ray analysis of nitrogen-containing compounds (76) reveals S-S distances of 2.8 A too long for bonding but indicative of strong mutual interaction.88 X-Ray diffraction studies of the aza-analogues (77)and (78) of 6a-thiathiophthens allow bond length comparisons to be made and further s-s-s s-s s (R:N R2 I s-s-s (76) (75) MeN-S-NMe S-S-N /Ph MeS-.. .S-NPh Ph Ph 1- Ph Ph (77) (79) 84 W. B. Farnham and K. Mislow J.C.S. Chem. Comm. 1972,469. 85 A.Hordvik and L. J. Saethre Israel f. Chem. 1972 10 239. 86 L. K. Hansen A. Hordvik and L. J. Saethre J.C.S. Chem. Comm. 1972 222. ” E. P. Goodings D. A. Mitchard and G. Owen J.C.S. Perkin I 1972 131 I. 88 J. E. Oliver J. L. Flippen and J. Karle. J.C.S. Chem. Comm. 1972 11 53. a9 F. Leung and S. C. Nyburg Canad. f. Chem. 1972,50 324. Heterocyclic Chemistry 437 studies on the methiodide of (77) shows that the resonance canonical (79) pre-dominates in the ~ation.~~~~' 1.r.spectroscopy and X-ray analysis of 2-(5-phenyl-1,2-dithiole-3-ylio) phenolate (80)permit comparison of the 0-S distance with that in structure (81) and indicate stronger S-0 attractive interaction in the former.' This is confirmed by CND0/2 calculation^.^^ A conclusion with implications for the nature of the bonding in these systems is that true valence tautomerism occurs on irradiation of the oxa- and aza-analogues (82; X = 0 or NPh).93 The nitrosation of 1,2-diselenonium salts yields a new series of hetero-cycles (83; X = Se) and similar reaction on 1,Zdithiolium salts allows ready access to the already known S-anal~gues.~~ The preparation of (84; X = S) has been reported95 and the symmetrical structure suggested on the basis of its n.m.r.spectrum which resembles that of the known selenium analogue whose crystal structure is reported this year.96 Cathodic reduction of 1,2-dithiolylium salts in acetonitrile at a platinum electrode is found to yield dimers (85),97 apparently via the radicals (86) some of which are particularly stable.98 Con-versely anodic oxidation of 1,2-dithiol-3-thiones gives the bis(dithioly1ium) dications (87),97 isoelectronic with the ditropylium cation.Radical formation in 1,2-dithiolylium salts can be induced by flash phot~lysis.~~ .I...... s-s 0-s-s .... . ...o x.. . ... . . . Ph Me Ph Ph CN (82) 0-x-0 R+Ax-x-0 RR (83) [-'-i-) S-S Ar Ar Ar' S-(86) Ar 2 (87) 90 A. Hordvik and K. Julshamn Acta Chem. Scand. 1972,26 343. 91 E. C. Llaguno I. C. Paul R. Pinel and Y. Mollier Tetrahedron Letters 1972. 4687. 92 R. Pinel Y.Mollier J.-P. de Barbeyrac and G. Pfister-Guillouzo Compt. rend. 1972 275 C 909. 93 R. Gleiter D. Werthemann and H. Belhinger J. Amer. Chem. Soc. 1972 94 651. 94 J. G. Dingwall A. R. Dunn D.H. Ried and K. 0. Wade J.C.S. Perkin I 1972 1360. 95 R. J. S. Beer and A. J. Poole Tetrahedron Letters 1972 1835 96 E. C. Llaguno and I. C. Paul J.C.S. Perkin If 1972 2001. 97 C. T. Pedersen and V. D. Parker Tetrahedron Letters 1972 767. 98 C. T. Pedersen K. Bechgaard and V. D. Parker J.C.S. Chem. Comm. 1972 430. 99 C. T. Pedersen and C. Lohse Tetrahedron Letters 1972 5213. I. D. Blackburne,M. J. Cook and C. D. Johnson Structural Properties.-The much disputed problem of dipole moment directions in pyrrole thiophen and furan has been resolved the heteroatom is at the negative end of the dipole in the latter two compounds and at the positive end in the former."' The investigation of heteroaromatic tautomerism by n.m.r. has been re-viewed.lo' 2-Amino-2-oxazolin-4-ones have been shown to exist as (88) unless locked by a methyl group in the form (89) but in no case could hydroxy-forms be detected."* The non-conjugated form (90) of 4H/SH-imidazoI-5/4-ones predominates in solution in non-polar solvents polar solvents and electron- donor substituents (R) favour the conjugated species (91).'03 A variety of 4-hydroxy-pyrazoles and 4soxazoles have been shown to exist as the enolic tauto- mers' O4 leading to a general statement on keto-enol tautomerism of hydroxylated H NH NIH (88) (89) (90) (91) five-membered heteroatomatic systems where the keto-form is a lactone or lactam it is the stable tautomer; where it is a ketone the enol is more stable.X-Ray crystallography shows that in the solid state 3,5-dichloro-2,6-dimethyl-4-hydroxypyridine exists in the pyridone form but that the pyridinol structure is favoured by tetrachloro-4-hydroxypyridine.1'5 Ionization potentials indicate that the unsubstituted hydroxy- and mercapto-pyridines exist as such in the gas phase which contrasts with the predominance of the pyridone and pyridthione tautomers in solution.lo6 In the tricyclic system (92a S93) the observed preference for the hydroxy-form can be explained in terms of greater bond fixation in the '-one' tautomer the oxygen analogue of which is so unstable that it has only been observed as a transient blue intermediate (92b) which may be Ph ph Ph Ph (92) a X = NH (93) b;X=O loo G.Marino J. Heterocyclic Chem. 1972 9 817; T. J. Barton R.W. Roth and J. G. Verkade J. Amer. Chem. Soc. 1972 94 8854. lo' A. I. Kol'tsov and G. M. Kheifets Russ. Chem. Rec. 1972 41 452. G. Rapi M. Ginanneschi E. Belgodere and M. Chelli J. Heterocyclic Chem. 1972 9,285. Io3 J. T. Edward and I. Lantos J. Heterocyclic Chem. 1972 9 363. '04 M. J. Nye and W. P. Tang Tetrahedron 1972,28,455,463; Ann. Reporrs (B) 1971,68 578. '05 F. P. Boer J. W. Turley and F. P. van Remoortere J.C.S. Chem. Comm. 1972 573. '06 T. Grnnneberg and K. Undheim Org. Mass Specrromerry 1972. Heterocyclic Chemistry 439 trapped by dienophiles."' Line-broadening n.m.r. studies together with D,O exchange rates have been used in accurate elucidation of the tautomeric equilib- rium of cytosine'08 and g~anine.'~' Extensive compilations of the influence of substituents on gas-phase basicities of pyridines,' '*and on pK values of amino- pyridine-2- and -4-thiones,' ' ' pyrimidines pyridazines and pyridazones' '' have been reported.Conformational analysis of heterocyclic systems continues to command considerable attention. A definitive review of 1,3-dioxans and -dithians has appeared' l3 and helium-I photoelectron spectra of 0 and S heterocycles have permitted general interpretation of lone-pair interactions.' ' N.m.r. studies have shown that a number of five-membered-ring systems exist in the 'twist- envelope' form and these include some 1,3,2-dio~aphospholans,~1,3,2-oxa-' thiaphospholans,' ' 1,3,2-dioxa-arsolans,' 'and ethylene sulphites.' ' Variable-temperature studies revealed the lowest pseudorotational barrier so far estimated for quinquecovalent phosphorus in the penta-alkylphosphoranes (94 :R = Me or Ph).lI9 Acautionary note is struck in work on the heterocycles (95) and (96) (R = Me or Ph) which shows that the position of equilibrium is apparently perturbed by electronic effects arising from complexation of the phosphoryl oxygen with europium shift reagent.'20 Appraisal of the conformation of 1,3,2-dioxaphosphorinansshows that (97) is favoured over (98)." ' Equatorial preference of R' = Me and Ph as well as the N-methyl groups is also indicated for NN'-dimethyl-l,3,2-diazaphosphorinans (991 which exist in a single chair conformation with N-hybridization and hence flattening of the ring dependent on the electronegativity of the group R' However the previously observed Me R 107 D.W. Jones and R. L. Wife J.C.S. Perkin I 1972 2722. 108 G. C. Y. Lee J. H. Prestegard and S. I. Chan J. Amer. Chem. Sac. 1972 94 951. I09 G. C. Y. Lee and S. I. Chan J. Amer. Chem. Soc. 1972,94 3218. 1 I0 M. Taagepera W. G. Henderson R. T. C. Brownlee J. L. Beauchamp D. Holtz and R. W. Taft J. Amer. Chem. Sac. 1972 94 1369. Ill G. B. Barlin J.C.S. Perkin /I 1972 1459. 112 R. F. Cookson and G. W. H. Cheeseman J.C.S. Perkin 11 1972 392. 113 E. L. Eliel Angew. Chem. Internat. Edn. 1972 11 739. I14 D. A. Sweigart and D. W. Turner J. Amer. Chem. Soc. 1972,94 5599. 115 R. H. Cox and M. G. Newton J. Amer. Chem. Soc. 1972,94,4212. 116 K. Bergeson M. Bjoroy and T.Gramstad Acta Chem. Scand. 1972 26 2156. I11 D. W. Asknes and 0.Vikane Acta Chew. Scand. 1972,26,2532. 118 P. Albriktsen Acta Chew. Scand. 1972 26 3671. I19 C. H. Bushweller H. S. Bilofsky E. W. Turnblom and T. J. Katz Tetrahedron Letters 1972 2401. I20 W. G. Bentrude H.-W. Tan and K. C. Yee J. Amer. Chem. Soc. 1972 94 3264. 121 W. G. Bentrude and H.-W. Tan J. Amer. Chem. Sac. 1972,94,8222;J. A. Mosbo and J. G. Verkade ibid. p. 8224. I22 R. 0. Hutchins B. E. Maryanoff J. P. Albrand A. Cogne D. Gagnaire and J. B. Robert J. Amer. Chem. Sac. 1972 94 9151. I. D.Blackburne M. J. Cook,and C. D. Johnson w (97) R2 R" axial preference' 23 for P substituents in six-membered saturated heterocycles has been confirmed in 1,3,2-dithiaphosphorinan~.'~~ Dipole moment measure- ments on the system (100; Z = CH, 0,or s)afford a comparison of the steric requirements of methylene oxygen and sulphur,' 25 and low-temperature n.m.r.studies indicate N-substituent effects on ring-flipping and N-inversion in hexa- hydr0-1,2,4,5-tetrazines.'~~N.m.r. studies have also indicated the equatorial preference for the imide function in thian-1-imide whereas the N-tosyl and N-benzenesulphonyl groups are like the sulphinyl oxygen predominantly axial ;' the axial preference of Se-0 S&H and S&Me groups in selenan derivatives is also reported.I2* N.m.r. spectroscopy has also been used to demonstrate the existence of non-chair conformations of alkyl-substituted trimethylene s~lphites'~~ and a chair-like conformation in (101) with an equatorial preference for substituents on nitrogen.I3* Application of the carbonyl octant rule to the 0.r.d.and c.d. spectra of optically active nitroxide radicals based on 2,2,8a-tri- methyldecahydroquinoline permits the determination of their conformations.' ' Lithiation studies ofthe dithians (102)'32 gave a value of 8.6for k,/k, a small kinetic stereoselectivity for equatorial lithiation compared with the value of 100 reported last year' for the thermodynamic preference. Ph 123 Ann. Reports (B) 1971 68 568. 124 R. 0. Hutchins and B. E. Maryanoff J. Amer. Chem. SOC.,1972 94 3266. 125 R. A. Y. Jones A. R. Katritzky P. G. Lehman A. C. Richards and R. Scattergood J.C.S. Perkin II 1972 41. 12h S. F. Nelson and P.J. Hintz J. Amer. Chem. SOC.,1972 94 3138. 127 J. B. Lambert C. E. Mixan and D. S. Bailey J. Amer. Chem. Soc. 1972 94 208; J. B. Lambert D. S. Bailey and C. E. Mixan J. Org. Chem. 1972 37 377. 128 J. B. Lambert C. E. Mixan and D. H. Johnson Tetrahedron Letters 1972 4335. 129 G. Wood G. W. Buchanan and M. H. Miskow Canad. J. Chem. 1972 50 521; P. Albriksten Acta Chern. Scand. 1972 26 3678. I30 F. A. Davis 1. J. Turchi B. E. Maryanoff and R. 0. Hutchins J. Org. Chem. 1972 37 1583. 131 J. S. Roberts and C. Thomson J.C.S. Perkin f 1972 2129. I32 E. L. Eliel A. Abatjoglou and A. A. Hartmann J. Amer. Chem. Soc. 1972,94 4786. 133 Ann. Reports (B) 1971 68 565. Heterocyclic Chemistry Synthesis.-A number of methods of heterocyclic synthesis particularly for five-membered rings have in common the introduction of three-atom units by cycloaddition with an appropriate dienophile such as an acetylene ethylene ketone imine etc.Nitrile ylides have already been mentioned (Section 1) and other three-atom precursors examined this year include nitrile oxides' 34 and the new versatile toluenesulphonylmethyl i~ocyanide.'~ The metal salts of alkyl isothiocyanates add the C-N-C unit to for example carbonyl com- pounds forming oxazolidinethiones. 36 Pyrroles have been found to result from photochemical closure of P-aminovinyl ketones. 37 o-Acylaminobenzenes may be used to form indoles in an analogous manner (104+103)13' or through an alternative transformation uia carbenoid insertion (104+105).13*Long postulated as the last stage of the Fischer indole synthesis a labile 2-aminoindoline (106)has been isolated for the first time and shown to undergo facile elimination (e.g.over alumina) as expected.139 Also described this year is a novel pyridine synthesis based on phosphoryl chloride treatment of cyanoacetamides. 40 The product pyridines are usefully substituted (amino chloro or cyano) to facilitate further transformations. I Me (103) Application of the hexatriene Scyclohexadiene electrocyclization as a principle of aromatic ring synthesis is illustrated by the conversion of (107) 134 K. Bast M. Christl R. Huisgen and W. Mack Chem. Ber. 1972 105 2825; H. Blaschke E. Brunn R Huisgen and W. Mack ibid. p. 2841; P. Beltrame P. L. Beltrame A.Filippi and G. Zecchi J.C.S. Perkin I/ 1972 1914. 135 A. M. van Leusen G. J. M. Boerma R. B. Helmholdt H. Siderius and J. Strating Tetrahedron Letters 1972 2367; A. M. van Leusen B. E. Hoogenboom and H. Siderius ibid. p. 2369; A. M. van Leusen and 0. H. Oldenziel ibid. p. 2373; 0. H. Oldenziel and A. M. van Leusen ibid. p. 2777; A. M. van Leusen H. Siderius B. E. Hoogenboom and D. van Leusen ibid. p. 5337. 136 D. Hoppe Angew. Chem. Internat. Edn. 1972 11 933. 13' H. Aoyama T. Nishio Y. Hirabayashi T. Hasegawa H. Noda and N. Sugiyama J.C.S. Chem. Comm. 1972 775. 38 M. Panunzio N. Tangari and A. U. Ronchi J.C.S. Chem. Comm. 1972,415. '39 T. P. Forrest and F. M.F. Chen J.C.S. Chem. Comm. 1972 1067. I4O A. L. Cossey. R. L. N. Harris J. L. Huppatz and J.N. Phillips Atzgew. Chem. Itzternat. Edn. 1972 11 1098 1099 1100. 442 I. D.Blackburne M.J. Cook and C. D.Johnson into (108).14' Aromatization provides the necessary driving force and not unex- pectedly naphthalenes yield angular derivatives the reaction proceeding at a lower temperature than the aniline --* quinoline transformation. Other intra- molecular cycloadditions such as the [4+ 21 cyclizations of (109)'42or the unisolable (112),'43have also found useful application in ring synthesis. Un- expected cyclizations though were reported for (1 13)'44 and (1 14),'45unusual Claisen rearrangements being invoked by way of explanation. R' R' Me2N+fR2 C02Et C0,Et I hv 4 T"" OH (109) (1 12) 1 Me0 14' C. Jutz and R.M. Wagner Angew. Chem. Internat. Edn. 1972 11 315. 14* W. Oppolzer and K. Keller Angew. Chem. Internat. Edn. 1972 11 728. 143 H. W. Gschwend and H. P. Meier Angew. Chem. Internat. Edn. 1972 11 294. 144 K. C. Majumdar and B. S. Thyagarajan J.C.S. Chem. Comm. 1972 83. 145 G. R. Brown N. F. Elmore and G. M. O'Donnell J.C.S. Chem. Cnmm. 1972 896. Heterocyclic Chemistry 443 CH,R I CH,RI Ill -% co L O CI tJIC' (1 13) Ic1 0 0 (1 14) Syntheses and interconversions of heterocyclic rings containing more than one heteroatom have been the objects of a number of studies Particularly interesting in this context is the novel reaction of benzofuroxans with nitroalkanes to yield the benzimidazole system. 146 Both primary and secondary nitroalkanes react and give 2-alkyl- 1-hydroxy-3-oxo- and 2,2-dialkyl-1,3-dioxo-benzimidazoles respectively.Analogous transformations occur with cyanoacetamide' 47 and 2-sulphonyl enolate14* anions. The novel compounds (116) have been obtained uia intramolecular Michael-type condensation of the vinylsulphonylthioureas (115),'49 and the methylated thiourea (117) affords access to the little-known 1,2,4-thiadiazine derivatives (1 18).150 NHR S II ArCH=CHSO,NHCNHR -+ SMe SMe I ArCH=CHSO,N=CNHR -+ (1 17) (1 18) A simple process has both aesthetic and practical appeal. Industry and chemical evolutionists could well be interested in the 71 % conversion of form-amide into purine by heat alone that has been achieved this year.'51 Other 146 M.J. Abu El-Haj J. Org. Chem. 1972.37,2519;D. W. S. Latham 0.Meth-Cohn and H. Suschitzky J.C.S. Chem. Comm. 1972 1040. 147 F. Seng and K. Ley Synthesis 1972 606. 14* D. P. Claypool A. R. Sidani and K. J. Flanagan J. Org. Chem. 1972,37 2372. 149 K. Hasegawa and S. Hirooka Bull. Chem. SOC.Japan 1972,45 525 1567. 50 K. Hasegawa and S. Hirooka Bull. Chem. SOC.Japan 1972,45 1893. 51 H. Yamada and T. Okamoto Chem. and Pharm. Bull. (Japan) 1972 20 623. I. D.Blackburne M. J. Cook and C. D.Johnson one-step syntheses of biologically important molecules are those of adenine and xanthine in good yield from (1 19 :R = CONH and CN respectively) by catalytic reduction in ammoniacal formamide'52 and a further rather simple synthesis is that of pteridines from (120).' 53 The novel ring-expansion of pyrrolopyrimidines (121) to the pyrimidino-compounds (122) has been effected by K2S20 [for (121 ; R = NO)] or lead tetra-acetate [for (121 ;R = NH,)].'54 A nitrene intermediate 0 0 OH II I Me H Me (121) Ar = Ph p-CIC,H, or ( 122) p-BrC,H is suggested.Nitrogen insertion from an external reagent provides the basis of several reports of other new syntheses in similar fashion to earlier pteridine work,' s5 diethyl azodicarboxylate is utilized as a nitrogen source in the prepara- tion of the alloxazine (123),'56 and 3-substituted uracils result from nitrogen insertion by trimethylsilylazide into (124).15' The intermediate (125) is a potentially valuable entry to nucleosides.' 57 Novel polyaza-bicyclics reported include pyridazino[2,3-a]- 1,3,5-triazines,' s-triazolo[2,3-b]pyridazines,' and pyrazolo[1,5-~]pyrimidines.'~~ The latter series (126; X = S 0,or NH) has been investigated the first two favouring tautomer (a) but the last preferring tautomer (b).0 0 Me Me (123) M. Sekiya and J. Suzuki Chern. and Pharrn. Bull. (Japan) 1972 20 209. 15' W. J. Irwin and D. G. Wibberley Tetrahedron Letters 1972 3359. 15' F. Yoneda and M. Higuchi Chern. and Pharrn. Bull. (Japan) 1972 20 2076; J.C.S. Chern. Comm. 1972,402. 155 F. Yoneda S. Fukazawa and S. Nishigaki Chern. Cornrn. 1971 83. '56 F. Yoneda and S. Fukazawa J.C.S. Chern. Cornrn. 1972 503. 15' S. S. Washburne W. R. Peterson and D. A. Berman J. Org. Chern. 1972 37 1738. M. Zupan B.Stanovnik and M. TiSler J. Org. Chem. 1972,37 2960. M. Zupan B. Stanovnik and M. TiSler Tetrahedron Letters 1972 4179. I6O E. Kranz J. Kurz and W. Donner Chern. Ber. 1972 105 388. Heterocyclic Chemistry SiMe (125) In the realm of p-lactam antibiotics the thiazoline-azetidone (127) which yields both penam and cepham nuclei on oxidation with per,acid has been suggested as a model for the intermediate in their biosynthesis.'61 The inter- conversion of the penam and cepham structures continues as one of the primary synthetic goals and reversible interconversions of this type uia the thiiranium ion (128) are reported. 162 Further procedures include the transformation of (129) into (130) by formation of a sulphonium ylide followed by a 2,3-sigma- tropic shift,'63 and the conversion of (131) into (132) by reaction with ethyl CH,OPh I H-CO,CH,CCI (128) Ft = Phthalimido -CHCO,Et I BzCON H BzCON H 0 Me Me COzMe C0,Me (I 29) ( 130) Ihl R.D.G. Cooper J. Amer. Chem. SOC.,1972,94 1018; R. D. G. Cooper and F. L. Jose ibid. p. 1021. Ib2 S. Kukolja and S. R. Lammert J. Amer. Chem. SOC.,1972,94 7169. Ih3 M. Yoshimoto S. Ishihara E. Nakayama and N. Soma Tetrahedror? Letters 1972 2923; M. Yoshimoto S. Ishihara E. Nakayama E. Shoji H. Kuwano and N. Soma ibid. p. 4387. I. D. Blackburne M. J. Cook and C. D.Johnson ?-Ph OCH ,CONHr Me PhOCH zCONHws\ 0 N- C0,Me (132) azodicarboxylate. 164 Other developments in synthesis include the production in high yield by a facile route of (133) a key intermediate in a total synthesis of cephalosporins,' 6s total stereospecific synthesis of nuclear analogues of 7-methylcephalosporin,166 the synthesis of 8-~-phenylacetamidohomoceph-4-em-5-carboxylic acid (134),' 67 and stereospecific synthesis of cis-p-lactams including (135; n = 1 or 2 R = OPh or OMe).16* The synthesis of the cis-and trans-isomers of (136) is also reported their configurational and conformational characterization involving a wide variety of physical techniques.' 69 The stereo- specific introduction of the C-6(7)-methoxy-group into penicillin and cephalo- sporin derivatives"' and facile exchangel7l of the aminoadipoyl for other acyl groups in cephamycin C are notable among contributions to methods for BzcoNbJ Me,CO,C 1 0 Ft 4> 0 H ( 134) (133) Ft = Phthalimido (136) R = Me or CH2C,H,.N02-p lb4 S.Terao T. Matsuo S. Tushima N. Matsumoto T. Miyawaki and M. Miyamoto J. C.S. Chem. Comm. 1972 1304. N. N. Girotra and N. L. Wendler Tetrahedron Letters 1972 5301. Ib6 D. M. Brunwin and G. Lowe J.C.S. Chem. Comm. 1972 589. 16' R. Scartazzini J. Gosteli H. Bickel and R. B. Woodward Helu. Chim. Acta 1972,55 2567. b8 A. K. Bose B. Dayal H. P. S. Chawla and M. S. Manhas Tetrahedron Letters 1972 2823. 169 S. Kukolja J. Amer. Chem. SOC.,1972 94 7590; S. Kukolja P. V. Demarco N. D. Jones M. 0.Chaney and P. W. Paschal ibid.,p. 7592. L. D. Cama W. J. Leanza T. R. Beattie and B. G. Christensen J. Amer. Chem. SOC. 1972,94 1408. "' S.Karady S. H. Pines L. M. Weinstock F. E. Roberts G. S. Brenner A. M. Hoinowski T. Y. Cheng and M. Sletzinger J. Amer. Chem. Soc. 1972 94 1410. Heterocyclic Chemistry structural modification ; EHMO calculations on the cepham and penam nuclei are also reported."2 The distinctive chemical and biological properties of heteroadamantanes are no doubt responsible for the degree of interest which this system continues to maintain.'73 Indeed their characteristic of abnormal or low reactivity is well illustrated by the inertness to hydrochloric acid of the Si-N bond of (137).173a A new entry to oxa-adamantanes has been achieved by oxidative photolysis of 2-adamantanol (138).173bThe reaction is believed to involve rearrangement of an intermediate hypoiodite and its success albeit limited in the conversion of cyclohexanol into tetrahydropyran indicates synthetic potential.The bicyclic (139)obtained from cyclo-octa-1,5-diene has found use as precursor to a number Me I / Me ( 137) of diheteroadamantanes.' 73c Generically linked to the adamantanes is another tricyclodecane class of compounds the twistanes a number of dihetero-deriva- tives of which have been prepared.' j4 Also reported are the 9-oxahomocubanes (140) formed probably viaan interesting bis-allylic radical,' j5 the propellane (141) which has an inversion barrier of 12.6kcal mol- and the phospha- bicycloheptane ( 142). 77 R MeOzC.'p Me0,C -c> + R = CO,Me H or D (140) CO,Me. D. B. Boyd J. Amer. Chem. Soc. 1972 94 6513.(a) C. L. Frye and J. M. Klosowski J. Amer. Chem. Sac. 1972 94 7186; (b) R. M. K. Heckel Tetrahedron Letters 1972 1907 801; (d) H. Stetter and G. J. Steffens Black G. B. Gill and D. Hands J.C.S. Chem. Comm. 1972 31 1 ; (c) H. Stetter and Chem. Ber. 1972 105 1755; H. Stetter and W. Reinartz ibid. p. 2773; Y. Kashman and E. Benary Tetrahedron 1972 28 4091 ; G. Snatzke and B. Wolfram ibid. p. 665; E. B. Hodge J. Org. Chem. 1972 37 320. I 74 C. Ganter and N. Wigger Heh. Chim. Acta 1972,55,481 ;P. Ackermann H. Tobler and C. Ganter ibid. p. 2731 ; K. Wicker P. Ackermann and C. Ganter ibid. p. 2744; N. Wigger and C. Ganter ibid. p. 2769; N. Wigger N. Stucheli H. Szczepanski and C. Ganter ibid. p. 2791. W. Eberbach and M. Perroud-Arguelles Chem.Ber. 1972 105 3078. B. Fuchs Y. Auerbach and M. Sprecher Tetrahedron Letters 1972 2267. '_I1 R. B. Wetzel and G. L. Kenyon J. Amer. Chem. Soc. 1972,94 9230. I. D. Blackburne,M. J. Cook and C. D. Johnson Reactions and Interconversi0ns.-A useful method for the alkylation and alkenyl-ation of heterocycles utilizing their readily available halogeno-derivatives has been described. Treatment with the appropriate Wittig reagent generates a new ylide which may be hydrolysed in situ or treated with carbonyl compounds forming alkenyl groups. A wide range of heterocycles is responsive to the pro-cedure shown in Scheme 1.'78 Homolytic reaction is an alternative well-investigated' 79 mode of heterocyclic substitution of which the use of the trioxanyl radical (143)for the introduction of the formyl group is notable.179aThe SR,1 radical chain mechanism relatively new in nucleophilic carboaromatic sub-stitution is believed to operate in the reaction of 2-chloroquinoline with (144); marked retardation is experienced in the presence of radical inhibitors.'8o n Scheme 1 M 1,) PhCOCHCOCH,.M 2-chloroquinoiine I ~ (143) (144) M = e.g. Li (144) M = e.g. Li 0-0 0 Heterocyclic N-oxides act as substrates in a number of new substitution reactions reported this year. A variety of heteroaromatic N-oxides with the exception of those of monocyclic systems has been found susceptible to a-cyanation. The process involves treatment with cyanide ferricyanide and a E. C. Taylor and S. F.Martin J. Amer. Chem. SOC.,1972 94 2874. (a) G. P. Gardini Tetrahedron Lerrers 1972 4113; (6) L. Benati A. Tundo and G. Zanardi J.C.S. Chem. Comm. 1972,590; C. M. Camaggi G. De Luca and A. Tundo J.C.S. Perkin II 1972 412; T. Caronna G. Fronza F. Minisci 0. Porta and G. P. Gardini ibid.,p. 1477; C. M. Camaggi G. De Luca and A. Tundo ibid. p. 1594; T. Caronna G. Fronza F. Minisci and 0. Porta ibid. p. 2035; P. Spagnolo M. Tiecco A. Tundo and G. Martelli J.C.S. Perkin I 1972 556; L. Benati C. M. Camaggi M. Tiecco and A. Tundo J. Heterocyclic Chem. 1972 9 9 19. 180 J. F. Wolfe J. C. Greene. and T. Hudlicky J. Org. Chem. 1972 37 3199. Heterocyclic Chemistry 449 protic solvent such as water.'" Direct acylation of pyridine N-oxide may be achieved by reaction with alkyl-lithium followed by carbon dioxide (to give acids) or esters or amides (to give acyl compounds).'82 Hydroxyalkylation of the initial 2-carbanion is achieved when ketones are used.'83 In contrast direct treatment of pyridine or quinoline N-oxides with 3-phenylpropynylnitrile results in deoxygenated 3-alkenyl derivatives as major products possibly via (145).'84 Another subject of recent interest is the reaction of pyridine N-oxides with Grignard reagents.Open-chain products (146) rather than the cyclic valence tautomers (147) are believed the norm but it now appears that low temperatures favour (148). On warming this either disproportionates or under- goes ring-opening. '' CN Ph f-/ 0- N+ N+ I 0-0 H 1PhMgBr Ph >=\ CN (145) 0-OH OH (148) (146) ( 147) Dihydropyridine chemistry has been reviewed this year,' 86 and direct synthesis of the 1,4-dihydropyridine system (150) has been reported by two groups each utilizing (149) as precursor.' 87 Controlled reaction of pyridine with sodium borohydride and methyl chloroformate gives a convenient preparation of both dihydro-isomers.' 88 At -70 "C the product is almost entirely(l51; R = CO,Me) whereas at 0-10 "C (150; R = C0,Me) is formed to the extent of 40% and may be enriched by removal of (151) as cycloadduct.Thermodynamic preference for the 1,4-isomer in simple derivatives of dihydropyridine has now been established I" Y. Kobayashi I. Kumadaki and H. Sato J. Org. Chem. 1972 37 3588. R. A. Abramovitch R.T. Coutts and E. M. Smith J. Org. Chem. 1972,37 3584. lX3 R. A. Abramovitch E. M. Smith E. E. Knaus and M. Saha J. Org. Chem. 1972,37 1690. R. A. Abramovitch G. Grins R. B. Rogers J. L. Atwood M. D. Williams and S. Crider J. Org. Chem. 1972 37 3383. P. Schiess and P. Ringele Tetrahedron Lerters 1972 31 1. U. Eisner and J. Kuthan Chem. Rev. 1972,72 1. 18' D. C. Horwell and J. A. Deyrup J.C.S. Chem. Comm. 1972,485;A. I. Meyers D. M. Stout and T. Takaya ibid. p. 1260. F. W. Fowler J. Org. Chem. 1972 37 1321. I. D. Blackburne M. J. Cook and C. D. Johnson by base equilibration of (150; R = Me) and (151; R = Me).'89 At 91.6"C the preference amounts to 2.29 kcal mol-' a considerable departure from the opposite long-standing HMO prediction.In the pyrazine system however the authenticity of a number of 1,4-dihydro-derivatives has been in doubt and indeed reduction of di- tri- and tetra-alkoxycarbonylpyrazinesis now believed to give quite stable 1,2-dihydro-products with no trace of the antiaromatic 1,4-isomers ob~ervable.'~~ In contrast however another group reports that polarographic reduction of polyphenylpyrazines gives initially the 1,4-dihydro- form which then isomerizes at a pH-dependent rate to the 1,2-i~omers.'~' A further interesting difference in another field between these mono- and di- azabenzenes is found in the photochemical behaviour of 2-pyridones and 2-pyrazinones. In the former case stable photo-2-pyridones (152; X = CR5) are produced including the parent system (R'-R5 = H),'92 whereas 2-pyr- azinones yield unstable photoisomers (152; X = N) whose constitutions were established by reductive trapping as diazabicyclohexanes (153).92a The utility of 1,3-diheterans in functionalization and group protection is a well known and rapidly expanding field (reviewed in ref. 193) and efficient modes of ring-cleavage continue as the objectives of many groups. Regeneration of ketones from dithiolans has been successfully accomplished by hydrolysis of the corresponding sulphonium salts. The salts are formed with methyl methyl fluoro~ulphonate,'~~~ i~dide,'~~",~ or triethyloxonium tetrafluorobor- ate'94c and facile cleavage ensues on treatment with water194 or perhaps better 3 cuprous ~ulphate.'~~' A novel ring-contraction under neutral conditions of 189 F.W. Fowler J. Amer. Chem. SOC.,1972 94 5926. 190 J. R. Williams J. J. Cossey and M. Adler J. Org. Chem. 1972 37 2963. 191 J. Armand P. Bassinet K. Chekir J. Pinson and P. Souchay Compt. rend. 1972 275 C 279. 192 (a) H. Furrer Chem. Ber. 1972 105 2780; (6) R. C. De Selms and W. R. Schleigh Tetrahedron Letters 1972 3563. 193 R. R. Schmidt Synthesis 1972 333. 194 (a) H.-L. W. Chang Tetrahedron Letters 1972 1989; (b) M. Fetizon and M. Jurion. J.C.S. Chem. Comm. 1972 382; (c)T. Oishi K. Kamemoto and Y. Ban Tetrahedron Letters 1972 1085; (d) M. Hetschko and J. Gosselck Tetrahedron Letters 1972 1691. Heterocyclic Chemistry 451 1,3-dioxan derivatives (154) accompanies nucleophilic substitution with tri- phenylphosphine in carbon tetrabromide or lithium bromide in acetonitrile.' g' In the latter instance [with (154; X = OTs)] the process was stereospecific.Heating appropriately substituted 2-alkylamino-l,3-dioxolansin dimethyl-formamide has been found to afford a novel and efficient route to 3-furanones via (155).'96 .<)-€% % 0 ( 154) o<NMe21rR2 - Me NMe b2 Me -* D R 2 R' R' R' (1 55) In contradiction of the belief that thiophens do not undergo Diels-Alder reactions a number of alkyl-substituted thiophens have been found to add in moderate ease to a variety of acetylenes. The products are substituted benzenes formed via bridged compounds (156) which rapidly extrude ~ulphur.'~' It was presumably sulphur extrusion that thwarted attempts to rearrange 7-thianor- bornadiene generated from (157) to thiepin (158) (as yet unknown),'98 though a derivative of (158) was found to be accessible by an alternative [2 + 21 cyclo-addition of certain substituted thiophens (see Section 3).Analogous silylene elimination is the standard behaviour of 7-silanorbornadienes but interestingly (159) on thermal treatment undergoes the unusual conversion into (16O).lg9 Novel addition to the 2,3-position of N-methylpyrrole occurs with the 1,3-dipole (161).200 Two moles of the latter add and give (162) along with products of alternative orientation. Me ,Me &; R' CI (157) (1 59) 19' R. Aneja and A. P. Davies J.C.S. Chem. Comm. 1972 722. 19' B. K. Carpenter K. E. Clernens E. A. Schmidt and H.M. R. Hoffrnann J. Amer. Chem. SOC.,1972,94 6213. 19' R. Helder and H. Wynberg Tetrahedron Letters 1972 605; H. J. Kuhn and K. Gollnick ibid. p. 1909. 19' T. J. Barton M. D. Martz and R. G. Zika J. Org. Chem. 1972 37 552. 199 T. J. Barton J. L. Witiak and C. L. McIntosh J. Amer. Chem. SOC.,1972 94 6229. M. Ruccia N. Vivona and G. Cusmano Tetrahedron Letters 1972 4703. &;3 I. D. Blackburne M. J. Cook and C. D. Johnson Ac Ac Ac&N-NPh The orientation of the addition of the ynamine (163) to the pyridazines (164) and (165) provides an interesting and perhaps useful contrast.201 The same ynamine was employed in the synthesis of the phosphathiabenzene (167) from the anhydride (166).202 The photochemical cyclization of (168) with dimethyl acetylenedicarboxylate (DMAD) parallels the known thermal reaction ;203 C0,Me NEt NEt, -Me -3’”;” Ill (164) (166) (167) however its reaction with isocyanides exemplifies a rare [3 + 11 addition and affords an alternative route to the interesting 1-azetines (169).204 Cycloaddition of (170) to ethyl propiolate has been shown to result in (171) presumably oia an unusual mode of decomposition of the primary add~ct.~’~ A new and efficient route to heterocyclic N-imines has been developed using O-mesitylenesulphonyl- hydroxylamine.206 The imines act as precursors to ylides of the type (172; 201 H.Neunhoeffer and G. Werner Tetrahedron Letters 1972 1517. 202 N. Schindler and W. Ploger Synthesis 1972 421. 203 K. Burger and J. Fehn Tetrahedron Letters 1972 1263.’04 K. Burger and J. Fehn Angew. Chem. Internat. Edn. 1972 11 47. *05 J. P. Freeman E. G. Duthie M. J. O’Hare and J. F. Hansen J. Org. Chem. 1972,37 2756. 206 Y.Tamura J. Minamikawa Y. Miki S. Matsugashita and M. Ikeda Tetrahedron Letters 1972 4133. Heterocyclic Chemistry R' R' R' = aryl (169) R' = Bu' or Ph R2 = C,H, or aryl 0 OH I -0' 0-C02Et X = N) the dipolar additions of which receive considerable attention ;(173a-c) for example provide convenient entry to (174),207 but it is notable that the course deviates with (173d) where (175) results possibly via a dimerization of the (173) a; X = CH R' = COPh R2 = Ph b; X = N R' = C02Me,R2 = C02Me c; X = CH R' = CO,Me R2 = Me d; X = CH R' = C02Me R2 = H R' C0,Me (175) ylide.208 A simple variation of the above intramolecular cyclizations has been applied to the syntheses of a variety of bicyclics (Scheme 2) using molecular sieve as a dehydrating agent.*Og The primary 1,3-adduct of (176) with diethyl acetylenedicarboxylate has been isolated for the first time.21o These initial 207 Y.Tamura N. Tsujimoto Y. Sumida and M. Ikeda Tetrahedron 1972 28 21; T. Sasaki K. Kanematsu and A. Kakehi J. Org. Chem. 1972 37 3106; T. Sasaki K. Kanematsu A. Kakehi and G. Ito Tetrahedron 1972 28 4947. 208 Y.Tamura Y. Sumida and M. Ikeda Chem. and Pharm. Bull. (Japan),1972,20 1058. 209 W. Oppolzer Tetrahedron Letters 1972 1707. 2'o T. Katsuma K. Fujiyama Y. Sekine and Y. Kobayashi Chem. and Pharm.Bull. (Japan),1972 20 1558. I. D. Blackburne M. J. Cook and C. D. Johnson k Scheme 2 products normally undergo elimination or rearrangement cf. the decomposition of (177).'" The reaction of the azimine ylide (178) with acetylene esters to give (179a) strongly suggests that it too acts as a 1,3-dip0le,~'~ and the dipolar addition of (179b) is itself most interesting. Of several potential modes of reaction viz. as a 4n-electron 1,3-dipole a 6n-electron 1,5-dipole or an 8n-electron 1,7-dipole it prefers the second giving (180) as primary adduct which then rearranges as shown." Pyridinium N-ylides have recently been recognized as nucleophiles a characteristic exploited in the quantitative conversion of tropone into its 2-amino-derivative using N-ethoxycarbonylaminopyridiniumylide.2l4 211 T.Sasaki K. Kanematsu A. Kakehi and G. Ito Bull Chrm. SOC.Japan 1972 45 2050. 'I2 S. F. Gait M. J. Rance C. W. Rees and R. C. Storr J.C.S. Chem. Comm. 1972 688. 213 S. F. Gait M. J. Rance C. W. Rees and R. %. Storr J.C.S. Chem. Comm. 1972 806. T. Sasaki K. Kanematsu and A. Kakehi Tetrahedron 1972 28 1469. Heterocyclic Chemistry DMAD d NC0,Et C0,Me (179) a R == Et ( 180) b R =Me 1 3 Medium-and Large-ring Compounds (4n + 2)~-ElectronSystems.-An X-ray structural determination of (18 1)2 and an independent n.m.r. study of various analogues such as (182)and (183)2'6 have revealed a lack of 6.n-electron delocalization in the azatropone system. In a series of 3,4-dihydrobenzazocines,e.g.(184),however the stability of the enolic form has been attributed to a pseudoaromatic 6.n-electron stabilization within the tautomer.217 H Me OEt OMe Me '0 (I 83) 215 W. A. Denne and M. F. Mackay Tetrahedron 1972 28 1795. 216 E. J. Moriconi and I. A. Maniscalco J. Org. Chem. 1972 37 208. 217 K. Yamada T. Konakahara S. Ishihara H. Kanamori T. Itoh K. Kimura and H. Iida Tetrahedron Letters 1972 25 13. I. D. Blackburne M. J. Cook,and C. D. Johnson The first preparation of simple 174-dioxocins is reported through the valence isomerization of syn-benzenedioxides.218,2 The structures are olefinic in character and equilibria between (1 85) and (186) have been established in which the dioxocins predominate. The dibenzo[b,g]oxocin (1 87) has an acidity inter- mediate between that of fluorene and xanthene indicating aromaticity of the dibenzoxocin anion conjugate base.” lox-Electron systems sustained by a nine-membered ring the heteronins (188) have continued to attract research effort and their chemistry has been the subject of an authoritative review.220 Values of the S-parameter (an n.m.r.solute shift parameter) for heteronins sub- stantiate the view that the parent azonine (188a) is aromatic but show that the aromatic character is somewhat reduced in the N-alkyl analogues possibly through distortion from planarity.220,221 By contrast oxonin (188b) and azonines carrying electron-withdrawing substituents at nitrogen have polyenic character ;the latter class readily add to 4-phenyl-172,4-triazoline-3,5-dione in a [,2 + ,4,]process.222 The azonin anion (189) has been generated and appears to be a planar delocalized lox-electron and the first polyheteronin (190) has been prepared.224 However an attempt to prepare the unknown and elusive thionin (188c) photochemically from (191) gave 9-thiabarbaralane (192).22 N (188) a; X = NH (1 89) (187) b;X = 0 c;x=s A number of papers have been concerned with hetero[l7]annulenes.Thus three geometric isomers of both oxa-226 and aza-227 [17]annulenes have been 218 E. Vogel H.-J. Altenbach and D. Cremer Angew. Chem. Internal. Edn. 1972 11 935. 219 H. S. Kasmai and H. W. Whitlock J. Org. Chem. 1972 37 2161. 220 A. G. Anastassiou Accounts. Chem. Res. 1972 5 281.221 A. G. Anastassiou and H. Yamamoto J.C.S. Chem. Comm. 1972 286. 222 A. G. Anastassiou R. P. Cellura J. M. Spence and S. W. Eachus J.C.S. Chem. Comm. 1972 325. 223 A. G. Anastassiou and S. W. Eachus J. Amer. Chem. SOC.,1972 94 2537; R. T. Seidner and S. Masamune J.C.S. Chem. Comm. 1972 149. 224 L. A. Paquette and R. J. Haluska J. Amer. Chem. Soc. 1972 94 534. 225 A. G. Anastassiou and B. Y.-H. Chao J.C.S. Chem. Comm. 1972. 277. 226 G. Schroder G. Plinke and J. F. M. Oth Angew. Chem. Internat. Edn. 1972 11 424. 227 G. Schroder G. Heil H. Rottele and J. F. M. Oth Angew. Chem. Infernat. Edn. 1972 11. 426. Heterocyclic Chemistry Me Me obtained and all appear to be best classified as polyenes. The greater rigidity of the bisdehydrothia[l7]annulenes ( 193)228 and of the bridged bisdehydro- aza[l7]annulenes (194),229 however renders these structures capable of sustaining Me I (193) (194) a diamagnetic ring current in the latter series the ring current is reduced on moving from R = H to R = alkyl presumably arising from greater deviation from planarity.Reduced flexibility is an important factor which renders the larger 22n-electron macrocycles (195) and (196) diatr~pic.~~' The question of Et Et Et Me R' R2 (195) (196) X = S R' = R2 = H X = NH R' = Et RZ = Me 228 R. H. McGirk and F. Sondheimer Angew. Chem. Internat. Edn. 1972 11 834. 229 P. J. Beeby and F. Sondheimer J. Amer. Chem. SOC.,1972 94 2128; Angew. Chem. Internat. Edn. 1972 11 833. 230 M. J. Broadhurst R.Grigg and A. W. Johnson J.C.S. Perkin I 1972 21 1 1. I. D.Blackburne M. J. Cook and C. D.Johnson the NH-tautomerism in porphyrins has been investigated by low-temperature 'H n.m.r. and the tautomeric process (197a) (197b) has been identified.231 4nn-Electron Systems.-X-Ray and n.m.r. studies have revealed that the lH-1,2-diazepine ring e.g. (198; R = Ts),exists in a shallow boat conformation and in this respect it compares with 1H-azepines and oxepin :232 such puckering should tend to relieve antiaromatic destabilization predicted for 4nn-electron structures. Antiaromaticity may account in part for the reduced stability relative to that of linear diaryltriazines of the first reported example of a 1,2,3- triazepine (199),233 and also for the low acidity of the 4H-1,2-diazepine (200) a conjugate acid of the anion (201).234 Interestingly protonation of (200) which was earlier believed to lead to the 8n-electron system (202) has now been shown to give either (203) or (204).235Two cycloaddition reactions involve the 231 C.B. Storm and Y.Teklu J. Amer. Chem. SOC., 1972,94 1745. 232 R. Allman A. Frankowski and J. Streith Tetrahedron 1972 28 581. 233 S. F. Gait M. E. Peek C. W. Rees and R. C. Storr J.C.S. Chem. Comm. 1972 982. 234 R. R. Schmidt and H. Vatter Tetrahedron Letters 1972 4891. 235 M. T. Thomas V. Snieckus and E. Klingsberg J.C.S. Chern. Cornrn. 1972 504. He tero cy c 1ic Chemistry IH-diazepine ring in different roles.236 In one (198; R = C0,Et) undergoes cycloaddition with the dienophile 4-phenyl-1,2,4-triazoline-3,5-dioneto give (205) whereas with 2-diazopropane the ring acts as a dipolarophile as exemplified by the conversion (206) -+ (207).Photolysis of the latter compound provides a route to the homodiazepine (208). \ C02Et (206) The synthesis and spectral studies are described for the monocyclic thiepin (21l) a member of a class which unlike the oxygen and nitrogen analogues has hitherto eluded preparati~n.~~’ The present example was obtained in solution by reaction of the thiophen (209) with dimethyl acetylenedicarboxylate the adduct (210) rearranging to give (211). It has been suggested that the relative ,CO,Me AN9 (209) R’ = H orMe,R2 = H (210) stability of (211) may be attributed to the effect of the electron-withdrawing groups which perhaps reduce formal antiaromatic character.The approach used for the preparation of (211) has also provided examples of 2,3-and 2,7- dihydr~thiepins~~~ and one of two new routes to members and l-benzo~epins,~~~ of the relatively rare 1-benzothiepin system e.g. (212).240 The second involves 23h G. Taurand and J. Streith Tetrahedron Letters 1972 3575. 237 D. N. Reinhoudt and C. G. Kouwenhoven J.C.S. Chem. Comm. 1972 1233. 238 D. N. Reinhoudt and C. G. Leliveld Tetrahedron Letters 1972 31 19. ’” D. N. Reinhoudt and C. G. Kouwenhoven Tetrahedron Letters 1972 5203. D. N. Reinhoudt and C. G. Kouwenhoven J.C.S. Chem. Comrn. 1972 1232. I. D. Blackburne M. J. Cook,and C. D. Johnson simply 0-acetylation or 0-methylation of ketones as exemplified by the con- version (213) +(214).241 The products are reported to have stability com- parable with that of the more familiar 3-benzothiepin series and somewhat surprisingly the hydrolysis product (215) derived from (212) exists in the formally antiaromatic tautomer hydrogen-bonding apparently stabilizing it relative to the non-aromatic keto-form.(213) (214) R = COMe or Me 3-Benzoxepin has been identified as an unexpected product of the photochemical oxidation of 1,4-dih~dronaphthalene,~~~ and the preparation of the novel pyrazole analogue (216) by the more usual condensation pathway has also been described.243 Good yields of tri- tetra- and penta-aryl-l,3-oxazepines have been obtained by photolysing the corresponding pyridine N-o~ides,~~~ and the first examples of stable 1,2-oxazapines (217) have been obtained as the primary photo- products of acridine N-~xides.~~~ By contrast light-induced rearrangements of phenazine N-oxide led to a variety of products which include small amounts of (218) and possibly (219).246 x N-0 (217) X = CN or C1 241 H.Hofman B. Meyer and P. Hofmann Angew. Chem. Internat. Edn. 1972 11 423. 242 A. M. Jeffrey and D.M. Jerina J. Amer. Chem. SOC.,1972.94 4048. 243 C. V. Greco F. C. Pellegrini and M. A. Pesce J. Heterocyclic Chem. 1972. 9. 967. 244 0.Buchardt C. L. Pedersen and N. Harrit J. Org. Chem. 1972 37 3592. 245 S. Yamada M. Ishikawa and C. Kaneka Tetrahedron Letters 1972 971 977; J.C.S. Chem.Comm. 1972 1093. 246 A. Albini G. F. Bettinetti and S. Pietra Tetrahedron Letters 1972 3657. Heterocyclic Chemistry 46 1 The formal 12x-electron trioxacyclononatriene (220) has been obtained for the first time by the valence isomerization of the all-syn-benzene trioxide (lo) the anti-isomer showing no change on thermolysis.' 'vl ' Unlike the equilibrium (185b)S(186b) here there is no evidence for reversibility :(220) is relatively stable and shows an absorption in the n.m.r. at S 5.87." The larger hetero[ll]annulenes (221a and b)247 and the benzo-fused systems (222)248 have also been synthesized and their n.m.r. and U.V. spectra compared with those of the carbocyclic analogues (221c) and (222c). (222a) is particularly stable to heat and indeed can be sublimed at 230 "C.The 4nn-electron systems are believed to be non-planar and there is no evidence of a significant paramagnetic ring current the U.V. spectra of (221b) and (222b) are almost superimposable on those of (221c) and (222c) respectively. (221) a; X = S (222) a; X = S (220) b;X=O b;X=O C; X = CH C; X = CH Saturated and Simple Unsaturated System.-A substantial amount of data is accumulating on the conformations of medium-sized heterocycles. An X-ray diffraction study has revealed that 1,3,5,7-tetrathiocan (223a) exists in the boat- chair conformation in the solid state and the same conformation is consistent with 'H n.m.r. solution data.249 Detailed variable-temperature 'H n.m.r. studies suggest that OXOC~~,~~'~ 5-oxocanone (224),250b and 1,3-dioxocan2500~c also exist in boat-chair conformations.On increasing the number of oxygen atoms further however as in (225) and (223b) this conformation is destabilized by transannular oxygen interactions and twisted boat-chairs twist chair<hair and crown forms become imp~rtant.~~'" A rigid crown conformation has been postulated for (226a) and this provides a sharp contrast with the oxygen analogue 247 E. Vogel R. Feldmann H.Diiwe1 H.-D. Cremer and H. Gunther Angew. Chem. Internat. Edn. 1972 11 217. 248 H. Ogawa and N. Shimojo Tetrahedron Letters 1972 4129. 249 G. W. Frank P. J. Degen and F. A. L. Anet J. Amer. Chem. SOC.,1972 94 4792. 250 F. A. L. Anet and P. J. Degen J. Amer. Chem. SOC.,1972 94 1390; (6)F. A. L. Anet and P.J. Degen Tetrahedron Letters 1972,361 3 ;(c) J. Dale T. Ekeland and J. Krane J. Amer. Chem. SOC.,1972 94 1389. I. D. Blackburne M. J. Cook and C. D. Johnson (226b) which is flexible on the n.m.r. time-scale even at -70°C.251U.v.-structure correlation^^^ and rates of racemization of bridged biphenyls e.g. (227),have been rep~rted,~ as have high-energy barriers (obtained by variable- temperature n.m.r. studies) for the conformational processes within systems such as (228),254 a series of bicyclic lactams e.g. (229),255 pyridinophanes (230),256 and the pyridine N-oxide series (231).257 The latter data provide useful insight into the steric requirements of the N-oxide moiety. 0 W0 EXD \ N / I Ac + (226) a; X = S (227) X = 0 or NMe,Br- (228) a; X = NMe b;X=S b;X=O s 0-s (230) RR = 0 or R = H Me or Ph (229) (231) n = 4 5 or 6 The skeletal rearrangements of 1,4-benzodiazepine derivatives to other heterocycle^^'^ and the use of bicyclic amidines as base are two subjects which have been reviewed.Thermolysis of the sodium salt of (232) has been shown to afford the 48-2,3-benzodiazepine (233) which isomerizes to the ’” K. Sato K. Uno and M. Kainosho J.C.S. Chem. Comm. 1972 579. 252 P. N. Braunton 1.T. Millar and J. C. Tebby J.C.S. Perkin It 1972 138. 253 P. A. Browne and D. M. Hall J.C.S. Perkin I 1972 2717. 254 A. Saunders and J. M. Sprake J.C.S. Perkin II 1972 1660. 255 K. Hemmi H. Nakai S. Naruto and 0.Yonemitsu J.C.S. Perkin It 1972 2252. 256 S. Fujita K. Imamura and H.Nozaki Bull. Chem. SOC.Japan 1972,45. 1881. *’’F. Vogtle and H. Rider Angew. Chem. Internat. Edn. 1972 11 727. ’” R. I. Fryer J. Heterocyclic Chem. 1972,9 747. 259 H. Oediger F. Moller and K. Eiter Synihesis 1972 591. Heterocyclic Chemistry 463 1H-isomer (234a) on standing.260 On photolysis the latter system (234b) collapses with no extrusion of nitrogen to the tricyclic structure (235) in marked contrast to the photodecomposition of the SH-isomer (236) which gives (237).261 The N N RZ (234) a;R' = Ph R2 = H b;R' = H,RZ = Ph q ,"N \ \ gN Ph Ph Ph (236) (237) (235) betaine (238a) obtained by methylation of (239) and the corresponding acyl analogue (238b) obtained by thermolysis of (240) both undergo 1,3-cyclo- addition reactions with dimethyl acetylenedicarboxylate.262 However further study of the reactions of (238a) revealed that it gives a 1,5-addition product (241) phfio h P Me e Ph&O N-N-N-N N /+ \ I R H RCO (238) a; R = Me (239) (240) R = Me or Ph b; R = COMe or COPh Me Me N-N N-N / Me 16' V.I. Bendall J.C.S. Chem. Comm. 1972 823. 261 A. A. Reid J. T. Sharp and S. J. Murray J.C.S. Chem. Comm. 1972 827. 262 0. S. Rothenberger R. T. Taylor D. L. Dalrymple and J. A. Moore J. Org. Chem. 1972 37,2640; 0.S. Rothenberger and J. A. Moore ibid. p. 2796. I. D. Blackburne M. J. Cook and C. D. Johnson with keten and a similar mode of addition is observed with aryl isocyanates though the products rearrange to the 1,3-adducts (242)even at -20 "C.Application of a general route to seven-membered-ring heterocycles by reaction of cyclobutenes and 1,3-dipolarophiles with subsequent cleavage of the internal single bond has afforded dihydroazepines e.g. the bicyclic structure (245)from (243)and (244).263Other derivatives of the ring system (245)have been obtained by valence isomerization of (246),and members of the series have been shown to undergo thermolysis to various dihydr~indoles.~~~ Cyclic NN'-disubstituted thioureas react with mercury bis(pheny1acetylide) in the presence of aryl iso- thiocyanates to give the bicyclic dithiazepines (247) in an intriguing one-pot reaction.265 Further syntheses of medium rings include those of the first medium- sized azo-compounds having a trans-azo-linkage e.g.(248),266the seven- to eleven-membered-ring phosphorus heterocycles (249) via the acyloin reaction on the corresponding die~ters,~~~ and the twelve-membered ring (251) in the photo-oxygena tion of (250). * Ph Me0,C \Ph (243) 1 (246) (247) n = 2 or 3 (248) 26 3 H.-D. Martin and M. Hekman Angew. Chem. Internat. Edn. 1972 11 926 264 A. G. Anastassiou S. W. Eachus R. L. Elliott and E. Yakali J.C.S. Chem. Comm. 1972 531 ; A. G. Anastassiou R. L. Elliott and A. Lichtenfeld Tetrahedron Letters 1972,4569. 265 W. Reid R. Oxenius and W. Merkei Angew. Chem. Internat. Edn. 1972 11 5 11. 266 C. G. Overberger M. S. Chi D. G. Pucci and J. A. Barry Tetrahedron Letters 1972 4565. 261 J. W. Van Reijenda.m and F.Baardman Tetrahedron Letters 1972 5181. 268 W. Adam and J. C. Liu J. Amer. Chem. SOC.,1972 94 1206. Heterocyclic Chemistry 00 (249) m = n = 2 3 or 4 (250) m = n -1 = 3 or4 The molecular geometry and physical and chemical properties of metacyclo-phanes have been reviewed269 and new nomenclature has been proposed for cyclophanes in general.270 Cyclophanes possessing cavities have been prepared e.g. (252),271 as have the macrocycles (253).272 Reports on crown ethers and 0 related compounds have again been numerous and include an authoritative review which lucidly describes the development of this area of research. It is reported that there are now more than 60 macrocyclic polyethers known and complexing of salts and other compounds by these as well as by nitrogen- and sulphur-containing rings is described.27 Analysis of i.r.vibrations of alkali-metal cations encaged in crown ethers shows that Na'-crown and K+-crown forces are nearly equal for dibenzo-18-crown-6 complexes and it follows that cation selectivity does not derive from differential ion-crown encagement forces but rather from the difference in stability of the solvated cations.274 An intriguing study on what have been termed 'proton cryptates' shows that the protons in the mono- and di-ammonium salts (254) and (255) are particularly firmly retained within the Thus (255) is unchanged after 18 days in 5M-KOH at room temperature and requires 80 h at 60 "C for partial conversion into (254). The n.m.r. spectrum of the latter shows that the cryptated proton is coupled to 2b9 F.Vogtle and P. Neumann Angew. Chem. Internat. Edn. 1972 11 73. 270 K. Hirayama Tetrahedron Letters 1972 2109; T. Kauffmann Terruhedron 1972 28 5183. 271 F. Vogtle and R. G. Lichtenthaler Angew. Chem. Internat. Edn. 1972 11 535; Tetrahedron Letters 1972 1905. 272 G. Schill K. Murjahn and W. Beckmann Chem. Ber. 1972,105 3591. 273 C. J. Pedersen and H. K. Frensdorff Angew. Chem. Internat. Edn. 1972 11 16. 2'4 A. T. Tsatsas. R. W. Stearns and W. M. Risen J. Amer. Chem. SOC.,1972,94 5247. '15 J. Cheney and J. M. Lehn J.C.S. Chem. Comm. 1972,487. 1. D. Blackburne M. J. Cook and C. D. Johnson protons c1-to the nitrogen atoms and that no H-D exchange occurs with the deuterons of D20. Dicyclohexyl-18-crown-6 (DCC) is another powerful proton- solvating agent having a high basicity and a low entropy of c~rnplexation,~~~ and further crystalline oxonium ion-DCC complexes have been obtained.277 papers of an essentially synthetic nature include reports of the facile syntheses of 18-crown-4 21-crown-7 24-crown-8 and aza-18-cro~n-6,~~ chiral crown amino-ether~,~’~ and the macrotricyclic ligand (256).280 The role played by (256) crown ethers in ion-pair dissociation e.g.in base-catalysed isomerizations2* and eliminations,282 continues to attract attention and details of the solubilizing effect of DCC on potassium permanganate in benzene and of the excellent oxidizing capabilities of that system emphasize the potential of these rings in organic ~hemistry.~ 83 ’16 E.Shchori and J. Jagur-Grodzinski J. Amer. Chem SOC.,1972,94 7957. ’’’ R. M. Izatt B. L. Haymore and J. J. Christensen J.C.S. Chem. Comm. 1972 1308. 2’0 R. N. Greene Tetrahedron Letters 1972 1793. 279 F. Wudl and F. Gaeta J.C.S. Chem. Comm. 1972 107. ”O J. Cheney J. M. Lehn J. P. Sauvage and M. E. Stubbs J.C.S. Chem. Comm. 1972 1100. 281 M. J. Maskornick Tetrahedron Letters 1972 1797. 282 M. Svoboda J. Hapala and J. Zavada Tetrahedron Letters 1972 265; J. Zavada M. Svoboda and M. Pankova ibid. p. 71 1 ;R. A. Bartsch G. M. Pruss R. L. Buswell and B. A. Bushaw ibid. p. 2621 ; R. A. Bartsch and K. E. Wiegers ibid. p. 3819. ’” D. J. Sam and H. E. Simmons J. Amer. Chem. SOC.,1972 94 4024.

ISSN:0069-3030    

DOI:10.1039/OC9726900425

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

14 Biosynthesis By E. McDONALD Universiry Chemical Laboratory Lensfield Road Cambridge CB2 I EW 1 Monoterpenes Studies of monoterpene biosynthesis have so far met with limited success and an excellent review' by Banthorpe et al. fully explains the problems involved in this work. The article critically surveys the experimental methods analyses the biological aspects and gives complete details of all incorporation studies to date. For the organic chemist the chief conclusions are firstly that radioactive carbon dioxide is often absorbed by plants and incorporated efficiently into mono- terpenes. If the specific activity of a number of compounds is then measured as a function of time an indication of their sequential relationship may be secured. These studies incidentally show that monoterpenes are metabolized quite rapidly.Secondly mevalonic acid [MVA (l)] is generally not incorporated well into HOH,C CO,H (1) monoterpenes for a variety of possible reasons. One problem the compart- mentalization of the key enzymes within impenetrable cells might be overcome by the development of tissue cultures and Banthorpe also reports' that such a culture of Tanaceturn uulgare had a 0.1 % monoterpene content with a range of compounds similar to that found in the intact plant albeit with a very different relative abundance. Thus the major component of the plant isothujone (2) is replaced by sabinene (3) in the culture perhaps because oxygenation is limiting A A (2) (3) ' D. V. Banthorpe B. V. Charlwood and M.J. 0. Francis Chem. Retl. 1972,72 115. D. V. Banthorpe and A. Wirz-Justice J.C.S.Perkin I 1972 1769. 467 468 E. McDonald in uitro. A third important conclusion is that when the experimental difficulties can be overcome and labelled MVA is incorporated into monoterpenes it is frequently noted that the two C units are labelled unequally. Two recent examples are seen in the feedings of [2-I4C]MVA (1) to Mentha pulegium3 and to Pinus radiata4 where pulegone (4)and a-pinene (5),respectively are predominantly (4) labelled at only one carbon atom as indicated. The current view that these mono- terpenes are derived from MVA via isopentenyl pyrophosphate [IPP (6)] dimethylallyl pyrophosphate [DMAPP (7)] and geranyl pyrophosphate [GPP (8)] reveals that the heavy labelling is always found in the IPP portion of the mono- terpene.Hence a reasonable explanation of the results is that a pool ofendogenous DMAPP traps the labelled IPP before it can be isomerized. O@ r (7) (8) In Saluia oficianalis [2- '4C]geraniol [cj. (S)] is specifically incorporated5 into camphor (lo) in accord with the intermediacy of ion (9). Extensive recrystalliza- tion of derivatives of camphor revealed the true level of incorporation (3.3 x lop3%),whereas a much higher apparent incorporation (120 x had D. V. Banthorpe B. V. Charlwood and M. R. Young J.C.S. Perkin I 1972 1532. D. V. Banthorpe and G. N. J. Le Patourel Biochern. J. 1972,130 1055. A. R. Battersby D. G. Laing and R. Ramage J.C.S. Perkin I 1972 2743.Biosynthesis 469 been indicated when the compound was 'pure' by g.1.c.-radioscan analysis a cautionary note for all who carry out crucial experiments on non-crystalline compounds. The crystalline monoterpene glycosides and the related monoterpene indole alkaloids have already revealed many of their biosynthetic secrets (reviews 677) and the feeding experiments' reported by Inouye et al. are straightforward additions to the established results. 2 Sesquiterpeneswith a Regular Carbon Skeleton A striking contrast between mono- and sesqui-terpenes is provided by studiesg on Mentha piperita. Its essential oil has 98 % monoterpenes and 2 % sesquiter-penes and radioactivity from 14C02 is distributed in a similar way. However the activity from [2-I4C]MVA (1) was located mainly in the sesquiterpene fraction and it was possible to isolate and degrade the caryophyllene (11).The pattern of labelling again shows a poor incorporation into the (presumed) DMAPP portion of the molecule (cf. monoterpene section). (by difference) Juvenile hormone (12) appears to be a twice-methylated derivative of farnesol (13); yet neither farnesol nor MVA are incorporated" into the hormone by the moth Hyalophora cecropia. In biosynthetic work a negative result is unreliable evidence on which to base or discard a theory and it seems likely that technical problems in reaching sites of biosynthesis are responsible in this example. ' A. R. Battersby Accounts Chem. Res. 1972 5 148. ' R. J. Parry Chem. Heterocyclic Compounds 1972 25 1.H. Inouye S. Ueda K. Inoue and Y. Takeda Tetrahedron Letters 1972,4069,4073. R. Croteau and W. D. Loomis Phytochemistry 1972 11 1055. lo M. Metzler K. H. Dahm D. Meyer and H. Roller Z. Naturforsch. 1971 26b,1270. 470 E. McDonald The sesquiterpenoid origin of mycophenolic acid (14) was discussed in last year's report' and the full details of the Italian contribution ' have now appeared. Siccanochromene A (15) is also a polyketide-sesquiterpeneand is formed in high yield when the mould Helrninthosporium siccans is incubated' with orsellinic acid (16) and either MVA(1) or farnesyl pyrophosphate [cJ (13)l. A different Helrninthosporium species H. sativum was used in a study14 of the isomerization of [l-2H2Jfarnesol [cf.(13)] to its geometrical isomer nerolidol (17). Both the recovered farnesol and its isomer had lost some deuterium from C-1 and it was concluded that the corresponding aldehydes are intermediates in the isomeriza- tion. HoQMe OH (16) The carbon skeleton of the plant hormone abscisic acid (18) is derived from three molecules of MVA (l),but the hormone is clearly at a higher oxidation level than MVA itself. The stereospecificities of the oxidations which introduce the 4,5 and 2',3' double bonds have been probed' 'by feeding stereospecifically- labelled samples of MVA to avocados (Perseagratissirna). The extent of labelling at C-3' was determined by base-catalysed exchange whereas that at C-4 was obtained by conversion into the lactone (19). Both of these hydrogen atoms seem to come from the 2-pro-R-H of MVA whereas that at C-5 is derived from the 5-pro-S-H .E. McDonald Ann. Reports (B) 197 1 68 395. L. Canonica W. Kroszczynski B. M. Ranzi B. Rindone E. Santaniello and C. Scolastico J.C.S. Perkin I 1972 2639. l3 K. T. Suzuki and S. Nozoe J.C.S. Chem. Comm. 1972 1166. l4 Y.Suzuki and S. Marumo Tetrahedron Letters 1972 5101. l5 B. V. Milborrow Biochem. J. 1972 128 1135. Biosynthesis 471 3 Sesquiterpenes with a Rearranged Carbon Skeleton The eremophilane skeleton of isopetasol (21) was shown16 by degradation to be labelled by [2-I4C]MVA in a manner consistent with the intermediacy of ion (20). Further support for the hydride shift came from feeding [4-3H,2-'4C]- MVA and the isolation of petasin (22)carrying tritium at C-4.Specifically tritiated copaborneol (24) was prepared' ' by vigorous base- catalysed exchange of the corresponding ketone (via an enolate which violates Bredt's rule) and subsequent reduction. The compound was incorporated' by Coriariajaponica into tutin (25) labelled at C-5. The specificity of labelling was proved by a subtle two-stage degradation to (26),which exchanges only the C-5 proton on mild treatment with wet pyridine. Furthermore tutin carries tritium at C-4 when the precursor is [(4R)-4-3H]MVA,'9 in accord with a predicted biosynthetic route to copaborneol via the ion (23). Considerable evidence has accumulated during 1972 concerning the bio- synthesis of the tricothecane group of sesquiterpenes.All of it supports the idea l6 C. J. W. Brooks and R. A. B. Keates Phytochemistry 1972 11 3235. " K. W. Turnbull S. J. Gould and D. Arigoni J.C.S. Chem. Comm. 1972 597. l8 K. W. Turnbull W. Acklin D. Arigoni A. Corbella P. Gariboldi and G. Jommi J.C.S. Chem. Comm. 1972 598. '' A. Corbella P. Gariboldi and G. Jommi J.C.S. Chem. Comm. 1972 600. 472 E. McDonald / A that farnesol folded as shown (27) is converted via the ions (28)-(30) into trichothecolone (31). Thus [2-3H]geraniol [cf (S)] [which should label the intermediate (28) as indicated] is converted by Helicobasidium rnompa into heli- cobasidin (32) without loss of tritium ;20 the fully substituted six-membered ring makes a hydride shift into the five-membered ring an obligatory step.This result and related ones obtained earlier rule out the intermediacy of y-bisabolene (33); therefore the non-incorporation2’ of (33) and two other compounds with the same skeleton into the trichothecane metabolites of T. roseurn is not surprising. In contrast trichodiene (34) which is closely related to the ion (30) is efficiently incorporated” by the same fungus into tricothecolone (31). Nozoe has also shownZ3 that one-third of the label from [2-I4C]MVA is located at C-8 of tri- cothecolone (31) thus precluding any rotation of the six-membered ring about the C-5-C-6 bond of the intermediates (28)-(30). Finally a large number of feeding experiments involving labelled MVA geraniol and farnesol are collected together24 and analysed by Hanson in support of the scheme discussed above.4 Diterpenes The literature (apparently through 1969) has been reviewed25 by Hanson who has also described26 the preparation from Gibberella Jkjikoroi of a cell-free extract capable of converting MVA into (-)-kaurene. Such preparations enable 2o P. M. Adams and J. R. Hanson J.C.S. Perkin I 1972 586. J. M. Forrester and T. Money Canad. J. Chem. 1972,50 3310. S. Nozoe and Y. Machida Tetrahedron Lefters 1972 1969. Y. Machida and S. Nozoe Tetrahedron 1972 28 5 113. ’‘ B. A. Achilladelis P. M. Adams and J. R. Hanson J.C.S. Perkin I 1972 1425. 25 J. R. Hanson Progr. Chem. Org. Natural Products 1971 29 395. ’’ R. Evans and J. R. Hanson J.C.S. Perkin I 1972 2382. Biosynthesis 473 I I (33) (34) the chemist to use heavy isotopes for biosynthetic studies and the present work involved the incorporation of [6-2H,]MVA (35) into (-)-kaurene (36) and the location of the deuterium by a combination of mass spectrometry and chemical degradation.The result rules out the intermediacy of pimaradiene (37). The bioconversion of (-)-kaurene into the gibberellins is known to proceed via the acid (38) ;of the hydroxylated derivatives of (38)so far tested only the 7P-hydroxy- compound (39) is incorporated. Furthermore the mechanism of its conversion into gibberellin AI2 aldehyde (40) must involve a shift of the 6P-H to C-7. This was deduced2' from a feeding of [l-3H,1-'4C]geraniol [cf @)I which gives J. R. Hanson J. Hawker and A. F. White J.C.S. Perkin I 1972 1892.474 E. McDonald I C0,H (38) R = H (39j R = OH / H 02'C (40) R = CHO (41) R = C02H gibberellin A, aldehyde without loss of tritium whereas oxidation to the acid (41)results in the loss of half the total tritium. By feeding [1-13C]- and [2-13C]-acetic acid to cultures of the mushroom Oospora uirescens Polonsky and Wenkert were able to prove by n.m.r. that the pimarane skeleton does indeed possess the predictable labelling pattern (42)." 5 Triterpenes The chemist's understanding of the pathways involved in triterpene biosynthesis is already fairly complete (review 29) and this year's contributions are mainly sophisticated refinements to the main pathways. Thus Ogura has investigated3' the substrate specificity of the enzymes responsible for converting farnesyl J.Polonsky Z. Baskevitch N. Cagnoli-Bellavita P. Ceccherelli B. L. Buckwalter and E. Wenkert J. Amer. Chem. SOC.,1972 94 4369. 29 L. J. Mulheirn and P. J. Ramm Chem. SOC. Rev. 1972 1 259. 30 K. Ogura T. Koyama and S. Seto J. Amer. Chem. SOC. 1972 94 307. Biosynthesis 475 pyrophosphate into squalene finding that either of the terminal monoethyl homologues will act as substrates but neither of the mono-n-propyl analogues is acceptable. The degradation of lanosterol (43) to the steroids involves the oxidative removal of the gern-dimethyl group at C-4 and of the methyl at C-14. OD t-CH,CO,H It was known that the 4cr-Me appeared as carbon dioxide (nor formaldehyde or formic acid) and Barton and Akhtar have now shown31 that in contrast the labelled diol(44) is oxidized via the corresponding aldehyde to the nortriterpene (45) and labelled formic acid by microsomes (presumably liver?).Canonica’s feeding32 to Digitalis /anam of [2-’4C,(4R)-4-3H]MVA should provide as an inter- mediate the labelled cholesterol (46) and he has shown by an unusual cyclical reaction scheme that the 24-H of cholesterol (46) becomes the 24-equatorial-H of tigogenin (47). An overall trans-hydrogenation of A24,25is apparent. H H (45) ” K. Alexander M. Akhtar R. B. Boar J. F. McGhie and D. H. R. Barton J.C.S. Chrm. Comm. 1972 383. ’’ L. Canonica F. Rouchetti and G. Russo J.C.S. Chrrn. Comm. 1972 1309. 476 E. McDonald 0% HO H 24 &F (47) The plant steroids frequently carry an ethyl side-chain at C-24 and two recent pieces of evidence are in support of the conversion of cholesterol (46)into the key intermediate ion (48) in which hydride has migrated from C-24 to C-25; sub-sequent proton loss may occur in several ways but only the A24*25intermediate (46) T J T s (46) + CH3CHO g+ I -r -Y&y 11 I’ H Biosynthesis 477 (49) is hydrogenated to p-sitosterol (50).The evidence comes first33 from a feeding to Larix decidua of stereospecifically-labelled MVA which should provide cholesterol (46) as an intermediate carrying three tritium atoms exactly as in Canonica's work (see above). Isofucosterol(51) had retained three tritium atoms despite the absence of hydrogen at C-24 while p-sitosterol (50)retained only two tritium atoms (all relative to five 14C atoms).The location of the labelled atoms was not proved in this piece of work but in the same experiment with Ochrornonas malharnensis the side-chain of poriferasterol (52) was degraded partially to give results consistent with the illustrated labelling pattern.34 The plant steroids are the insects' dietary source of cholesterol and it appears3' that removal of the ethyl group of isofucosterol (51) by the yellow meal worm Tenebrio rnolitor involves a reverse hydride shift back from (2-25 to C-24. The relative efficacy of various ethyl derivatives has also been tested36 and a reasonable scheme has been postulated for (51)-+(46). 6 Carotenoids It is satisfying to observe how quickly the important presqualene pyrophosphate work reported last year" has been applied here also.Altman and Rilling have now synthesized the analogous prephytoene alcohol (53) in labelled form and shown37 that it is converted by Mycobacteria into lycopersane (55). Radioactive prephytoene alcohol was isolated from the bacteria after incubating with labelled geranylgeraniol. The central portion of the lycopersane molecule is at a higher 11 CHTOH JL RCH, RCH, *Me (54) (55) R = farnesyl skeleton cf (13) (56) 33 P. J. Randall H. H. Rees and T. W. Goodwin J.C.S. Chem. Comm. 1972 1295. 34 A. R. H. Smith L. J. Goad and T. W. Goodwin Phytochemistry 1972 11 2775. 35 P. J. Randall J. G. Lloyd-Jones I. F. Cook H.H. Rees and T. W. Goodwin J.C.S. Chem. Comm. 1972 1296. 36 M. Morisaki H. Ohtaka M. Okubayashi N. Ikekawa Y. Horie and S. Nakasone J.C.S. Chem. Comm. 1972 1275. 37 L. J. Altman L. Ash R. C. Kowerski W. W. Epstein B. R. Larsen H. C. Rilling F. Muscio and D. E. Gregonis J. Amer. Chem. SOC. 1972 94 3257. 478 E. McDonald oxidation level than that of squalene and it appears that their analogous cationic intermediates (54) respectively lose a proton and capture a hydride ion. An unexpected result has been obtained by feeding certain monoterpenes to Thuja vulgare. Radioactivity from ~-['~C]terpineol(56) and [G-'4C]isothujone (2) was found38 in the carotenoid fraction and degradation showed that it was located only in the terminal rings. The initial response that these incorporations must be non-specific must therefore be modified and if degradation-reincorporation is the explanation then the degradation must specifically provide DMAPP (7) but not IPP (6).7 Polyketides The quinone shanorellin (57)39 and the antibiotics citreoviridin (58),"' X 537 A (59);' and aureothin (60)42 have been isolated after feedings to the appropriate micro-organism of I3C- or l4C-1abelled acetate propionate butyrate and methionine. The results of these preliminary experiments confirm that the carbon skeleta of (57)-(60) have been built up in a now predictable polyketide manner; no intermediates or mechanistic details are available with the exception43 that ,.&he OMe . oo*y HO CH,OH -* 0 AA (57) (58) HO Me (59) CH CH 2@02 CH,CH,CH,FO,H H 38 D.V. Banthorpe H. J. Doonan and A. Wirz-Justice J.C.S. Perkin I 1972 1764. 39 C.-K. Wat A. G. McInnes D. G. Smith and L. C. Vining Canad. J. Biochem. 1972 50 620. 40 D. W. Nagel P. S. Steyn and N. P. Ferreira Phytochemistry 1972 11 3215. 41 J. W. Westley D. L. Pruess and R. G. Pitcher J.C.S. Chem. Comm. 1972 161. 42 M. Yamazaki F. Katoh J. Ohishi and Y. Koyama Tetrahedron Letters 1972 2701. 43 R. Cardillo C. Fuganti D. Ghiringhelli D. Giangrasso and P. Grasselli Tefrahedron Letters 1972 4875. Biosynthesis 479 OH 0 T T 0 (611 (60) CH,CH2C0,H the non-polyketide portion of aureothin (60)is provided by the novel amino-acid (61). The synthetic and degradative aspects are of unusual interest in a paper44 by Hassall who reports the intact incorporation of doubly-labelled questin (62)into sulochrin (63) by Aspergillus terreus.Additionally the inter-relation of several anthraquinones related to questin has been reported.45 Scott has considered two alternative mechanisms for the bioconversion of 3-methyl orsellinic acid (64) into stipitatonic acid (65) and has incubated Pen-cillium stipitaturn in the presence of "0,in an attempt to distinguish between them. The situation is complicated by the possibility that the intermediates may 0 1 RoG H HO HO 0 0 (65) R = H (66) R = OH 44 R. F. Curtis C. H. Hassall and D. R. Parry J.C.S.Perkin I 1972 240. 45 W. Steglich R. Arnold W. Losel and W. Reininger J.C.S.Chem. Comm. 1972 102. 480 E. McDonald exchange oxygen atoms with the aqueous medium but the results are inter- ~reted~~ in favour of the mono-oxygenase mechanism (b). Studies on a similar tropolone puberulonic acid (66)are also rep~rted.~’ 8 Shikimate Metabolites Floss has reported4* that during aromatic amino-acid biosynthesis in Reseda lutea the 6-pro-R-H of shikimic acid (67)is lost but the 6-pro-S-H is retained in the indicated positions of Phe (69),Tyr (70) and rn-carboxyphenylalanine (72). These results are explained in terms of chorismic acid (68) partitioning itself between a direct Cope rearrahgement [to eventually give (69)and (70)]and an isomerization to the postulated intermediate (71). I OH OH (67) (70) HO,C GTco2H OH (48) C02H (71) [1,6-14C2]Shikimic acid [cc (67)]was fed49 to Pseudornonas aureofaciens and the metabolite phenazine-1-carboxylic acid (73)was degraded to pyrazinetetra-carboxylic acid (74) and pyrazine (75)carrying 100 % and 50 % respectively of C02H aN;fJ N R -pJR (73) (74) R = COzH (75) R = H 46 A.I. Scott and K. J. Wiesner J.C.S. Chem. Comm. 1972 1075. 47 A. I. Scott and E. Lee J.C.S. Chem. Comm. 1972,655. 48 P. 0.Larsen D. K. Onderka and H. G. Floss J.C.S. Chem. Comm. 1972 842. 49 U. Hollstein and L. G. Marshall J. Org. Chem. 1972 37,3510. Biosynthesis 481 the incorporated radioactivity. This result somewhat restricts the possible modes of combination of two shikimate residues but the symmetry prevents a definite assignment.The situation is also discussed50 by Holliman and Herbert who report additional sequence studies5 in the phenazine series. A cautionary note52 from Kirby describes the unexpected zxchange of the 3’-pro-S-H of Phe (69) with protons of the medium during Trichoderrna uiride incubations. The phenomenon could easily lead to misinterpretation of the results of incorporation of Phe into more complex systems. Full details have appeared of Battersby’s work5 on L-phenylalanine ammonia lyase along with the extensions4 of this study to L-tyrosine ammonia lyase; the full details” of the early stages of colchicine biosynthesis have also been published. The latter topic and other aspects of alkaloid biosynthesis are being covered this year in the Report on Alkaloids but one new development in this field deserves a special mention here namely the study of enzyme specificity in plants.Such studies have recently appeared for isolated enzymes e.g. the work of Corey and van Tamelen on oxidosqualene cyclase,’ and Kirby now reportss6 the simultaneous feeding of [N-Me-’4C]codeine (76)and one of a series of tritiated analogues (C’) to Papaver sornniferurn. By dilution with radioinactive material the alkaloids codeine (C) morphine [M (77)] and the modified ‘alkaloids’ C’ and M’ were (76) R = Me (77) R = H isolated and purified. The ratio M’/M gives an indication of how efficiently the modified precursors are metabolized and a surprising result is that the compound (78)is metabolized equally as well as codeine itself.The authors conclude that neither the hydroxy-group nor the double bond is required for enzyme binding. A somewhat similar study” of nicotine biosynthesis appeared in 1971. Betanin (79) the red pigment of beetroot can be degraded to betalamic acid (80) and earlier labelling studizs have shown that this portion of the molecule R. B. Herbert F. G. Holliman and P. N. Ibberson J.C.S. Chem. Comm. 1972 355. ” M. E. Flood R. B. Herbert and F. G. Holliman J.C.S. Perkin I 1972,622. 52 J. D. Bu’Lock A. P. Ryles N. Johns and G. W. Kirby J.C.S. Chem. Comm. 1972 100. 53 R. H. Wightman J. Staunton A. R. Battersby and K. R. Hanson J.C.S. Perkin I 1972,2355. 54 P. G. Strange J. Staunton H. R. Wiltshire A. R. Battersby K. R. Hanson and E.A. Havir J.C.S. Perkin I 1972 2364. 55 A. R. Battersby R. B. Herbert E. McDonald R. Ramage and J. H. Clements J.C.S. Perkin I 1972 1741. ” G. W. Kirby S. R. Massey and P. Steinreich J.C.S. Perkin I 1972 1642. ” M. L. Rueppel and H. Rapoport J. Amer. Chem. Soc. 1971,93 7021. 482 E. McDonald HO,C QC0,H H (79) is derived from DOPA (82). Similar pigments are present in Opuntia decurnbens and Dreiding fed to this cactus [3,S3H,]Tyr (81) in an effort5* to distinguish between the illustrated modes of cleavage of the aromatic ring. Tritium was retained in betalamic acid (80) supporting pathway (a). Another example of oxidative cleavage of a shikimate-derived aromatic ring is provided by the cyanogenic glucoside (84).Feeding experiment^^^ with Thalictrurn aquilegifbliurn support the sequence Tyr -+ (83)-+ (84)as illustrated.CH0 HO,C*OC02H H Tyrosine (81) + ArYN-*" + Ar-CN CO H 1 0 glucose 'O2'YCN Me0,C (84) (83) 58 N. Fischer and A. S. Dreiding Helv. Chim. Acra 1972 55 649. 59 D. Sharples M. S. Spring and J. R. Stoker Phytochemistry 1972. 11 2999. Biosynthesis 483 9 Porphyrins and Vitamin B The 'Type-111 problem' in porphyrin biosynthesis was discussed in last year's report and although the solution is not yet available several recent results will assist the final analysis. [l 1-i3C]P~rphobilin~gen [PBG (85)l was converted by a cell-free preparation from Euglena gracilis into [13C]protoporphyrin-IX (86)whose 'H-decoupled I3Cn.m.r. spectrum clearly showed 6o only four singlets of equal intensity proving beyond any doubt that all of the rneso-carbons (86; a.p y and 6) originate from C-11 of PBG. Two molecules of PBG (85) Co2H A = CHzCOzH P = CHzCH,C02H may conceivably condense to give four simple pyrromethanes (87H90). Abiological evaluation6' of (89) may now be compared with last year's results on the isomers (87) and (88) but no entirely convincing proof has yet been pub- lished to favour any one of these intermediates. Bogorad has reported62 the isolation of a bilane after incubating spinach-leaf tissue with PBG (85) in the (87) 'H H NH (89) (90) 'O A. R. Battersby J. Moron E. McDonald and J. Feeney J.C.S. Chem. Comm. 1972 920. 61 R. B. Frydman A. Valasinas H. Rapoport and B.Frydman F.E.B.S. Letters 1972 25 309. " R. Radmer and L. Bogorad Biochemistry 1972 II 904. 484 E. McDonald presence of inhibitors. Structure (91) is proposed for this labile intermediate but it is claimed that the compound is not a substrate for any of the enzymes which convert PBG (85) into uroporphyrinogens [e.g.(92)]. Specifically-labelled uroporphyrinogen I11 (92) and coproporphyrinogen 111 (93) were efficiently converted without scrambling into the protoporphyrin IX (86)skeleton by haemo- lysed duck blood63 and E. gr~cilis,~~ respectively. APAPAPAP JJiijiUJ N N N NH2 N H H H H *\ NH HN /' CO,H A Me Me (92) (93) An aspect of porphyrin biosynthesis unrelated to the Type-I11 problem is the conversion of the propionate side-chains of coproporphyrinogen I11 (93) into the vinyl side-chains of protoporphyrin-lX (86).Several mechanisms may be postulated for this double oxidative decarboxylation but these are restricted by the results of two rather different experimental approaches to the problem. Bat tersby demonstrated 65 that [p-'H J-and [a-* H'1 -PBG (85) gave respectively ['H6] and ['HJ samples of protoporphyrin-IX (86) and the location of the deuterium was proved by n.m.r. to be in the expected sites. In further experiments with [p-3H]PBG (85) the retentions of tritium in protoporphyrin-IX and its degradation products were consistent with a stereospecific attack at the P-carbon during the oxidative decarboxylation. In Akhtar's approach66 the earlier precursor 6-aminolaevulinic acid [S-ALA (94)] was converted by haemolysed b3 B.Franck D. Gantz P.-F. Montforts and F. Schmidtchen Angew. Chem. Infernat. Edn. 1972 11 421. 64 A. R. Battersby J. Staunton and R. H. Wightman J.C.S. Chem. Comm. 1972 1118. 65 A. R.Battersby J. Baldas J. Collins D. H. Grayson K. J. James and E. McDonald J.C.S. Chem. Comm. 1972 1265. 66 Z. Zaman M. M. Abboud and hh. Akhtar J.C.S. Chem. Comm. 1972 1263. Biosynthesis 485 duck blood into haemin (96) presumably labelled multiply as shown. Degrada- tion gave the imides (97) and (98) and the ratio of their specific radioactivities provided an analysis of the extent of tritium loss during the oxidative decarboxyla- tion step. (The assumption that there is no incidental loss of tritium from rings .+C02H &C02H HO,C HR CO,H CO,H H.5 c and D nor any migration of tritium between c1 and P carbons is justified by Battersby’s deuterium work.) Akhtar’s further experiments with stereospecific- ally-tritiated succinic acids [cf.(95)] provide the first evidence that the attack at the P-carbon involves removal of the pro-S hydrogen atom in both cases. The corrin nucleus (99) of vitamin B, bears a close structural relationship to the nucleus of uroporphyrinogen I11 (92). The vitamin has apparently gained seven extra methyl groups (at carbons 1 2 5 7 12 15 and 17) at the expense of the 486 E. McDonald 6-rneso-carbon atom and CO from the acetate side-chain of ring c. Two research gro~ps~~?~’ have failed to observe any significant incorporation of uroporphyr- inogen-111 into the vitamin by Propionibacterium sherrnanii but Scott reports6* that if sufficiently large concentrations of uroporphyrinogens are used then the type-111 isomer (92) labelled equally with I3C in all four propionate side-chains does give vitamin B, with four strong n.m.r.signals in the region expected for the propionamide side-chains. In 1958 Shemin had concluded with reservations that the unique angular methyl group at C-1 of vitamin B, was derived from C-5 of 8-ALA but in revised work6’ on this topic Shemin and Katz have recently highlighted the special value of l3C-1abelling in biosynthetic work. It is now clear in the I3C n.m.r. spectrum of vitamin BI2 biosynthesized from 6-[5-I3C]ALA (94) that the angular methyl group is not labelled.Scott has confirmed this re~ult’~ using a more highly enriched specimen of d-ALA so that the resultant n.m.r. signals of the sp2 carbons are more clearly defined. A further 13Cexperiment showed that all seven ‘extra’ methyl groups have a common origin in the methyl group of methionine. Further details have appeared’ concerning the 5,6-dimethylbenzimidazole moiety whose origin was discussed in last year’s report. 67 G. Muller and W. Dieterle Z. physiol. Chem. 1971 352 143. A. I. Scott C. A. Townsend K. Okada M. Kajiwara and R. J. Cushley J. Amer. Chem. Soc. 1972,94,8269. 69 C. E. Brown J. J. Katz and D. Shemin Proc. Nut. Acad. Sci.U.S.A. 1972 69 2585. ’O A. I. Scott C. A. Townsend K.Okada M. Kajiwara P. J. Whitman and R. J. Cushley J. Amer. Chem. SOC.,1972 94 8267. 71 P. Renz and R. Weyhenmeyer F.E.B.S. Letters 1972 22 124. 72 S. H. Lu and W. L. Alworth Biochemistry 1972 11 608.

ISSN:0069-3030    

DOI:10.1039/OC9726900467

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

15 Alkaloids By H. F. HODSON The Wellcome Research Laboratories Beckenham Kent BR3 3BS 1 Introduction The excellent comprehensive coverage provided by Volume 1 of the Specialist Periodical Reports on Alkaloids has been maintained in Volume 2,2 which covers the period July 1970 to June 1971 and deals with the whole alkaloid field with the exception of the steroidal bases of the Solanurn and Veratrurn groups. The first volume of the Specialist Periodical Reports on Biosynthesis3 has also been published the chapter on alkaloid biosynthesis includes a tabular survey of all incorporations reported during 1971. Two papers4,’ describe in tabular form the screening for alkaloid content of plant extracts which had previously been tested for antitumour activity and found to be inactive.The 2000 extracts examined to date represent 1688 species of diverse geographical origin ;490 gave positive alkaloid tests and 288 of these had not previously been reported to contain alkaloids. As more species are examined and as separation techniques and structural elucidations become more refined there have been an increasing number of reports in which alkaloids or alkaloid types previously thought to be unique to one particular genus or family have been isolated from a completely unrelated plant species ; this trend has continued during the year under review. Repeating the pattern noted last year most newly isolated alkaloids are either examples of known types or have structures which can readily be accommodated within biogenetic schemes which are well established or currently accepted.A considerable amount of synthetic work has appeared but unlike that discussed last year6 most of the notable synthetic achievements involve ingenious applica- tions of known reactions rather than new ones. It is striking that so many of the syntheses reported this year have been motivated (at least in part) by the actual or potential therapeutic value of the target compound ;thus there have been four ‘The Alkaloids’ ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 197 1 vol. 1. ’ ‘The Alkaloids’ ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 1972 vol. 2. ‘Biosynthesis’ ed. T. A. Geissman (Specialist Periodical Reports) The Chemica Society, London 1972 vol.1. S. J. Smolenski H. Silinis and N. R. Farnsworth Lloydia 1972 35 1. H. H. S. Fong M. Trojankova J. Trojanek and N. R. Farnsworth Lloydia 972 35 117. ‘ H. F. Hodson Ann. Reporrs (B) 1971 68 493. 487 488 H. F. Hodson syntheses of camptothecin two of cephalotaxine and two of ellipticine all alkaloids with antitumour activity. 2 Pyridine and Pyrrolizidine Alkaloids In a biomimetic synthesis,' (f)-nicotine has been prepared (Scheme 1) in a yield of 7 % from an aqueous solution of glutaraldehyde ammonia and 1-methyl-A'- pyrrolinium acetate in aqueous solution at pH 10 in the presence of air. Reagents i NH,; ii ;iii [O] Me Scheme I Swazine (l),a new alkaloid from Senecio swaziensis is unique in having an epoxide ring in the diacid moiety.Acidic hydrolysis of (1) gave the base retro- necine together with the novel spirodilactone (2),whose structure was deduced' by X-ray crystallography of the p-bromobenzoate. The mode of attachment of the diacid is the reverse of that at first suggested and was establishedg by an X-ray study of the methiodide of (1). It is now well established that the dramatic hepatotoxicity of the toxic pyrrolizi- dine alkaloids depends on their metabolic conversion into pyrrole esters of part structure (3) these being potent alkylating agents. A full account of the recent extensive chemical and biochemical work in this area has been published." ' E. Leete J.C.S. Chem. Comm. 1972 1091. * C. G. Gordon-Gray R. B. Wells N. Hallak M.B. Hursthouse S. Neidle and T. P. Toube Tetrahedron Letters 1972 707. ' M. Laing and P. Sommerville Tetrahedron Letters 1972. 5183. A. R. Mattocks in 'Phytochemical Ecology' Academic Press London and New York 1972 p. 179. Alkaloids 489 3 Quinoline Alkaloids A new and convenient general procedure' 'for the preparation of furanoquinoline alkaloids of the dictamnine type is illustrated by the synthesis (Scheme 2) of dictamnine (4; R' = R2 = H) itself. R'@ / OMe i,ii \ ~ Rlw R2 R2 (6)R' = R2 = Me0 liii Reagents i BuLi then BrCH,CH =CMe,; ii HCl; iii 0 or Os0,-10,-; iv PPA Scheme2 In two plant species labelled dictamnine [cf (4)]prepared by the method of Scheme 2 was efficiently incorporated (1.7-2.1 % and 1.2-3.5 %) into the dimethoxy-alkaloid skimmianine (4; R1= R2 = OMe).' ' Since platydesmine (5 ;R = H) is known to be a highly efficient precursor of dictamnine this suggests the pathway platydesmine (5; R = H)+ dictamnine (4; R' = R2 = H)-+ skimmianine (4;R' = R2 = OMe) with aromatic hydroxylation and methyla- tion as the last steps.However a newly isolated alkaloid from Dictamnus albus has been proved by synthesis,I2 to have structure (6),suggesting itself as a likely biogenetic precursor via (5; R = OMe) of skimmianine which has long been J. F. Collins W. J. Donnelly M. F. Grundon D. M. Harrison and C. G. Spyropoulos J.C.S. Chem. Comm. 1972 1029. I' R. Storer and D. W. Young Tetrahedron Letters 1972 2199. 490 H. F. Hodson known as a constituent of this plant ;this new base has been named preskimmia- nine.If (6) is indeed a precursor of skimmianine then different pathways may be followed in different plants or possibly even in the same plant. However pre- skimmianine is not proved to be a precursor of skimmianine and it should be noted that in several recent cases detailed investigations have shown that the ‘obvious’ chemical pathway is not the one followed in the plant. 4 Isoquinoline Alkaloids A reviewI3 provides an account of developments in this field over the past five years. Imeluteine (7; R = OMe) and rufescine (7; R = H) from Abuta spp. (Meni- spermaceae) are alkaloids of a new structural type. l4 The azafluoranthene skeleton of (7) must surely be derived from 1-phenylisoquinoline precursors ; alkaloids of this latter type are rare and have only recently been recognized although not in the Menispermaceae.The structures (7) were suggested by spectroscopic data and confirmed by unambiguous syntheses which incorporated a Pschorr cyclization of the appropriate 1-phenyldihydroisoquinolinediazonium salts (8). OMe OMe 6 OMe (7) Two new alkaloids are minor but intriguing variants of aporphine bases. The first of these variabiline (lo),” a unique example of an amino-substituted benzylisoquinoline-derived alkaloid was isolated from Ocotea uariabilis where it occurs together with the aporphine (+)-apoglaziovine (11) and its precursor (+)-glaziovine (9). Variabiline was synthesized by heating (9) with a mixture of dibenzylamine and dibenzylamine hydrochloride; it appears not to be an artefact ; dibenzylamine could not be detected in the crude extract and does not react with glaziovine under the conditions of the extraction.The other aporphine modifica- tion from Thalictrum pofygumum is the quaternary alkaloid thalphenine (12),16 with a biogenetically interesting methylenedioxy bridge which figures pro- minently in the n.m.r. spectrum; the structure and absolute configuration were established by X-ray analysis of the iodide. The methine base derived from l3 T. R. Govindachari and N. Viswanathan J. Sci.Ind. Res. India 1972 31 244. l4 M. P. Cava K. T. Buck and A. I. da Rocha J. Amer. Chem. Soc. 1972.94 5931. l5 M. P. Cava M. Behforouz and M. J. Mitchell Tetrahedron Letters 1972 4647.’‘ M.Shamma J. L. Moniot S. Y. Yao and J. A. Stanko J.C.S. Chem. Comm. 1972,408. Alkaloids 491 Me0 ,-’ Me0 ,-’ (10) RR\ H°FMe = (PhCH,),N( k) HFMe 0 (9) (11) R = OH I (12) thalphenine was also present in T. polygamum and was recently isolated” from T. rugosum. The benzylisoquinoline alkaloid reticuline has been converted into ( & )-cepharamine (15) one of the simpler alkaloids with the hasubanan skeleton in a sequence’ * which commenced with the ring-opening [by (F3€C0)20] of 2’-bromoreticuline to give a stilbene which was reduced to (13; X = Br). Photo- lytic dehydrobromination’ (path a) produced the dienone (14) and hydrolytic removal of the N-acyl group in (14) was followed by internal Michael addition to give the hasubanan skeleton ;the product an isomer of (+)-cepharamine was converted into (1 5) by acid-catalysed transetherification.In an earlier approach2’ ” N. M. Mollov L. N. Thuan and P. P. Panov Compt. rend. Acad. bulg. Sci.,1971 24 1047. T. Kametani H. Nemoto T. Kobari K. Shishido and K. Fukumoto Chem. andInd. 1971 538. l9 T. Kametani and K. Fukumoto Accounts Chem. Res. 1972. 5 212. 2o T. Kametani T. Kobari and K. Fukumoto J.C.S. Chem. Comm. 1972 288. 492 H. F. Hodson the dihydrostilbene (13; X = H) from reticuline was subjected to phenolic oxidation ;ppcoupling (path b)gave an intermediate with the ‘wrong’ oxygena- tion pattern. Most synthetic routes to the spirobenzylisoquinoline system have employed a Pictet-Spengler condensation.In a new approach a synthesis of (i-)-ochro-birine (17)2’ makes use of the Bobbitt modification of the Pomeranz-Fritsch reaction to convert (16) into the corresponding dihydroisoquinoline. EtO OEt Several benzylisoquinoline-aporphine ‘dimer’ alkaloids are now known and presumably arise from bisbenzylisoquinoline precursors by way of benzyliso- quinoline-proaporphine bases. Pakistanamine ( 18)22 from Berberis baluchi-stanica now provides the first example of a benzylisoquinoline-proaporphine alkaloid ; it underwent acid-catalysed dienone-phenol rearrangement to give a benzylisoquinoline-aporphine base differing only in its degree of methylation from a new alkaloid pakistanine isolated from the same source. ’0-cz Another interesting bisbenzylisoquinoline-derived structure is provided by stepinone (19)from Stephaniajaponica.Structure (19) was deduced23 by standard methods which included cleavage with sodium in liquid ammonia of NO-dimethyltetrahydrostepinone to give (S)-(-)-armepavine [A portion cf (19)] N. E. Cundasawmy and D. B. MacLean Canad. J. Chem. 1972,50 3028. 22 M. Shamma J. L. Moniot S. Y. Yao. G. A. Miana and M. Ikram J. Amer. Chem. SOC. 1972,94 1382. 23 T. Ibuka T. Konoshima and Y. Inubushi Tetrahedron Letters 1972 4001. Alkaloids 493 and a new phenolic base. The 0-ethyl derivative of this new base was identical with the phenylbenzazepine (20) synthesized by an unambiguous route,24 thus establishing the B portion [cf. (19)] of stepinone itself. Deuterium exchange prior to cleavage followed by location (n.m.r.) of deuterium in the cleavage product^,^' helped to define the C-terminal positions of the head-to-head ether linkage.This method was also used by other workers in the structure determina- tion of a new bisbenzylisoquinoline alkaloid neumarine.26 The past few years have seen the isolation from CephaEotaxus harringtonia of a unique series of bases all with the same skeleton exemplified by the principal alkaloid cephalotaxine (21). Interest in these alkaloids has been heightened by the antitumour activity of the esters e.g.harringtonine (22),27 and two syntheses of ( &)-cephalotaxine have now been reported. One synthesis” proceeded via the tricyclic enamine (23) the elements of the fourth ring being introduced by acylation to give (24),which was converted into the wdicarbonyl compound (25).Cyclization of (25)with magnesium methoxide gave ( +)-demethylcephalotaxinone (26) which has recently been isolated29 from C. harringtonia; methylation and reduction of (26)gave (+)-cephalotaxine (21). The enamine (23) was prepared independently in connection with another 24 Y. Inubushi T. Harayama and K. Takeshima Chem. and Pharm. Bull. (Japan) 1972 20 689. 25 Y. Inubushi T. Kikuchi T. Ibuka and I. Saji Tetrahedron Letters 1972,423. 26 I. R. C. Bick H. M. Leow and N. W. Preston J.C.S. Chem. Comm. 1972,980. 27 K. L. Mikolajczak R. G. Powell and C. R. Smith Tetrahedron 1972 28 1995 and references there cited. 28 J. Auerbach and S. M. Weinreb J. Amer.Chem. Soc. 1972,94 7172. 29 Ref. 28 footnote I I. 494 H. F. Hodson (9 0 RO R (21) R = H OMe (23) R = H (24) R = COCH(0Ac)Me(25) R = CO-COMe OHI OHI I(22) R = Me2CCH2CH2.CCH2C02Me co- projected ~ynthesis.~' The second synthesis3 I involved the assembly of the spiro-compound (27). Generation of the benzyne carbanion (2 equivalents of potassium triphenylmethide) was followed by internal nucleophilic addition to give (+)-cephalotaxinone (28) in yields of 13-16 %; the synthesis was completed by reduction to (-t)-(21). 0 0 OMe OMe (27) X = C1 Br or I (28) The Cephalotaxus bases are tantalizingly similar to the Erythrina alkaloids and a plausible biosynthetic origin from an Erythrina precursor has been sug-ge~ted.~~ of C.harringtonia has shown however that Further in~estigation~~ in this species the typical Cephabtaxus alkaloids are accompanied by small amounts of five Homoerythrina alkaloids closely related to schelhammericine 30 L. J. Dolby S. J. Nelson and D. Senkovich J. Urg. Chem. 1972,37 3691. 31 M. F. Semmelhack B. P. Chong and L. D. Jones J. Amer. Chem. SOC.,1972,94,8629. 32 V. Snieckus in Ref. 2. 33 R. G. Powell Phytochemistry 1972 11 1467. Alkaloids 495 (29);also a hitherto unexamined species C. wils~niana,~~ has furnished cephalo- taxine together with two Homoerythrina alkaloids of the 6,7-epoxy type [cf.(29)] previously encountered only in the completely unrelated plant Phelline comma. These observations suggest3 an equally plausible biogenetic origin from a Homoerythrina precursor such as (30),via a tetracyclic intermediate such as (31).5 Amaryllidaceae Alkaloids A synthesis35 ofanhydrolycorine(33) from (32)in 67% yield provides yet another” example of the application in alkaloid synthesis of the formation of a biphenyl linkage by photochemical dehydrobromination. (33) The lactam alkaloid narciclasine of widespread occurrence among plants of the Amaryllidaceae has been the subject of a number of recent biosynthetic studies which suggest that it is derived from a precursor of the crinine type [cf. (35)] by elimination of the two-carbon bridge. An X-ray of the tetra-acetate has now firmly established the structure (34)for narciclasine which differs from the previously revised37 structure only in the configuration at C-2; further degradative and n.m.r.studies38 are also in accord with the formulation (34). Feeding experiment^^^ demonstrate that vittatine (39 of known stereo- chemistry is incorporated (0.8%) into narciclasine thus supporting the depicted absolute stereochemistry (34). 34 R. G. Powell K. L. Mikolajczak D. Weisleder and C. R. Smith Phytochemistry 1972 11 3317. 35 H. Hara 0.Hoshino and B. Umezawa Tetrahedron Letters 1972 5031. 36 A. Immirzi and C. Fuganti J.C.S. Chem. Comm. 1972,240. ’’ H. F. Hodson Ann. Reports (B),1970 67,476. 38 A. Mondon and K. Krohn Tetrahedron Letters 1972 2085. 39 C. Fuganti and M. Mozza J.C.S. Chem. Comm. 1972 239. 496 H. F. Hohon -OH OH 0 (35) (34) 6 Indole Alkaloids Paraensine (36)from Euxylophora paraensis (Rutaceae) is an addition to the small group of quinazolinocarboline alkaloids and the first one to possess an isoprenoid moiety.40 It is interesting to note that isoprenoid units abound in other alkaloids (furanoquinolines acridones) from the Rutaceae.Me Me (36) Glycosides and Covynanfk-Sfvychnos Alkaloids.-Vincoside (37 ; R = H) derived from tryptamine and secologanin is now unequivocally established as the key early intermediate in the biosynthesis of the vast array of indole mono- terpenoid alkaloids.41 Last year a 5-carboxyisovincoside (38 ; R = CO,H) (37) 38-H (38) 3a-H (39) 3B-H (40) 3a-H 40 B. Danieli P. Manitto F. Ronchetti G. Russo and G. Ferrari Experientia 1972 28 249.41 See for example A. R. Battersby in ref. 1 p. 31. Alkaloids 497 derived from tryptophan and secologanin was isolated for the first time. This has now been followed by the isolation42 from Adina rubescens in a work-up which involved acetylation and methylation of the two epimeric lactams (39) and (40),derivatives of 5-carboxyvincoside (37 ;R = C0,H) and 5-carboxyiso- vincoside (38 ;R = C0,H) respectively. Structures (39) and (40)were confirmed by synthesis from L-tryptophan and secologanin and the depicted stereo-chemistry was firmly e~tablished.~~ 5-Carboxyvincoside (37 ; R = C02H) could be an end-product off the main biosynthetic pathway or it could serve as well as vincoside as a precursor of some monoterpenoid indole alkaloids.More interestingly it might function as the precursor of a whole range of more highly evolved carboxy-substituted alkaloids. This possibility stimulated a deliberate search for such alkaloids which has been rewarded by the discovery43 in Adina rubescens of adirubine shown to have the tryptophan- based Corynanthi-type structure (41). Et The biogenetically interesting structure (42) earlier (without stereochemistry) for roxburghine D has been confirmed by a biosynthetically modelled via the acid (43; R = OH) and its tryptamide (43;R = p-Ind.-CH,CH,-NH); detailed n.m.r. support the stereochemistry depicted in (42). Me MeO,CH CORD (42) (43) 42 W. P. Blackstock R.T. Brown C. L. Chapple and S. B. Fraser J.C.S. Chem. Comm.1972 1006. 43 R. T. Brown C. L. Chapple and G. K. Lee J.C.S. Chem. Comm. 1972 1007. 44 Ref. 37 p. 479. 4s H. Riesner and E. Winterfeldt J.C.S. Chem. Comm. 1972 786. 46 C. Cistaro L. Merlini R. Mondelli and G. Nasini J.C.S. Chem. Comm. 1972 785. 498 H. F. Hodson In suaveoline (45;R = H)from Rauwo@a suaveofens the monoterpenoid moiety is incorporated into a pyridine ring." The structure was confirmed by synthesis4' of Nb-methylsuaveoline (45;R = Me) via the compound (44) obtained from ajmaline. Many (but not all) of the simple monoterpenoid pyridine bases are artefacts arising from seco-iridoid precursors by the action of ammonia used in the work-up. Suaveoline was obtained in an ammonia-free extraction process and is not therefore an artefact.H (44) (45) A new variation of the Nb-C-21secosarpagine [cf. (44)]carbon skeleton seen in suaveoline is provided by talcarpine (47)from Pleiocarpa talbotii :48 talpinine (46)from the same species was methylated with ring-opening to give the C-20 epimer of talcarpine :mild base treatment of talcarpine (47)gave this C-20epimer exclusively. H HI H (46) (47) Plants of the genus Alstonia have furnished a number of bisindole alkaloids all with macroline (48)as one half being linked via the a-methyleneketone function to either the aromatic or alicyclic portion of the other 'half' molecule. Now three of these alkaloids have been synthe~ized~~ in biomimetic reactions which begin with the acid-catalysed Michael addition between (48)and an appropriate nucleophilic centre in the other 'half '.Thus quebrachidine [Aportion of (50)]and (48)gave an adduct which was characterized as a labile hemiacetal with part structure (49)and which could be cyclized (BF,,Et,O) to give the alkaloid alstonisidine which is now therefore formulated as (50);490 this differs from the structure advanced last year5' only in the reversal of the A-B linkages. 47 S. P. Majumdar P. Potier and J. Poisson Tetrahedron Letters 1972 1563. 48 J. Narango M. Pinar M. Hesse and H. Schmid Helv. Chim. .4cta 1972 55 752. 49 (a) D. E. Burke J. M. Cook and P. W. Le Quesne J.C.S. Chern. Comm. 1972 697; (6) D. E. Burke and P. W. Le Quesne ibid. p. 678; (c) D. E. Burke C. A. De Markey P. W. Le Quesne and J.M. Cook ihid. p. 1346. 50 Ref. 6 p. 507. Alkaloids 499 H CH,OH -'N' I (50) Similar syntheses of two other bisindole alkaloids ~illalstonine~~~ and macral~tonine,~~~ involved Michael additions of (48)to an indole fi-position and an activated aromatic position respectively. An elegant new synthesis of (f)-yohimbine5' centred on the formation (Scheme 3) of the decahydroisoquinoline (52) with the full D,E-ring functionality and stereochemistry of the alkaloid itself. Application of a new enamine annelation reaction to give (51) was followed by successive stereospecific (trans ring junction) and stereoselective (mainly axial alcohol) reduction steps finally the N-methyl group was removed by von Braun cleavage followed by reductive decyanation to give (52),which led to yohimbine by standard operations.Me Me H -(i--HB + Me02C$ -P 0 Me0,C Me0,C" 0 OH (51 1 (52) Reagents i PhH -MeOH reflux ii Li-NH ,-Et,O-Bu'OH ; iii Pt-H ; iv BrCN and chromatog.; v Zn-82 AcOH Scheme 3 Several natural oxindole alkaloids have now been converted into their indole counterparts a transformation not hitherto realized although the reverse process G. Stork and P. N. Guthikonda J. Amer. Chem. SOC.,1972,94 5109. 500 H. F. Hodson is well documented. The sequence is illustrateds2 for pteropodine (53) ;O-alkyla-tion to the imido-ester (mixture of C-7 epimers) was followed by reduction (NaBH in acetic acid) to the indole (54). Oxidative cyclization of this 2,3- seco-alkaloid (54) with mercuric acetate in the usual manner gave a mixture of tetrahydroalstonine (55) and akuammigine (56).An alternative cyclizationS3 employed a modified Polonovski reaction; (54) was converted into the N-oxide (epimeric mixture) which on treatment with trifluoroacetic anhydride furnished akuammigine (56) unaccompanied by its 3-epimer. A similar ferrous-ion- catalysed cyclization of model N-oxides has also been reported.54 Me02Cbo (53) (54) ,Me (55) 3a-H (56)38-H The ester (57),prepared in connection with the recent extensive synthetic efforts in the quinine series has been utilized in a synthesis (Scheme 4) of (57) 0 Reagents i THF 90 "C; ii SiO sepn. of epimers; iii NaNH,; iv MeMgI-fi Scheme 4 52 N. Aimi E.Yamanaka J. Endo S. Sakai and J. Haginiwa Tetrahedron Letters 1972 1081. 53 H.-P. Husson L. Chevolot Y. Langlois C. Thal and P. Potier J.C.S. Chem. Comm. 1972,930. 54 C. A. Scherer C. A. Dorschel J. M. Cook and P. W. Le Quesne J. Org. Chem. 1972 37 1083. Alkaloids 50 1 ( & )-dihydrocinchonamine,' incorporating a Madelung synthesis in the indole- forming stage. Aspidosperma Types.-Rhazinilam is an interesting neutral compound first isolated from Rhazya stricta and also from Melodinus australis and Aspidosperrna quebracho-blanco; it gradually accumulates in basic fractions of R. stricta presumably arising from an alkaloid precursor. It is converted by acid into a mixture of closely related bases with the chromophore of a 3,4-dialkylpyrrolo- quinoline (58),and a consideration of the probable nature of this change together with spectroscopic studies provided convincing evidence in favour of structure (59) for rhazinilam;56 this was confirmed in an independent X-ray A plausible derivation from a hypothetical Aspidosperma precursor such as (60)is ~uggested.~~ I.l-i Iboga Types.-The absolute stereochemistry of catharanthine (61) was un-equivocally established some ten years ago by anomalous dispersion studies and although the opposite configuration had earlier been suggested for ibogaine this assignment has not generally been accepted ; the chemical correlations within this group have not included optical data. It has now been shown5* that the c.d. spectra of a number of Zboga alkaloids including coronaridine (62) voacangine ibogamine and tabernanthine are similar but with Cotton effects of reverse sign to those of catharanthine (61) and the absolute configuration of these alkaloids must therefore be enantiomeric with that of catharanthine.Skeletal Interconversions-In 1968 Scott and Qureshi reported that in refluxing acetic acid (+)-tabersonine (66) rearranged to a mixture of (&)-catharanthine (70) (12%) and pseudocatharanthine (68) (28%) and that (+)-stemmadenine 55 G. Grethe H. L. Lee and M. R. Uskokovic Synthetic Comm. 1972 2 55. " K. T. De Silva A. H. Ratcliffe G. F. Smith and G. N. Smith Tetrahedron Letters 1972,913. 57 D. J. Abraham and R. D. Rosenstein Tetrahedron Letters 1972 909. '* K. Blaka Z. Koblicova and J.Trojanek Tetrahedron Letters 1972 2763. 502 H. F. Hodson (63) under these conditions gave 12% of (66) 9% of (70) and 16% of (68).59 These rearrangements which were postulated to proceed via the achiral dihydro- pyridine acrylic ester (71) appeared to establish an in vitro link between alkaloids of the Covynanthd-Strychnos [e.g. (63)] Aspidospema [e.g. (66)] and Zboga [e.g. (70)]skeletal types and provided a welcome analogy for the biosynthetic skeletal transformations of these alkaloids. (63) R = H (66) (64) R = Ac 19,20-dihydro (67) 14,15-dihydro (65) R = AC C!O,Me C0,Me // (68) (69) 15,20-dihydro Other workers though were unable to effect these rearrangements under the conditions described and full details of their efforts have now been published.60,61 A further chapter in the story is provided by a series of papers62 from Scott and Wei who show that the skeletal rearrangements can indeed be detected in vitro and can plausibly take place via the intermediate (71) and double-bond isomers thereof.However the conditions under which they have now been realized and the yields obtained bear little resemblance to those described in the 1968 paper and it is therefore not surprising63 that this earlier work could not be reproduced s9 J. A. Joule in Ann. Reports (B) 1969 p. 483 and in ref. 1 p. 193. R. T. Brown J. S. Hill G. F. Smith and K. S. J. Stapleford Tetrahedron 1971,27,5217. 61 M. Muquet N. Kunesch and J. Poisson Tetrahedron 1972 28 1363.A. I. Scott and C. C. Wei J. Amer. Chem. SOC.,1972,94 8263,8264 8266. 63 Cf.A. I. Scott J. Amer. Chem. SOC.,1972.94 8262. Alkaloids 503 by others; it is also now clear that aerial oxidation and oxidation-reduction disproportionation processes are intimately involved. Thus for example dihydrostemmadenine 0-acetate (64) adsorbed on to silica gel and heated to 150 "C in air for 45 minutes gave (+)-pseudocatharanthine (68) (1 %) and dihydropseudocatharanthine (69) (0.5%) ; a higher yield (2.5 %) of (68) was obtained through the intermediacy of dihydropreakuammicine acetate (721 prepared from (64) by a regiospecific catalytic oxygenation. Exemplifying the transformation to an Aspidosperrna skeleton thermolysis on silica gel of the hydrochloride of (65) gave ( +)-vincadifformine (67) (0.2 %).Alternatively stemmadenine acetate (65) was converted regiospecifically by platinum-catalysed oxidation into (73) which was reduced to dihydroprecondylocarpine acetate (74);thermolysis of (74) on silica gel gave 0.2 % each of (+)-vincadifformine (67) and (f)-tabersonine (64). Me(02C' 'CH20Ac MeO,C' 'CH OAc (73) (74) 19,20-dihydro 7 Quinoline Alkaloids Biogenetically Derived from Indoles Previously obtained only from Carnptothecaacurninata (0.005 % yield) campto- thecin (79) has now been isolated in yields approaching 0.1% from Mappia foetida (Nyssaceae) where it is accompanied by the new base 9-methoxycampto- thecin [cJ (79)].64 Underlining the keen interest in this alkaloid the two syntheses of (*)-camptothecin reported last year have been followed by no fewer than four all six together providing a superb illustration of the diversity possible in approaches to a complex target molecule.One of the new syntheseP is a culmination of the Bu'02C *C02Bu' Bu'0,C *C02BuL (75) (76) 64 T. R. Govindachari and N. Viswanathan Indian J. Chem. 1972,10,453;Phytochemistry 1972,11 3529. E. Winterfeldt T. Korth D. Pike and M. Boch Angew. Chem. Internat. Edn. 1972 11 289; M. Boch T. Korth J. M. Nelke D. Pike H. Radunz and E. Winterfeldt Chem. Ber. 1972 105 2126. 504 H. F. Hodson 0 (77)R' = R2 = H (78)R' = Et R2 = H (79)R' = a-Et R2 = P-OH biogenetically motivated approach described previously66 in which suitably substituted tetrahydrocarbolines are autoxidized to bases with the camptothecin chromophore.Thus the key indole intermediate (75) was autoxidized to the corresponding quinolone (76; R = OH) and thence via (76 R = Cl) to (76; R = H). Selective reduction (di-isobutylaluminium hydride) of the methoxy- carbonyl function of (76; R = H) gave an alcohol which was readily converted into the lactone (77); ethylation to (78) was followed by autoxidation under carefully controlled conditions [DMF-Et,N-Cu(OH),-O,] to give (*)-campto- thecin (79). 7-Chlorocamptothecin [cf. (79)] was also prepared from (76; R = Cl). Another synthesis6' also proceeded by way of deoxyde-ethylcamptothecin (77) constructed in this case (Scheme 5) by attaching the ring E elements to the pyridone (80) to give (81) followed by reduction of the aldehyde function lac- tonization (with deformylation) and finally dehydrogenation.(77) OMe (80) (81) Reagents i Vilsmeir; ii NaH-CH,(CO,Bu'),; iii NaBH,; iv HCl; v DDQ Scheme 5 From the laboratory in which camptothecin was first isolated comes a synthesis6* in which the key step is the Michael condensation of (82) and (83) to give (84) the cyanohydrin of which contains all the necessary structural elements of the alkaloid. 66 Ref. 6 p. 510; J. Warneke and E. Winterfeldt Chem. Ber. 1972 105 2120. '' T. Sugasawa T. Toyoda and K. Sasakura Tetrahedron Letters 1972 5109. 68 M. C. Wani H. F. Campbell G.A. Brine J. A. Kepler M. E. Wall and S. G. Levine J. Amer. Chem. Soc. 1972,94,3631; M.E. Wall H. F. Campbell M. C. Wani and S. G. Levine ibid. p. 3632. Alkaloids 505 C0,Me C0,Me (84) 0t (83) Pyridine-2,5-dicarboxylicacid providing the D-ring of camptothecin in the fourth ~ynthesis,~’ was converted into the diol(85) and thence utilizing a Claisen rearrangement into (86).The ketone derived from (86) was then used in a Fried- lander quinoline synthesis to provide (87) which was transformed via (fj-deoxycamptothecin (78) into (fj-camptothecin (79) in 11 % overall yield from the pyridine diacid. EtACO,Me (87) In a new general method” for the introduction of alkyl or alkenyl groups into heterocycles a Wittig reagent displaces halide ion from a suitable halogeno- heterocycle [e.g.(SS)] to give a new ylide (e.g.(89)l which can be hydrolysed to an alkyl heterocycle or can be subjected to the usual reaction of Wittig reagents with carbonyl compounds to give an olefin.The latter modification has been incor- porated into a new synthesis’l of (+)-quinine via (88) (89j and (90); further C. Tong and H. Rapoport J. Amer. Chem. SOC.,1972,94 8615; J. Plattner R. D. Gless and H. Rapoport ibid. p. 8613. 70 E. C. Taylor and S. F. Martin J. Amer. Chem. Soc. 1972 94 2874. ” E. C. Taylor and S. F. Martin J. Amer. Chem. Soc. 1972 94 6218. 506 H. F. Hodson (88) 2CH 2= PPh H 1 VNA~ CH=PPh IH CHO -6J (89) elaboration of (90) followed the methods employed by the Roche group in their 1970 synthesis.72 8 Lycopodium Alkaloids A new alkaloid gymnamine (91) very closely related to lycodine (92),has been isolated from the leaves of the flowering plant GyrnnernasyIvestre (Asclepiadaceae) and is the first base of this type to be encountered outside the Lycopodiaceae.Structure (91) was established by the conversion of gymnamine into lycodine (92),as ill~strated.'~ A synthe~is'~ of (+)-luciduline (Scheme 6) depended on the stereoselective formation of the cis-decalin (94). Noteworthy features of the sequence are the diene synthesis in the first stage and the stereoselective oxy-Cope rearrangement of (93). l2 Ref. 37 p. 470. 73 G. S. Rao J. E. Sinsheimer and H.M. McIlhenny Chem. and Ind. 1972 537. 74 W. L. Scott and D. A. Evans J. Amor. Cliem. Soc. 1972 94 4779. Alkaloids 507 C1 I + H,C=C.CN -+ A OMe (93) NHMe Me t " 0 H 0DMe (95I MgBr Reagents i A ; ii 250°C; iii (CH,OH),-H,O+; iv HCHO Scheme 6 9 Terpenoid Bases Staphisine first isolated from Delphinium stuphisagria over thirty years ago has now been shown by an X-ray study75 of its monomethiodide to have the novel bis-diterpenoid structure (96).Both halves are clearly derived from atisine- type units although the B unit has suffered an unprecedented rearrangement. Me /N\ Me -75 S. W. Pelletier A. H. Kapadi I. H. Wright S. W. Page and M. G. Newton J. Amer. Chem. SOC.,1972,94 1754. 508 H. F. Hodson The twenty or so alkaloids hitherto isolated from Daphniphyllum macrophyllum comprise a fascinating set of complex bases with a common carbon skeleton classified into three types on the basis of their N-heterocyclic m~ieties.’~ X-Ray studies of two new alkaloids from this species daphnilactone A (97)” and daphnilactone B (98),’*show them to be examples of a fourth and fifth type.0 H MeNgH H’ 0 Hitherto only the carbon skeleton of (+)-dendrobine [(99) as natural (5)-enanti~mer’~] of this orchid had been prepared but now two total syntheses80*81 alkaloid have been reported; nothing less than a full account could do justice to the skill and ingenuity of these notable achievements. 7h 0.E. Edwards in Ref. 1 p. 375; M. Toda Y. Hirata and S. Yamamura Tetrahedron 1972 28 1477; H. Irikawa S. Yamamura and Y. Hirata ibid. p. 3727. 7’ K. Sasaki and Y.Hirata Tetrahedron Letters 1972 1275; J.C.S. Perkin II 1972 1411. 78 H. Niwa M. Toda and Y. Hirata Tetrahedron Letters 1972 2697; K. Sasaki and Y. Hirata ibid. p. 1891. 79 D. Behr and K. Leander Acra Chem. Scand. 1972,26,3196. Y. Inubushi T. Kikuchi T. Ibuka T. Tanaka I. Saji and K. Tokane J.C.S. Chem. Comm. 1972 1252. 81 K. Yamada M. Suzuki Y. Hayakawa K. Aoki H. Nakamura H. Naguse and Y. Hirata J. Amer. Chem. SOC. 1972 94 8278.

ISSN:0069-3030    

DOI:10.1039/OC9726900487

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

16 Terpenoids and Steroids By B. A. MARPLES Department of Chemistry The University of Technology Loughborough Leicestershire LEI 1 3TU 1 Introduction The third annual volume of the Chemical Society’s Specialist Periodical Report on Terpenoids and Steroids giving comprehensive literature cover from Septem- ber 1971 to August 1972 will be available in 1973.’ Reviews have appeared on natural products derived from marine sources’ and from echinoderms3 In addition some aspects of biogenetic-type synthe~es,~ the synthetic use of chloro-olefin annelation reactions,’ and the chemistry of naturally-occurring plant-growth regulators6 have been reviewed. 2 Monoterpenoids The chemistry of thujane derivatives has been reviewed.’ Selective reduction of the conjugated double bond of unsaturated a/?-enones is achieved using Et,SiH-(Ph,P),RhCl ;thus citral is smoothly reduced to citronellal.* Cyclization of(+)-citronella1 to( +)-neoisopulegol(1) and( -)-isopulegol(2) with( Ph,P),RhCl is rep~rted.~ Remarkably the cis-product (1) is the major product.Treatment ‘Terpenoids and Steroids’ ed. K. H. Overton (Specialist Periodical Reports) The Chemical Society London 1973 vol. 3. ‘ E. Premuzic Fortschr. Chem. org. Naturstoffe 1971 29,417. J. S. Grossert Chem. SOC.Rev. 1972 1 1. D. Goldsmith Fortschr. Chem. org. Naturstoffe 1971 29 363. P. T. Lansbury Accounts Chem. Res. 1972,5 31 1. W. J. Fleming and M. E. H. Howden Pure Appl. Chem. 1972,22 67. D. Whittaker and D. V. Banthorpe Chem. Rev. 1972,37 305. * I. Ojima and T.Kogure Tetrahedron Letters 1972 5085. K. Sakai and 0.Oda Tetrahedron Letters 1972,4375. 509 510 B. A. Marples of compounds of the type (3) with mercuric trifluoroacetate or mercuric nitrate followed by borohydride reduction gives good yields of cyclized products (4).' Solvolysis of linalyl p-nitrobenzoate is accompanied by rearrangement to give cc-terpinyl p-nitrobenzoate suggesting considerable overlap of the isopropylidene (31 (4) group n-electrons with C-1 during ionization.' ' This overlap was detected from a kinetic deuterium isotope effect in the solvolysis of neryl chloride labelled with deuterium at position 6. Geranyl chloride did not show this effect and thus confirmed that the original configuration of these molecules is retained in the ionic species.l2 Nucleophilic substitution of 4-bromoisophorone (5) gives a number of rearranged products.Thus base hydrolysis leads to compounds (6),(7),and (8)(interalia)and gives no 4-hydroxyisophorone as was expected from previous reports.' (5) Further in vitro studies supporting the biogenic link between the chrysanthemyl artemisyl santolinyl and iavandulyl systems are reported by a number of groups. Yomogi alcohol (10) is the major product resulting from the solvolysis of the chrys- anthemyl derivative (9) and is accompanied by a small quantity of santolina alcohol (1l).14 Deuterium labelling establishes that the preferred conformation for reaction is as depicted in (9)." The absolute configuration of santolina alcohol at C-3 is shown to be the same as in chrysanthemyl derivatives as would be expected if the two skeletons are biogenetically linked.I6 Cleavage of the cyclopropane ring in chrysanthemic acid derivatives is dependent upon sub- stituents and can be controlled to give santolinyl artemisyl and lavandulyl skeletons.' Whereas the conversion of chrysanthemyl derivatives into tail-to- lo M. Kurbanov A. V. Semenovsky W. A. Smit L. V. Shmelev and V. F. Kucherov Tetrahedron Letters 1972 2175. I' S. Winstein G. Valkanas and C. F. Wilcox jun. J. Amer. Chem. SOC.,1972,94 2286. C. A. Bunton J. P. Leresche and D. Hachey Tetrahedron Letters 1972 2431. l3 J. N. Marx A. W. Carnick and J. H. Cox J. Org. Chem. 1972 37 2308. l4 C. D. Poulter S. G. Moesinger and W. W. Epstein Tetrahedron Letters 1972 67.l5 C. D. Poulter J. Amer. Chem. SOC.,1972 94 5515. Ih C. D. Poulter R. J. Goodfellow and W. W. Epstein Tetrahedron Letters 1972 71. L. Crombie P. A. Firth R. P. Houghton D. A. Whiting and D. K. Woods J.C.S. Perkin I 1972 642. Terpenoids and Steroids -+ a I PyO ‘cH-/L;,” 51 1 \ t Py =Me-N tail monoterpenoids was achieved previously in extremely low yield,’ the alcohols (13) and (14) are obtained satisfactorily by the solvolysis of the cyclo- propylmethyl-p-nitrobenzoate(12) or the cyclobutyl tosylate (15). 8b,c These transformations parallel those proposed for the conversion of presqualene alcohol into squalene. U The six natural pyrethrins and (+)-allethronyl (+)-trans-chrysanthemate have the 4s absolute configuration.’The natural occurrence of the campholenyl skeleton is reported for the first time ;campholenic aldehyde (16)and the epoxide (17) have been isolated from Juniperus ~omrnunis.~~ Linarioside (18) is the first natural chlorine-containing iridoid glucoside.’ (a) Ann. Reports (B) 1971 68 468; (b)C. D. Poulter 0.J. Muscio C. J. Spillner and R. J. Goodfellow J. Amer. Chem. Sor. 1972 94 5921 ;(c) R.M. Coates and W. H. Robinson ibid. p. 5920. M. J. Begley L. Crombie D. J. Simmonds and D. A. Whiting J.C.S. Chem. Comm. 1972 1276. A. F. Thomas Hefv. Chim. Acta 1972 55 81 5. I. Kitagawa T. Tani K. Akita and I. Yosioka Tetrahedron Letters 1972 419. 512 B. A. Marples 3 Sesquiterpenoids Some aspects of hydroazulene synthesis have been reviewed.’ ’New conventions for representing germacranolide sesquiterpenes are proposed to avoid the present conf~sion.’~The endo-structure for isolongifolene epoxide is supported on the assumption that the steric course of hydrogenation of 9-0x0-isolongifolene is the same as that for ep~xidation.’~ This may not be valid.The co-occurrence in Chamaecyparis nootkatensis of a-alaskene (19) and P-alaskene (20) which are members of enantiomeric series is uniq~e.’~ a-Alaskene (19) is identical with y-acoradiene and P-alaskene (20) is the enantiomer of 6-acoradiene.’ Revised structures are presented for albene (21)26 and futronolide (Z).”Fungal meta- bolism of ( f)-epoxyfarnesol allows the assignment of the R-configuration to the ( +)-form.28 Pseudoclovene a rearrangement product of caryolan-1-01 has the structure (23).29 The S absolute configuration of (+)-abscisic acid (24) has been assigned by correlation with malic acid3’ and by synthetic ~tudies.~’ Blumenols A (25) B (26) and C (27) which have the same configuration as (+)-abscisic acid (24) at the asymmetric ring carbon have been isolated from Podocarpus bl~rnei.~’ 22 J.A. Marshall Synthesis 1972 517. 23 D. Rogers G. P. Moss and S. Neidle J.C.S. Chem. Comm. 1972 142 576. 24 (a) D. V. Banthorpe A. J. Curtis and W. D. Fordham Tetrahedron Letters 1972 3865; (6)CL Ann. Reports (B),1971,68 470. 25 N. H. Andersen and D. D. Syrdal Tetrahedron Letters 1972 899. 26 K. VokaE 2.Samek V. Herout and F. Sorm Tetrahedron Letters 1972 1665.27 T. Kato T. Iida T. Suzuki Y. Kitahara and K. H. Overton Tetrahedron Letters 1972,4257. Y. Suzuki and S. Marumo Tetrahedron Letters 1972 1887. 29 R. I. Crane C. Eck W. Parker A. B. Penrose T. F. W. McKillop D. M.Hawley, and J. M. Robertson J.C.S. Chem. Comm. 1972 385. 30 G. Ryback J.C.S. Chem. Comm. 1972 1190. 31 T. Oritani and K. Yamashita Tetrahedron Letters 1972 31. 32 M. N. Galbraith and D. H. S. Horn J.C.S. Chem. Comm.. 1972 113 576. Terpenoids and Steroids 513 H 0wco2H (25) R' R2 = OH I x IR' (26) R' = H2c~OH ~2 = OH (27) R' = H2C31.0H R2 = H 0 Further synthetic approaches to the C-17 JH,33 C-18 JH,34 and imino- derivatives of the C-18 JH3' are reported. Of particular interest is the stereo- specific preparation of the intermediate (29)by cleavage of the dihydrothiopyran rings of compound (28).34d The formic acid-catalysed cyclization of the cyclopentane (30) surprisingly gave the hydroazulene (31).36 Stereoselective transannular cyclization routes to hydroazulenes are exemplfied by conversion of the cyclododecadienyl-p- nitrobenzoate (32) into the hydroazulene (33).37 &-+&OH 33 (a)R.J. Anderson C. A. Henrick J. B. Siddall and R. Zurfluh J. Amer. Chem. Soc. 1972,94,5379; (6) P. A. Grieco J.C.S. Chem. Comm. 1972,486. 34 (a)C. A. Henrick F. Schaub and J. B. Siddall J. Amer. Chem. SOC.,1972 94 5374 8647; (6) K. Mori M. Ohki A. Sato and M. Matsui Tetrahedron 1972 28 3739; (c) K. Mori ibid. p. 3747; (d) K.Kondo A. Negishi K. Matsui D. Tunemoto and S. Masamune J.C.S. Chem. Comm. 1972 13 1 1 ;(e)J. S. Cochrane and J. R. Hanson J.C.S. Perkin I 1972 361. 35 R. J. Anderson C. A. Henrick and J. B. Siddall J. Org. Chem. 1972 37 1266. 36 K. E. Harding and W. D. Nash Tetrahedron Letters 1972 4973. 3' J. A. Marshall W. F. Huffman and J. A. Ruth J. Amer. Chem. SOC.,1972,94,4691. 514 B. A. Marples PNBO H (33) A synthesis of (+)-junenol utilizes the biogenetic-type cationic cyclization of a farnesol derivative as a key step.38 The previously reported biogenetic-type cyclizations of acetylenic olefin~~’~ are modified in the absence of a good nucleo- ~hile.~’~ Thus compound (34)is converted uia the cations (35) and (36) into the ring-expanded compound (37) in CH,CI,-CF,CO,H.Attempts to cause the 1 eudesmols (38)and (39)to rearrange to eremophilane-type sesquiterpenes failed,40 whereas dihydroalantolactone (40)is converted by reaction with formic acid into compound (41)and its formate ester.41 The conversion of elemol to 01-and P-eudesmois with silver(r) ion is the first cyclization of this type.42 38 M. A. Schwartz J. D. Crowell and J. H. Musser J. Amer. Chem. Sac. 1972,94,4361. 39 (a)Ann. Reports (B) 1971,68 490; (b) W. S. Johnson M. B. Gravestock R. J. Parry and D. A. Okorie J. Amer. Chern. Soc. 1972 94 8604. 40 J. W. Huffman J. Org. Chem. 1972 37 2736. 4‘ I. Kitigawa Y. Yamazoe R. Takeda and Y. Yosioka Tetrahedron Letters 1972,4843. 42 T. C. Jain and J. E. McCloskey Tetrahedron Letters.1972. 5139. Terpenoids and Steroids methyla at ion"^ and a-hydro~ymethylation~~ of y-butyrolactones is reported. The hydroxymethyl compounds44 and the rx-methyl ~ompounds~~,~~ are readily converted into the r-methylene-pbutyrolactones. For a-methyl compounds containing cis-fused cyclohexane and y-butyrolactone rings a bromination-dehydrobromination procedure is used. Thus compound (42) is converted into the compound (44) which gives ( -)-frullanolide (46).4s The corresponding trans-compound (43) is converted into the ester (45),which on pyrolysis gives ( +)-arbusculin-B (47).’6 si,,<-* -$q+ -r-”--L 0 0 0 (42) 6P (44) 6P R = r-Br (46) 6P (43) 6cr (45) 6a R = p-PhC02 (47) 6cr Gymnomitrol (48),which was isolated from Gyrnnomitrion obtusurn has a novel carbon skeleton which could be biogenetically derived from 7-bisabolene uia a trichodiene intermediate.47 Johnston01 (49) a relative of pacifenol occurs in the red alga Laurenciajohnstonii and is identical with a previously reported ‘dibromide’ from L.~karnurai.~* Three chlorinated sesquiterpene lactones have H 0 H c1 43 G. H. Posner and G. L. Loomis J.C.S. Chem. Comm. 1972 892. 44 P. A. Grieco and K. Hiroi J.C.S. Chem. Comm. 1972 1317. 45 A. E. Greene J.-C. Muller and G. Ourisson Tetrahedron Letters 1972 2489. 46 A. E. Greene J.-C. Muller and G. Ourisson Tetrahedron Letters 1972 3375. 47 J. D. Connolly A. E. Harding and I. M. S. Thornton J.C.S.Chem. Comm. 1972 1320. 48 J.J. Sims W. Fenical R. M. Wing and P. Radlick Tetrahedron Letters 1972 195. 516 B. A. Marples been isolated from Centaurea specie^.^' The norsesquiterpenes gyridinal (50)’’ and gyridinone (51)’ have been isolated from gyrinid beetles. 4 Diterpenoids Grandiflorenic acid which is shbwn to be identical with a previously isolated and wrongly identified compound has the structure (52).52Tetrahydrogibberellin A CO H (from Sonneratia apetala) has the structure (53).53Assignment of stereochemistry at C-9 in gibbanes is assisted by a study of the ‘H n.m.r. signals for the 6-H and of the 16-carbonyl group stretching frequencies in the i.r.54 Full structural assign- ments and corrections are reported for the various oxidation products derived HO/lq-JqOH H C0,H 49 (a)A.G. Gonzalez J. Bermejo J. L. Breton and J. Triana Tetrahedron Letters 1972 2017; (b)J. Harley-Mason A. T. Hewson 0. Kennard and R. C. Pettersen J.C.S. Chem. Comm. 1972,460. (a)J. Meinwald K. Opheim and T. Eisner Proc. Nat. Acad. Sci. U.S.A. 1972 69 1208; (b)H. Schildknecht H. Neumaier and B. Tauscher Annalen 1972 756 155. s1 J. W. Wheeler S. K. Oh E. F. Benfield and S. E. Neff J. Amer. Chem. Soc. 1972,94 7589. 52 F. Piozzi S. Passannanti M. L. Marino and V. Sprio Canad. J. Chem. 1972 50 109. s3 P. Gaskin J. MacMillan S. N. Ganguly T. Sanyal P. K. Sircar and S. M. Sircar Chem. and Ind. 1972,424. 54 A. J. Baker A. C. Goudie U. R. Ghatak and R. Dasgupta Tetrahedron Letters 1972 1103. Terpenoids and Steroids from levopimaric acid with KMnO and OSO,.~~ The observation that the aldehyde (54) is rapidly autoxidized in benzene lends further support to the suggestion56b that 4-hydroxy-l9(or 18)-norditerpenoids are artefacts.CHO Selective reduction of the severely hindered 10-carboxyl group in gibberellin A (55)is effected uia the lactone (56),in which the carbonyl group is held in an accessible orientation and leads to a partial synthesis of gibberellin A, (57).5’ The C, antibiotic LL-Zl271a (58)was synthesized from a degradation product of marr~biin.~~ Selective metalation of the diene (59) with Bu”Li-TMEDA followed by reaction with the bromo-compound (60)gave racemic ar-arternisene (61).” Full details of syntheses of steviol and erythroxydiol are now available.60 0 ” W.Hen and R. C. Ligon J. Org. Chem. 1972,37 1401. 56 (a)0.Tanaka S. Mihashi I. Yanagisawa T. Nikaido and S. Shibata Tetrahedron 1972 28 4523 ;(b)cf. Ann. Reporrs (B) 1971 68 478. 57 D. H. Bowen D. M. Harrison and J. MacMillan J.C.S. Chem. Comm. 1972 808. 58 (a)W. Adinolfi L. Mangoni G. Barone and G. Laonigro Tetrahedron Letters 1972 695; (6)cf. Ann. Reporrs (B) 1970 67 412. ’’ R. J. Crawford J. Org. Chem. 1972 37 3543. B. A. Marples Acetolysis of the epimeric alcohols (62) gave (+)-14a-hybyl acetate (64) via the cation (63) which is a proposed biogenetic intermediateq6' The full details are available of the acid-catalysed cyclizations of manool which with formic acid + 'OAc fiFH8 H 163) gives (inter ah) 14a-hybyl formate.62 Treatment of levopimaric acid with concentrated sulphuric acid in dichloromethane leads through the stable cations (65) and (66) to the ring-contracted diene (67).63 Dehydrogenation of dihydro- allogibberic acid methyl ester (68)causes migration of the 7,8-bond and gives the ketone (69).64 Similar reactions in the 7-deoxygibbanes result in the migration I .+ HO,C I +OHz H of the 9,9a-bond. The bromoester (70)undergoesconsecutivedehydrobromination and demethoxycarbonylation by 0-alkyl cleavage to give the enone (71) when treated with DBN in refluxing ~ylene.~~ Decomposition of the diazoketone (72) " (a) K. Mori Y. Nakahara and M. Matsui Tetrahedron 1972 28 3217; (b) cf. Ann. '' Reports (B) 1970,67 414. D. K.M. Duc M. Fetizon and J.-P. Flament J.C.S. Chem. Comm. 1972 886. '' S. F. Hall and A. C. Oehlschlager Tetrahedron 1972 28 3155. h3 G. Mehta N. Pattnaik and S. K. Kapoor Tetrahedron Letters 1972 4947. 64 B. E. Cross and R. E. Markwell J.C.S. Chem. Comm. 1972,442. 65 D. H. Miles and E. J. Parish Tetrahedron Letters 1972 3987. 519 Terpenoids and Steroids ?Me OMe co OC @ & I (73) N ,CH (72) with CuSO gives the ketone (73) by carbene insertion into the benzylic C-10-H bond.66 Functionalization of the A-ring of the hydrofluorene (74) is achieved using the hypoiodite rea~tion,~’ and functionalization of the 4P-methyl group in the rosane (75) is achieved with lead tetra-acetate.68 All-trans-geranylgeraniolis found to be the esterifying alcohol in the bacterio- chlorophyll of the purple photosynthetic bacterium Rhodospirillurn r~brurn.~~ Cyathin A (76)and its 1,2-dehydro-derivative allocyathin B, which have been isolated from Cyathus helenae are members of a new class of diterpenes.” Aphidicolin (77) is a member of a new class of tetracyclic diterpenoids called U.R. Ghatak and S. Chakrabarty J. Amer. Chem. SOC.,1972 94 4756. 67 A. Tahara and T. Nakata Tetrahedron Letters 1972 4507. T. Nakano and A. K. Banerjee Tetrahedron 1972 28 471. 69 J. J. Katz H. H. Strain A. L. Harkness M. H. Studier W. A. Svec. T. R. Janson and B. T. Cope J. Amer. Chem. SOC.,1972,94 7938. ’O A. A. Ayer and H. Taube Tetrahedron Letters 1972 1917. 520 B. A. Marples HO\ CH,OH ,*’ aphidicolanes.’’ Three diterpene triepoxides with the novel 18(4 -+ 3)-abeo-abietane structure have been isolated from Tripterygiurn~ilfordii,’~ and a new quinone methide coleon E (78) is reported from Coleus barb~tus.~~ Neo-cembrene-A (79) is a termite trail pher~mone.’~ H .../o 5 Sesterterpenoids Retigeranic acid (81) is isolated from Lobaria retigera.” Initial cyclization of geranylfarnesyl pyrophosphate in the conformation (80) could give this novel carbon skeleton. Marine sponges have yielded a number of furanoid linear ” K. M. Brundret W. Dalziel B. Hesp J. A. J. Jarvis and S. Neidle J.C.S. Chem. Comm. 1972 1027. 72 S. M. Kupchan W. A. Court R. G. Dailey jun. C. J. Gilmore and R. F. Bryan J. Amer. Chem. SOC.,1972 94 7194. ” P.Ruedi and C. H. Eugster Helv. Chim. Acra 1972 55 1994. l4A. J. Birch W. V. Brown,J. E. T. Dorrie and B. P. Moore J.C.S. Perkin I 1972,2653. l5 M. Kaneda R. Takahashi Y. Itaka and S. Shibata Tetrahedron Letters 1972 4609. Terpenoids and Steroids 521 sesterterpene~~~,~~ and several new and similar C2 compounds which are believed to be partially degraded ~esterterpenes.’~ It is suggested that some of the C, acyclic hydrocarbons detected in African cretaceous shale could be derived from sesterterpenes.’’ 6 Triterpenoids The chemistry of the cucurbitanes has been reviewed.” Revised structures are presented for baccharis oxide (82)8 and macedonic acid.82 Marker’s ‘cr-keto- dihydrolanosteryl acetate’ is identified as 3P-acetoxy-Scr-lanost-9(1l)-en-7-0ne.~~ The tetranortriterpene bussein is shown84 to be a mixture of two compounds designated bussein A (83)and bussein B (84).I ,Me‘ OCOCH \ R (83) R = Et (84) R = Me The view that a common intermediate is involved in the biosynthesis of dammaranes and euphanes is supported by the isolation of the former in a species of Meliacemg5 Phragmalin (85) is a novel meliacin containing a nor- bornane skeleton.86 The isolation and structure determination of datiscoside (86)establishes for the first time the configuration at C-20 in the cucurbita~ins.~~ Further support for the bacterial origin of some triterpenes in sediments and oils 76 G. Cimino S. de Stafano L. Minale and E. Fattorusso Tetrahedron 1972 28 333 2 146. 77 F. Cafieri E.Fattorusso C. Santacroce and L. Minale Tetrahedron 1972 28 1579. 18 (a)G. Cimino S. de Stafano L. Minale and E. Fattorusso Tetrahedron 1972,28,267 2146; (b)CJ Ann. Reports (B) 1971 68,479. 79 C. Spyckerelle P. Arpino and G. Ourisson Tetrahedron 1972 28 5703. 80 D. Lavie and E. Glotter Fortschr. Chem. org. Naturstofle 1971 29 307. 81 (a)F. Mo T. Anthonsen and T. Bruun Acta Chem. Scand. 1972,26 1287; (6)cJ.Ann. Reports (B) 1970 67 423. 82 A. D. Zorina L. G. Matyukhina A. G. Chavva and L. A. Saltikova Tetrahedron Letters 1972 1841. 83 L. H. Briggs J. P. Bartley and P. S. Rutledge J.C.S. Perkin I 1972 581. 84 R. Hanni and Ch. Tamm J.C.S. Chem. Comm. 1972 1253. 85 S. S. Cascon and K. S. Brown Tetrahedron 1972 28 31 5. 86 R. R. Arndt and W.H. Baarchers Tetrahedron 1972 28 2333 cf. ref. 84. 81 S. M. Kupchan C. W. Sigel L. J. Guttman R. J. Restivo and R. F. Bryan J. Amer. Chem. Sor. 1972,94 1353. 522 B. A. Marples 0 HO 0 is provided by the isolation from Messel oil shale of homohopane which could arise by microbiological methylation of the 3-deo~y-triterpene.~~ The degraded limonoids odoratin (87)89 and calodendrolide (88)’’ are reported in natural sources. The latter is the logical precursor of fraxinellone for which a total synthesis is reported.” ..&o H 0 A. Ensminger P. Albrecht G. Ourisson B. J. Kimble J. R. Maxwell and G. Eglinton Tetrahedron Letters 1972 3860. 89 W. R. Chan D. R. Taylor and R. T. Aplin Tetrahedron 1972 28 431. 90 J. M. Cassady and C.4.Liu J.C.S. Chem. Comm. 1972 86. 91 Y. Fukuyama T. Tokoroyama and T. Kubota Tetrahedron Letrers 1972 3401. Terpenoids and Steroids A total synthesis of fusidic acid is rep~rted,’~ and the fusidic acid carbon skeleton is obtained by BF,-catalysed rearrangement of 3P-acetoxy-4/?-demethyl-9,11 a-epo~y-5a-lanostane.’~ The perhydrophenanthrene (89) with the trans-syn-trans-configurationof fusidic acid is prepared by BF,-catalysed rearrangement of the 5,6P-e~oxide.’~ (89) 1-Alkyl substituents in A1(’)-2-octalones and related systems are as important as angular substituents in influencing the stereoselectivity of reductive alkyla- tion.’’ Biogene tic- type total syntheses of te tracyclic’ and pen tacyclic’ ’ triterpenes continue to be studied.This very elegant work is exemplified by the synthesis of isoeuphenol(91) and 23,25-dihydro-A1 3(1 ’)-protosterol (93) from the all-chair epoxide (90) and its chair-boat-chair conformer (92) respectively. Deuterium (92) (93) 92 W. G. Dauben G. Ahlgren,T. J. Leitereg W. C. Schwarzel and M. Yoshioko J. Amer. Chem. SOC.,1972,94,8593. y3 R. Kazlauskas J. T. Pinhey and J. J. H. Simes J.C.S. Perkin I 1972 1243. 94 R. E. Ireland and U. Hengarter J. Amer. Chem. SOC.,1972 94 3652. 9s (a)P. T. Lansbury and G. E. DuBois Tetrahedron Letters 1972 3305; (b) J. W. ApSimon P. Baker J. Buccini J. W. Hooper and S. Macauley Canud. J. Chem. 1972 50 1944. 96 E. E. van Tamelen and R. J. Anderson J. Amer. Chem. Soc. 1972,94 8225. 97 (a) E. E. van Tamelen R. A.Holton R. E. Hopla and W. E. Konz J. Amer. Chern. SOC.,1972 94 8228; (6) E. E. van Tamelen M. P. Seiler and W. Wierenga ibid. p. 8229. 524 B. A. Marples incorporation into isoeuphenyl acetate produced by D +-catalysed backbone rearrangement of euphenyl acetate indicates that a protonation-deprotonation mechanism is largely involved and that protonated cyclopropanes are probable intermediate^.^^ The unusual BF,-catalysed rearrangement of the P-amyrin dienol (94) to the or-amyrin enone (95) is reported.99 The bromine-initiated rearrangement of the tirucall-7-ene (96) to the 7or-bromoapotirucall-14-ene (97) takes place via the 7a,8a-bromonium ion 24,25-dibr0mide.’~~~’O~ The shift of the 13-Me to position 14 is thought to be sterically inhibited by the 7a-bromine.Br AcO . (96) (97) 7 Steroids Two useful volumes on a variety of preparative methods applied to steroid systems have appeared.’” A review on some aspects of biomimetic chemistry has been published.’ O3 The absolute configurations of doisynolic acid (98)’04 and wortmannin (99)loS are reported. The ‘cholestane-3,4,6-trione’of Windaus and Kuhr is now shown to be the 3-ethyl ether of the corresponding dienone 98 Y. Nakatani G. Ponsinet G. Wolff J. L. Zundel and G. Ourisson Tetrahedron 1972 28 4249; c’ ref. 112. 99 R. Leonard and J. B. Thomson J.C.S. Chem. Comm. 1972 1281. loo T. G. Halsall and R. J. Weston J.C.S. Chem. Comm. 1972 1212. lo’ C’ Ann. Reports (B),1970 67 421. O2 ‘Organic Reactions in Steroid Chemistry’ ed.J. Fried and J. A. Edwards Van Nostrand Reinhold New York 1972 vols. 1 and 2. lo’ R. Breslow Chem. SOC.Rev. 1972 1 553. Io4 J. Iriarte and P. Crabbe J.C.S. Chem. Comm. 1972 110. lo5 (a)T. J. Petcher. H.-P. Weber and Z. Kis J.C.S. Chem. Comm. 1972 1061; (6) J. MacMillan T. J. Simpson and S. K. Yeboah ibid.,p. 1063; (c) J. MacMillan A. E. Vanstone and S. K. Yeboah J.C.S. Perkin I 1972 2898. Terpenoids and Steroids diol'06 and inotodiol is shown to have a 22-OH group.'" It is suggested that the ergosterol peroxide which has been reported in a number of fungal extracts is an artefact arising from natural pigment-sensitized photo-oxygenation. '** Phenol to dienone rearrangements in superacid media are reported,"' and the generality of the 'medium effect' in dienone-phenol rearrangements is questioned.' lo The HC1-catalysed rearrangement of the seco-steroid (100) to the tricyclo[5,2,1,03~8]decan-2-one (101) is remarkable.' ' Further studies on backbone rearrangements are reported.Deuterium incorporation into the products of rearrangment of 3a-amino- and 3P-dimethyl- amino-pregn-5-en-20-one in D2S0 indicates that a protonation-deprotonation mechanism is involved and that in the latter case protonated cyclopropane and/or spiro-cation intermediates are involved. ' ' Other rearrangements of 3-amino-As-compounds are reported and the importance of the reaction medium on the course of these reactions is noted.' l3 The importance of C/D intracyclic strain in promoting backbone rearrangements is again illustrated in amino-' l4 and other steroids."' The isomerization of the enone (102) to its 14P-isomer '06 J.T. Pinhey and E. Rizzardo J.C.S. Perkin I 1972 1358. lo' F. De Reinach-Hurtzbach and G. Ourisson Tetrahedron 1972,28 2259. '08 J. Arditti R. E. M. H. Fisch and B. H. Flick J.C.S. Chem. Comm.. 1972 1217. 109 (a)J.-M. Coustard J. P. Gesson and J.-C. Jacquesy Tetrahedron Letters 1972,4929; (6)J.-M. Coustard and J.-C. Jacquesy ibid. p. 1341. 'lo H. J. Shine and C. E. Schoening J. Org. Chem. 1972 37 2899. 'I1 T. R. Kasturi R. Ramachandra and K. M. Damodaran Tetrahedron Letters 1972 5059. M.-M. Janot F. Frappier J. Thierry G. Lukacs F.-X. Jarreau and R. Goutarel Tetrahedron Letrers 1972 3499; cf. ref. 98. 'I3 (a)F. Frappier M.Pais and F.-X. Jarreau Bull. Sac. chim. France 1972 610; (b)F. Frappier and F.-X. Jarreau ibid. p. 625. 'I4 F. Frappier J. Boivin and F.-X. Jarreau Compt. rend. 1972 274 C 2190. 'I5 (a)J. Bascoul D. Nicolaidis and A. Crastes de Paulet Bull. SOC. chim. France 1972 184; (6)J. Bascoul E. Noyer and A. Crastes de Paulet ibid.. p. 2744. 526 B. A. Marples in HF-SbF involves an interesting reversible protonation-deprotonation backbone rearrangement.' The 3P,SP-bridge in the epoxide (103) facilitates backbone rearrangement.' The full details of backbone and related rearrange- ments of 9-and 10-hydroxy-5P-methyl compounds and their susceptibility to substituent and reaction media variations are discussed.' l8 A dependence of the stereoselectivity of dienolate alkylation on solvent is noted.' l9 Selective hydrogenation of the up-enones to the saturated ketones is achieved using a combination of Fe(CO) and NaOH in aqueous methanol.'20 The stereochemistry of the selective reduction of the dienone (104) to the enone (105) with Ph,SnH is controlled by the configuration of the 12-aceto~y-group.'~' The 11-keto-group of the dienedione (106) may be reduced selectively if the 3-carbonyl is protected as a sodium or lithium enolate.lZ2 ' J.-C.Jacquesy R. Jacquesy and G. Joly Tetrahedron Letters 1972 4739. ' J. Wicha Tetrahedron Lerters 1972 2877. I*' J. G. Lloyd Jones and B. A. Marples J.C.S. Perkin I 1972 792. 'I9 Y. Nakadaira J. Hayashi H. Sato and K. Nakanishi J.C.S.Chem. Comm. 1972,282. lZo R. Noyori I.Umeda and T. Ishigami J. Org. Chem. 1972 37 1542. 12' U. Pommerenk H. Sengewein and P. Welzel Tetrahedron Letters 1972 341 5. ''' D. H. R. Barton R. H. Hesse M. M. Pechet and C. Wiltshire J.C.S. Chem. Comm. 1972. 1017. Terpenoids and Steroids Reaction of 3~-hydroxy-A5-steroids with dialkyl or diary1 phosphites in the presence of acid provides a new etherification procedure.' 23 Cyclic carbonates are useful acid-stable protecting groups for 20,21- 17,21-,and 17,20-diols.' 24 The trityl cation and the tris-(p-bromopheny1)aminium cation-radical are very efficient catalysts for the oxygenation of ergosteryl acetate.I2' The reactive species (107) is formed in the trityl cation-catalysed process by reaction between (107) (108) ground-state oxygen and the photo-excited triplet state of the trityl cation.The steroidal oxetans (108) give the acetals (109) on reaction with BF and ace- tone.'26 The preparation of the annulene (110) is rep~rted.'~' (1 10) Functionalization of saturated steroids at C-5 and C-14 is achieved by irradia- tion in the presence of peracetic acid,12* whereas irradiation in the presence of CC1,Br or C,H,IC12 resulted in functionalization predominantly at C-9.'29 The isolation of the pyrrolidine (111) from the photolysis of the corresponding (1 11) 12.3 Y. Kashman J. Org. Chem. 1972 37 912. I24 (a) M. L. Lewbart J. Org. Chem. 1972,37 1233; (b)M. L. Lewbart ibid.,p. 3892. 125 D. H. R. Barton G. Leclerc P. D. Magnus and I. D. Menzies J.C.S. Chem. Comm. 1972,447.I26 Gy. Schneider I. Weisz-Vincze A. Vass and K. Kovacs J.C.S. Chem. Comm. 1972 713. 127 P. H. Bentley M. Todd W. McCrae M. L. Maddox and J. A. Edwards Tetrahedron 1972,28 141 1. I28 A. Rotman and Y. Mazur J. Amer. Chem. Sac. 1972,946228. I29 R. Breslow J. A. Dale P. Kalicky S. Y. Liii and W. N. Washburn J. Amer. Chem. SOC.,1972 94 3276. B. A. Marples 6fi-azide supports the existence of a discrete nitrene.13' The liquid-phase photo- decarbonylation of the py-epoxyketone (112) to the olefin (113) is accompanied by hydride shifts from C-7 to C-5 and from C-8 to C-7.' ' The photoaddition of butadiene to 17~-acetoxyandrost-4,6-dien-3-one ( 114).'32 remarkably gives the compound OAc :-(I 14) Further steroidal carboxylic acids are reported in and four D-ring aromatic steroids including nicandrenone (115),have been isolated from the insect-repellant plant Nicandra physaloides.' 34 Withanicandrin (1 16)is the first HO '0 A.Pancrazi Q. Khuong-Huu and R. Goutarel Tetrahedron Letters 1972 5015. I3l R. J. Chambers and B. A. Marples J.C.S. Chem. Comm. 1972 1122. 132 G. R. Lenz Tetrahedron Letters 1972 3027. (a)W. K. Siefert E. J. Gallegos and R. M. Teeter J. Amer. Chem. Sac. 1972,94 5880 8647 ;(6)CJ Ann Reports (B),1971 68 491. 134 (a)R. B. Bates and D. J. Eckert J. Amer. Chem. SOC.,1972,94 8258; (6)M. J. Begley L. Crombie P. J. Ham and D. A. Whiting J.C.S. Chem. Comm. 1972 1250. Terpenoids and Steroids ikemaoyl-0 OH natural 12-0x0-withanolide to be isolated,' 35 and glycocynanchogenin (117) is a novel polyoxypregnane.36 3,25-Dihydroxy-24-methylcholest-5-ene is the first C-25 oxygenated marine ster01.'~' The principal sterols of the marine sponge Aplysina aerophoba have the unusual 26-methyl side-chain and are 24,26-dimethylcholest-5-en-3P-ol(aplysterol) and 24,28dehydroaplysterol. 38 A number of starfish species yield the aglycone (118) and several other minor novel compounds.139 Asynthesis of the aglycone (118)is rep~rted.'~' Synthetic studies on antheridiol (119)are reported by three groups.141 The synthesis of the diene (120)is achieved by dehydrobromination of 22,23-dibromo-SP-ergostane with DBN.14' 135 I. Kirson D. Lavie S. S. Subramanian P. D. Sethi and E. Glotter J.C.S. Perkin I 1972 2109.13' T. Yamagishi K. Hayashi R. Kujama and H. Mitsuhashi Tetrahedron Letters 1972,4005. 13' J. P. Engelbrecht B. Tursch and C. Djerassi Steroids 1972 20 121. 13' P. De Luca. M. De Rosa L. MinaIe and G. Sodano J.C.S. Perkin I 1972 2132. 139 (a)Y. M. Sheikh B. M. Tursch and C. Djerassi J. Amer. Chem. Soc. 1972,94 3278; (6)Y.Shimizu ibid. p. 4051 ;(c) S. Ikegami Y. Kamiya and S. Tamura Tetrahedron Lerrers 1972 1601 ; (4 S. Ikegami Y. Kamiya and S. Tamura ibid.,p. 3725; (e) Y. M. Sheikh B. Tursch and C. Djerassi ibid. p. 3721. 140 D. S. H. Smith and A. B. Turner Tetrahedron Letters 1972 5263. 14' (a)T. C. McMorris T. Arunachalam and R. Seshadri Tetrahedron Letters 1972 2673 ;(b)G. A. Smith and D. H. Williams J.C.S. Perkin I 1972,28 I I ;(c)3. A.Edwards J. Sundeen W. Salmond I. Iwadare and J. H. Fried Tetrahedron Letters 1972 791 142 A. B. Garry J. M. Midgley W. B. Whalley and B. J. Wilkins J.C.S. Chem. Comm. 1972 167. 530 B. A. Marples OH (1 19) Studies of micro biological hydroxylations of mono-and di-oxygeneated 5a-androstanes are reported using Aspergillus ochraceus and Calonectria de~0ra.I~~ Oxygen functions in rings A and D act as primary directing groups. Other studies in this area include the use of Curvularia lunata and Coniosporium rhizophillum with pregnane derivatives. 144 143 (a)A. M. Bell J. W. Browne W. A. Denny Sir E. R. H. Jones A. Kasal and G. D. Meakins J.C.S. Perkin I 1972,2930; (b)A. M. Bell W. A. Denny Sir E. R. H. Jones G. D. Meakins and W. E. Miiller ibid.p. 2759; (c) A. M. Bell P. C. Cherry I. M. Clark W. A. Denny Sir E. R. H. Jones G. D. Meakins and P. D. Woodgate ibid. p. 208 1. 144 (a) G. Cleve G.-A. Hoyer K. Kieslich and H. Wieglepp Chem. Ber. 1972 105 658; (h)V. Schwarz and J. Protiva Coll. Czech. Chem. Comm. 1972 37 1577.

ISSN:0069-3030    

DOI:10.1039/OC9726900509

出版商:RSC    

年代:1972

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17 Nucleic Acids By R. T. WALKER Department of Chemistry Birmingham University Birmingham B 15 2T T The output of those engaged in nucleic acid research has increased by over 15 % during 1972 so that the number of publications for the year is nearly 8 500,’ a number which includes over 150 review articles. It is to be hoped that the application of the principle of pyramid selling which has been proposed2 is not received with favour as participants in the scheme were promised co-authorship of 16 million publications ! The outstanding book to appear during the year is a new edition (in paperback) of the late Professor Davidson’s book3 ‘The Child’s Guide to the Nucleic Acids’. Although the contents have become more sophisticated over the years since the first edition in 1950 the price has remained at a very reasonable level.Many 1972 references appear in the present edition and it is to be hoped that this publication will continue to get its regular revision. Another volume in the series ‘Progress in Nucleic Acid Research and Molecular Biology’ has a~peared.~ Several books dealing with practical aspects of the methods used in in vitro protein biosynthesis,’ -’nucleic acid hybiidization,8 and fractionationg have been published. Two other books deal with the physics and chemistry of DNA and RNA” and the biosynthesis of macromolecules.” The report of a 1972 symposium on gene transcription has appeared in a somewhat unusual placei2 I ’Nucleic Acids Abstracts’ ed. E. S. Krudy and A. Williamson Information Retrieval Ltd.London 1972. 7 See Nature 1972 237 58. 3 J. N. Davidson ‘The Biochemistry of the Nucleic Acids’ Chapman and Hall and Science Paperbacks London 1972. 4 ‘Progress in Nucleic Acid Research and Molecular Biology’ ed. J. N. Davidson and W. E. Cohn Academic Press London 1972 vol. 12. 5 ‘Protein Biosynthesis in Bacterial Systems. Methods in Molecular Biology’ ed. J. A. Last and A. I. Laskin Dekker New York 1971 vol. 1. 6 ‘Protein Biosynthesis in Nonbacterial Systems. Methods in Molecular Biology’ ed. J. A. Last and A. I. Laskin Dekker New York 1972 vol. 2. 7 E. Thack and M. R. Newburger ‘Research Techniques in Biochemistry and Molecular Biology’ Addison-Wesley London 1972. 8 ‘Results and Problems in Cell Differentiation; Nucleic Acid Hybridisation in the Study of Cell Differentiation’ ed.H. Ursprung Springer-Verlag Berlin 1972 voi. 3. 9 S. R. Ayad ‘Techniques of Nucleic Acid Fractionation’ Wiley London 1972. 10 J. H. Spencer ‘The Physics and Chemistry of DNA and RNA’ Saunders London 1972. I1 V. M. Ingram ‘Biosynthesis of Macromolecules’ Addison-Wesley London 1972. 12 See Acta endocrinofogica Suppl. 168 1972. 531 532 R. T. Walker and contains papers on such subjects as identification of mammalian chromo- somes structure of eukaryotic chromatin methods for studying protein-nucleic acid interaction DNA-RNA hybridization and degradation of mRNA in mammalian cells. Once again although much of the progress has occurred in Molecular Biology some really significant papers dealing with more chemical aspects have appeared.In a burst of publishing probably without parallel Khorana in a series of thirteen consecutive papers in the Journal of Molecular Biology,’ has at last explained in detail how to synthesize genes. As can be seen in the following section outstanding progress has been made in the synthesis of some pyrimidine- base analogues and their nucleosides. The latter have been synthesized by chemical modifications of preformed nucleosides by a series of mild and specific reactions to give products in very high yield. The sequence of a viral RNA gene has been determinedI4 and the partial sequence of 16s ribosomal RNA has been elucidated.” Both these results and many others show that now the only obstacles remaining in the sequencing of any RNA molecule are the availability of the pure molecule and the need for infinite supplies of patience students and money.A start has been made on the sequencing of DNA.’ At last some progress can be reported on one of the outstanding problems in Molecular Biology -the specific recognition of an amino-acid sequence in a protein by a nucleotide sequence in a nucleic acid. For some years it has been likely that the tRNA-synthetase or the ribosome-mRNA recognition might provide the first insight into this problem but now three papers have described the binding of the lac repressor protein to DNA.17-19 A study of repressor binding to synthetic double-stranded DNA’ ’ showed that the affinity for repressor was dependent upon both nucleotide composition and sequence.Another reportI8 showed that the amino-terminal section of the repressor is necessary for direct binding to DNA and this was confirmed by Miiller-Hill and his colleagues.” They also predicted that the lac repressor protein binds to the lac operator DNA by means of the three-dimensional surface of a protrusion rather than the normal enzyme-substrate recognition site of a cleft. Experiments with mutants have revealed that a sequence of about 50 amino-acids at the amino-terminus of the protein binds to the DNA with some of the amino-acids binding to the phosphate backbone and others to polar groups in the deep groove of the DNA. A model has been proposed which explains the interactions l3 See H.G. Khorana et al. J. Mol. Biol. 1972,72 209492. l4 W. Min Jou G. Haegeman M. Ysebaert and W. Fiers Nature 1972,237 82. l5 P. Fellner C. Ehresmann P. Stiegler and J.-P. Ebel Nature New Biol. 1972 239 1. l6 R. Wu J. Donelson R. Padmanabhan and R. Hamilton Bull. Insr. Pasreur 1972 70 203. A. D. Riggs S. Lin and R. D. Wells Proc. Nut. Acad. Sci. U.S.A. 1972,69 761. T. Platt K. Weber D. Ganem and J. H. Miller Proc. Nut. Acad. Sci. U.S.A. 1972 69 879. l9 K. Adler K. Beyreuther E. Fanning N. Geisler B. Gronenborn A. Klemm B. Muller-Hill M. Pfahl and A. Schmitz Nature 1972 237 322. Nudeic Acids 533 observed and a partially ambiguous DNA sequence has been predicted 5‘ C,A-T-A-G,T-C,A-3’ G,T-A-T-C,A-G,T-It is further postulated that each of the four identical subunits of the repressor molecule recognizes an identical sequence and that these sequences are separated by (probably) identical sequences.It is suggested that a code must exist which describes the binding of protein sequences to DNA sequences and no doubt much effort will be expended to try to solve this code. Some people have been star-gazing” while others have been labouring in simulated desert conditions’ (although why one has to simulate desert conditions in San Diego is not explained). Computers and their accompanying mathe- maticians have apparently progressed from trying to explain the hydrogen molecule and are now predicting polyribosome behaviour22 and mimicking protein synthesis.23 In case some people did not realise it Molecular Biology having passed from the romantic period through the dogmatic period is now in the academic period24 and therefore as an academic exercise readers may like to write down the structure of the compound methyl-4-{ 7-(4,6-dimethyl-8- oxydi-imidazo[1,2-a],[4,5-d]pyrimidinyl))-2-rnethoxycarbamoylbutyrate2’ (with- out first looking up the structure of Y base as given in this Report last year).1 Bases Nucleosides and Nucleotides Many different suggestions have been published during the year for the separation of the bases and their derivatives. Those of more general interest include the separation in one hour of nanomole amounts of the four common ribonucleosides together with 4-thiouridine pseudouridine and ribothymidine by ion-exclusion chromatography on cation- exchanger^.'^ A critical and detailed survey of the use of anion-exchange chromatography (Dowex-1) has also a~peared,~’ and details of the single-solvent separation of the nucleosides of the uridine group (uridine ribothymidine and pseudouridine) which are very difficult to separate by cation-exchange chromatography are given.It is emphasized that cation- exchange chromatography can often separate mixtures of nucleosides which are difficult to separate by other methods. Nucleosides can be separated from deoxynucleosides on a specially prepared dihydroxyboryl-substitutedpolymer.28 m-Aminobenzeneboric acid when treated with methacryloyl chloride gives a 2o C. Sagan Nature 1972 238 77. 21 M. J. Bishop R. Lohrmann and L. E. Orgel Nature 1972 237 162.22 K. L. Li M. T. Wasan and R. Kisilevsky Biochim. Biophys. Acta 1972,272,435. 23 K. L. Li R. Kisilevsky M. T. Wasan and G. Hammond Biochim. Biophys. Acta 1912,272,45 1. 24 P. Thuillier Recherche 1972 3 439. 25 R.L. Hancock L. Ghertner and D. Dougan Physiof. Chem. Phys. 1971,3 559. 26 R. P. Singhal and W. E. Cohn Biochim. Biophys. Acta 1972 262 565. 2’ R. P.Singhal and W. E. Cohn Biochim. Biophys. Acta 1972,262 585. H. Schott Angew. Chem. Internat. Edn. 1972 11 824. 534 R.T. Walker boric acid derivative (1) which can be copolymerized with tetramethylene dimethacrylate to give a cross-linked polymer with the desired exclusion limit. A fast simple method for the base analysis of DNA and RNA by gas-liquid chromatography has the advantage of reducing the transfer and manipulative steps previously involved.29 The revolution brought about by the very-high- pressure column liquid chromatography (3000 lb per sq in) of nucleic acid con- stituents has been re~iewed.~' It is expected that further developments in detection methods and the speed of separation will enable even faster separation of smaller amounts of material and an apparatus capable of preparative-scale separation should soon be available.Already medium-pressure columns3 have been used to separate ribosomal RNA32 and amino-acylated ~RNAs~~ -the latter taking only 30 minutes and the most time-consuming process now being the analysis of the eluent ! Once again adenine-containing residues have been the target for a chromato- graphic spray reagent this time to give a fluorescent derivative when treated with chl~roacetaldehyde.~~ Although the reagent reacts to give adenine (2) and cytosine (3) derivative^,^' the fluorescence maximum of the former is 410nm whereas that of the latter is at 347 nm which is below the visible range.N6-(A2-1sopentenyl)adenosineis the only other nucleoside found to react3' [to give (4)] but the product is only weakly fluorescent. Chloroacetaldehyde has also been used to study tRNA and it also reacts with ATP to give a fluorescent product which should be a valuable probe for the determination 29 D. B. Lakings and C. W. Gehrke Clinical Chem. 1972 18 810. 30 J. N. Done G. J. Kennedy and J. H. Knox Nature 1972,237 77. 31 A.D. Kelmers and D. E. Heatherly Analyt. Biochem. 1971,44,486. 32 B. Z. Egan and A. D. Kelmers Prep. Biochem. 1972 2 265. 33 H. 0.Weeren A. D. Ryon and A. D. Kelmers Biotechnol. and Bioeng. 1972 14 617. 34 N. J. Leonard J. R. Barrio and J. A. Secrist Biochim. Biophys. Acra 1972 269 531. '' J. R. Barrio J. A. Secrist and N. J. Leonard Biochem. Biophys. Res. Comm. 1972 46 597. Nucleic A cids 535 of enzyme mechanism and structure.36 Adenine derivatives have also been shown to give fluorescent compounds with fluorescence maxima at 382nm when treated with glyoxal hydrate trimer.37 The tautomerism of cytosine38and guanine,39which for some years now have been thought to exist only in the amino and lactam tautomers respectively has been investigated by n.m.r.techniques. An analysis of the temperature-and pD-dependence of the H-5 and H-8 linewidths has led to the startling conclusion that cytosine exists as the imino tautomer to the extent of 15 f.3 % and guanine as the lactim tautomer to the extent of 16 f.3 % at room temperature in neutral aqueous solution. It is suggested that the minor forms could account for the stability of many A-C (5)and G-U base pairs which occur in tRNA. The lactim U I H I R R (5) form of guanine has an electronic structure which is superimposable on adenine and can form G-T base pairs (6). Evidence has also been found for the presence of G-U base pairs in dimethyl sulphoxide-water mixtures (containing a high proportion of water) of guanosine and 2'-deo~yuridine.~~ Evidence for T-G base pairs has been found during transcription of polydeoxypyrimidines in uitro.RNA polymerase from Escherichia coIi catalyses the formation of poly rG in the presence of repeating d(T-C)n.40" HY H -o+,. H H NH ............ N/ \ )=N R .........H-N ...H-N' R \ H 36 J. A. Secrist J. R. Barrio and N. J. Leonard Science 1972 175 646. " H. Yuki C. Sempuku M. Park and K. Takiura Analyt. Biochem. 1972 46 123. 38 G. C. Y. Lee J. H. Prestegard and S. I. Chan. J. Amer. Chem. SOC.,1972 94 9S1. 39 G. C. Y. Lee and S. I. Chan J. Amer. Chem. Soc. 1972,94 3218. 40 S. I. Chan G. C. Y. Lee C. F. Schmidt and G. P. Kreishman Biochern. Biaphys. Res. Comm. 1972 46 1536. 40aV.Paetkau M. B. Coulter W. F. Flintoff and A.R. Morgan J. Mol. Biol. 1972 71 293. 536 R. T. Walker A new synthesis of uracil derivative~~l involves the reaction of a NN-dialkyl- amide-dimethyl sulphate adduct (7) with cyanoacetylurea (8) to give a dialkyl- aminoalkylidene derivative (9) which cyclizes in the presence of strong base to give 5-cyanouracil(lO) in 70 % overall yield. CN -c II 0 There are several novel reactions which give bases and nucleosides in high yield which were hitherto only obtainable by long and tedious routes. However the full papers dealing with a reaction mentioned last year4* for the preparation of 2’-deoxyuridine by treatment of Zf,3’-O-benzylideneuridine with N-bromo- succinimide reveal that the yields quoted were for the crude products and the analytical data were for recrystallized material.43 The stereochemical and mechanistic aspects of the reaction have been further explored.44 The reagent fluoroxytrifluoromethane (CF,OF) first discovered to be a useful reagent for the direct electrophilic fluorination of aromatic compounds by has been used by Robins46 and Barton4’ to make 5-fluorouraci1(11) in 85 % yield and also to give the 5-fluoro-nucleoside and -deoxynucleoside from the corresponding uracil O-acetylated nucleosides.The reaction may proceed via 5-fluoro-6-trifluoromethoxy-5,6-dihydrouraci146 or 5-fluoro-6-hydroxy-5,6- dihydr~uracil,~’ as the initial addition of the reactants causes the complete loss of the uracil chromophore at 260 nm; this is only restored either by addition of 41 H.Meindl and H. Ackermann Helu. Chim. Acra 1972 55 1039. 42 R. T. Walker Ann. Reports (B) 1971 68 425. 43 M. M. Ponpipom and S. Hanessian Canad. J. Chem. 1972 50 246. 44 M. M. Ponpipom and S. Hanessian Canad. J. Chem. 1972 50 253. 45 D. H. R. Barton A. K. Ganguly R. H. Hesse S. N. Loo and M. M. Pechet Chern. Comm. 1968 806. 46 M. J. Robins and S. R. Naik J. Amer. Chem. SOC.,1971 93 5277. 47 D. H. R. Barton R. H. Hesse H. T. Toh and M. M. Pechet J. Org. Chem. 1972,37 329. Nucleic Acids 537 trieth~lamine~~ or by sublimation of the produ~t.~’ A similar reaction48 has been applied to cytosine derivatives to give 5-fluorocytosine (85 % yield) 5- fluorocytidine (55 % yield) and the antineoplastic and antiviral agent 5-fluoro- cytosine arabinoside (83% yield).An analogous reaction49 using another pseudohalogen thiocyanogen chloride (prepared by the addition of chlorine gas in glacial acetic acid to potassium thiocyanate) with uridine or deoxyuridine has given good yields (48%) of 5-thiocyanato-nucleosides (12). From the 0-acetylated nucleoside a 96 % yield was obtained. The 5-mercapto-nucleosides (13)can be obtained from the thiocyanato derivatives by reduction with dithio- threitol. The 5-thiocyanatopyrimidine nucleosides are of interest because they may exert biological activity after in vim reduction to the corresponding mer- captan or alternatively they may behave like 5-halogenopyrimidine nucleosides owing to the pseudohalogen nature of the thiocyanato-group.(11;X= F,R = H) (12;X = SCN R = Ribosyl or 2‘-Deoxyribosyl) O AN (13 ;X = SH,R = Ribosyl or 2’-Deoxyribosyl) I 8-Chloroadenosine7 8-chloro-AMP and 8-chloro-ADP have been prepared in good yield by the direct chlorination of the corresponding adenine derivative with tetrabutylammonium iodotetrachloride (n-C4H,),NIC14 .” These are the first 8-chloropurine nucleosides to be prepared and unlike the corresponding 8-bromo derivatives they are presumably in the anti-conformation since the pyrophosphate is a substrate for polynucleotide phosphorylase. A method for the isolation of pseudouridine from commercial uridine5 ’ depends upon the stability of the pseudouridine present as an impurity to hydrazinolysis which destroys the uridine such that the C-nucleoside can be isolated by a one-step chromatographic separation on a Dowex-bicarbonate column to give about 2 milligram of pseudouridine from each gram of uridine.A number of papers have appeared which attempt to rationalize the acid- catalysed hydrolysis of ribo- and deoxyribo-nucleosides.52-5a No-one has yet managed to put forward a convincing argument to explain the problem which causes most embarrassment to those involved in lecturing to undergraduates -namely why the purine nucleosides hydrolyse so easily whereas the pyrimidine nucleosides do not although the difference at some pH values is not as great as it is sometimes thought to be.” At least all the authors agree that the initial bond cleaved is that joining the heterocycle to the protonated nucleoside (C-N 48 M.J. Robins and S. R. Naik J.C.S. Chem. Comm.. 1972 18. 49 T. Nagamachi P. F. Torrence J. A. Waters and B. Witkop J.C.S. Chem. Comm. 1972 1025. 50 H. J. Brentnall and D. W. Hutchinson Tetrahedron Letters 1972 2595. ” R. Kaplan and I. Lulav Internat. J. Biochem. 1972 3 12. ” R. Shapiro and M. Danzig Biochemistry 1972 11 23. R.T. Walker OH X Path A e N H + products OH X OH X Path B Scheme 1 cleavage; Scheme 1,path A)and the reaction does not proceed as was previously favoured through a Schiff’s base (Scheme 1 path B). Despite the -I effect of the 2’-hydroxy-group which is expected to hinder the reaction the AH‘ values are smaller for the nucleosides than for the deoxy- nucleosides.The presence of the 2’-hydroxy-group therefore helps the departure of the protonated base by neighbouring-group parti~ipation.~ However the reactivity sequence is reversed by large differences in AS‘ values which makes the deoxynucleosides more susceptible to acidic hydrolysis. No evidence has been obtaineds4 for the postulated diprotonated speciess3 but their existence has not been disproved. It is not thought that water participates in the transition state52 and the mechanism is therefore of the A-1 type -pre-equilibrium pro- tonation of the heterocyclic base followed by rate-limiting cleavage of the glycosyl- heterocycle bond.54 The deamination of cytosine by nitrous acid has been shown not to be prevented by the presence of the cytosine residues in a d~uble-helix.~~ The ratio of the rate of deamination of cytidine as the free nucleoside to that of cytidine in polyI polyC (1 0.2) is probably due to steric effects.The addition of O-methyl- hydroxylamine to a mixture of sodium bisulphite and cytidine 5’-phosphate prevents the deamination of the ~ytosine,~’ and the intermediate sulphonate 53 J. A. Zoltewicz D. F. Clark T. W. Sharpless and G. Grahe J. Amer. Chem. Sac.. 1970,92 1741. 54 R. P. Panzica R. J. Rousseau R. K. Robins and L. B. Townsend J. Amer. Chem. Sac. 1972 94 4708. 55 L. Hevesi E. Wolfson-Davidson J. B. Nagy 0.B. Nagy and A. Bruylants J. Amer. Chem. Sac. 1972,94,4715. 554E. R. Garrett and P. J. Mehta J. Amer. Chem. Soc. 1972 94 8532. 56 R. Shapiro and H. Yamaguchi Biochim.Biophys. Acta 1972,281 501. 57 E. Budowsky E. Sverolov and G. Monastyrskaya F.E.B.S. Letters 1972 25 201. Nudeic A cids 539 (14) reacts to give the two stable diastereoisomers (at C-6) of N4-methoxy-5,6- dihydrocytidine-6-sulphonate5’-phosphate (15). It is hoped to use the reaction as a specific reaction for cytidine residues in tRNA. Sodium bisulphite has also been shown to dehalogenate 5-chloro- 5-bromo- and 5-iodo-ura~il~~ to give R R R = ribosyl 5’-phosphate (14) (15) the 5-halogeno-5,6-dihydrouracil-6-sulphonate and then uracil as intermediates and 5,6-dihydrouracil-6-sulphonateas the final product. With 5-flo~rouraci1,~~ the 5-flouro-5,6-dihydrouracil-6-sulphonate, formed by stereoselective addition of bisulphite is stable.Sodium bisulphite also adds in an anti-Markownikoff sense (and hence by a radical mechanism) to the exocyclic double-bond of N6-(Az-isopen teny1)adenosine. Several reactions with the primary hydroxy-group of nucleosides have been reported. The 5’-aldehydes from uridine and adenosine have been made by photolysis of the corresponding 5’-azido derivatives.60 The aldehydes are unstable and have been characterized after their reduction back to the alcohol with sodium borodeuteride. The 5-aldehyde of 2’,3’-O-isopropylidene-adeno-sine is formed in 85% yield by oxidation of the blocked nucleoside with the Pfitzner-Moffatt reagent.6 The primary hydroxy-group of thymidine has been selectively acylated by a reaction involving activation of the alcohol rather than the carboxylic acid,62 and hence the reaction is restricted to the less sterically hindered primary hydroxy-group.Treatment of thymidine with diethyl azodicarboxylate (Et0,C-N=N-C0,Et) and triphenylphosphine with benzoic acid in hexa- methylphosphoric triamide gives a 74 % yield of the 5’-acylated thymidine and 26 % unchanged thymidine. The reaction is thought to go by the pathway shown in Scheme 2. A method for the transformation of nucleosides into their 5’-deoxy derivatives in 50 % overall yield63 depends upon the fact that dimethylformamide dineopentylacetal [Me,N-CH(OR) ;R = neopentyl] cannot alkylate mercapto derivatives (2-thiouracil with dimethylformamide dimethylacetal in boiling acetonitrile gives 2-methylthio-3-methyluracil in 70 % yield).However its 58 E. G. Sander and C. L. Deyrup Arch. Biochern. Biophys. 1972 150 600. 59 H. Hayatsu Y. Watawa Y. Furuichi and Y. Kawazoe Chemosphere 1972,2 75. ‘O D. C. Baker and D. Horton Carbohydrate Res. 1972 21 393. ” P. Howgate and A. Hampton Carbohydrate Res. 1972 21 309. 62 0. Mitsunobu J. Kimura and Y. Fujisawa Bull. Chem. SOC.Japan. 1972 45 245. 63 A. Holy Tetrahedron Letters 1972 585. 540 R.T. Walker 0 II + R-C-O-QY3 Thymine 0 0 11 -II -u EtO-C-N-N-C-OEt I Ph,P+ OH Scheme 2 autocatalysed ‘reacetalization’ by other alcohols affords intermediates capable of the alkylation reaction. The high affinity of 2-mercaptopurine (16) for the alkylation process can be used to transform the primary hydroxy-group of a nucleoside sugar to a nucleoside-5’-(pyrimidin-2-yl-thio)-5’-deoxy derivative (17) which can then be reduced to the 5’-deoxynucleoside.The reaction proceeds on brief refluxing of the nucleoside with a smaI1 excess of 2-mercaptopyrimidine and the acetal in acetonitrile. A method for the selective 2’(3’)-phosphorylation of unprotected ribonucleo- sides64 depends upon the reaction of ethyl trichloromethanephosphonate in the presence of triethylamine with a cis-diol grouping to give a ribonucleotide ester which can be hydrolysed by alkali to give the free ribonucleotide. Yields depend upon the heterocyclic base moiety and are 67 % for uridine 45 % for adenosine and 23 % for cytidine. Thymidine does not react and 9-(a+lyxofuranosyl)- adenine which can give two cyclic intermediates gives 23 % of the 2’- 37 % of the 3’- and 35 % of the 3’,5’-(cyclic) phosphate.3’,5’-Ditrityluridine is partially detritylated at 50 “C in 80 % acetic acid65 after 1 hour. Under similar conditions 2’,5’-ditrityluridine is stable and thus mild acidic hydrolysis of mixed ditrityluridines enables 3’-trityluridine to be easily chromatographically separated from the mixture in 14 % yield (from uridine). 64 A. Holy Tetrahedron Lerrers 1972 157. 65 G. Kowollik K. Gaertner and P. Langen Tetrahedron Letters 1972 3345. Nucleic Acids 541 N6-Substituted adenosines can be prepared by the action of amines in the presence of stannic chloride on persilylated nucleoside~.~~ Much overlapping and interlocking work on anhydronucleosides involving the 8-position of the purine ring has been published.A general synthesis of 8,2’-thioanhydropurine nucleosides by simultaneous displacement of bromine from position 8 and carbonate from the 2-position of the parent nucleoside with thiourea has been de~cribed.~’ A similar reaction using diphenyl carbonate and 8-mercapto- or 8-oxy-adenosine in dimethylformamide at 150 “C with sodium bicarbonate resulted in the formation of 8,2’-S-anhydro- and 8,2’-O-anhydro- adenosine respectively.68 A novel synthesis of purine p-D-nucleosides includes The reaction of the intermediate formation of an 8,5’-anhydronucleo~ide.~~ adenine-8-thiol with methyl 5-iodo-5-deoxy~2,3-0-isopropylidene-~-~-r~bofur-anoside (18) gives (19) as the key intermediate which reacts via the anhydro- nucleoside (20)which can be oxidized to the sulphoxide.Subsequent benzoylation and reduction gives the nucleoside in 6% yield which could be improved and extended to deoxynucleoside synthesis where again only the p-anomer will be formed. NH H Me Me 9-P-~-Arabinofuranosyladeninehas been synthesized via the anhydro-nucleoside 8,2’-anhydro-8-oxy-9-~-~-arabinofuranosyladenine,~~ and 9-p-~-arabinofuranosyladenine 3’,5’-cyclic phosphate has been prepared in a similar 5’-manner. 8,2’-Anhydro-8-mercapto-9-~-~-arabinofuranosyladenineand 3’,5’-cyclic phosphates have been prepared by using a specific 2’-O-tosylation reaction performed under Schotten-Baumann condition^.^^ 66 H. Vorbruggen Angew. Chem.Internaf. Edn. 1972 11 304. 67 K. K. Ogilvie L. Slotin J. B. Westmore and D. Lin Canad. J. Chem. 1972,50 2249. 6g M. Ikehara and S. Tezuka Tetrahedron Letters 1972 1169. 6q Y. Mizuno C. Kaneko Y. Oikawa T. Ikeda and T. Itoh J. Amer. Chem. SOC.,1972 94 4737. ’O M. Ikehara and Y. Ogiso Tetrahedron 1972,28 3695. T. A. Khwaja R. Harris and R. K. Robins Tetrahedron Letters 1972,4681. 72 M. Ikehara and S. Uesugi Tetrahedron 1972 28. 3687. 542 R. T. Walker 2’,3’-0-Isopropylidene-5’-keto-8,5’-anhydroadenosine (21) has been prepared by the action of methyl-lithium in tetrahydrofuran on 2’,3’-O-isopropylidene- adenosine-5’-carboxylic acid.? 02,2’-Anhydro-5,6-dihydrouridine (22)has been synthesized by the action of methyl acrylate on the reaction product (23) of arabinose and ~yanamide.?~ Mass spectra of some 6-substituted ureidopurine~,’~ 0 HoH2ca OF0 Me Me OH OH (21) N‘-a~yladenines,~~ pyrimidine anhydronucleosides,76 trimethylsilyl derivatives of pyrimidine and purine bases,?’ and trifluoracetylated adenosine analoguesT8 have been determined.It is found that a-and p-anomers and furanose and pyranose ring systems can be di~tinguished.~~ The conformations of adenosine S‘-pho~phate?~ and some dinucleoside monophosphates” in aqueous solution have been investigated by n.m.r. with the lanthanide-probe technique. The results enable the solvent-dependent conformational changes of the molecule to be defined and the conformations of all the dinucleoside monophosphates investigated were found to be anti-anti.The structures of 5-diazouracil (24) 5-diazouracil hydrate (25) 5-diazouridine (26) and 5-diazo-2’-deoxyuridine (27) have been revised.’ X-Ray diffraction studies on crystalline 3-deazauridine suggest that it should be regarded as a cytidine analogue.82 N6-(A2-1sopentenyl)adeninehas been shown to have the isopentyl moiety pointing away from the adenine imidazole ring.83 The N-1 is completely shielded and is inaccessible to possible hydrogen-bond donors. Also the amino-group can only form hydrogen-bonds on the backside of the purine ring and consequently the two sites N-1 and N6-H that are normally utilized by adenine bases for complementary pairing within double-helical nucleic acids 73 P. J. Harper and A. Hampton J.Org. Chem. 1972 37 795. 74 C. M. Hall G. Slomp S. A. Mizak and A. J. Taylor J. Org. Chem. 1972 37 3290. S. M. Hecht and J. J. McDonald Analyt. Biuchem. 1972,47 157. ’6 S. Tsuboyama and J. A. McCloskey J. Org. Chem. 1972 37 166. ’7 E. White V. P. M. Krueger and J. A. McCloskey. J. Org. Chem. 1972 37,430. 78 W. A. Konig K. Zech R. Uhmann and W. Voelter Chem. Ber. 1972 105 262. l9 C. D. Barry J. A. Glasel A. C. T. North R. J. P. Williams and A. V. Xavier Biuchem. Biuphys. Res. Comm. 1972 47 166. C. D. Barry J. A. Glasel A. C. T. North R. J. P. Williams and A. V. Xavier Biuchim. Biuphys. Acm 1972 262 101. 81 T. C. Thurber and L. B. Townsend J. Heterocyclic Chem. 1972 9 629. 82 C. H. Schwalbe H. G. Gassen and W. Saenger Nature New Bid. 1972 238 171.83 C. E. Bugg and U. Thewalt Biochem. Biophys. Res. Cumm. 1972,46 779. Nucleic Acids 543 0 0 (26; X = OH) (27 X = H) are blocked by the isopentenyl substituent. 6-Methyluridine has been shown to be in the syn-conformation in the crystalline state84 as well as in solution and it appears to be in a more relaxed form than the only other pyrimidine nucleoside to occur in this conformation 4-thiouridine. A polynucleotide poly 8-amino- adenylic acid which exists in the syn-conformation forms a three-stranded structure with poly U having a stability very similar to that of poly A.2 poly U.85 2 Oligonucleotides As has already been mentioned,I3 the methodology for gene synthesis has been revealed. A shorter account emphasizes the strategy and the problems which remain to be solved86 because of the low yields obtained in the condensation reaction.Trityl cellulose can be used for the separation of trityl- and non-trityl- containing components.86 Alternatively the excess of unreacted nucleotide bearing a 3’-hydroxy-group need not be removed from the reaction mixture as it can be specifically and quantitatively blocked with an aromatic isocyanate.” Two successive condensations with a suitably blocked TpTpT oligomer and pA followed by pG using this method resulted in the production of a pentanucleotide which was about 95% pure. This technique could possibly be applied to solid- phase synthesis. Khorana is no longer the only person synthesizing polydeoxynucleotides ;88 -90 by using their S-ethyl group for 5’-phosphate protection Nussbaum and co-workers have synthesized a dodecanucleotide corresponding to a fragment of the nonsense strand of the gene coding for a modified S-peptide of pancreatic ribotiuclease A.9 The ‘sticky end’ of lambda phage DNA r-strand has also been 84 D.Suck W. Saenger and H. Vorbriiggen Nature 1972 235 333. 85 F. B. Howard J. Frazier and H. T. Miles J. Biol. Chem. 1972 247 6733. 86 K. L. Agarwal A. Yamazaki P. J. Cashion and H. G. Khorana Angew. Chem. Internat. Edn. 1972 11 451. 87 K. L. Agarwal and H. G. Khorana .I.Amer. Chem. SOC.,1972,94 3578. 88 V. D. Smirnov V. N. Kagamanov I. A. Kozlov Z. A. Shabarova and M. A. Prokofiev Molekulyarnaya Biol. 1972 6 292. 09 A. F. Cook E. P. Heimer M. J. Holman D. T. Maichuk and A.L. Nussbaum J. Amer. Chem. SOC.,1972 94 1334. 90 E. Heimer M. Ahmad S. Roy A. Ramel and A. L. Niissbaum J. Amer. Chem. SOC. 1972,94 1707. 91 M. S. Poonian E. F. Nowoswiat and A. L. Niissbaum J. Amer. Chem. SOC.,1972 94 3992. 544 R. T. Walker ~ynthesized.'~ The chemical synthesis of two deoxyribopolynucleotide fragments containing the sequence of T4 lysozyme gene e has been ~ompleted,'~ as the DNA sequence coding for a penta-peptide sequence can be deduced from work with mutants. The 5'-end of the oligonucleotide is blocked with a 2-phenyl- mercaptoethyl purification is achieved by B.D-cellulose chromatography Sephadex gel-filtration and preparative t.1.c. The 5'-protecting group can be removed with alkali after oxidation to the sulphoxide.It is hoped to join the two fragments aligned on the appropriate T4 strand with ligase and to elongate the oligomer from the 3'-hydroxyl end with DNA p~lymerase.~~ This approach has also been used to confirm that the C-C-A terminus in tRNAtyr is encoded in the r-strand of &30psulll DNA ;the following twelve nucleotides were found to be T-C-A-A-C-T-T-T-C-A-A-A.9 Phosphodiester formation by oxidation of a nucleoside 5'-phosphoro-p- hydroxyanilidate with bromine in anhydrous methanol in the presence of a suitably blocked nucleoside gives high yields.96 Thymidine need not be protected and the method which can be used for ribo- and deoxyribo-oligonucleotide synthesis should be capable of producing polymers from mono- and di-nucleo- tides.Poly-(3,5-diethylstyrene)sulphonylchloride has been used for dinucleotide synthesis instead of tri-isopropylbenzenesulphonylchloride.97 It is claimed that protection of the amino function of adenosine and guanosine bases in deoxy- ribonucleotide synthesis is not required.'* Oligothymidylates can be prepared by the thermal activation of 02,5'-anhydrothymidine 3'-phosphate in solution or in the solid state to give oligonucleotides up to twelve units long." 34"-Diethylaminomethy1)aniline gives a 5'-phosphoroanilidate derivative with a 5'- nucleotide and the linkage can be cleaved with isoamyl nitrite. The derivatives are stable neutral and easily isolated by DEAE-celluloseshromatographysince they are eluted before the other components of the reaction."' Anilidates of 3'-phos- phates have been used in oligoribonucleotide syntheses on a polymer support.'" An enzyme isolated from E.coli B can be used in the unprimed polymerization of deoxyribonucleoside 5'-phosphates by the stepwise addition (in 30-70 % yield) of single deoxyribonucleotides to the 3'-terminus of a deoxyribonucleotide 4-4units long.lo2 Attempts to transcribe oligoribonucleotides with RNA polymerase from chemically synthesized oligodeoxyribonucleotides have only been partially 92 E. P. Heimer M. Ahmad and A. L. Niissbaum Biochem. Biophys. Res. Comm. 1972,48 348. 93 S. A. Narang K. Itakura C. P. Bahl and Y. Y. Wigfield Biochem. Biophys. Res. Comm. 1972,49,445. 94 S. A. Narang 0. S. Bhanot J. B. Goodchild R. H. Wightman and S.K. Dheer J. Amer. Chem. SOC.,1972 94 6183. 95 P. C. Loewen and H. G. Khorana J. Biol. Chem. 1972,247,6. 96 E. Ohtsuka S. Morioka and M. Ikahara Tetrahedron Letters 1972 2553. M. Rubinstein and A. Patchornik Tetrahedron Letters 1972 2881. 98 S. A. Narang K. Itakura and R. H. Wightman Canad. J. Chem. 1972,50,769. 99 J. Nagyvary and K. L. Nagpal Science 1972 177,272. 'O0 T. Hata I. Nakagawa and N. Takebayashi Tetrahedron Letters 1972 293 1. lo' E. Ohtsuka S. Morioka and M. Ikehara J. Amer. Chem. SOC.,1972,94 3229. Io2 S. Gilham and M. Smith Nature New Biol. 1972 238 233. 9' Nucleic Acids 545 successful. Transcription of short synthetic bihelical DNAs gives rise to hetero- geneous RNA because of multiple initiation sites and transcription of both strand~.''~ When a short primer oligoribonucleotide was used with a single- strand oligodeoxyribonucleotide 29 units long multiple products were still produced because termination occurred at points prior to the end of the template although initiation was correct.'O4 Much of the work on oligoribonucleotide synthesis has been concerned with examining the blocking groups and condensation methods used in order to improve the yields and so no new medium-sized oligonucleotides have been synthesized although several are known to be nearing completion. Smrt has investigated the triester synthesis of oligoribonucleotides. lo5 -'O7 The trichloroethyl phosphate protecting group gives higher yields of product but its removal from completed oligomers is difficult so that the cyanoethyl group is more satisfactory as a protecting group.lo6 The size of the phospho- diester group lowers the reactivity for the formation of triester and in a new approach it is found that higher yields are obtained if a monoester is condensed and then protected in situ by the 2-cyanoethyl group to give oligonucleotides which can be easily isolated.Yields in the condensation step remain fairly high even with increasing chain length. ' An alkali-labile group (triphenylmethoxy- acetyl Ph,COCH,CO-) for the specific protection of the 5'-hydroxy-group of the terminal nucleotide has been suggested in the continuing search for a block synthesis of oligoribonucleotides.' O8 It is lipophilic and can be detected using the standard method for trityl groups on t.1.c.Yields of over 90% are claimed for tetranucleotide syntheses. 3 Polynucleotide Analogues A polydeoxyribonucleotide with internucleotide phosphoramidate bonds synthesized by the action of DNA polymerase in the presence of a template of 4x174 DNA on 5'-aminonucleoside triphosphates,' O9 could well be useful for studying DNA sequences. The P-N bonds which are stable in neutral and alkaline solution could serve as sites for selective cleavage as they are more acid-labile than the sugar-purine bonds. Several polynucleotides with modification of the sugar and base moieties have been prepared by the action of polynucleotide phosphorylase on the correspond- ing nucleoside 5'-diphosphates. '' ' Poly 2'-deoxy-2'-aminouridylic acid Io3 R.Kleppe and H. G. Khorana J. Biol. Chem. 1972 247 6149. '04 T. Terao J. E. Dahlberg and H. G. Khorana J. Biol. Chem. 1972,247 6157. lo' J. Smrt Coil. Czech. Chem. Comm. 1972,37 846. '06 J. Smrt Coll. Czech. Chem. Comm. 1972,37 1870. lo' J. Smrt Tetrahedron Letters 1972 3437. lo* E. S. Werstiuk and T. Neilson Canad.J. Chem. 1972 50 1283. log R. L. Letsinger J. S. Wilkes and L. B. Dumas J. Amer. Chem. Soc. 1972,94 292. 'lo J. Hobbs H. Sternbach and F. Eckstein Bioihem. Biophys. Res. Comm. 1972 46 1509. 'I1 B. Janik M. P. Kotick T. H. Kreiser L. F. Reverman R. G. Sommer and D. P. Wilson Biochem. Biophys. Res. Comm. 1972 46 1153. '12 P. F. Torrence J. A. Walters and B. Witkop J. Amer. Chem. SOC. 1972,94 3638. M. K. A. Khan and F.M. Rottman F.E.B.S. Letters 1972 28 25. 546 R. T. Walker has no demonstrable secondary structure nor does it form a complex with poly A.' lo Poly 2'-fluoro-2'-deoxyuridylic acid has no secondary structure but forms a 1 :1 complex with poly A and poly X,' ' and poly 2'-azido-2'-deoxyuridylic acid has a secondary structure with a T of 12°C.'12 Poly 2'-O-ethyladenylic acid has a much more ordered structure than poly A and at pH 5.7 has a T of 55 "C (poly A 35 "C).' ' The properties of copolymers containing saturated pyrimidine bases' 14*1' show that base-stacking interactions decrease linearly with increasing dihydro- pyrimidine content of the copolymers.' ' Poly N6-(A2-isopenteny1)adenylic acid' and poly 8-chloroadenylic acid' ''have also been prepared.Poly 8,2'-anhydro-S-oxy- and poly 8,2'-anhydro-8-mercapto-9-P-~-arabinofurano-syladenylic acid have been shown to have left-handed helices and do not form hybrids with poly U.' ' The mechanism of interaction of interferon is still not clear and experiments have shown that the primary action can be at the translational or transcription level.' l9 Several poly I.poly C analogues have been synthe~ized."~ Poly 5-chlorocytidylic acid'2o and poly 2-thiocytidylic acid12' form hybrids with poly I that have higher thermal stability than poly I.poly C. Poly 2-methyl- thioinosinic acid forms a 2 :1 or 1 :1complex with poly A but not with poly C.'22 Poly 2'-O-methylcytidylic acid forms a double-stranded complex with poly I having a stability intermediate between those of the corresponding complexes formed by poly I with poly rC and poly dC.'23 Neither poly 2'-O-methyl- cytidylic acid :poly I'24 nor poly 2'-chlorocytidylic acid :poly I'25 induce interferon production and poly thiophosphate ribocytidylic acid :poly I is a slightly less potent interferon inducer than poly I :poly C.12' Replacement of the 2'-hydroxy-groups with 2'-acetoxy-groups in polyribonucleotides invariably results in a loss of antiviral activity,I2 despite the fact that 2'-O-acetylated poly C is considerably more resistant to nuclease digestion than poly C.Acetylation of poly I does not prevent complex formation with poly C but acetylation of poly C prevents its interaction with poly I.'27 114 P. F. Torrence and B. Witkop Biochemistry 1972 11 1737.1I5 J. Swinehart A. Bobst and P. Cerutti F.E.B.S. Letters 1972 21 56. 116 R. Thedford and D. B. Straus Biochem. Biophys. Res. Comm. 1972 47 1237. 117 H. J. Brentnall and D. W. Hutchinson Tetrahedron Letters 1972 2595. I18 M. Ikehara S. Uesugi and J. Yana Nature New Biol. 1972 240 16. 119 See Nature 1972 238 369. I20 M. A. W. Eaton and D. W. Hutchinson Biochemistry 1972 11 3162. 121 P. Faerber K.-H. Scheit and H. Sommer European J. Biochem. 1972 27 109. I22 M. Ikehara and M. Hattori Biochim. Biophys. Acra 1972 269 27. 123 B. Zmudzka M. Tichy and D. Shugar Acta Biochem. Polon. 1972 19 149. I24 E. de Clercq B. Zmudzka and D. Shugar F.E.B.S. Letters 1972 24 137. 125 D. R. Black F. Eckstein J. B. Hobbs H. Sternbach and T.C. Merigan Virology 1972 48 537. 126 D. L. Steward W. C. Herndon and K. R. Schell Biochim. Biophys. Acta 1972 262 227. 127 G. G. Shamovsky and N. S. Tikhomirova-Sidorova Molekirlyarnava Biol. 1972 6 179. Nuc leic Ac ids 547 Leukaemia virus replication has been inhibited by polyadenylic acid,' 28 and poly 2'-O-methyladenylic acid is 30 times more effective. Cellular DNA synthesis is not affected and it is suggested that inhibition is due to the poly A suppressing polymerization of virus-specific DNA by directly interfering with the function of viral DNA polymerase in cells. Poly 2'-O-methyluridylic and cytidylic acids are templates for Pseudornonas putida DNA-dependent RNA polymerase but the corresponding 2'-0-methylated purine polynucfeotides are not.' 29 Pofy adenylic acid has also been shown to inhibit RNA polymerase in uitro.'30 4 RNA The sequence of the 96 nucleotides in a 4.5s RNA localized in the extranucleolar portion of the nucleus of Novikoff hepatoma ascites cells has a purine-rich 5'-end and a pyrimidine-rich 3'-end.13' The nucleotide sequence of marsupial 5s RNA'32 is probably identical to the sequence of human and mouse 5s RNA and the sequence of Xenopus laeuis 5s RNA'33 differs only in 8 positions. Saccharornyces carlsbergensis 5s RNA'34 has a marked homolozy with the sequence of KB cell 5s RNA but the GAAC sequence found in both the E. coli and KB cell sequences and considered as a candidate for recognition of the common GT$C sequence in tRNA is not present.Ribosomes containing periodate-oxidized 5s RNA are fully active.' 3s The sequence of a large proportion (70%)of the 16srRNA of E. coli has been determined.'36 Some information on the sequence of 23s rRNA is also available. Suggested secondary structures (Figure 1)for many of the 16s rRNA fragments show that the molecule probably has a highly base-paired and ordered structure. Some heterogeneity in the sequence has been found because about 6 cistrons code for the rRNA. Most of the methylated bases occur in the 3'-terminal25 % of the molecule. The location of ribosomal binding sites in 16s rRNA has also been determined.' Eukaryotic messenger RNA has received much attention. The silk messenger (which like the collagen messenger contains a high proportion of guanine owing to the amino-acid composition of the protein) and many other messengers have been isolated by ~edimentati0n.l~~ Analysis of the silk mRNA shows that glycine is coded for by GGU and GGA alanine by GCU and serine by UCA.' 38 IZR R.W. Tennant F. T. Kenney and F. W. Tuominen Nurure New Biol. 1972 238 51. 129 G. F. Gerard F. Rottman and J. A. Boezi Biochem. Biophys. Res. Comm. 1972 46 1095. 13' E. de Robertis P. Ezcurra N. Judewicz and P. Pucci F.E.B.S. Lerters 1972 25 175. 13' T. S. R. Cho R. Reddy D. Henning T. Takano C. W. Taylor and H. Busch J. Biol. Chem. 1972 247 3205. I 32 M. J. Averner and N. R. Pace J. Biol. Chem. 1972 247 4491. '33 G. Brownlee E. Cartwright T. McShane and R. Williamson F.E.B.S. Lelters 1972 25 8.134 J. Hindley and S. M. Page F.E.B.S. Letters 1972 26 157. 13' S. R. Fahnestock and M. Nomura. Proc. Nut. Acad. Sci. U.S.A.,1972,69 363. 136 P. Fellner C. Ehresmann P. Stiegler and J.-P. Ebel Nature New Biol. 1972 239 1. 13' R. A.Zimmermann A. Muto P. Fellner C. Ehresmann and C. Branlant Proc. Nut. Acud. Sci. U.S.A. 1972 69 1282. 13* Y. Suzuki and D. D. Brown. J. Mol. Biol.,1972 63 409. U uc C-G C-G AG G-C CF-C G-U G-C G-U A-U GC F C 'A CA G-C G-C A G-C GA cu U-G C-G A-U C-G C-G' C-G C C-G U-A UA U-A G~G CA GA AA GG A-U C-G AC GA G-C A-U A (C) C-G C-G G-C G-U C-G AC U-A U-G C-G A-U A-U G-C A-U U-A G-C U-A GA C-G GA PC C A-U uc C-G G-U 0 6 m6 G-C C-G G-U G-C 4 A-U C-G U-A U-G C G A' C-G G-C CA G Gm' C G Am U-A cc uu G-C G-C G-IJ A U-G UGCAU UG G-C G-C G-C A C-G G-C A-U A-U AA G-c D C-G G-C U-G G-C U-G 0 GU-A G-C C-G U-G A-U A-U C-G G-C G-C A-U U-A G-C G-C A-U U-A U-A AA A-U U-G U-G U-G G-C G d c-C G-U A AUUAAA'-~ GU~AACAAGG A .I c UG E P Figure I Secondury structures for some of the sections of 16srRNA Nucleic Acids 549 Other mRNAs have been isolated by phenol e~traction,'~~ binding to poly- thymidylate-cellulose,'40~'41unreacted cell~lose,'~~ nitrocellulose filters,'43 or poly U immobilized on fibreglass filters.'44 Poly A sequences seem to occur in most eukaryotic mRNAs except histone mRNA14' but they are not found in E.coli mRNA.'46 Poly A sequences have also been found in polio~irus,'~' tumour virus,148 and SV40 mRNA.149 Milligram quantities of mRNA from the slime mould Dictyostelium discoideum are readily available.' The present position on the translation of eukaryotic mRNAs in heterologous cell-free systems seems to be that 'anything can be translated by anything'.' 51 Among the mRNAs to be translated either by oocyte injection or cell-free protein synthesis to give identifiable proteins are :chick lens crystallin,' 52 calfcrystallin,' 53 the mouse gl~bin,'~~ separate a-and /3-globins from rabbit,'55 immuno- globulin,' 56 and interferon.'57 The precursor of mRNA is thought to be heterogeneous nuclear RNA of high molecular weight (HnRNA otherwise known as D-RNA or MIRT'14 and now called pre-mRNAI5*).The mRNA precursor has been studied by RNA :RNA hybridization using mRNA and antimessenger RNA synthesized using Micro-coccus lysodeikticus RNA polymerase.' s9 The belief that the poly A residues which are at the 3'-end of mRNA,16' are added after the RNA has been synthesized and are not coded for in the genetic material rests on circumstantial evidence 139 G. Brawerman J. Mendecki and S. Y. Lee Biochemistry 1972 11 637. I4O H. Aviv and P. Leder Proc. Nut. Acad. Sci. U.S.A. 1972 69 1408. I4l H. Nakazato and M. Edmonds J. Biol. Chem. 1972,247 3365. P. A. Kitos G.Saxon and H. Amos Biochem. Biophys. Res. Comm. 1972,47 1426. 143 G.C. Rosenfeld J. P. Comstock A. R. Means and B. W. O'Malley Biochem. Biophys. Res. Comm. 1972 47 387. L44 R.Sheldon C. Jurale and J. Kates Proc. Nat. Acad. Sci. U.S.A. 1972 69 417. 145 M. Adesnik and J. E. D. Darnell J. Mol. Biol. 1972 67 397. 146 R. P. Perry D. E. Kelly and J. La Torre Biochem. Biophys. Res. Comm. 1972 48 1593. 14' J. A. Armstrong M. Edmonds H. Nakazato B. A. Philips and M. H. Vaughan Science 1972 176 526. M. Green and M. Cartas Proc. Nat. Acad. Sci. U.S.A. 1972 69 791 ;D. D. Gillespie S. Marshall and R. C. Gallo Nature New Biol. 1972,236,227;M. M. C. Lai and P. H. Duesberg Nature 1972 235 383. I4"S. Kwan and G. Brawerman Proc. Nat. Acad. Sci. U.S.A. 1972 69 3247. R. A. Weinberg Z. Ben-Ishai and J. E. Newbold Nature New Biol. 1972 238 111. R. A. Firtel A. Jacobsen and H. F. Lodish Nature New Biol. 1972 239 225. 15' See Nature New Biol.1972 239 223. Is2 R. Williamson R. Clayton and D. E. S. Truman Biochem. Biophys. Res. Comm. 1972,46 1936. 153 A. J. M. Berns M. van Karrikamp H. Bloemendal and C. D. Lane Proc. Nut. Acad. Sci. U.S.A. 1972 69 1606. 15' R. E. Lockard and J. B. Lingrel J. Biol. Chem. 1972 247 4174. H. H. Kazazian Nature New Biol. 1972,238 166; G. F. Temple and D. E. Housman Proc. Nat. Acad. Sci. U.S.A, 1972,69 1574. 156 R. H. Stevens and A. R. Williamson Nature 1972 239 143. 15' J. De Maeyer-Guignard E. De Maeyer and L. Montagnier Proc. Nat. Acad. Sci. U.S.A. 1972,69 1203. 58 See Nature 1972 239 250 ;Nature New Biol. 1972 239 191. L59 M. Melli and R. E. Pemberton Nature New Biol. 1972 236 172. I60 G. R. Molloy M. B. Sporn D. E. Kelley and R. P. Perry Biochemistry 1972,11 3256.550 R. T. Walker apart from a report that many RNA viruses do not contain poly U tracts.16' Cordycepin inhibits the addition of the polyA sequences and results indicate that the adenylate residues are added sequentially.' 62 The addition of adenylate residues to the HnRNA occurs in the cell nucleus a few minutes after the DNA- dependent synthesis of the RNA molecules destined to form mRNA.163 It is thought that the poly A sequences may in some way contribute to the stability of eukaryotic mRNA'46 and help its tran~lation,'~~ or act as an anchoring point for some of the protein that accompanies the messenger into the cytoplasm and on to the p~lysornes.'~~" A poly-A-synthesizing activity has been claimed for the a-subunit of RNA p~lymerase'~~ and it is proposed that this activity may contribute to the forma- tion of the poly A sequence in mRNA.'65 It is not clear whether this poly A polymerase activity is actually due to the a-subunit or to a protein with a molecular weight such that it co-chromatographs with the a-su5unit during purification.Such an enzyme not associated with RNA polymerase has previously been reported.' 66 5 ViralRNA Many viral RNA sequences have been reported the most significant of which is the nucleotide sequence of the RNA gene coding for the bacteriophage MS2 coat protein together with the nucleotide sequence of the ribosomal binding site for the coat protein cistron the intercistronic region and the ribosome attachment site of the RNA polymerase geneI4 -a total of 476 nucleotides.A flower model (Figure 2) is proposed for the secondary structure which is highly ~rdered.'~,'~~ The amino-acid sequence of the coat protein is also known and the codon randomness has been investigated.168 -'70 It would appear that codons which give rise to a high degree of secondary structure are selected,"' and the third base in the codon is also selected to restore the random overall composition of the mRNA which is distorted by the fixed assignments for most of the first and second bases in the c0d0n.I~~ It is unlikely that many mutations in viral RNA are viable as not only may the amino-acid be important for the function of the protein but the base sequence in the gene may be important and it is also likely to be paired with another base in another part of the mole- cule.' 68 The A-protein cistron terminates in the nonsense codon UAG.' '>' 72 A further sequence of 160 nucleotides coding for the last 45 amino-acids of the 16' S.Marshall and D. Gillespie Nature New Biol. 1972 240 43. IbZ J. Mendecki S. Y. Lee and G. Brawerman Biochemistry 1972,11 792. Ib3 M. Adesnik M. Salditt W. Thomas and J. E. Darnell J. Mol. Biol. 1972,71 21. 164 S. Ohasa and A. Tsugita Nature New Biol. 1972 240 35. 16' S. Ohasa A. Tsugita and S. Mii Nature New Biol. 1972 240 39. 166 H. J. Gross and H. Alberty Biochem. Biophys. Res. Camm. 1972 46 1581. Ib7 W. Min Jou G. Haegman M. Ysebaert and W. Fiers Arch. Internat. Physiol. Biochim. 1972 80 401. lh8 A.C. T. North Nature New Biol. 1972 239 76. 169 R. Grantham Nature New Biol. 1972 237 265. L. A. Ball J. Theor. Biol. 1972,36 313. E. Remaut and W. Fiers Arch. Internat. Physiol. Biochim. 1972 80 405. E. Remaut and W. Fiers J. Mol. Biol. 1972 71 243. Nucleic Aciak 55 1 552 R. T. Walker A-protein and the intercistronic region has been dete~mined'~~ and some nucleotide sequences for the RNA polymerase gene have been obtained.' 74 All 61 sense codons and two of the nonsense codons are used in the phage genome and the majority of this phage RNA has now been sequenced. Several nucleotide sequences of the related phage R17' 75 -'78 and a sequence of qp RNA'79,'80 ha ve been reported. The extent of variation in three related bacteriophage RNA molecules namely R17 f2 and MS2 has been investigated.81 The coat protein of R17 represses translation of the RNA synthetase cistron in vitro. Nuclease digestion and analysis of the repressor-protected fragment of RNA reveals that the 59 protected nucleotides occur between the coat-protein and synthetase cistrons. The left-hand half of this sequence is nuclease-resistant due to its secondary structure and the right-hand half is probably the site of repression.'82 A somewhat analogous situation has been found for qp where the replicase represses RNA synthesis. The replicase has been found to bind to the ribosome binding site for the coat cistron.lB3 6 tRNA Over 40 tRNA nucleotide sequences are now known and this number does not include the large number of minor tRNAs or tRNAs from.mutants which differ from their 'parent' molecule by only one or two bases.New sequences to be announced this year include for E. coli :tRNAArs,'84 tRNAG'"7 '"*'86 tRNAF'", 11 and tRNA:'";lB7 for yeast tRNAfMet,lB8 tRNAkyS,lB9 and tRNAt:g;'90 for Torulopsis utilis :tRNAA'";'91 tRNALeu from T4-infected E. coli ;'92 for Salmonella typhimurium tRNAHis'93 and tRNALeU;'94 for S. typhimurium hisT mutant tRNAHiS,195 and tRNALeU.' 94 173 R. Contreras M. Ysebaert W. Min Jou and W. Fiers Nature 1973 241 99. R. Contreras A. Vandenberghe G. Volckaert W. Min Jou and W. Fiers F.E.B.S. Letters 1972 24 339. 75 J. M. Adams P. F. Spahr and S. Cory Biochemistry 1972,11,976. 176 S. Cory J. M. Adams P. F. Spahr and U. Rensing J.Mol. Biol. 1972 63 41. '" P. E. N. Jeppesen B. G. Barrell F. Sanger and A. R. Coulson Biochem. J. 1972 128 993. ''13 J. M. Adams S. Cory and P. F. Spahr European J. Biochem. 1972 29,469. 17' J. A. Steitz Nature New Biol. 1972 236 71. A. Porter and J. Hindley F.E.B.S. Letters 1972,26 139. H. D. Robertson and P. G. N. Jeppesen J. Mol. Biol. 1972 68,417. A. Bernardi and P. F. Spahr Proc. Nut. Acad. Sci. U.S.A. 1972.69 3033. lS3 H. Weber M. A. Billeter S. Kahane C. Weissmann J. Hindley and A. Porter Nature New Biol. 1972 237 166. K. Murao T. Tanabe F. Ishii M. Namiki and S. Nishimura Biochem. Biophys. Res. Comm. 1972,47 1332. Z. Ohashi F. Harada and S. Nishimura F.E.B.S. Letters 1972 20 239. K. 0.Munninger and S. H. Chang Biochem. Biophys.Res. Comm. 1972 46 1837. W. R. Falk and M. Yaniv Nature New Biol. 1972 237 165. M. Simsek and U. L. RajBhandary Biochem. Biophys. Res. Comm. 1972 49 508. lE9 J. T. Madison S. J. Boguslawski and G. H. Teetor Science 1972,176 687. ''O B. Kuntzel J. Weissenbach and G. Dirheimer F.E.B.S. Letters 1972,25 189. S. Takemura K. Ogawa and K. Nakazawa F.E.B.S. Letters 1972 25 29. 192 T. C. Pinkerton G. Paddock and J. N. Abelson Nature New Biol. 1972,246,88. lg3 C. E. Singer and G. R. Smith J. Biol. Chem. 1972 247 2989. lg4 H. S. Allaudeen S. K. Yang and D. SOU F.E.B.S. Letters 1972 28 205. 195 C. E. Singer G. R. Smith R. Cortese and B. Ames Nature New Biol. 1972 238 72. Nucleic Acids 553 The tRNAr sequence from yeastls9 differs in 21 nucleotides from the sequence of tRNALys from a haploid The tRNALe" from TCinfected E.coli cells is found instead of a host tRNALe" which is destroyed and which recognized the codon CUG.lg2 The anticodon of the phage tRNA is -NpApA- where N is probably 5-methyl-2-thiouridine and thus the tRNA should recognize the codons UUA/UUG. In the binding assay only UUA is recognized which is characteristic for a 2-thiouridine in the wobble position. It is possible that the new tRNALe" is required for synthesis of T4proteins. The yeast initiator tRNA (Figure 3) sequence'88 contains no fewer than 12 modified nucleosides but does A OH C C A PA-U G-C C-G C-G G-C C-G G-C G' D ","Zc m7G C-G A * A-U G-C G-C G-C CA U t6A CAU t* Figure 3 Structure of yeast tRNAyt;bases G and A are unknown not contain the G-T-$-C which is common to all those tRNAs active in protein synthesis which have been sequenced to date.The sequence is replaced by G-A-U-C and several other eukaryotic initiator tRNAs have been found to lack the G-T-$-C sequence. The first and last nucleosides of this same loop are both purine nucleosides and in all sequences so far determined these residues have always been pyrimidine nucleosides. The four stem regions contain only 3 base pairs which are other than G-C. 196 C. J. Smith A. N. Ley P. D'Obrenau and S. K. Mitra J. Bid. Chem. 1971 246 7819. 554 R.T. Walker His-tRNAHis has been shown to be involved in the regulation of the histidine operon and mutants (hisT) have been obtained where derepression of the enzymes of the histidine biosynthetic pathway in S.typhimurium occurs. Thus hisT mutants are defective in regulation of the His'95 (and Leulg4) operons. Analysis of the tRNAHis and tRNALe" from normal and hisT strains of S. typhimurium has shown that both normal tRNAs contain three t,b nucleotides one in the G-T-rl/-C sequence and the other two near the anticodon. In both tRNAs from the mutant species the G-T-rl/-C sequence is still present but both the other 11/ residues are replaced by U. The data suggest that the wild-type hisT gene specifies an enzyme which converts U into rl/ in tRNA in positions other than G-T-$-C. Incubation of tRNALe" from hisT mutants with E. coli cell-free extracts has resulted in the formation of $ residues.194 Once again tRNATyr from E.coli has received more than its fair share of attention. tRNA isolated from E. coli harvested in the early log phase of growth has been shown to contain equal amounts of tRNA:Yr (the so-called minor species) and tRNAZYr.l9' A dimer of tRNA:y' can be formed by heating a solution at 50°C in buffer containing 0.5 M-Na'. The dimerization can be reversed and is thought to occur because of the self-complementarity in the pseudouridine and dihydrouridine loops.' 98 The dimer does not accept tyrosine and this may explain the well-known phenomenon that tRNATyr in particular loses its ability to be amino-acylated when solutions are subjected to successive melting and freezing. The enzyme (RNase P) responsible for the cleavage of the 41 nucleotides from the 5'-end of the precursor tRNATyr species has been purified.' 99 Many tRNA~~~l species from mutants have been sequenced.Four mutations giving rise to mis-suppression are tightly clustered in the CCA stem of the clover- leaf structure and show that the mechanism of mis-suppression probably involves charging.200 Two other series of tRNATyr molecules from mutants have been obtained one contains a G-U base change at position 31 in the stem of the anticodon loop and the other has a C+A base change at the same position.201 Analysis of the tRNA of revertants of these mutants shows that suppression is restored either by changing base 45 such that it now pairs with the changed base 31 or by the tRNAs from both mutants having a C-+U base change at position 16 in the dihydrouridine loop or a C-+U base change in the finger loop.It is easier to explain the reversion conferred by the first of these base changes as it restores the base pairing in the anticodon stem. The other two changes seem to have no connection with the original base change that causes the mutation. It is proposed that in some way these base changes must be restoring the overall three-dimensional structure of the tRNA distorted by the base change in the original mutation. 19' H. J. Gross and C. Raab Biochem. Biophys. Res. Cornm. 1972,46 2006. S. K. Yang D. G. Soll and D. M. Crothers Biochemistry 1972 11 2311. 199 H. D. Robertson S. Altmann and J. D. Smith J. Biol. Chem.1972 247 5243. M. L. Hooper R. L. Russell and J. D. Smith F.E.B.S. Letters 1972 22 149. 'O' K. W. Anderson and J. D. Smith J. Mol. Biol. 1972 69 349. Nucleic Acids 555 Another mutant hPs a tRNATyr with a base change of A82-G2O2 (adjacent to the CCA end). This tRNA now accepts glutamic acid in uitro but the in viuo results are not definite except that not all glutamic acid is inserted. This suggests that the stem of the cloverleaf structure plays an important part in the recognition of tRNA by the aminoacyl-tRNA synthetase. This conclusion has been arrived at independently by other w~rkers.~~~,~'~ From correlations that have emerged from heterologaus charging experiments in particular by yeast phenylalanyl-tRNA synthetase which charges nine E.cob tRNA's it is concluded that the fourth residue from the 3'-end and the stem of the dihydrouridine loop are the critical recognition points for the synthetase. All eight of these tRNAs which have been sequenced have an A as the fourth base and a common sequence of eight nucleotides in the stem of the dihydro- uridine Other tRNA species which have very similar sequences except for either the A residue or the dihydrouridine stem region are not charged. Another paper allocates to the fourth nucleotide a preliminary sorting function of the tRNA's on the basis of the chemical nature of the amino-acid. After being found acceptable by this site the tRNA can then interact with the synthetase by way of other sites.204 It is suggested that this may be relict from a primitive recognition system.All the tRNAs can unambiguously be allocated to one of the four groups except for lysine and arginine tRNA and it is thought that the probability of such a correlation being due to chance is remote. Thus the A group consists of Ala Leu Tle Val Phe Tyr Met and Cys the G group contains Ser Thr Glu Gln Asp and Aspn the C group contains His and Pro and the U group contains only Gly. X-Ray crystallographic studies on yeast phenylalanine tRNA at 4A resolution using isomorphous heavy-atom replacements containing platinum osmium and samarium205 have enabled the folding of the polynucleotide chain in the tRNA to be determined,206 and this has been shown to be different from that proposed in any model. The molecule is made of two double-stranded helical regions oriented at right angles to each other in the shape of an L.One end of the L has the CCA acceptor; the anticodon loop is at the other end and the dihydrouridine and T$C loops form the corner. Yeast tRNAPhe has been crystal- lized in a new form to give only one molecule per asymmetric unit and crystals with good stability in the X-ray beam. Resolution down to 3A has been obtained.20 Further attempts have been made to incorporate heavy atoms into tRNA to enable the structure of tRNA to be obtained by the method of heavy-atom 202 Y. Shimura H. Aono H. Ozeki A. Sarabhai H. Lamfrom and J. Abelson F.E.B.S. Letters 1972 22 144. 203 B. Roe and B. Dudock Biochem. Biophys. Res. Comm.,1972,49 399. 2"4 D. M. Crothers T.Seno and D. G. Soll Proc. Nat. Acad. Sci. U.S.A.,1972,69 3063. 205 S. H. Kim G. J. Quigley F. L. Suddath A. McPherson D. Sneden J. J. Kim J. Weinzierl P. Blattman and A. Rich Proc. Nat. Acad. Sci. U.S.A. 1972 69 3746. '06 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. '07 T. Ichikawa and M. Sundaralingam Nature New Biol. 1972 236 174; J. E. Ladner J. T. Finch A. Klug and B. F. C. Clark J. Mol. Biol. 1972,72 99. 556 R.T. Walker isomorphous replacement. Nucleotidyl transferase can incorporate 5-iOdO- cytidine into tRNAPhe which has had the CCA end removed.208 The derivative can be amino-acylated. N-Hydroxysuccinimide esters of p-chloromercuribenzoic acid have been allowed to react with the amino-group of amino-acylated tRNA to give a mercury derivative which is stable under crystallizing conditions.209 An intriguing reaction between K20s04in pyridine and crystalline tRNA results in an average of one 0s atom per tRNA molecule being incorporated into the crystals over a period of days.2 lo Preliminary X-ray data have been obtained but it is not yet known whether the osmium is reacting specifically with the tRNA.It was hoped to produce a complex with the 2',3'-cis-diol of the tRNA but the complex is capable of being amino-acylated. A further suggestion was that it might be reacting with the T residue but unknown to the workers at the time the tRNA used -tRNAF"' from yeast -is the only tRNA so far sequenced which does not contain T ! p-Chloromercuribenzoate reacts with the 4thiouridine in E.coli tRNA to give a mercury derivative which is unfortunately unstable.2' ' Pentafluorophenylmercury chloride gives a similar derivative which is more stable but the derivative with tRNATY' cannot be amino-acylated.212 High- resolution shadowing of tRNA with tantalum-tungsten for visualization under the electron microscope gives results which confirm the X-ray data so far obtained -rod-shaped particles with dimensions of about 40 x 85 An improved method for the purification of tRNA synthetases has been proposed214 which has given tRNAPhe synthetase completely pure after two column fractionations. Now that pure synthetases are available some hitherto unsuspected properties of these enzymes are being discovered.Isoleucyl-tRNA synthetase for E. coli synthesizes isoleucyl-tRNAPhe (E. coli) this being rapidly hydrolysed by the phenylalanyl-tRNA synthetase.2 This reaction has been studied216 and the effect of mis-acylation in uivo discussed.21' Chemical modifications of tRNA continue. Cytidine residues in unfractionated tRNA can be converted into uridine residues by a combination of hydroxylamina-tion and subsequent oxidation.218 In pure E. coli tRNA?"' six cytidine residues are converted into uridine residues by the action of bi~ulphite.~" The converted residues are present only in single-stranded regions and the results obtained are '08 M. Sprinzl F. von der Haar E. Schlimme H. Sternbach and F. Cramer European J. Biochem. 1972,25 262.209 F. J. Schmidt R. M. Bock and S. M. Hecht Biochem. Biophys. Res. Comm. 1972,48 451. 210 R. W. Schevitz G. Cornick P. B. Sigler M. A. Navia J. J. Rosa D. A. Bantz and M. D. H. Rosa Science 1972 177 429. *I1 B. C. Pal L. R. Shugart K. R. Isham and M. P. Stulberg Arch. Biochem. Biophys. 1972 150 86. 2'2 A. S. Jones R. T. Walker and V. Youngs Biochim. Biophys. Acta 1973 299 293. 'I3 R. J. Abermann and D. Yoshikami Proc. Nat. Acad. Sci. U.S.A. 1972,69 1587. '14 P. Remey C. Birmele and J.-P. Ebel F.E.B.S. Letters 1972 27 134. M. Yarus Proc. Nat. Acad. Sci. U.S.A. 1972 69 1915. 216 M. Yarus Biochemistry 1972 11 2352. 217 M. Yarus Nature New Biol. 1972 239 106. 218 Y.Mizuno Y.Kawamura and A. Nomura Biochim. Biophys. Acta 1972 259 76. '19 J.P. Goddard and L. H. Schulman J. Biol. Chem. 1972 247 3861. Nucleic Acids 557 compatible with some tertiary structure proposed for tRNA. Similar results have been obtained by the reaction of uridine and guanosine residues with a di-imide,220 and of methoxylamine with cytidine residues in tRNATy'. The 4-thiouridine residues in tRNATy' and tRNAp' from E. coli have been converted into uridine with little obvious effect on the properties of the tRNA.221 The modification of guanosine residues by ketoxal has been studied in three pure tRNAs.222 7 DNA It is now possible to insert new genetic information into the DNA of SV40. Berg and co-worker~~'~ have inserted A phage genes and the galactose operon of E. coli into the SV40 phage genome.Phage DNAs still have some surprises in store ; Bacillus subtilis phage SP- 15 has 5-(4,5'-dihydroxypenty1)uracil (28) present to the extent of 12mole % of all the bases.224 0 Probably the most significant advance in the nucleic acid field during 1972 has been in the determination of nucleotide sequences in DNA. It is not coin- cidental that Sanger has turned his attention to this problem that has for many years been thought to be insoluble ;however using standard methods of degrada- tion and fractionation Sanger and co-workers have produced some impressive results. A somewhat uncritical but nonetheless welcome review l6 covers the literature until December 1971. The main difficulties associated with the determination of nucleotide sequences in DNA have been the lack of specific enzymes lack of sufficient quantities of pure DNAs and the size of the smallest DNA molecules which are available.However now that the sequence of phage RNA molecules is in sight the sequenc- ing of phage DNA molecules has started. Large pyrimidine tracts (20 units) from fd A and 4x174 have been isolated by standard techniques and sequenced very elegant techniques such that the sequence can finally be deduced from 220 S. E. Chang A. R. Cashmore and D. M. Brown J. Mol. Biol. 1972 68 455. 221 R. T. Walker and U. L. RajBhandary J. Biol. Chern. 1972 247 4879. 222 M. Litt and C. M. Greenspan Biochemistry 1972 11 1437. 223 D. A. Jackson R. H. Symons and P. Berg Proc. Nut. Acad. Sci. U.S.A. 1972 69 2904. 224 J.Marmur C. Brandon S. Neubort M. Ehrlich M. Mandel and J. Konvicka Nurure New Biol.,1972 239 68; C. Brandon P. M. Gallop J. Marmur H. Hayashi and K. Nakanishi Nature New Biol. 1972 239 70. 558 R.T. Walker one two-dimensional ~hrornatogram.~~~~~~~ Another fragment from 4x174 DNA 48 residues long has been using a variety of enzymes in particular endonuclease IV which has a high specificity for single-stranded DNA and cleaves TpC phosphodiester bonds to give oligonucleotides of the type pC-OH. Using a variety of tricks and various combinations and permutations of the chemical depurination method and enzyme-degradation methods this sequence and the sequence of an oligonucleotide 52 units long have been deter- mined.228 This latter fragment was isolated from a ribosome-protected DNA and has been found to contain an ATG ‘start signal’ and eight further triplets which as luck would have it happen to code for the first eight amino-acids in the only coat protein of 4x174 whose sequence is known.The RNA poly- merase binding site of phage fd has also been isolated but its sequence is not yet known.229 The complete sequence of the left-hand cohesive end of coliphage 186 DNA has been obtained by repairing it with E. coli DNA polymerase.230 The 3’-terminal sequence of several phage DNA’s has also been determined by the same method.231 The use of endonuclease 111 has also been investigated as a suitable candidate for the hydrolysis of a limited number of nucleotides from the 3’-terminus of a DNA such that the single-stranded portion remaining could be repaired with DNA polymerase.232 The idea of using a primer oligonucleotide which would specifically hybridize to a DNA strand which could then be repaired with DNA polymerase has been investigated.An octanucleotide was found not to be long enough,233 but a polypyrimidine tract C9Tl specifically hybridized to phage fd DNA.234 The use of a dodecaribonucleotide of such a sequence as to hybridize to a definite part of the DNA that unambiguously codes for a known amino-acid sequence has been suggested,235 but first one has to synthesize the dodecaribonucleotide. The ribosubstitution technique whereby DNA poly- merase in the presence of Mn2 + can incorporate ribonucleotides into DNA,236 has been investigated to see whether it can be used in DNA sequencing.237 Using a variety of chemical reagents it is now possible to distinguish between mammalian chromosomes because of specific bands which are produced.The medical biochemists who find this technique so useful have many theories as to why bands (which occur in specific positions usually independent of the 225 V. Ling J. Mol. Biol. 1972 64 87. 226 V. Ling Proc. Nar. Acad. Sci. U.S.A. 1972 69 742. 227 E. B. Ziff J. W. Sedat and F. Galibert Nature New Biol. 1973 241 34. ”* H. B. Robertson B. G. Barrell H. L. Weith and J. E. Donelson Nature New Biol. 1973 241 38; G. M. Air and J. Bridgen ibid.,p. 40. 229 B. Heyden C. Niisslein and H. Schaller Nature New Biol. 1972 240 9. 230 R. Padmanabhan and R. Wu J.Mol. Biol. 1972 65 447. 23‘ J. E. Donelson and R. Wu J. Bid. Chem. 1972 247,4654. 232 J. E. Donelson and R. Wu J. Biol. Chem. 1972 247 4661. 233 R. Padmanabhan R. Padmanabhan and R. Wu Biochem. Biophys. Res. Comm. 1972 48 1295. 234 W. Oertel and H. Schaller F.E.B.S. Letters 1972 27 316. 235 R. Wu Nature New Biol. 1972 236 198. 236 J. H. van de Sande P. C. Loewen and H. G. Khorana J. Biol. Chem. 1972,247,6140. 237 W. Salser K. Fry C. Brunk and R. Poon Proc. Nat. Acad. Sci. U.S.A.,1972,69,238. Nucleic Acids 559 chemical used) should appear. A chemist would be a little rash to try to equate the chemical reactions of such widely divergent reagents as quinacrine mustard,238 39 acridine,’ Giem~a,~~ trypsin + q~inacrine,~ potassium ~ermanganate,~~~ Giem~a,~~~ and extracts from Papaveraceae and Fumariaceae species.244 Although people hope that A-T-rich regions245 are being selected the size of the bands and the amount of genetic material being stained is so large that a much more probable explanation is that one is distinguishing between parts of the chromosome rich and poor in DNA.It is still not apparent why this should cause banding but at least it is now possible to distinguish individual chromo- somes from each other. The structure and function of chromosomal nucleohistones has been re-viewed,246 and the function of histones investigated by tryptic prote~lysis~~’ or by reconstitution Models for the organi~ation~~~ and general structure of chromosomes2 have been proposed. 8 Polymerases Kornberg’s DNA polymerase I relegated from its supreme role of DNA replica-tion to the humbler one of proofreading,252 has suffered further humiliation by being cut into two!253 One fragment contains the polymerase activity and the other the exonuclease function.DNA polymerase I1 has been purified and its mode of action st~died.~~~,~~~ However the same fate has befallen this enzyme as happened to polymerase I-a mutant deficient in the enzyme but happily replicating its DNA has been isolated.256 Thus DNA polymerase I11 is the enzyme essential for DNA repli~ation.~~’ It is present in sufficient amounts 238 T. Caspersson S. Farber G. E. Foley J. Kudynowski E. F. Modest E. Simonsson U. Wagh and L. Zeck Exp. Cell. Res. 1968 49 219. 239 W.R. Breg P. W. Allderdice D. A. Miller and 0.J. Miller Nature New Biol. 1972 236 76. 240 J. C. Stockert and J. A. Lisanti Chromosoma 1972,37 1 17. 241 J. P. Frey R. L. Neu H. 0. Powers and L. I. Gardner Canad. J. Genetics Cytof. 1972 14 195. 242 T. Utakoji Nature 1972 239 168. 243 H. C. Wang and S. Fedoroff Nature New Biol. 1972 235 52. 244 C. G. Vosa G. d’Amato R. Capineri P. Marchi and G. de Dominicis Nature 1972 239 405. 245 B. Weisblum and P. L. de Haseth Proc. Nut. Acad. Sci. U.S.A. 1972 69 629; J. R. Ellison and H. J. Barr Chromosoma 1972 36 375. 246 E. Zimmerman Angew. Chem. Znternat. Edn. 1972 11 496. 247 R. T. Simpson Biochemistry 1972 11 2003. 248 E. W. Johns Nature New Biol. 1972 237 87. 249 J. Paul and I. R. More Nature New Biol.1972 239 134. 250 E. C. Cox Nature New Biol. 1972 239 133; W. D. Sutton Nature New Biol. 1972 237 70. 251 J. Paul Nature 1972 238 444. 252 D. Brutlag and A. Kornberg J. Biol. Chem. 1972 247,241. 253 P. Setlow D. Brutlag and A. Kornberg J. Biol. Chem. 1972 247 224. 254 R. B. Wickner B. Ginsberg I. Berkower and J. Hurwitz J. Biol. Chem. 1972 247 489. 255 R. B. Wickner B. Ginsberg and J. Hurwitz J. Biol. Chem. 1972 247 498. 256 J. L. Campbell L. SOH,and C. C. Richardson Proc. Nut. Acad. Sci. U.S.A. 1972,69 2090. *” T. Kornberg and M. L. Gefter J. Biol. Chem. 1972 247 5369. 560 R.T. Walker in cells to account for the in vivo rate of replication and it uses deoxyribonucleo- side triphosphates and DNA that has been partially degraded by exonuclease I11 as a template.It will not use linear duplex or single-stranded DNA as template requires a primer and proceeds 5' -+3' by extension of the primer. RNA primers are becoming increasingly implicated in DNA replicati~n.~ 58*259 It is suggested that short DNA chains are formed by extension of RNA primers and the primer is removed before 'ligation' of the DNA fragments.259 Okazaki (and his pieces) really seem to have come back into favour in the continuing attempts to explain DNA replication.260 One DNA strand is probably replicated as a single piece and the strand which has to be synthesized in the 3'-5' direction is synthesized as a series of short pieces.26' Evidence is now available which suggests that E. coli DNA undergoes bidirectional replication.26 la RNA-dependent DNA polymerase has been the subject of another review.262 The enzyme has been used to prepare radioactively labelled DNA from RNA templates and this product has been extensively used in hybridization studies.Human globin DNA has been synthesized from globin mRNA,263 and experi- ments using a similarly prepared mouse globin DNA have enabled previous estimates of 50 000 globin genes in mouse chromosomes to be reduced to and a question mark must be placed by the deductions drawn from the results of many other hybridization experiments. On a more practical and sinister note DNA prepared using RNA-dependent DNA polymerase and a template of Rauscher leukaemia virus RNA has been shown to hybridize to RNA from sarcomas obtained from 18out of 25patients.265 Following a detailed experimental procedure that was developed for the detection of 70s RNA associated with RNA-dependent DNA polymerase from mouse mammary carcinomas,266 such a reverse transcriptase associated with a high- molecular-weight RNA has been isolated from human leukaemic cells.The DNA synthesized in vim by this complex has been shown to hybridize specifically to Rauscher leukaemia virus RNA.267 Particles from human milk also contain a reverse transcriptase and a high-molecular-weight RNA which serves as a template.268 The 70s RNA/RNA-dependent DNA polymerase complex has been isolated from human breast tumours and the DNA synthesized in vitro 258 K. G. Lark J. Mol. Biol. 1972 64,47. 259 A. Sugino S. Hirose and R.Okazaki Proc. Nar. Acad. Sci. U,S.A. 1972 69 1863. 260 H. Schaller B. Otto V. Niisslein J. Huf R. Herrmann and F. Bonhoeffer J. Mol. Biol. 1972 63 183. 261 B. M. Olivera and F. Bonhoeffer Nature New Biol. 1972 240 233; R. Hermann J. Huf and F. Bonhoeffer ibid. p. 235 K. G. Lark ibid. p. 237. 2610 W. G. McKenna and M. Masters Nature 1972 240 536; D. M. Prescott and P. L. Kuempel Proc. Nat. Acad. Sci. U.S.A. 1972 69 2842. 262 R. C. Gallo Blood 1972 39 117. 263 D. L. Kacian S. Spiegelman A. Bank M. Terada S. Metafora L. Dow and P. A. Marks Nature New Biof. 1972 235 167. 264 P. R. Harrison A. Hell G. D. Birnie and J. Paul Nature 1972 239 219. 265 D. Kufe R. Hehlmann and S. Spiegelman Science 1972 175 182. 266 S. C. Gulati R. Axel and S. Spiegelman Proc.Nut. Acad. Sci. U.S.AI 1972,69 2020. 267 W. Baxt R. Hehimann and S. Spiegelman Nature New Biol. 1972 240,72. 268 J. Schlom and S. Spiegelman Science 1972 175 542. Nucleic Acids 561 hybridizes with mouse mammary tumour virus RNA.269 The conclusion to be drawn from these experiments is inescapable -a viral agent (although not neces- sarily the cause) is usually associated with these and probably several other forms of cancer. A comprehensive investigation into the binding of E. coli DNA-dependent RNA polymerase to phage T7 DNA has attempted to define how the enzyme selects the sites on DNA templates at which to begin tran~cription.'~' The results show that the T7 early promoter region contains at least three distinct initiation sites.Not only will DNA polymerase I use ribonucleoside tripho~phates~~~ but DNA-dependent RNA polymerase will catalyse the incorporation of deoxy-nucleoside triphosphates into polynucleotides in the presence of Mn2+ .271 269 R. Axel S. C. Gulati and S. Spiegelman Proc. Nat. Acad. Sci. U.S.A.,1972 69 3133. ''O See M. J. Chamberlin et al. J. Mof.Biol. 1972 70 157-237. J. Hurwitz L. Yarbrough and S. Wickner Biochem. Biophys. Res. Comm. 1972 48 628.

ISSN:0069-3030    

DOI:10.1039/OC9726900531

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

18 Aromatic Compounds By J. W. BARTON School of Chemistry University of Bristol Cantock's Close Bristol BS8 1 TS 1 General Once again the use of the term 'aromatic' has been criticized' and the suggestion made that systems be described as Huckel counter-Huckel or in the case of larger annulenes as non-Hiickel according to their ground-state stability. Other terms are suggested to cover structural features and chemical reactivity. The 'scrambling' processes which take place after impact ionization of benzene have received further study,2 as has the structure of the abundant C7H7+ ion formed from toluene and the higher alkyl benzene^.^ A marked difference between the decomposing (C7H,NH2)+ ions from benzylamine and p-aminoto- luene is rep~rted.~ In the gas-phase radiolysis of toluene about one third of the C7H7+ions produced arise uia a symmetrical intermediate.the rest via benzyl cations. Radiolysis of ethylbenzene in the presence of dimethylamine gave NN-dimethylbenzylamine from unrearranged benzyl cations and no NN-dimethyltropylamine. Owing to steric interactions there is considerable twisting in 1,8-di-t-butyl- naphthalenes the t-butyl groups lying on opposite sides of the mean plane of the naphthalene ring. The barrier to flipping from this conformation to its mirror- image is greater than 24 kcal mol- ',but the barrier to rotation around a t-butyl- naphthalene bond is estimated to be only 6.5 kcal mol-1.6 Contrary to an observation discussed in last year's Rep~rt,~ it is unlikely that the energy barrier to ring inversion of any tetraphenylene derivative can be lower than that for cyclo-octatetraene (-15 kcal mol- '1 owing to the considerable non-bonded interactions of the benzene-ring hydrogens in the former.8a,e Although an n.m.r.' D. Lloyd and D. R. Marshall Angew. Chem. Internat. Edn. 1972 11,404. J. H. Beynon R. M. Caprioli W. 0.Perry and W. E. Baitinger J. Amer. Chem. Soc. 1972,94 6828. T. Ast J. H. Beynon and R. G. Cooks J. Amer. Chem. Soc. 1972,94 1834. A. P. Bruins N. M. Nibbering and T. J. de Boer Tetrahedron Letters 1972 1109. S. Takamuku N. Sagi K. Nagaoka and H. Sakurai J. Amer. Chem. Soc. 1972 94 6218. 'J. E. Anderson R. W. Franck and W. L. Mandella J. Amer. Chem. Soc. 1972,94,4608. ' H. Heaney Ann. Reports (B) 1971,68 516.(a) G. H. Senkler D. Gust P. X. Riccobono and K. Mislow J. Amer. Chem. Soc. 1972 94 8626; (6) G. W. Buchanan Tetrahedron Letters 1972 665; (c) A. Rosdal and J. Sandstrom ihid. p. 4187; (6) D. Gust G. H. Senkler and K. Mislow J.C.S. Chem. Comm. 1972 1345; (e)C. J. Finder D. Chung and N. L. Allinger Tetrahedron Letters 1972 4677. 563 564 J. W.Barton method has indicated a slightly lower barrier in (1) than in (2)," further n.m.r. studies on the 2-substituted tetraphenylenes [3;R = CH(OH)Me]'" and (3 ; R = COCHMe2)8' have given estimated lower limits of 21 and 26 kcal mol-' and the barrier to racemization of tetraphenylene-2-carboxylicacid (3; R = C02H) is found to be at least 45 kcal mol- 1.8d Certain 2,6-disubstituted aryl alkyl I I ketones show temperature-dependent n.m.r.spectra which are accountable for in terms ofrestricted rotation about the Ar-CO bond;'barriers to rotation lie in the range 9-15 kcal mol-'. The preferred conformations of mesityl 1- and 2-naphthyl ketones have been determined." Assignment of the left-handed (M) configuration to (-)-hexahelicene by a chemical method' agrees with the findings of a recent X-ray crystallographic study details of which have now appeared.12 The synthesis of (+)-(P)-pen- tahelicene from optically pure ( -)-(S)-2,2'-bis(bromomethyl)-1,l'-binaphthyl has been reported ;I3 it appears likely that all (+)-helicenes belong to the (P)and all (-)-helicenes to the (M)series. Mechanistic studies of the asymmetric syn- thesis of [6]-,[7]- [8]- and [9]-helicenes using circularly polarized light in- dicate that the optical activity induced is due to selective reactions of enantiomeric conformations of the cis-1,2-diarylethylene precursors ;I4 a recent study of the n.m.r.spectra of 1,2-diarylethylenes supports this view. ' The use of specific deuterium labelling combined with I3C n.m.r. spectroscopy has been used to study the course of photocyclization of 1,2-diarylethylenes to helicenes. Optically active 6,6'-diethyl-2,2-dimethylbiphenyl is photoracemized to an extent of 17% in 2 h loss of activity also occurring by arrangement involving benzvalene intermediates. In contrast this biphenyl is exceptionally stable to thermal racemization having a half-life of 283 h at 345"C.l7 The biphenyl (4) N.Nakamura and M. Oki Bull. Chem. SOC.Japan 1972,452565. lo C. L. Cheng G. L. D. Ritchie P. H. Gore and M. Jehangir J.C.S.Perkin If 1972,1432. l1 J. Tribout R. H. Martin M. Doyle and H. Wynberg TetrahedronLetters 1972,2839. D. A. Lightner D. T. Hefelfinger T. W. Powers G. W. Frank and K. N. Trueblood J. Amer. Chem. SOC.,1972 94 3492. l3 H. J. Bestmann and W. Both Angew. Chem. Internat. Edn. 1972 11 296. l4 W. J. Bernstein M. Calvin and 0. Buchardt J. Amer. Chem. SOC.,1972,94 494. ' R. H. Martin N. Defay H. P. Figeys K. LC Van J. J. Ruelle and J. J. Schurter Heh. Chim. Acta 1972 55 2241. l6 R. H. Martin and J. J. Schurter Tetrahedron 1972 28 1749. H. E. Zimmermann and D. S. Cramrine J. Amer. Chem. SOC.,1972 94 498. Aromatic Compounds Me Ph \/ CONHCH NO CONHCH /\ Me Ph (4) and its diastereomer which possess an axis of pseudoasymmetry have been synthesized.Homo- Spiro- and Bicyclo-aromaticity.-There is no 'scrambling' of the deuterium label amongst the ring carbon atoms in solutions of the homotropylium ion (5);thus the circumambulatory rearrangement observable with the bicyclo- [3,1,0]hex-3-enyl cation (6) does not take place in this ~ystem.'~ Confirmation that the primary product in the chlorination of cyclo-octatetraene is the endo-8-chlorohomotropylium ion (7)20 has been afforded by its isolation as the hexa- chloroantimonate ; further kinetic studies concerned with this reaction are (5) (6) (7) reported.2 When 1-methoxycyclo-octatetraene is dissolved in fluorosulphonic acid at -78 "C it protonates to give the ion (8) which at higher temperatures rearranges to the phenylmethylmethoxycarbonium ion (9) and further to ,Me H 9' \/H I; acetophenone and methyl fluorosulphonate.2 * The dibenzohomotropylium ion (10)has been generated and its reactions with nucleophiles have been studied.23 " G.Helmchem and V.Prelog Helu. Chim. Acta 1972 55 2599. l9 J. A. Berson and J. A. Jenkins J. Arner. Chem. SOC.,1972 94 8907. 2o I. 0.Sutherland Ann. Reports (B) 1967 64 296. 21 R. Huisgen and J. Gasteiger Angew. Chem. Internat. Edn. 1972,11 1104; Tetrahedron Letters 1972 3661 3665. 22 M. S. Brookhart and M. A. M. Atwater Tetrahedron Letters 1972 4399. 23 R. F. Childs M. A. Brown F. A. L. Anet and S. Winstein J.Amer. Chern. SOC. 1972,94,2175. 566 J. W.Barton The syn and anti forms of 4,5-benzo-2,3 :6,7-bishomotropone undergo reversible protonation to give the hydroxycations which are stable below -20 “C. From their n.m.r. spectra it is concluded that there is bishomoaromatic stabilization of the syn cation (1 1) but not of the anti.24 (10) (1 1) In a discussion of the topology of aromatic-type systems it has been suggested that certain spirocyles with continuous ribbons of p-orbitals in each ring may show special stabilization or ~piroaromaticity,~ examples being the ions (12) and (13) and biradical (14). In the first study of such systems it is found that spiroaromatic stabilization of the anion (I 5) is not a significant factor in its rate of formation.26 (15) The question of bicycloaromatic stabilization has been re-examined and the concepts have been tested by study of the ions derived from bicyclo[3,2,2]nona- 2,6,8-triene.Theanion (16) is a stable delocalized ion which undergoes a degenerate ‘~crambling’.~’ (16) Benzene Isomers and Benzene Oxides.-Reviews have appeared dealing with valence bond isomers of aromatic systems28 and with rearrangements and interconversions of (CH) Silver-ion-catalysed valence isomerization of 1,l’-dimethylbicyclopropenyl(17) gives the Dewar-benzenes (18) and (19) together with 0-and p-xylene. From the 24 H. A. Carver and R. F. Childs J. Amer. Chem. Soc. 1972 94 6201. 25 M. J. Goldstein and R. Hoffmann J. Amer. Chem. SOC.,1971 93 6193.26 M. F. Semmelhack R. J. DeFranco Z. Margolin and J. Stock J. Amer. Chem. Soc. 1972,94 2116. ‘’ J. B. Grutzner and S. Winstein J. Amer. Chem. SOC.,1972 94 2200. ’* E. E. van Tamelen Accounts Chem. Res. 1972,5 186. 29 L. T. Scott and M. Jones Chem. Rec. 1972 72 181. Aromatic Compounds Me Me Me vv Me (17) absence of isomer (20)amongst the products it is concluded that the reaction cannot involve a prismane intermediate.3 Photolysis or low-pressure thermolysis of the cyclopropene anhydride (21) gives a similar result in that 1,2,3,5- and 1,2,4,5-tetraphenylbenzenes are formed but not the 1,2,3,4-isomer. It is suggested that the intermediate anhydride (22) fragments to the benzvalene (23) which Ph pco-0 404Ph PhOPh PhDPh Ph Ph Ph Ph Ph Ph (21) (22) (23) rearranges to give the observed prod~cts.~' Several studies of the reactions of hexamethyl-Dewar-benzene have been reported,32 together with one study of the kinetics and thermodynamics of interconversions in the series hexakis(trifluoro- methyl)-benzene,-Dewar-benzene,-benzvalene and -prismane ;3 the 'downhill' reactions all require large activation energies (-40 kcal mol- ').Whereas the dichloro-Dewar-benzene derivative (24; X = Y = C1) is more stable than the parent (24; X = Y = H) the less symmetrical monochloro (24; X = C1 Y = H) and monofluoro (24; X = F. Y = H)derivatives rearrange to the corresponding X Y (24) benzenes some 10 and 40 times faster than the parent.34 cis-Hexa-1,5-diyn-3-ene undergoes a thermal degenerate rearrangement in which p-benzyne must be an intermediate.3s Trapping experiments e.g.the rearrangement in carbon tetra- chloride which gives only 1,4-dichlorobenzene suggest that the biradical form 30 W. H. de Wolf J. W. von Straten and F. Bickelhaupt Tetruhedron Letters 1972 3509. 31 E. B. Hoyt E. J. Reineberg P. Goodman P. Vaughan and V. Georgian Tetrahedron Letters 1972 1579. 32 L. Paquette R. J. Haluska M. R. Short L. K. Read and J. Clardy J. Amer. Chem. SOC.,1972 94 529; G. R.Crow and J. Redly Tetrahedron Letters 1972 3129 3133; L. Paquette S. A. Lang S. K. Porter and J. Clardy Tetrahedron Letters 1972 3 137 ; H. Hogeveen and R. W. Kwant Tetrahedron Letters 1972 3197. 33 D. M. Lemal and L. H. Dunlap J. Arner. Chem. SOC., 1972 94 6564.34 R. Breslow J. Napieralski and A. H. Schmidt J. Amer. Chem. SOC.,1972 94 5906. 35 R. H. Jones and R. G. Bergmann. J. Amer. Chem. Soc. 1972 94 661. 568 J. W.Barton (25c) may best represent the structure. The mechanism of aromatization of arene oxides36 and concomitant alkyl migrations37 have been further studied. syn-Benzene dioxide (26)38and the syn- and anti-forms (27) and (28) of benzene tri~xide~~ have been synthesized; there is also a report of the isolation of a benzene dioxide derivative (29),"' which probably has the anti-configuration 0 wo Ou 0 as a fungal metabolite. The dioxide (26) interconverts rapidly with 1,4-dioxocin (30) at temperatures above 50 "C the equilibrium favouring the latter (5 :95 at 60°C).The dioxocin (30) a lox-electron system is shown by its spectra and chemical behaviour to be olefinic in character. The syn-trioxide (27) undergoes an irreversible thermal isomerization to cis,cis,cis-trioxacyclonona-1,4,7-triene.39a 2 Benzene and Derivatives Current problems concerning the structure of the transition states and inter- mediates in heterolytic aromatic substitution have been discussed."' Recent reviews include accounts of the reactions of nucleophiles with aryl halides,42 36 G. J. Kasperek and T. C. Bruice J. Amer. Chem. Suc. 1972,94 198; G. J. Kasperek T. C. Bruice H. Yagi and D. M. Jerina J.C.S. Chem. Comm. 1972 784. 3' E. A. Fehnel J. Amer. Chem. Suc. 1972,94,3961; G.J. Kasperek T. C. Bruice H. Yagi and N. Kaubisch J. Amer.Chem. SOC.,1972 94 7876. 38 E. Vogel H. J. Altenbach and D. Cremer Angew. Chem. internat. Edn. 1972 11 935 931. 39 (a) E. Vogel H. J. Altenbach and C. D. Sommerfeld Angew. Chem. internat. Edn. 1972 11,939; (b) R. Schwesinger and H. Prinzbach ibid. p. 942; fc) C. H. Foster and G. A. Berchtold J.-Amer. Chem. SOC.,1972 94 7939. 40 D. B. Borders P. Shu and J. E. Lancaster J. Amer. Chem. SOC.,1972 94 2540. 4' P. Rys P. Skrabal and H. Zollinger Angew. Chem. Internat. Edn. 1972 11 874. 42 J. F. Bunnett Accounts. Chem. Res. 1972 5 139. Aromatic Compounds 569 the use of organocopper compounds in new nitrene-induced aro- matic rearrangement^,^^ and the oxidation of primary aromatic amine~.~~ Measurements of equilibrium ion-pair acidities for some polyfluorobenzenes have led to a pK value (per hydrogen) of 43.0 0.2 for benzene.46 Very rapid and in some cases selective deuterium exchange occurs when aromatics are treated with perdeuteriobenzene in the presence of metal halide catalysts.47 Comparison of the rates of protodetritiation of 1,3,5-triphenylbenzene with those of biphenyl indicate that the angular hydrogens in the former may show slight steric hindrance towards acid-catalysed hydrogen exchange.48 The first spectroscopic study of the C6H,+ (benzenium) ion in solution has been reported.49 Sigma-complexes corresponding to Wheland intermediates are isolable in the protonation alkylation and halogenation of certain 1,3,5-tris- For example the addition of bromine to 1,3,5-(dialky1arnino)ben~enes.~~ tripyrrolidinobenzene at -60 "C gives the dark red complex (31) which is stable for some time at ambient temperature but is deprotonated readily by strong bases.Good nucleophiles and reducing agents cleave off a bromine cation from the complex tertiary amines give the biaryl (32) probably via radical inter- mediates and carboxylate ions give some of the quinone iminium salt (33). I RR (33) 43 J. F. Normant Synthesis 1972 63. 44 J. I. G. Cadogan Accounts. Chern. Res. 1972,5 303. 45 M. Hedayatullah Bull. Soc. chim. France 1972 2957. 46 A. Streitweiser P. J. Scannon and H. M. Niemeyer J. Amer. Chem. SOC.,1972. 94 7937. " J. L. Garnett M. A. Long R. F. W. Vining and T. Mole J.C.S.Chern. Comm. 1972 1 172;J. Arner. Chern. SOC.,1972,94 591 3.48 H. V. Ansell R. B. Clegg and R. Taylor J.C.S. Perkin II 1972 766. 49 G. A. Olah R. H. Schlosberg R. D. Porter Y. K. Mo D. P. Kelly and G. D. Mateescu J. Arner. Chern. Soc. 1972,94 2034. 50 P. Mensel and F. Effenberger Angew. Chern. Internal. Edn. 1972 11 61 922. 570 J. W.Barton Electrophilic attack at positions occupied by groups other than hydrogen has received further attention. Rate studies are reported for dehalogenation’ la and des~lphonation~ by diazonium ions and the influence of ‘electrofugal’ Ib leaving groups5 has been discussed. The reaction of p-trimethylsilyltoluene with nitric acid in acetic anhydride to give p-nitrotoluene takes place predom- inantly by initial nitrosodesilylation ;5 nitrosodeiodination is thought to be involved in the conversion of 4-iodoanisole into 2-iodo-4-nitroanisole by nitric acid.54 The ratio of 3-nitro- to 4-nitro-o-xylene formed varies from -0.5 to -1.5 when o-xylene is nitrated in sulphuric acid solutions varying in strength from 50 to 70%.This is due to the behaviour of the 1,2-dimethyl-l-nitrocyclo-hexadienyl cation (34) formed in competition with the other two Wheland inter- mediates (35) and (36). At higher acid strengths the ion (34) rearranges to (35)’ leading to 3-nitro-o-xylene but not to (36) and thus the observed ratio of products is altered.55 Several electrophilic substitutions of preparative importance have been reported. Mixed trifluoromethanesulphonic-carboxylic acid anhydrides are highly active acylating agents which react directly with arenes to give ketones ; a catalytic system of trifluoromethanesulphonic acid together with an acid chloride is also effe~tive.~~ Arenes are formylated by reaction with hexamethyl- enetetramine in trifluoroacetic acid,’ and thiocarboxylate groups may be introduced using ethyl chlorothioformate in the presence of a Friedel-Crafts catalyst.Full details of an extensive study of thallium-catalysed bromination have appeared.59 Photolysis of arylthallium bistrifluoroacetates obtained by direct thallation of arenes in aqueous potassium thiocyanate gives aryl thio- cyanates in moderate yield ;60 copper cyanides in pyridine or acetonitrile convert arylthallium(m) salts into cyanides.6 Alkali-metal tetrafluorocobaltates are found to be useful for the polyfluorination of arenes;62 fluorination of the 51 P.B. Fischer and H. Zollinger (a)Helc. Chirn. Acfa 1972 55 2139; (b)ibid. p. 2146. 52 C. L. Perrin J. Org. Chem. 1971 36 420. 53 C. Eaborn Z. S. Salih and D. R. M. Walton J.C.S. Perkin II 1972 172. 54 A. R. Butler and A. P. Sanderson J.C.S. Perkin II 1972 989. 55 P. C. Myhre J. Amer. Chem. SOC.,1972 94 7921. 56 F. Effenberger and G. Epple Angew. Chem. Internat. Edn. 1972 11 299 300. 57 W. E. Smith J. Org. Chem. 1972 37 3972. 5M G. A.Olah and P. Schilling Annalen 1972 761 77. ” A. McKillop D. Bromley and E. C. Taylor f.Org. Chem. 1972,37 88. E. C. Taylor F. Kienzle and A. McKillop Synthesis 1972 38. 61 S. Uemura Y. Ikeda and K. Ichikawa Tetrahedron 1972 28 3025. ‘’ A. J. Edwards R.G. Plevey I. J. Sallomi and J. C. Tatlow J.C.S. Chem. Comm. 1972 1028. Aromatic Compounds aromatic ring of griseofulvin has been achieved under very mild conditions using trifluorofluoroxymethane.63 Following earlier observation^,^^ the reaction of aromatics with lead tetrakistrifluoroacetate has been shown to proceed by an electrophilic substitution mechanism ;65a the trifluoroacetoxy-compounds pro-duced are easily hydrolysed to Concerning nucleophilic substitutions various studies of rates of formation and stabilities of Meisenheimer complexes of di- and tri-nitro-benzenes66 and -naphthalenes6' have been reported. In the first recorded nucleophilic photo- substitution of hydrocarbons it is found that cyanide ion attacks biphenyl naphthalene and azulene at the positions where they are attacked by electro- philes.6 Cerium(1v) oxidation of the cyanocyclohexadienyl complex (37) I Mn(COh (37) prepared by reaction of the cationic complex (PhH)Mn(CO),+ with cyanide ion gives benzonitrile (80%)in what amounts to an indirect nucleophilic substitu- ti~n.~~ Arylnitrenium ions (38) generated by the silver-ion-assisted solvolysis + (38) of N-chloroanilines undergo nucleophilic attack at the 0-and p-positions.' In methanol simple electron-rich N-chloroanilines give mainly anisidines whereas with anilines possessing electron-withdrawing substituents nuclear chlorination is the main reaction." D. H. R. Barton R. H. Hesse L. Ogunkoya N. D. Westcott and M. M. Pechet '' J.C.S.Perkin I 1972 2889. R. E. Partch J. Amer. Chem. SOC.,1967 89 3662. (a) J. R. Kalman J. T. Pinhey and S. Sternhell Tetrahedron Leirers 1972 5369; (6) J. R. Campbell J. R. Kalman J. T. Pinhey and S. Sternhell ibid. p. 1763. 66 E. J. Fendler J. H. Fendler N. L. Arthur and C. E. Griffin J. Urg. Chem. 1972 37 812; E. J. Fendler and J. W. Larsen ibid.p. 2608; M. R. Crampton and H. A. Khan J.C.S. Perkin II 1972 1173 1178 2281 ; M. R. Crampton M. A. El Ghariani and H. A. Khan Tetrahedron 1972 28 3299; F. Terrier F. Millot and R. Schaal J.C.S. Perkin II 1972 1 192. " E. J. Fendler and J. H. Fendler J.C.S. Perkin II 1972 1403. " J. A. Vink C. M. Lok J. Cornelisse and E. Havinga J.C.S. Chem. Comm. 1972 71 1. 69 P. J. C. Walker and R.J. Mawby J.C.S. Chem. Comm. 1972 330. 70 P. Gassman G. A. Campbell and R. C. Frederick J. Amer. Chem. SOC.,1972 94 3884 3891. 572 J. W.Barton Phenol and NN-diethylaniline both react with chloroform under U.V. irradiation in methanolic solution to give the corresponding 0-and p-substituted benzalde- hydes. It is suggested that the reaction involves attack of an electron from the excited substrate on chloroform to give chloride ion and a dichloromethyl radical then coupling of the latter with a phenoxyl radical or its ~ounterpart.~’ Separate competing pathways have been postulated for the ring-expansion and ring-contraction reactions of phenylcarbene ; however when 3C-labelled phenylcarbene (39)is rearranged at 770 “C the I3C label is found to be uniformly distributed over all the carbon atoms of the resulting fulveneallene (40).72This result indicates that ‘scrambling’ takes place prior to the formation of a pre- fulvene-type intermediate (41) and is consistent with a ‘pre-equilibrium’ in which 11 phenylcarbene interconverts rapidly with the bicyclic intermediate (42) and with cycloheptatrienylidene (43) which can undergo hydrogen shifts.The rearrange- ment and insertion reactions of 2-methylphenylcarbenes have also been studied. Treatment of N-chloroaniline with n-butyl-lithium at -100 “C gives the nitren- oid (44) which eliminates lithium chloride on warming and gives products derived from ~henylnitrene.’~ Several photoadditions of olefins to benzene have been reported. The additions with cis-and trans-1,2-dichloroethylenes give P-chlorostyrenes as the main ” K.Hirao and 0.Yonemitsu J.C.S. Chem. Comm. 1972 812. l2 W. D. Crow and M. N. Paddon-Row J. Amer. Chem. SOC.,1972,94,4747. 73 G.G. Vander-Stouw A. R. Kraska and H. Schecter J. Amer. Chem. Soc. 1972 94 1655. l4 C. A. Wilkie and D. R. Dimmel J. Amer. Chem. Sor. 1972 94 8600. Aromatic Compounds (44) products not 1,8-dichloro-octatetraenesas previously rep~rted.~ With allene the 1,3-and 1,4-adducts (45) and (46) are formed the latter predominating;76 cyclonona- 1,2-diene behaves similarly. The primary products from the sensitized reaction of benzene with vinylene carbonate are the endo-and exo-1,2-cyclo- adducts of which the 4x0-isomer (47) can be isolated.These then undergo rearrangement to the 1,4-cycloadduct (48) retroaddition dimerization or addition of a further molecule of reagent.77 Molecular Rearrangements.-The migration of trimethylsilyl groups attached to aromatic rings is shown to be acid-catalysed. At 150 “C in the presence of trifluoroacetic acid 1,2-bistrimethylsilylbenzene rearranges rapidly to an equilibrium mixture of the 1,3-and 1,4-isomers the former predominating. A mechanism involving ring protonation isomerization of the cation then deproto- nation is suggested (Scheme l).78 SiMe SiMe SiMe SiMe SiMe -3 etc. Scheme 1 The results of a recent study of the Fischer-Hepp rearrangement of N-methyl- N-nitrosoaniline in hydrochloric acid do not accord with the accepted mechanism involving C-nitrosation by nitrosyl chloride but suggest that rearrangement 75 D.Bryce-Smith B. E. Foulger and A. Gilbert J.C.S. Chem. Comm. 1972 769. 76 D. Bryce-Smith B. E. Foulger and A. Gilbert J.C.S. Chem. Comm. 1972 664. ” P. Lechten and G. Hesse Annalen 1972,754 1 ;H. D. Scharf and R. Klar Chem. Ber. 1972 105 575. ’* D. Seyferth and D. L. White J. Organometailic Chem. 1972 34 119; J. Amer. Chem. SOC.,1972 94 3132. 574 J. W.Barton occurs intramolecularly by a unimolecular reaction of the protonated nitro- ~amine.'~ There is evidence that the benzidine rearrangement proceeds via the arenium ion (49)and may be regarded as an intramolecular alkylation reaction (Scheme 2)." The corresponding rearrangement of tetraphenylhydrazine (49) 1 Scheme 2 probably proceeds through radical cation intermediates.' Ally1 phenyl ethers undergo an ortho-Claisen rearrangement on dissolution in trifluoroacetic acid at room temperature.A transition state akin to (50) is envisaged ; a methyl or HH methoxy substituent gives approximately the same rate enhancement whether present in a rneta-or para-position.82 Gas-phase pyrolysis of phenyl propargyl ether at 460 "C gives P-indanone (26 %) together with benzocyclobutene (31%).83 The mode of formation of the latter is yet unknown but the former is thought to arise by a series of four thermally-allowed six-electron concerted reactions starting with a Claisen-type rearrangement (Scheme 3). Biary1s.-Aromatics react with tellurium tetrachloride in the presence of Lewis catalysts to give bis(ary1)tellurium dichlorides.These are easily reduced to diaryltellurides and on heating with degassed Raney nickel give the corresponding '' T. D. B. Morgan and D. L. H. Williams J.C.S. Perkin II 1972 74. *O G. A. Olah K. Dunne and D. P. Kelly J. Amer. Chem. SOC.,1972 94 7438; D. V. Banthorpe Tetrahedron Letters 1972 2707. 81 U. Svanholm K. Bechgaard 0. Hammerich and V. D. Parker Tetrahedron Letters 1972 3675. U. Svanholm and V. D. Parker J.C.S. Chem. Comm. 1972 645. 83 W. S. Trahanowsky and P. W. Mullen J. Amer. Chem. SOC.,1972,94 591 1. Aromatic Compounds DOta% s=c=O Scheme 3 biaryls in good yield.84 Arylboranes formed by treating Grignard reagents with diborane give biaryls on reaction with alkaline silver nitrate.85 In aprotic solvents allyl(prop- 1-yn-3-y1)ammonium salts (51) undergo a base-catalysed concerted 2,3-sigmatropic rearrangement to the amines (52) which cyclize to R' I //C-C?Ye R2-C N-CH,-C-C I+ H I Me x-R',RZ = H Me or Ph.R'/c=cH2 \ R2 & R2-CH CH-C-C (53) I NMe (52) the unsymmetrical biaryls (53) on heating.86 The formation of biaryls by photo- lysis of triaryl phosphates is also reported but the reaction appears to be limited in scope.M7 The bridged oxonium salt (54) has been obtained by heating Me BF (54) 84 J. Bergman Tetrahedron 1972,28 3323. S. W. Breuer and F. A. Broster Tetrahedron Letters 1972 2194. 86 R. W. Jemison T. Laird and W. D. Ollis J.C.S. Chem.Comm. 1972 556. R. A. Finnegan and J. A. Matson J. Amer. Chem. Soc. 1972 94,4780. 576 J. W.Barton 2-methoxybiphenyl-2’-diazonium fluoroborate in benzene ; it is an extremely powerful Meerwein-type methylating agent. 88 Arynes and Aryne Precursors.-The reaction of toluene with benzyne is less selective than that with tetrafluorobenzyne. In addition to the two [2 + 41 cycloadducts considerable amounts of 2-benzylbiphenyl are formed probably Scheme 4 via consecutive ‘ene’ reactions (Scheme 4) together with traces of diphenyl-methane a C-H insertion product.89 Generation of the arynecarbanion (55) from N-methyl-2-chlorobenzylaminoacetonitrileis followed by ring closure and elimination of cyanide ion to give 2-methylisoindole (56)directly in high yield.” CH,-NXHCN I-The aprotic diazotization of thioanthranilic acid affords the benzothiadiazine (57) rather than benzenediazonium-2-thiocarboxylate.Thermal decomposition of (57) with anthracene as a benzyne acceptor gives low yields of triptycene.” Diazotization of tetrafluoroanthranilic acid with nitrosylsulphuric acid in acetic acid proceeds with replacement of fluorine to give the very stable diazonium N I H N-N=N-N-Ts (57) F Li + (59) salt (58).Addition of an ethereal solution of toluene-p-sulphonyl azide to a solu- tion of the monoanion of 1-aminobenzotriazole in tetrahydrofuran gives a yellow precipitate assumed to be the tetrazene salt (59) which decomposes rapidly forming benzyne nitrogen and lithium toluene-p-sulphonamidate.92 A. J. Copson H. Heaney A. A. Logun and P. P. Sharma J.C.S. Chem. Comm. 1972 315. 89 J. M. Brinkley and L. Friedman Tetrahedron Letters 1972,4141 90 B. Jaques and R. G. Wallace J.C.S. Chem. Comm. 1972 397. 91 A. T. Fanning G. R. Bickford and T. D. Roberts J. Amer. Chem. SOC.,1972.94,8505. 92 M. Keating M. E. Peek C. W. Rees and R. C. Storr J.C.S. Perkin I 1972 1315. Aromatic Compounds 577 Quinone Methides Dimethides and Related Compounds.-p-Quinone methides have been prepared by the silver oxide oxidation of p-alkylphenols in carbon tetra~hloride.~~ When salicyl alcohols are oxidized with sodium periodate the spiro-epoxycyclohexa-2,4-dienones(60) are formed.94 These are stable if a bulky alkyl or halogen substituent is present in the nucleus otherwise they under- go Diels-Alder dimerization.On photolysis they give the corresponding sali- cylaldehydes in high yield. The synthesis of tetraquinocyclobutane was mentioned in last year’s Report ;95 it is now found that oxidative coupling of the acetylenic phenol (61) gives the bright orange diquinocyclobutene (62).96The so-called stilbene quinone (63) readily undergoes acid-catalysed hydration to the diphenyl- methanealdehyde (64).” OH R R (61) R = Bu‘ 0 OH RfJR RQR CH I CHCHO CH R 0.R OR OH 0 (64) (63) R = Bu‘ Diels-Alder additions of o-quinone dimethide generated by thermal re-arrangement of the Dewar isomer (65) are >98 % stereo~pecific.~~ Intra-molecular additions to o-quinodimethides discussed in last year’s Report.93 L. K. Dyall and S. Winstein J. Amer. Chem. SOC.,1972,94 2196. 94 H. D. Becker T. Bremhott and E. Adler Tetrahedron Letters 1972 4205. 95 H. Heaney Ann. Reports (B) 1971 68 521. 96 S. Hanff and A. Rieker Tetrahedron Letters 1972 1451. 97 L. Taimr and J. PospiSil Tetrahedron Letters 1972 4279. 98 N. L. Bauld F. R. Farr and C. S. Chang Tetrahedron Letters 1972 2443. 578 J. W.Barton have now been carried out photochemically ;99 cyclizations are also possible where the dienophilic function is carbonyl 'OOa,b azomethine or nitrile loob as with 1-acylbenzocyclobutenes which give chromenes (Scheme 5). Ooa Dianions Scheme 5 of ad-diphenyl-o-quinone dimethides are formed by the reaction of potassium metal with cis-and trans- 1,2-diphenylbenzocyclobutenesin methyltetrahydro- furan at -78 "C.From the products found on subsequent treatment with di- chlorodimethylsilane it is concluded that the ion formed from the cis-compound has the (E,Z) configuration (66) and that from the trans-isomer the (E,E) con-figuration (67) i.e. that the ring-opening reactions are conrotatory." ' Diels-Alder addition of tetrachlorocyclopropene to the dimethide from trans-1,2-diphenylbenzocyclobutenehas been used as the basis of a synthesis of the cyclo- propa[h]naphthalene (68). O2 It may be mentioned here that the photolysis of 2 Ph Ph Ph (48) trans-1,2-diphenylbenzocyclobutenehas given the dihydroazulene (69) by a rearrangement thought to be initiated by homolytic cleavage of the 1,2-bond.lo3 Thermolysis of the cis-dideuteriated sulphone (70)at 430 "Cgives almost entirely 99 W. Oppolzer and K. Keller Angew. Chem. Internar. Edn. 1972 11 729. lo" (a)R.Hug H. J. Hansen and H. Schmid Helv. Chim. Acta 1972,55 10;(6)W. Oppol-zer Angew. Chem. Internat. Edn. 1972 11 1031. N. L. Bauld C. S. Chang and F. R. Farr J. Amer. Chem. SOC.,1972,94 7164. lo2 A. R. Browne and B. Halton J.C.S. Chem. Comm. 1972 1341. '03 M. Sauerbier Tetrahedron Letters 1972 547. Aromatic Compounds 579 trans-1,2-dideuteriobenzocyclobutene,this being consistent with disrotatory formation of o-quinone dimethide by extrusion of sulphur dioxide followed by conrotatory closure to benzocyclobutene. 'O4 Thermal ring-opening of benzo- cyclobuten-1-01s is via a conrotatory process where the (E)-dienols (71)are formed esc; H P @ \ \ \H H 'D H (70) (71) R = H or Ph preferentially as shown by the adducts formed with maleic anhydride.'05 The o-quinone dimethide (72) has been characterized in solution ;on irradiation it yields 9,lO-phenanthrocyclobutene.'O6 An elegant synthesis of the [2,2]para- cyclophane (73) has been achieved by dimerization of the p-quinone dimethide (74) generated in situ from biallenyl and dimethyl acetylenedicarboxylate. O7 (72) Me0,C' C0,Me Quinones.-The y-radiolysis of 1,4-quinones in benzene results in nuclear phenylation ;'O8 n-allylnickel bromide complexes have been used to introduce ally1 substituents. 'O9 The Thiele-Winter acetoxylation of quinones has been reviewed;' lo' further studies of the reaction show that t-butyl groups are often replaced by acetoxy and that acetoxylation rarely occurs ortho to a t-butyl substituent.lob Oxidation of 2-benzylphenol with 2,3-dichloro-5,6-dicyanoben-zoquinone in methanol gives 2-benzyl-l,4-benzoquinone, not 4-hydroxybenzo- phenone as previously reported ; the coupled product (75) is an isolable intermediate.' ' ' The oxidative rearrangement of polyporic acid (76) to the pulvinic acid dilactone (77) takes place smoothly in dimethyl sulphoxide-acetic anhydride ; the mechanism of the reaction has been discussed in relation to the lo' J. R. Du Manoir J. F. King and R. R. Fraser J.C.S.Chem. Comm. 1972 541. B. J. Arnold and P. G. Sammes J.C.S. Chem. Comm.1972 1034. lo' J. P. Anhalt E. W. Friend and E. H. White J. Org. Chem. 1972 37 1015. lo' H. Hopf Angew. Chem. Internat. Edn. 1972 11 419. J. G. Wilson and J. W. Sweeting Austral. J. Chem. 1972 25 1877 2383. log L. S. Hegedus E. L. Waterman and J. Catlin J. Amer. Chem. SOC.,1972,94 7155. 110 (a) J. F. W. McOmie and J. M. Blatchly Org. Reactions 1972 19 199; (h) J. M Blatchly R. J. S. Green and J. F. W. McOmie J.C.S. Perkin I 1972 2286. 'I' J. M. Singh and A. B. Turner J.C.S. Perkin I 1972 2294. 580 J. W.Barton OH CH2Ph 0 0 HOp h ~0 oPh H 0 ph$0 Ph NC OH (76) (77) known biosynthetic conversion of (76) into (77). ' ' Photochemical and thermal reactions of 2-substituted naphthoquinones with ynamines have given inter alia the cyclobutenes (78).Eliminations with removal of the angular (R') sub-stituent were only possible with (78 ;R' = SEt R2 = Ph) and (78 ;R' = OC0,-Me R2 = Ph) when dimers of the corresponding naphthocyclobutadienes 0 (78) R' = OMe OAc OCO,Me or SEt R2= CO,Me CN;or Ph were obtained. '' The thermal reaction of phenanthrene-9,lO-quinonewith sodium chlorodifluoroacetate gives the carbonate (79 ; Z = >C=O) probably via (79;Z = >CF,) formed by the 1,4-addition of difluorocarbene. Surprisingly when the lithium salt is employed the main product is the hydroxy-ketone (80); it is suggested that this results from attack of chloride ion on epoxide (81) the corresponding 1,2-adduct of difluorocarbene. ' 'I2 R. J. Wikholm and H. W. Moore J. Amer. Chem.SOC.,1972,94 6152. 'I3 M. E. Kuehne and H. Linde J. Org. Chem. 1972,37 4031. 'I4 M. Derenberg and P. Hodge J.C.S.Perkin I 1972 1056. Aromatic Compounds 58 1 Cyc1ophanes.-The stereochemistry of [2,2]metacyclophanes has been re-viewed' ' and an alternative nomenclature for cyclophanes has been put for- ward.' l6 Syntheses of [7]meta-' 170 and [7]para-cyclophanes,' 17* of the syn- and anti-forms of [2,2] (1,4)anthracenophane lI8 and of optically active [2,2]meta- cyclophane' and doubly bridged cyclophanes l2 have been described. Further studies of multilayered [2,2]paracyclophanes are reported including an X-ray crystallographic study of a four-layered compound ' syntheses of optically active derivatives with three and four layers,12' and of a six-layered compound.123 Cycloalkylation of benzene using 2,Z'-bis(hydroxymethy1)diphenylmethane gives a remarkably good yield (75%) of the nine-membered ring compound (82; Z = CH,); the analogues (82; Z = 0 or S) are obtainable in the same way.'24 (82) Nuclear magnetic resonance methods have been used to study the rates of in- ternal rotation of the benzene rings in bridge-substituted paracyclophanes. ' Additions of bromine and deuterium bromide to 1,2-dehydro[2,2]paracyclophane follow a cis stereochemical course. The addition products and their diastereomers undergo silver-ion-assisted acetolysis with retention of configuration. 26 As with the solvolysis of l-tosyloxy[2,2]paracyclophane discussed in last year's Report,'27 these results are best interpreted as involving the formation of ben- zylic ions which are delocalized over both benzene rings.Photo-oxygenation of benzo[2,2]paracyclophane in methanol gives rise to the [2,2]metaparacyclo- phane (84),presumably by solvolytic rearrangement of the initially formed endoxide (83). Thermal rearrangement of l-~iny1[2,2]paracyclophanein the 115 F. Vogtle and P. Neumann Angew. Chem. Internat. Edn. 1972 11 73. K. Hirayama Tetrahedron Letters 1972 2 109. 'I7 (u)S. Fujita S. Hirano and H. Nozaki Tetrahedron Leffers 1972 403; (b) N. L. Allinger and T. J. Walter J. Amer. Chem. SOC.,1972 94 9268. " T. Toyoda 1. Otsubo Y. Sakata and S. Misumi Terruhedron Letters 1972 I73 I. H. W. Gschwend J. Amer. Chem. SOC. 1972 94 8430. M. Nakazaki K. Yamamoto and M. Ito J.C.S.Chem. Comm. 1972. 433. 12' H. Mizuno K. Nishiguchi T. Otsubo S. Misumi and N. Morimoto Terrahedrnn Letters 1972 498 I. 122 M. Nakazaki K. Yamamoto and S. Tanak J.C.S. Chem. Comm. 1972,433. T. Otsubo Z. Tozuka and S. Mizogami Tetrahedron Letters 1972 2927. I 24 T. Sato K. Uno and M. Kainosho J.C.S. Chem. Comm. 1972 579. 125 M. Nakazaki K. Yamamoto and S. Okamoto Bull. Chem. SOC.Japan 1972 45, 1562; S. E. Potter and I. 0.Sutherland J.C.S. Chem. Comm. 1972 754. R. E. Singler and D. J. Cram J. Amer. Chem. SOC.,1972 94 3512. H. Heaney Ann. Reports (B) 1972. 68 539. 12' H. H. Wasserman and P. M. Keehn J. Amer. Chem. SOC.,1972 94. 298. 582 J. W.Barton range 100-160 "C gives cis-l,2-dehydro[4,2]paracyclophane(85) via biradical intermediates.29 Transannular reactions of [2,2]metacyclophane to give 4,5,9,10-tetrahydropyrenederivatives are well known. Recently quantitative rearrangement to 1,2,3,3a,4,5-hexahydropyrene (86) has been observed when @/ (85) [2,2]metacyclophane is heated at 60 "C with iodine in benzene. 130 Deuterium-labelling experiments indicate the operation of an intermolecular hydrogen- transfer mechanism. 3 Non-benzene Systems Three- and Four-membered Rings.-Cyclopropenone has now been obtained in a pure stateI3' and many of its reactions have been studied.'32 When it is treated with bromine at -30 "C attack occurs at carbonyl rather than at the ring double-bond forming thecyclopropeniumsalt (87 ;R = X = Br) which rearranges to trans-p-bromoacryloyl bromide on warming to 0 "C ; with triethyloxonium fluoroborate at 0 "C the ethoxypropenium fluoroborate (87 ;R = Et X = BF,) is obtained.Diethoxycyclopropenone (88 ;R = OEt) 'three-cornered acid' diethyl ester has been obtained in 107; yield by irradiation of diethoxycyclobutene-1,2-dione (89 ;R = OEt) the diethyl ester of squaric acid. '33 Attempted hydrolysis of (88; R = OEt) resulted in decomposition and gave some squaric acid (89; R = OH). The corresponding photo-induced ring-contraction of 4,4-dichloro-2 (87) (88) (89) M. H. Delton and D. J. Cram J. Amer. Chem. SOC.,1972 94 1669. 130 T. Sat0 and K. Nishiyama J.C.S. Chem. Comm. 1972 163; J. Org. Chem. 1972. 37 3254. j3' R. Breslow and M. Oda J. Amer. Chem. SOC.,1972 94. 4787. 13' R. Breslow M.Oda and J. Pecoraro Tetrahedron Letters 1972 4415 4419. '33 E. V. Dehmlow Tetrahedron Letters 1972 1271. Aromatic Compounds 3-diphenylcyclobutenone gives 3,3-dichloro-1,2-diphenylcyclopropene,easily hydrolysed by water to diphenylcyclopropenone (88; R =Ph).'33 Whereas the condensation of diphenylcyclopropenone with phenylmalonodinitrile in acetic anhydride leads to the quinone dimethide (90) that with phenylcyanoacetone gives the triafulvene (9 1). 34 Calculations and n.m.r. spectroscopic studies have suggested that the preferred KekulC structure for benzocyclopropene is (92); Ph Ph however an X-ray crystallographic study of the ester (93) gives no indication of this type of bond fixation and if anything the 3,4 and 5,6 bonds are longer than the mean value and the fused rings are not quite coplanar.'35 The chemistry of phenylcyclobutenediones has been reviewed.l3 Low-temperature matrix preparations of cyclobutadiene by the photolysis of a-pyr~ne'~'~ and of the bridged cyclobutene (94),' 37b have been reported.Treat- ment of the aromatic-type palladium complex (95) with ethylenebis(dipheny1- phosphane) gives the highly hindered cyclobutadiene (96) which although \/ \/ \/ \/ isolable reacts rapidly with oxygen to give inter alia the corresponding furan. 13* An X-ray study is in progress to determine the bond orders in the four-membered ring of (96). There is evidence that the dianion of cyclobutadiene (97) a Huckel aromatic system is generated when cis-3,4-dichlorocyclobutenereacts with sodium naphthalide at -40 "C as quenching with deuteriomethanol gives H.U. Wagner R. Seidl and H. Fauss Tetrahedron Lerters 1972 3883. '35 E. Carstensen-Oeser B. Muller and H. Durr Angew. Chem. Internat. Edn. 1972 11 422. '36 W. Ried and A. H. Schmidt Angew. Chem. Internat. Edn. 1972 11 997. 13' (a) C. Y. Lin and A. Krantz J.C.S.Chem. Comm. 1972 1111; (b) S. Masamune M. Suda H. Ona and L. M. Leichter J.C.S. Chem. Comm. 1972 1268. 13' H. Kimling and A. Krebs Angew. Chem. Internat. Edn. 1972 11 932. 584 J. W.Barton 3,4-deuteriocyclobutene,together with the syn and anti dimers of cyclobuta-diene.13' A direct synthesis of the dianion of squaric acid (98) has been achieved by the electrolytic reduction of carbon monoxide dissolved under pressure in an aprotic solvent containing tetrabutylammonium bromide.40 The thieno- cyclobutadiene derivative (99) results from a Wittig reaction of 3,4-diphenylcyclo- butenedione. There appears to be extensive conjugation in the molecule and the n.m.r. spectrum indicates the presence of a paramagnetic ring current arising from the four-membered ring.141 Predictably the reaction of (99) with tetra- cyanoethylene is a [2 + 21 cycloaddition to the four-membered ring rather than a [4 + 21 addition to the hetero-ring. Vacuum pyrolyses of the cis-and truns-isomers of the epoxide (100) have given the parent furocyclobutadiene (101). 142 Compared with (99) it is highly reactive and although moderately stable in solution it dimerizes slowly to the bisfurocyclo-octatetraene(102).Five- Seven- and Nine-membered Rings.-Thermogravimetric analysis of reactions of tetraphenyldiazocyclopentadienewith various substrates containing heteroatoms indicates that carbene formation is the initial common step. 143 Several salts of the pentachlorocyclopentadienideanion with large cations have been isolated and characterized spectroscopically. 144 Dechlorination of the perchlorocyclopentadiene (103) with triethyl phosphite gives hexachlorofulvene (104) in 94 %yield.145" Under Diels-Alder conditions (104) can act as an electron- deficient diene and as a dienophile; it reacts with nucleophiles at C-6 and is protonated at C-l.'45b Fulvenes have been obtained from the ring-expansion 139 J. S. McKennis L. Breuer J. R. Schweiger and R.Pettit J.C.S. Chem. Comm. 1972 365. 140 G. Silvestri S. Gambino G. Filardo M. Guainazzi and R. Ercoli Gazzetta. 1972 102 818. 141 P. J. Garratt and K. P. C. Vollhardt J. Amer. Chem. SOC.,1972,94 1023. 142 K. P. C. Vollhardt and R. G. Bergman J. Amer. Chem. Soc. 1972 94 8950. I43 B. H. Freemann G. S. Harris B. W. Kennedy and D. Lloyd J.C.S. Chem. Cumm. 1972 912. 144 G. Wulfsberg and R. West J. Amer. Chem. SOC.,1972 94 6069. 145 (a)E. T. McBee E. P. Wesseler D. L. Crain R. Hurnaus and T. Hodgkins J. Org. Chem. 1972 37,683; (6)E. T. McBee E. P. Wesseler R. Hurnaus and T. Hodgkins ihid. p. 1100. Aromatic Compounds c1 clFlc1 \I cl&cl \I CI c1 CI c1 (103) ( 104) of methylenecyclopropenes with ynamines.These products themselves behave as enamines and undergo further ring-expansion on treatment with dimethyl acetylenedicarboxylate to give heptafulvenes (Scheme 6). 46 The vinylogous NC CN Ph-CSC-NEt PhNgh Ph Ph Ph NEt MeO,CC~CCO Me I NC CN Scheme 6 fulvalene (105) has been isolated in pure form. In solution at room temperature it isomerizes rapidly and quantitatively to (106) which rearranges to the ben- zenoid isomer (107) at 80 "C.14' Full details of the synthesis of 1-methylpentalene have been published; the spectra of the compound and its reactivity confirm (105) 14' T. Eicher and T. Pfister Tetrahedron Letters 1972 3969. 14' H. Sauter and H. Prinzbach Angew. Chem. Internat. Edn. 1972 11 296. 586 J. W. Barton that it is non-aromatic.148 The isolation of sandwich complexes of pentalene with iron cobalt and nickel has been re~0rted.I~~ Treatment of octachloro-bicyclo[3,3,0]octa-l,3,7-trieneor its 1,4,6-isomer with antimony pentachloride has given the bis(hexach1oroantimonate) of a dication C8Cl,2+,which from the simplicity of its infrared spectrum is thought to be the hexachloropentalenyl dication (108). '50 Cl c1 Cycloheptatrienyldiazomethane decomposes thermally or photochemically by three pathways to yield heptafulvene (109) cyclo-octatetraene or benzene together with acetylene. 15' Perchloroheptafulvene has been obtained by the thermal isomerization of (1 10). 52 Treatment of cycloheptatrienyl-7-carboxylic acid chloride with triethylamine at -20°C generates the highly reactive hepta- fulvene keten (111).153" A number of cycloadditions of (111) have been des- cribed with 2-methoxytropones it reacts to give inter aka the heptafulvalenes (1 12).153bOn the basis of its n.m.r.spectrum and dipole moment it has been HH (109) (110) (1 11) (112) R = HorBr suggested that methylenenorbornadiene (1 13) should be regarded as a bicyclo- heptafulvene with a significant contribution from the charge-separated form (114).154 Tropolone reacts with the 1,2-diphenylcyclopropeniumion to give ion (1 15) isolable as the perchlorate salt which on treatment with triethylamine gives the stable fulvalenedione (1 16) formally a quinone of this system.' Dissolution of (116) in acids regenerates cation (115) and there is evidence of further protonation to dication (1 17) at high acidities.14* R. Bloch R. A. Marty and P. de Mayo Buff. Soc. chim. France 1972 2031. 14' T. J. Katz N. Acton and J. McGinnis J. Amer. Chem. Soc. 1972 94 6206; T. J. Katz and N. Acton ibid. p. 3281. 150 K. Kusuda and N. Osaka J.C.S. Chem. Comm. 1972 508. lJ1H. E. Zimmerman and L. R. Sousa J. Amer. Chem. SOC.,1972 94 834. 152 A. Roedig M. Forsch B. Haveux and D. Scheutzow Tetrahedron Letters 1972 2613. 153 (a)T. Asao N. Morita and Y. Kitahara J. Amer. Chem. SOC.,1972 94 3655; (b)T. Asao N. Morita C. Kabuto and Y. Kitahara Tetrahedron Letters 1972 4379. lJ4R. W. Hoffmann R. Schiittler W. Schafer and A. Schweig Angew. Chem. Internat. Edn. 1972 11 512. 15' K. Takahashi and K. Takase Tetrahedron Letters 1972 2227.Aromatic Compounds Ph . HO Ph The cyclization of a doubly-vinylogous fulvalene is the basis of the Hafner-type synthesis of azulenes some particularly facile examples of which have been des- cribed recently,' 56 as have examples of the alternative approach the cyclization of a vinylogous heptafulvene.'57 It is found that the relative acidities of the azuloic acids (1 < 2 < 5 < 6) are consistent with decreasing n-electron density at these positions of the azulene ring system. 15* Stable dibenzononafulvenes ( 1 18) have been obtained by reactions of aromatic aldehydes with the anion of the parent dibenzononatetraene or the ylide (119)' 59 Although the latter reacts readily with oxygen it shows relatively low reactivity towards carbonyl groups and is considered to be intermediate in structure between the corresponding cyclopentadienyl ylide which shows aromatic stabilization and a normal unstabilized phosphorane.' 56 W. Bauer and U. Miiller-Westerhoff Tetrahedron Letters 1972 1021. Is' H. Prinzbach and H. J. Herr Angew. Chem. Interoat. Edn. 1972 11 135. R. N. McDonald and R. R. Reitz J. Org. Chem. 1972 37 2703. M. Rabinowitz and A. Gazit Tetrahedron Letters 1972 721 3361. 588 J. W.Barton A~ulenes.-New reviews of the annulene~,'~' one limited to [lO]annulenes and other (CH) hydrocarbons,"' and the heteronins'62 have been published. The relationship between ring current and proton chemical shifts in annulenes has been in~estigated,'~~ as has the use of the benzenoid proton coupling constants to study the x-election structure of the annulene ring in benzo[n]annulenes.164 New syntheses of bisdehydro-[ 141- -[181- -[22]- and -[26]-annulenes have been reported. 165 Dehydrogenation of the [6 + 41-cycloadduct (120) of butadiene with tropone has given 1,6-rnethano[lO]annulen-ll-one(121).'66 The results of a 0 (120) (121) three-dimensional X-ray crystallographic study on [14lannulene have been reported ;16' the deduced structure is compatible with the n.m.r. spectrum measured at low temperature and shows a considerable departure from planarity. Electron spin resonance has been used to study the relative planarity in a series of bridged [14]ann~lenes.'~* The synthesis of a bisdehydro[ 1S]annulenium cation has been reported;'69 as expected it shows the aromatic character of a 14~- electron system.Favorski rearrangement of the bridged [14lannulene (122) has given after removal of the bridge carboxy-group the hydrocarbon (123).' It is stable and surprisingly resistant towards dehydrogenation. The expected dehydrogenation product (124) was eventually obtained l7Ob by hydride abstrac- tion from (123) with trityl borofluoride and treatment of the resulting cation with "O F. Sondheimer Accounts Chem. Res. 1972 5 81. ''I S. Masamune and N. Darby Accounts Chem. Res. 1972 5 272. '62 A. G. Anastassiou Accounts Chem. Res. 1972 5 281. '63 R. C. Haddon Tetrahedron 1972 28 3613 3635. D. Creme and H. Giinther Annulen 1972 763 87. ''' K. Fukui T.Nomoto S. Nakatsuji and M. Nakagawa. Tetrahedron Letters 1972 3 157; M. Iyodo and M. Nakagawa ibid. pp. 3 161,4253 ; M. Iyodo and M. Nakagawa J.C.S. Chem. Comm. 1972 1003. 16' S. Ito H. Ohtani S. Narita and H. Honma Tefrahedron Letters 1972 2223. lb7 C. C. Chiang and I. C. Paul J. Amer. Chem. Soc. 1972 94 4741. '" F. Gerson K. Miillen and E. Vogel J. Amer. Chem. SOC.,1972 94 2924. P. D. Howes and F. Sondheimer J. Amer. Chem. SOC.,1972 94 8263. ''O (a)E. Vogel and H. Reel J. Amer. Chem. SOC.,1972,94,4388; (b)H. Reel and E. Vogel Angew. Chem. Internat. Edn. 1972 11 1013. 16' Aromatic Compounds water. Its spectra are in keeping with those of (123) and other bridged annulenes of this type and indicate an important contribution by the Kekule structures with a peripheral 147c system.Electrochemical reduction of [16lannulene has given the radical anion and the dianion,I7' both of which appear to be planar. Unlike that of [18]annulene the n.m.r. spectrum ofthe dianion is not temperature- dependent and the resonance of the inner protons appears at very high field; it is concluded that the delocalization is better in the dianion than in [181annulene by ca. 6 kcal mol- '. The thermolysis of [18]annulene at 90 "Cgives an isomeric material probably containing (125) and angular isomers of it which on further heating gives benzene and 1,2-benzo-1,3,7-cyclo-octatriene. Low-temperature photolysis of the isomer mixture gives benzene and [12]annulene the bicyclododecapentaene (126) being a likely intermediate in both processes (Scheme 7).'72 Syntheses designed to A 90 "C A d -or hv -100°C L J 1 A Scheme 7 lead to the tetradehydro[l8]annulenes (127; R' = Ph R2 = Bu') and (127; R' = Bu' R2 = Ph) give the same product thus providing chemical evidence of the identity of the acetylenic and cumulenic linkages in this system.'73 The upper limit for aromaticity in [4n + 2lannulenes was discussed in last year's Report.'74 Another [26]annulene a bisdehydro-derivative has now been shown to sustain a diamagnetic ring current. 75 "I J. F. M. Oth H. Baumann J. M. Gilles and G. Schroder J. Amer. Chem. Soc. 1972 94 3498. K. Stockel P. J. Garratt F. Sondheimer Y. de Julien de Zelicourt and J. M. Oth J. Amer. Chem. SOC.,1972 94 8644. T.Nomoto K. Fukui and M. Nakagawa Tetrahedron Letters 1972 3253. H. Heaney Ann. Reports (B) 1971 68 543. M. Ioda and M. Nakagawa Tetrahedron Letters 1972 4253. 590 J. W.Barton Ill II I II Ill II R2 R' (127) The aromaticity of annulenones has been investigated using an HMO method. 176 A simple route to certain bisdehydroannulenones has been des- cribed.' 77 Base-catalysed condensation of the acetylenic aldehyde (128) with acetone gives the diacetylene (129) which undergoes oxidative coupling to the [13]annulenone (130) in 45-5004 yield. The method can be extended for the 0 0 synthesis of [151- and [17]-annulenones ; similar syntheses have given bis- dehydro[ 17lannulenones containing ring heteroatoms. 78 A l0n-electron analogue of tropolone (131) has been synthesized.' 79 Like tropolone it forms salts with both acids and bases giving rise to the delocalized ions (132) and (133).Syntheses of the cyclopenta- and cyclohepta-phenalenones (134) and (135) are reported.'*' Their n.m.r. spectra indicate that the peripheral conjugated systems can sustain a diamagnetic ring current and they may be regarded as bridged annulenones. B. A. Hess and L. J. Schaad Tetrahedron 1972 28 5299. 17' P. D. Howes E. LeGoff and F. Sondheimer Tetrahedron Letters 1972 3691 3695. P. J. Beeby and F. Sondheimer J. Amer. Chem. Soc. 1972 94 2128; R. H. McGirk and F. Sondheimer Angew. Chem. Internat. Edn. 1972 11 834. 179 J. Reisdorf and E. Vogel Angew. Chem. Internat. Edn. 1972 11 2 19. I. Murata K.Yamamoto T. Hirotsu and M. Morioka Tetrahedron Letters 1972. 33 I 3389. Aromatic Compounds 4 Polycyclic Compounds The modern concept of aromaticity and its application to polycyclic benzenoid systems forms the subject of a recent monograph embodying a wealth of ex- perience in this field.’*l An annelation reaction of general utility has been reported. For example the trimethine (136) reacts with the carbanion from 1-naphthoa.cetonitri1e to give the base (137) which undergoes thermal cyclization to 4-cyanophenanthrene in 91 % yield.182 The relative ease of photocyclization of diarylethylenes has been related to the sum of the free valence indices in the first excited state (CF*) at the two positions which become bonded. There is further evidence of a lower limit for CF* below which cyclization does not occur.183 Photolysis of 2,2’-distyrylbiphenyl gives the cyclobutane (138) as the product of kinetic control but a tetrahydropyrene probably (139) as that of thermodynamic control. By irradiation under oxidative conditions the benzo[c]chrysene derivative (140) is formed in addition to the dehydrogenation Ph Ph ’” E. Clar ‘The Aromatic Sextet,’ Wiley London 1972. C. Jutz and J. M. Wagner Angew. Chem. Internat. Edn. 1972 11 315. D. D. Morgan S. W. Horgan and M. Orchin Tetrahedron Letters 1972 1789; T. Sat0 and T. Morita Bull. Chem. SOC.Japan I972,45 1548. 592 J. W.Barton product of (139). 184 The corresponding thermal reaction gave the all-cis isomer of (1 38).Intramolecular thermal rearrangements of 1,8-distyryInaphthalenesand related compounds have been reported. Octamethylnaphthalene has been synthesized ;'86a reactions of this and other polymethylnaphthalenes have been described.' 86b Thedianions ofnaphthalene '87 and acenaphthylene'" have been generated by the action of n-butyl-lithium on 1,4-dihydronaphthalene and acenaphthene respectively. The former has been characterized as bis[(tetramethylethylenediamine)lithium(~)]naphthalenide and the crystal structure of this salt has been determined. There is continued interest in the photochemical reactions of naphthalenes. 1,4-endo-Peroxides are formed in good yield by the dye-sensitized photo-oxygenation of di- and poly-methyl- na~htha1enes.I~~ The structure of the photodimer of methyl 2-naphthoate has been determined ;190 irradiation of the methyl naphthoates in the presence of sodium borohydride results in reduction of the unsubstituted ring to give the 5,8-dihydro-derivatives; naphthalene itself gives a mixture of 1,6dihydronaph- thalene and tetralin."' The photoaddition of 2,3-dimethylbut-2-ene to 2-naph- thonitrile in methanol gives adducts (141) and (142) incorporating a molecule of the solvent ; a mechanism involving ion-pair formation is suggested.lg2 -4-H' 'H OMe (141) ( 142) Full reports have been published of the synthesis and reactions of the macro- cyclic diacetylene (143) and related compounds having acetylenic functions in close proximity.193 Electrophilic additions to (143) and hydrogenation over a Lindlar catalyst proceed with transannular coupling of the acetylene groups as does the reaction with iron pentacarbonyl which gives the complex (144) of 184 W.H. Laarhoven and J. H. M. Cuppen J.C.S. Perkin I 1972. 2074. 185 J. Meinwald and J. A. Kapecki J. Amer. Chem. Soc. 1972,94 6235; S. F. Nelson and J. P. Gillespie J. Amer. Chem. SOC.,1972 94 6237 6238. I86 (a)H. Hart and A. Oku J. Org. Chem. 1972 37 4269; (6)A. Oku Y. Ohnishi and F. Mashio ibid. p. 4265; H. Hart and A. Oku ibid. p. 4275. I87 J. J. Brooks W. Rhine and G. D. Stucky J. Amer. Chem. SOC.,1972 94 7346. 188 L. D. Kershner J. M. Gaidis and H. H. Freedman J. Amer. Chem. Sor. 1972 94 985,4400. 189 H. H. Wasserman and D. L. Larsen J.C.S. ChPm. Comm. 1972 253 H. Hart and A.Oku ibid. p. 254. 1 YO P. J. Collin D. B. Roberts G. Sugowdz D. Wells and W. H. F. Sasse Tetrahedron Letters 1972 32 1. 191 J. A. Barltrop and R. J. Owers J.C.S. Chem. Comm. 1972 592. 192 J. J. McCullough and W. S. Wu J.C.S. Chem. Comm.. 1972 1136. I93 H. A. Staab E. Wehinger. and W. Thorwart Chem. Ber. 1972. 105 2290; H. A. Staab H. Mack and A. Nissen. ibid. p. 23 10;H. A. Staab and B. Draeger. ibid.. p. 2320. 593 Aromatic Compounds tetrabenzo[a,c,g,i]biphenylene.Birch reduction of biphenylene gives the tetra- hydro-compound (143 together with (147) which is presumably formed by valence isomerization of the tetrahydrobiphenylene (146) 194 compound (147) was previously isolated from the addition of benzyne to cyclohexa-l,3-diene.Full details of the synthesis of 2-thianorbiphenylene (148) have appeared ;I9' 2,6-diazobiphenylene(149)or the 2.7-isomer has been made by the flash photolysis of pyridine-3-diazonium-4-carboxylate'9h and the corresponding perfluoro- compounds by pyrolysis of the silver salt of 2,5,6-trifluoropyridine-3,4-dicarboxyl-ic acid.'97 A Wittig reaction of glyoxal with ylide (150) has given cyclo-octa- [d,ef]biphenylene (151) which contains a fused [8 + 4]n-electron system and shows definite antiaromatic properties.'98 I" C. A. Matusak and L. Dickson J. Org. Chem. 1972,37 3345. P. J. Garratt and K. P. C. Vollhardt J. Amer. Chem. Soc. 1972 94 7087. Ig6 J. Kramer and R. S. Berry J. Amer. Chem. Soc. 1972 94 8336. 19' E. G. Bartoch A. Golloch and P.Sartori Chem. Ber. 1972 105 3464. C. F. Wilcox J. P. Uetrecht and K. K. Grohman J. Amer. Chem. Soc. 1972.94.2532. 594 J. W.Barton The generation and reactions of naphtho[b]cyclobutadiene (152) have been investigated,199 and an interesting synthesis of cyclobutadienopleiadene (1 54) is reported.200 In the final step treatment of the diol(153) with hydrochloric acid in tetrahydrofuran resulted in decomplexation and concomitant elimination to F;e(CO) \ I & give (154). The cycloheptatriene derivative (155 ; R = H) has been synthesized. It rearranges to fluorene at 170°C and is converted into the salt (156) of the homobiphenylene cation by reaction with trityl hexafluorophosphate. The salt reacts with sodium methoxide to give 9-methoxyfluorene together with the ether (155; R = OMe).20' PF,-The acidities of a number of 9-alkylfluorenes have been measured.O2 A synthesis of 1H-cyclopent[c,d]indene (157) is reported,203 but attempts to iso- merize it to the 2aH-compound which is expected to be relatively acidic failed. The carbene phenalenylidene (158) has been generated. It is found to give 4 ., 1 2 ( 157) (1 58) (159) ''' M. P. Cava and A. C. Hsu J:Amer. Chem. SOC.,1972,94 6441. 'O0 B. W. Roberts and A. Wissner J. Amer. Chem. SOC.,1972 94 7168. 'O' L. Lombard0 and D. Wege Tetrahedron Letters 1972 4859. '02 A. Streitweiser C. J. Chang and D. M. E. Reuben J. Amer. Chem. Soc. 1972 94 5730. 203 B. L. McDowell and H. Rapoport. J. Org. Chem.. 1972 37 3261. Aromatic Compounds 1,2- and 1,6-cycloadducts to the peri-positions with a~rylonitrile~~~" and cyclo- he~tatriene,''~' the results obtained being best interpreted as involving the triplet species (159).The addition of dichlorocarbene generated from chloroform and aqueous sodium hydroxide in an emulsifying system to phenanthrene has given the stable dibenzonorcaradiene (160) which rearranges to 6-chlorodibenzo[a c]-tropylium chloride at 140 OC.'05 The mechanism of photodimerization of 9-anthroic acid has been investigated.206 Conjugated acyclic dienes and cyclohexa- 1,3-diene undergo [4 + 41 photoaddition to the 9,lO-positions of anthracene. With acyclic dienes the metastable trans-adducts (161) are primary ( 160) (161) products being converted into the stable cis-adducts on sensitized irradiation ; 9-cyanoanthracene and 9-anthraldehyde undergo stereospecific [4 + 21 addition In the photoreaction of anthracene with cyclopentadiene both [4 + 41 and [4 + 21 additions are observed the former being reversible.208 Analogous [4+ 41 photoadditions to naphthalene have been reported very recently.209 Syntheses of dibenzobarrelene2 lo and polycyclic triptycene2 derivatives from linear acenes have been described.1-Bromomethyltriptycene is found to be extremely unreactive under solvolysis conditions being some 10' 2-fold less reactive than the unbridged l-chlor0-2,2,2-triphenylethane.~ Pentacene reacts with sulphur to give a stable hexasulphide for which the structure (162) is pro-posed ;hexacene behaves similarly.' ' The kinetics of protonation of perylene radical anions have been inve~tigated.''~ The reaction of perylene radical cation with cyanide ion gives equal amounts of 1- and 3-cyanoperylene together with the parent hydrocarbon.'l' It is now shown that electrophilic nitration of '04 (a) I.Murata T. Nakazawa and S. Yamamoto Tetrahedron Letters 1972 2749; (6)I. Murata T. Nakazawa and T. Amanishi ibid. p. 5089. '05 G. C. Joshi N. Singh and L. M. Pande Synthesis 1972 317. 206 D. 0.Cowan and W. W. Schmiegel J. Amer. Chem. Soc. 1972 94 6779. '07 N. C. Yangand J. Libman J. Amer. Chem. SOC.,1972,94,1405; N. C. Yang J. Libman L. Barrett M. H. Hui and R. L. Loeschen J. Amer. Chem. Soc. 1972 94. 1408. '08 G. Kaup Angew. Chem. Internat. Edn. 1972 11 718.209 N. C. Yang J. Libman and M. Savitzky J. Amer. Chem. SOC.,1972 94 9226. O H. P. Figeys and A. Dralants Tetrahedron 1972 28 303 1. *I1 M. Sugihashi R. Kawagita T. Otsubo Y. Sakata and S. Misumi Bull. Chem. SOC. Japan 1972,45 2836. 'I2 J. W. Wilt and T. P. Mallory J. Org. Chem. 1972 37 2781. '13 E. P. Goodings D. A. Mitchard and G. Owen J.C.S. Perkin I 1972 1310. G. Levin C. Sutphen and M. Szwarc J. Amer. Chem. Sac. 1972. 94. 2652. 215 H. J. Shine and C. V. Ristagno J. Org. Chem. 1972 37 3424. 596 J. W.Barton s-s-s perylene gives the I-nitro-derivative’ l6 in addition to the 3-nitroperylene which was obtained previously. The major product of photoaddition of thymine to 3,4-benzopyrene has the singly-bonded structure (163) and not a cyclobutane bridge as previously thought.217 The theory has been advanced that 3,4- benzopyrene may be able to couple at other positions and thus cross-link DNA strands.H (163) The name ‘circulene’ is suggested for polycyclic compounds which possess a closed ring of aromatic or heteroaromatic nuclei. In this class are coronene (planar) corannulene (bowl-shaped) and the thiophen derivative (la),the synthesis of which is reported.218 Because of the relationship between the inner and outer diameters of (164) it is expected to have a ‘corrugated’ outer edge. ’I6 J. J. Looker J. Org. Chem. 1972 37 3379. ’I7 G. M. Blackburn R. G. Fenwick and M. H. Thompson Tetrrrhedron Letters 1972 589. ‘IM J. H. Dopper and H. Wynberg Tetrahedron Letters 1972 763.

ISSN:0069-3030    

DOI:10.1039/OC9726900563

出版商:RSC    

年代:1972

数据来源: RSC

摘要:

Aarons L. J. 71 Abasova S. G. 281 Abatjoglou A. 440 Abboud M. M. 484 Abeles R. H. 141 Abelson J. N. 552 555 Abermann R.J. 556 Abley P. 173 270 388 Abraham D. J. 501 Abraham R. J. 407 Abramovitch R. A. 219 220 221 222 228 251 398,449 Absar I. 51 Abu El-Haj M. J. 443 Achenback H. 318 Achilladelis B. A. 472 Achinetti G. F. 276 Achiwa K. 343 Achmatowicz O. 133 Ackermann H. 536 Ackermann P. 447 Acklin W. 471 Acton N. 281 586 Adam W. 326 331 340 385,430,464 Adams D. B. 68 72,76 Adams J. M. 552 Adams P. M. 472 Adams R. N. 309 Adesnik M. 549 550 Adinolfi W. 5 17 Adler A. D. 116 Adler E. 577 Adler K. 532 Adler M. 450 Adrian F. J. 19 Advena J. 372,435 Agarwal K.L. 543 Agdeppa D. A. 242 Ager 1. R. 117 Agosta W. C. 233 249 322 335 386 Ahlberg P. 1’71 Ahlgren G. 523 Ahmad M. 543 544 Ahmed M. G. 203 Ahmed R. 222 Aida T, 401 Aimi N. 500 Ainshtein A. A. 273 Ainsworth C. 180 388 Air G. M. 558 Ajisaka K. 37 Author Index Akabon S. 259 Akhtar M. 140 157 475 484 Akhtar M. H. 428,433 Aki O. 304 Akita K. 51 1 Albek M. 182 Albelo G. 278 Alberman K. B. 383 Alberry H. 550 Albery W. J. 118 Albini A. 460 Albrand J. P. 439 Albrecht P. 522 Albriktsen P. 439,440 Albrizzio J. 161 Alcais P. 395 Aldersley M. F. 385 Alekseeva V. P. 192 Alexakis A. 362 Alexander C. W. 132 Alexander K. 475 Alexanian V. 228 Alford J.A. 248 430 Alger T. D. 30 32 Alich A. 269 Allan Z. J. 263 Allandoerfer R. D. 204 Allaudeen H. S. 552 Allderdice P. W. 559 Allen G. R. jun. 258 278 419 Allen L. C. 56,224 Allerhand A. 31 Allinger N. L. 395 407 424 563 581 Allman R. 458 Alpatova N. M. 303 Alper H. 393 Altenbach H. J. 265 416 426,456 568 Altenburg H. 103 Althaus J. R.. 15 Altman L. J. 477 Altmann S. 554 Altona C. 407 Alwair K. 293 Alworth W. L. 486 Amanishi T. 595 Ames B. 553 Amrnon H.L. 93 185 Amos H. 549 Anastassiou A. G. 122 125 126,456,464,588 Anatol J. 355 Andersen N. H. 343 512 Anderson D. J. 222,429 Anderson D. N. 14 Anderson D. R.,36 Anderson E. 177 Anderson H.W. 376 Anderson J. E. 563 Anderson K. W. 554 Anderson L. B. 250,292 Anderson R. J. 513 523 Anderson R. L. 348 Anderson S. N. 179 Anderson W. G. 373 Ando W. 137 225 228 229 Andre J. M. 82 Andreetta A. 270 286 Andrews G. 346 Andrews G. C. 237 Andrews G. D. 127 252 Andrieux C. P. 293 Andrist A. H. 127 251 256 Aneja R. 451 Anet F. A. L. 31,461 565 Angelici R. J. 286 385 Anh N. T. 394 Anhalt J. P. 579 Annino R. 297 Ansell H. V. 569 Anselme J.-P. 222 Aasmann A. 128 Anthonsen T. 521 Antropov L. I. 291 Aoki K. 508 Aono H. 555 Aoyagui S. 303 Aoyama H. 441 Aoyama M. 279 Aoyama T. 21 8 Aoyama Y. 2 12 Aplin R. T. 522 Appleton T. C. 285 ApSimon J.W. 36 523 Aratani M. 340 Archer J. F. 293 Archie W. C. 124 Archila J. 161 Arditti J. 525 Arend G. 247 Aresta M. 270 Arhart R. J. 332 Arigoni D. 151 153 471 597 Arimura A. 16 Armand J. 450 Armarego W. L. F. 432 Armitage I. 36 Armstrong J. A. 549 Arndt R. R. 521 Arnett E. M. 396 Arnold B. J. 579 Arnold D. R. 427 Arnold R. 479 Arnold R. T. 355 Arpino P. 521 Arsenault G. P. 10 Arthur N. L. 571 Arunachalam T. 529 Arzoumanian H. 376 Asahi Y. 304 Asao T. 128 586 Ash L. 477 Ashby E. C. 338 Ashby J. 221 Ashe A. J. 435 Ashida T. 101 Ashworth P. 198 Asknes D. W. 439 Ast T. 17 563 Atherton N. M. 199 207 Atkins G. M. 429 Atkins T.J. 258 277 419 Atkinson A. J. I5 Atwater M. A. M. 565 Atwood J. L. 449 Aubrichon C. 199 Aue D. H. 396 Auerbach J. 493 Auerbach Y . 447 Augustyn 0.P. H. 390 Aumann R. 278 Avaca L. A. 303 Averner M. J. 547 Aviv H. 549 Avraaoides J. 184 Avrutskaya I. A. 295 Axel R. 560 561 Aya T. 348 Ayad S. R. 531 Ayer A. A. 519 Ayronomov A. E. 270 Baarchers W. H. 521 Baardman F. 464 Baba Y. 16 Babad E. 341 Babior B. M. 142 Bach R.D. 122 186 Bachhuber H. 398 Baciocci E. 181 Backes J. 253 Backett D. N. 289 Bacon C. C. 401 Bacquet C. 344 Badshah A. 354 Baeckstrom P. 317 Baer Y. 68 Baeza J. 331 Bagal L. I. 113 Bagus P. S. 70 Bahl C. P. 544 Bahn C.A. 123,241 Baigrie B. 213 Bailar J. C. jun. 290 Bailey D. S. 183 407 440 Bailey N. A. 90 Baird M. S. 166 Baird N. C. I2 I Baitinger W. E. 563 Baizer M. M. 299. 304 357 Baker A. D. 66 Baker A. J. 516 Baker D. C. 539 Baker P. 523 Baker R. 117 163 283 289,416 Balasubramaniyan V. 128 186 Balch A. 210 Baldas J. 484 Baldwin J. E. 127 134 136 137 232 249 251 255,256 346 Baldwin K. E. 252 Ball L. A. 550 Ballard D. H. 179 Baltimore B. G. 144 Baltzer B. 391 Bambach G. 389 Bambenek M. A. 210 Ban Y.,450 Bandurco V. T. 132 Banerjee A. K. 519 Banhidai B. 227 Bank A. 560 Bank S. 205 Banks D. 15 Banks R. L. 271 278 376 Banner B. L. 360 Banthorpe D.V. 250,262 263 467 468 478 509 512 574 Bantz D. A. 556 Bapat J. B. 254 Baranova G. G. 273 Barber M. 68 82 Barchardt J. K. 183 184 Barcza S.,27 Bard A. J. 205 293 Barer S. 279 Bares L. A. 291 Baret P. 227 Barili P. L. 38 12 I 407 Author Index Barker H. A. 144 Barker M. 279 Barlex D. M. 284 289 Barlin. G. B.. 439 Barlow G. H. 385 Barltrop J. A. 592 Barnall W. E. 187 Barnes D. S. 367 376 Barnett B. 280 Barnett B. K. 342 Barnett B. L. 283 Barnett E. F. 67 Barnett W. E. 175 385 Barnier J. P. 242 Barone G. 517 Barr H. J. 559 Barr P. A. 357 Barrell B. G. 552 558 Barrett E. K. 94 Barrett L. W. 325 595 Barrio J. R. 534 535 Barry J. A, 464 Bartholomew R.F. 324 Bartlett P. D. 17 381 Bartley J. P. 521 Bartoch E. G. 593 Barton D. H. R. 171 321 337 353 356 475 526 527 536 571 Barton J. W. 214 Barton R. E. 89 Barton T. J. 216,429,434 438 451 Bartsch R. A. 184,466 Barwell C. J. 172 Barscoul J. 525 Bash H. 56 Baskevitch Z. 474 Bassinet P. 450 Bast K. 441 Bastide J. 132 Batch A. L. 276 Bates R. B. 126 131 178 528 Batich C. 279 Battersby A. R. 468 469. 48 I 483,484,496 Battioni J.-P. 338 Battiste M. A. 217 Battisti A. 248 Bau R. 266 Bauer K. 159 Bauer W. 587 Bauld N. L. 124,205,424 577 578 Baumann H. 204 589 Baumann M. 409 Baxt W. 560 Bayer A. C. 123 Bayer E. 16 Bayer H. O. 370 Baynton W.A. 172 Author Index Beames D. J. 362 Beare S.D. 37 Beattie T. R. 446 Beatty H. R. 341 Beauchamp J. L. 396,439 Bechgaard K. 202 264 306 308,437 574 Beck A. K. 346 Beck F. 291,292 Beck W. 268 Becker E. D. 26,32,37,39 Becker Y. 276 Beckey H. D. 10 577 Beckley R. S. 278 Beckmann W. 465 Becquet C. 240 Beeby P. J. 457 590 Beecham A. F. 86 Beer R.J. S. 437 Begley M. J. 51 1 528 Behforouz. M. 490 Behr. D. 508 Behr F. E. 223 Behrman E. I. 174 Beierbeck H. 36 Beijer B. 359 Beileryan N. M. 194 Beissner C. 283 Belgodere E. 438 Belhinger H. 437 Belikova Z. V. 273 Bell A. M. 530 Bell A. P. 285 Bell R. 26 Bell R. A. 28 Belletire.J. L. 262 Bellucci G. 121 407 Beltrame P. 181 182 441 Beltrame P. L. 441 Belvedere G. 15 Belyakova 2.V. 273 Benary E. 447 Benati L. 448 Bendall V. I. 463 Bender C. F. 56 59 64 224,401 Benderly H. 390 Benecke H. P. 180 Ben-Efraim D. A. 279 Benezra S. A. 8 Benfield. E. F. 5 16 Ben-Ishai Z. 549 Berkovic S.J. 112 Benlian D. 285 Benn M. H. 397 Bennet C. D. 16 Bennett J. E. 190 193 Bennett M. A. 277 Bennett R. L. 275 Bentley M. D. 401 Bentley P. H. 527 Bentley T. W. 8 162 Bertrude W. G. 195 439 Benz F. W. 34 Benziman M. 155 Benzon M. S. 127 136 254 Berchtold G. A. 416 426 568 Beres J. A. 259 Berg P. 557 Berger R. 168,244 Berger S. 24 Bergeson K.439 Bergman D. 251 Bergman J. 330 575 Bergman R. G. 132 172 214 227 254 368 383 432 567 584 Bergmann G. 373 Bergmark T. 68 Berk H. 250 Berking B. 103 Berkower I. 559 Berkowitz W. F. 352 Berliner E. 186 Berman. D. A. 444 Bermejo J. 51 6 Bernard D. 300 Bernard R. E. 264 Bernardi A. 552 Bernasconi C. F.. 114 Bernauer K. 428 Bernhard S. A. 149 Berns A. J. M. 549 Bernstein W. J. 325 564 Berry R. S. 215 593 Berson J. A. 137,25I 255 424 565 Berthod H. 45 Berti G. 121 Bertilsson L. 15 Bertrand M. 17 128 335 374,420 Bertrand R. D. 24 Berwin H. J. 170 Bestmann H. J. 41 5 564 Bethell D. 24 25 Betkouski M. 334 415 Bettinetti G. F. 460 Bettoni G.88 Betz W. 125 Bewick A. 303 Beynon J. H. 17 563 Beyreuther K. 532 Bhagwat M. M. 272 334 Bhanot 0. S. 544 Biale G. 181 182 Bianchi R. 95 Bianco V. D. 270 285 Bick I. R. C. 493 Bickel H. 446 Bickelhaupt F. 22 435 567 Bickford G. R. 576 Bickley H. T. 194 Biedermann G. 152 Biehl E. R. 219 338 Biemann K. 10 13 384 Bigeleisen J. 160 Biggi G. 113 Bigley D. B. 134 387 Bilevitch K. A. 24 Billeter M. A. 552 Billmann J. H. 29 Bilofsky H. S. 439 Bingham D. 276 Binkley R. W. 3 17 Binsch G. 125 Biondi L. 88 Birch A. J. 366 520 Bird C. W. 268 376 Birdsall B. 28 Birdsall N. J. M. 28 Birmele C. 556 Birnberg G. H.,247 Birnie G. D. 560 Biros F. J. 16 Bishop M.J. 533 Bijorpry M. 439 Black D. R. 546 Black D. St. C. 254,352 Black R. M. 447 Blackburn G. M. 596 Blackett B. N. 283,416 Blackhurst A. J. 199 Blackstock W. P. 497 Blaha K. 87 88 89 Blair J. A. 427 Blaka K. 501 Blakley R. L. 142 Blaney F. 417 Blaschke H. 441 Blatchly J. M. 579 Blatt K. 130 363 383 Blattman P. 156 555 Bleaney B. 36 Blessington B. 15 Bloch R. 586 Block E. 400 B!oemendal H. 549 Bloemer W. L. 50 Blomberg C. 22 Bloomer J. L. 385 Bloomfield J. J. 345 388 Bloothoofd-Kruisbeek A. M. 124 Bliissemeier B. 280 Bluhen A. L. 207 Blum J. 274 276 Blumbergs P. 344 Boar R. B. 475 Boblet F. 31 1 Bobst A. 546 Boccalon C. 30 Boch M.503 Boche G. 122 123,412 Bocher S. 241 Bochkarev N. N. 273 Bock R. M. 556 Bockrath B. 205 Boczkowski R. J. 297 Bodewitz H. W. H. J. 22 Bodor N. 57,406 Boehme H. 268 Boelema E. 246 Boelhouwer C. 279 Boer F. P. 92,431 Boerboom A. J. H. 10 Boerma G. J. M. 441 Boezi J. A. 547 Bogard T. D. 248 BogdanoviC B. 377 420 Bogdanowicz M. J. 360 415,427 Bogentoft C. 16 333 Boggs R. A. 321,348 Bognar R. 89 Bogorad L. 483 Boguslawski S. J. 552 Boikess R. S. 38 Boivin J. 525 Boler J. 16 Bollinger J. M. 175 Bol’shinskova T. A. 279 Bolton D. J. 297 Bolton. M. 321 Bonastre J. 301 Bonhoeffer F. 560 Bonnaud B. 272 Bonner R. F. I1 Bonnett R. 431 Bonnier J.M. 190 Bonviani P. 289 338 Bopp T. T. 384 Borch R. F. 340 357 Borden W. T. 252 Borders D. B. 426 568 Bordwell F. G. 118 160 184,242 Borga O. 15 Borgen G. 37 Bornstein J. 431 Boron W. F. 175 Bose A. K. 446 Borshoff P. R. 390 Bosslet F. 243 41 1 Both W. 564 Botteghi C. 286 Bottin J. 394 Bottini A. T. 215 Bouchal K. 281 Boudjouk P. 236 Boue S. 316 Boulton A. A. 15 Bovey F. A. 30 38 39 Bowden K. 116 179 385 Bowen D. H.. 517 Bower B. K. 268 Bowers C. Y. 16 Bowers M. T. 396 Bowman R. H. 435 Boyd D. B. 447 Boyd J. 134 Boyd M. R. 264 Boyd R. J. 132 137 224 Boyd S. D. 180 Boyer J. H. 251 392 Boyer P. D. 146 Boyle M. 564 Boyle W. J. 118 Bradbury E.M. 30 Bradford C. W. 275 Bradley J. S. 275 Bradshaw C. P.,378 Brady W. T. 239 Brandstrom A. 366 Brandon C. 557 Brandsma L. 254 367 Branlant C. 547 Braterman P.S. 268 Brauman J. I. 38 124 Braun M. 346 353 Braunton P. N. 462 Brawerman G. 549 550 Bredereck H. 391 Breg W. R. 559 Bremhott T. 577 Brener L. 41 1 Brenner G. S.,446 Brenner M. 223 Brenner S. 126 178 Brentnall H. J. 537 546 Breslow D. S.,221 Breslow R. 124 136 166 246 410 423 524 527 567 582 Breton J. L. 516 Breuer L. 584 Breuer S. W. 575 Breuninger M. 264 426 Brewster A. I. 39 Brewster J. H. 405 Bridgen J. 558 Bridson J. N. 345 Briggs J. M. 34 36 Briggs J. P. 396 Briggs L.H. 521 Brine G. A. 504 Brinen J. S. 222 Brinich J. M. 175 Brinkley J. M. 218 576 Brinkman M. R. 24 25 Broadbent S. J. 68 Broaddus C. D. 361 Broadhurst M. J. 138 457 Brocard J. 413 Brodie A. M. 288 Brodie J. 142 Author Index Brodsky L. 132 Broens J. B. 130 Brokker-Zijp J. 20 Brokow M. L. 179 Bromilov R. H. 176 Bromley D. 570 Brook P. R. 239 Brookes P. R. 272 Brookhart M. 169 288 Brookhart M. S. 565 Brooks C. J. W. 471 Brooks J. J. 592 Broquet C. 350 Brossi A. 339 Broster F. A. 575 Brot N. 159 Brouillard R. 395 Brouwer D. M.. 167 373 Brower K. K. 160 Brown C. E. 486 Brown D. D. 547 Brown D. G. 142 Brown D. M. 557 Brown E. S.. 273 Brown G.R. 442 Brown H. C. 127 165 182 185 338 340 350 358 378,423 Brown J. C. 175 Brown J. N. 96 Brown K. S. 521 Brown M. 279 Brown M. A. 565 Brown P. 16 Brown R. F. C. 232 233 250. 254,431 Brown R. S. I70 Brown R. T. 497 502 Brown W. V.,520 Browne A. R. 578 Browne J. W. 530 Browne P. A. 462 Brownlee G. 547 Brownlee R. T. C. 439 Bruce M. I. 267 275 Bruice T. C. 112 174 176 260,427 568 Bruins A. P. 563 Brunck T. K. 272 279 Brundle C. R. 66 Brundret K. M. 520 Brunee C. 13 Brunelle D. J. 329 Bruner B. L. 50 Brunk C. 558 Brunn E. 441 Brunwin D. M. 446 Brusted T. 207 Brutlag D. 559 Bruun T. 521 Bruylants A. 538 Bryan C. A. 333 380 Author Index Bryan R.F. 102 104,520 Bryce G. F. 159 Bryce-Smith D. 325 573 Bubnov N. N. 24 197 Bucci P. 38 Buccini J. 523 Buchachenko A. L. 19.23 Buchanan B. G. 14 Buchanan. G. L. 408 Buchanan G. W. 440.563 Buchardt O. 325 326 460 564 Buchecker C. 264 Buchholz H. 268 280 Buck K. T. 490 Buckel W. 151 152 Buckwalter B. L. 474 Budnik M. 251 Budowsky E. 538 Buchi G. 378 Buenker R. J. 63 120 Buffet H. 227 Bugg C. E. 542 Bugge H.,207 Buhs R. P. 16 Buiger P. 281 Bull T. E. 391 Bullen G. J. 91 Bu’Lock J. D. 481 Bunce N. J. 336 Buncel E. 114 Bundgaard T. 435 Bunge K. 428 Bunnett J. F. 181. 182 214,259,341,363,568 Bunton C. A. 161 164 169 510 Buono G.335 Burger B. V. 390 Burger K. 452 Burgess E. M. 130 429 Burgett G. A. 35 Burgmaier G. J. 406 Burke A. R. 27 Burke D. E. 498 Burkhardt T. J. 347 Burley J. W. 178 Burlingame A. L.,7 Burnell E. E. 37 Burns P. 241 Bursey M. M. 8 Burton D. J. 179 Bus J. 77 Busch H. 547 Busch P. 403 Buschmeier V. 152 Bushaw B. A. 466 Bushweller C. H. 373,439 Buss V.,57 241 406,407 Buswell R. L. 466 Butcher M. 232 Butler A. R. 1 1 I 570 Butler D. N. 332 Buttemann H.J. 13 Buu N. T. 249 Buurman D. J. 215 Byrd J. E. 173 388 Byrd L. 306 Byrd L. R. 128 186 374 420 Byrn. S. R. 92 99 Byrne R. 148 Cacace F. 108 109 Cacchi S. 359 Cadioli B. 41 Cadogan. J. I.G..213.214.223,264 569 Cafien F. 521 Caglioti L.. 359 Cagnoli-Bellavita N. 474 Cahiez G. 362 Cainelli G. 340 Calder A. 210 Calderon N. 268,279,334 Caldwell R. A. 207 315 Calb V. 343 Calvin M.,325 564 Calvo C. 284 Cama L. D. 446 Camaggi C. M. 190 197 202,207,448 Cambisi F. 280 Camerman A. 101 Camerman N. 101 Cameron A. F. 91 Cameron T. S. 93 Cammack K.L. 239 Camms A. 270 Campbell G. A. 248 571 Campbell H. F. 504 Campbell J. L. 559 Campbell J. R. 36 39 226 329,571 Campbell-Crawford A. N. 118 Canas-Rodriguez A.. 270 Candlin J. P. 287 Cannell L. C. 282 Canonica L. 470 475 Cantacuzene J. 407 Cantrell J. S. 128 Capineri R.. 559 Capka M. 272,273 Capon B.177 Capozzi G. 241 Caprioli R. M. 17 563 Carbonaro A. 280 Cardillo R. 478 Cardin D. J. 226 268 280,418 601 Carey F. A. 346,347 365 Cargioli J. D. 26 Carless H.A. J. 128 Carlin J. R.,16 Carlson G. R.,121 Carlson R. G. 415 Carlsson L.-0.. 116 Carmichael P. J. 398 Carnahan J. C. jun. 332 Carnick A. W. 510 Caronna S. 109 Caronna T. 448 Carpenter B. K.,451 Carrie R. 382 428 Carroll F. A. 324 Carroll M. 155 156 Carstensen-Oeser E. 583 Cartas M. 549 Carter J. V. 243 Carter 0. L. 268 Carter P. 163 Carter R. E. 33 Cartwright E. 547 Cartwright W. F. 384 Carty A. J. 284 Carver H. A. 566 Casadevall A. 11 1 Casanova J.. 297 393 Cascon S. S. 521 Caserio M.C. 128 186 374,420 Casey C. P. 321. 347. 348 Casey J. P. 88 Cashion P. J. 543 Cashmore A. R. 557 Cason J. 336 Caspersson T. 559 Cassady J. M. 522 Cassar L. 287 Castells J. 264 Casteton A. 301 Catlin J. 579 Caughlan C. N. 280 Caullet C. 31 1 Cava M. P. 432,490 594 Cazes B. 235 Ceccherelli P. 474 Ceccon A.. 182 Cellura R. P. 456 Cepciansky I.. 315 Cerimele B. J. 8 Cerutti P. 546 Cesario M. 104 Cetinkaya B. 226 268 269,418 Cha C. Y.,327 Chabala J. C. 426 Chakrabarti J. K. 359 Chakrabarty S. 519 Chakraborty K. P.,146 Chalk A. J. 272 283 369 Challand S. R. 221 222 Challis B. C. 11 1,118,119 39 1 Chalmers A. A. 36 Chamberlin M.J. 561 Chambers R. D. 71,238 Chambers R. J. 528 Chan C. L.,28 Chan C. Y. 270 Chan S. I. 439 535 Chan T. H. 339 340,427 Chan W. K. 88 Chan W. R. 522 Chaney M. O. 446 Chang C. J. 116 177 178 179,594 Chang C.-S. 124,424,577 578 Chang H.-L. W. 353,450 Chang J. 16 Chang L. 408 Chang S. E. 557 Chang S. H. 552 Chang Y. C. 133,327 Chao 8. Y.-H. 456 Chapman 0.L. 326 385 430 Chappelet D. 148 Chapple C. L. 497 Charles R. 277 Charlwood B. V.,467,468 Charney E.,86 Chatrousse A.-P. 115 Chatt J. 279 Chauvin Y. 355 Chawa A. G. 521 Chawla H.P. S. 446 Chee-Man Lee,242 Cheer C. J. 407 Cheeseman G. W. H. 439 Chekir K. 450 Chelli M. 438 Chen C. H. 340 Chen F.185 388 Chen F. M. F. 441 Chen H. J. 116 Chen K. S.,286 Chen R. H. K. 333 Chenard J. Y. 355 Cheney A. J. 275 Cheney B. V. 50 Cheney J. 465,466 Cheng C. L. 564 Cheng H. N. 37 Cheng T.-C. 128 186 Cheng T. Y. 446 Cheng Y. M. 259 Chernyshev V.0..275 Cherry P. C. 530 Chertkov A. A. 270 Chesnut D. B. 123 Chevolet L. 500 Chi M. S.,464 Chia H. L.. 126 Chiang C. C. 588 Chiang J. F. 51,406 Chiang Y. 1 16 Childs R.F. 244 565 566 Chini P. 286 Chinsoli G. P. 282 Chirinko J. M.,jun. 355 Chisholm M. H. 289 Chizhov.0. S. 16 Cho T. S.R. 547 Chodak G. W. 183 Chodkiewicz W. 338 Chong B. P. 494 Chong J. A. 168,245,408 Chow Y.L. 391 Christensen B. G.. 446 Christensen J.J. 466 Christensen L. W. 225 Christiansen G. D. 86 Christl M. 30 441 Christoffersen R. E. 50 Chruma J. L. 299 304 357 Chu S. Y. 56 224 Chu W. K. C. 179 Chuang V. T. 133 Chuche J. 254,265 Chuit C. 362 Chung D. 563 Chung H. 28 1 Chvalovsky V.,272 Ciabattoni J. 243 Cimino G. 521 Cioffari A. 192 Cipollini R. 108 109 Cistaro C. 497 Claesson A. 333 Clar E. 591 Clardy J. 216 278 423 567 Clardy J. C. 242 409 Clare R. A. 15 Clark B. F. C. 555 Clark D. 307 Clark D. C. 162 Clark D. F. 538 Clark D. R.. 287 344 Clark D. T. 68 71 72 74 76.80.403 Clark H. C. 285,289 Clark I. M. 530 Clark M. 238 Clark S. D. 376 Clark W. D. K. 324 Clarke T.C. 172 383 Claus P. 236 Claypool D. P. 443 Clayton R. 549 Clearfield A. 94 Clegg R.B. 569 Cleland J. H. 342 Author Index Clemens K. E. 131 170 381 393,413,451 Clementi E.,40 67 Clementi S. 117 Clements J. H. 481 Clerc J. T. 14 Cleve G. 86 530 Clifford K. 154 Clifford K. H. 155 Clifford P. R. 167 Clinton N. A. 170 Clive D. L. J. 336 Closs G. L. 225 Closson W. D. 332 Clough S.,132 428 Coates R. M.,243 331 51 1 Cocevar C. 270 Cochrane J. S.,513 Cocivera M.,23 197 Cockle S. A, 141 Cocknell J. R. 298 Cocks A. T. 128 Cody V. 103 Coetzer J. 102 Cogne A. 439 Cohen B. J. 294 Cohen G. M. 381 Cohen S. G. 324 Cohen T. 185 Cohn M. 150 154 Cohn W.E. 533 Cohn W. H. 187 Coke J. L. 376 Cole C. M. 126 178 Coleman R. A. 338 Collette J. W. 282 Collin P. J. 592 Collins B. A. 110 Collins J. 484 Collins J. F. 489 Collins J. H. 9 Collman J. P. 287 344 Cometti A. 287 Commereuc D. 355 Commeyras A. 11 1 Cornstock J. P. 549 Condit. P. B. 132 227 Conia J. M. 238,239 242 330,411,413 Conley R. T. 250 Connolly J. D. 515 Connor D. E. 275 Connor J. A. 68 Consiglio G. 286 Contreras. R. 552 Conway P. 243 Cook A. F. 543 Cook D. 171 181 Cook I. F. 477 Cook J. M. 498 500 Cook M.J. 434 Author Index Cook R. S.,116 179 Cooke M. P. 287 Cooks R. G. 17 563 Cooksey C. J. 285 Cookson R. C. 254 283 289 322 351,416 Cookson R.F. 439 Coombes R. G. 110 Cooper G. D. 184 Cooper G. F. 362 Cooper J. 191 Cooper R. A. 20,21 Cooper R. D. G. 445 Cooper T. G. 155 Cope B. T. 519 Cope J. F. 215 Copson A. J. 161 362 576 Corbella A. 471 Cordes E. H. 161 Corey E. J. 332 333 334 336 339 342 343 350 358,362 365,415 Corio P. L. 39 Cornelisse J. 571 Cornet D. 203 Cornforth J. W. 151 152 154 155 Cornforth R. W. 151 Cornick G. 556 Corrie J. E. T. 520 Corriu R. 11 1 Corriu R. J. P. 273 Corson F. P. 215 Cortese R. 553 Corwin L. R. 424 Cory S.,552 Cossey A. L. 441 Cossey J. J. 450 Cotton F. A. 125,268 Coulson A. R.,552 Coulson D. R. 282 Coulter M.B. 535 Coupek J.28 1 Courchene. W. L. 9 Court A. S.,346 347,365 Court J. 190 219 251 398 Court W. A. 520 Courtney J. 41 7 Courtois G. 235 Cousse H.,272 Coussemant F. 116 Coustard J.-M. 525 Coutts R. T. 449 Covey D. F. 28 241 Cowan D. O. 595 Cox E. C. 559 Cox J. H.,510 Cox L. E. 72 Cox M. R. 102 Cox R. H.,439 Coxon D. T. 390 Crabbt P. 88 332 376 524 Craddock J. H. 287 Cradwick P. D. 93 102 Craig J. 13 Craig R. L. 252 Crain D. L. 278 584 Cram D. J. 581 582 Cramer F. 556 Cramer R. 376 Crampton M.R. 114 115 571 Cramrine D. S.,564 Crane R. I. 512 Crane-Robinson C. 30 Crastes de Paulet A. 525 Crawford R. J. 361 517 Creary X.,233 248 249 354,430 Cree R.13 Creger P. L. 356 358 Cremer D. 265 456 568 588 Crerner H.-D. 461 Cresson P. 237 254 Cretney W. 270 Crider S.,449 Crist D. R. 11 1 Cristol S.J. 163 Crombie L. 510 511 528 Cromwell N. H. 243 Cronin J. R. 16 Crook S.W. 160 Cross B. E. 518 Cross R. C. 289 Cross R. J. 268 Crossley N. S.,271 Croteau R. 469 Crothers D. M.,554 555 Crow G. R. 567 Crow W. D. 231,232,250 572 Crowell J. D. 514 Cryberg R. L. 248 Csizmadia I. G. 47 426 Cundasawmy N. E. 492 Cunningham M. 250 Cuppen J. H. M. 592 Curran J. S.,118 Currie B. 16 Curtin D. Y.,98 99 Curtins H.Ch. 16 Curtis A. J. 512 Curtis R. F. 479 Cusack N.J. 329 Cushley R. J. 36 486 Cusmano G.,451 Cutler A.288 Cvetovich R. J. 352 Cyrnerman-Craig J. 240 Dabard R. 290 Dabek H.,392 Dabek R. A. 259 Daganello G. 125 Dagonneau M. 203 Dahlberg J. E. 545 Dahm J. 373 Dahm K.H.,469 Dai S.-H., 128 257 374 420 Dailey R. G. jun. 520 Dale J. 461 Dale J. A. 527 Dall'asta G. 279 Dalling D. K.,30 Dalrymple D. L. 463 Dalsin P. J. 174 Dalton J. 16 Daly J. J. 435 Daly N. J. 134 392 D ziel W. 520 d'gmato G. 559 Damodaran K.M.,525 D'Amore M.B. 368 Danen W. C. 208 391 Dang T. P.,289 Danieli A. 108 Danieli B. 496 Daniels F.. 327 Daniels P.f. L. 133 Dannenberg J. J. 241 Dann Sargent G. 243 Danzig M.,537 Darby N. 122 258 277 403,419 588 Darling T.R.,321 Darnall D. W.,148 Darnell J. E. 549 550 da Rocha A. I. 490 Das K.D. 16 Dasgupta R.,516 Das Gupta T. K.,130,363 383 Dastur K.P.,366 Daub J. 125 Dauben W. G. 125 258 277.419 523 Daver A. 302 David M. P. 117 Davidaud G.,362 Davidson D. E.,279 Davidson J. N. 531 Davidson R.S. 324 Davie E. S.,279 Davies A. G. 192 195 Davies A. P. 451 Davies S. P.,141 Davies V. H.,102 Davis D. W. 69 72 Davis E.R. 288 Davis F. A.,440 Davis G. A. 324 604 Author Index Davis G. T. 209 Davis J. H. 424 Davis M. 95 Davis R. E. 64 Dawans F. 290 Dayal B. 446 Deady L. W. 119 174 Dean D. 428 De’Ath N. J. 425 de Barbeyrac J.-P. 437 De Boer C.D. 238 de Boer J. L. 100 de Boer TP. J. 398 563 De Bruyn,’D. J. 340 de Clercq E. 546 Dedieu A. 64 de Dominicis. G. 559 Deeb G. M. 185 Defay N. 564 De Franco R. J. 172 298 329,410 566 Degelaen J. 37 Degen P. J. 461 de Haan J. W. 264 de Haseth P.L. 559 Dehmlow E. V. 582 De Jarnette F. 103 de Julien de Zklicourt Y. 589 de Karter F. J. J. 20 Delay F. 243 Del Bene J. E. 56 Del Cima F. 113 De Leo A. B. 156 Delhalle J. 82 Delton M. H. 582 De Luca G. 190,202,448 529 De Maeyer E. 549 De Maeyer-Guignard J. 549 Demarco P.V.,446 De Markey C. A. 498 de Mayo P.,586 De Member J. M. 112 de Member J. R. 167 Demet M. M. 209 De Nadai F. 15 Denes A. S. 426 den Hertog H.J. 21 5 den Hollander J. A. 25 Denis J. M. 239 330 Denne W.A. 95,455 Denney D. B. 425 Dennis N. 218 Denny R. W. 133 Denny W. A. 530 Denyer C V. 336 De Reinach-Hurtzbach F. Derenberg M. 580 Dereppe J. M. 37 De Ridder J. J. 16 de Robertis E. 547 De Rosa M. 529 Dervan P. B. 137 255 De Selms R. C. 124,450 De Silva K. T. 501 Dessau R. M. 348 Dessolin M. 174 Dessy R. E. 291 de Stafano S.,521 De Valk J. 216 Devaprabhakara D. 272 334 Devaquet A. 56 Dewar M. J. S. 44 55 57 59 64 256 262 401 406 de Wit J. 87 de Wolf W. H. 567 Deyrup C. L. 539 Deyrup J. A. 334 415 449 Dharan M. 428 Dheer S. K. 544 Diaz A. 171 Diaz A. F.,165 Dickson L.593 Dickstein J. I. 160 373 Diefenbach H. 150 Diehl P. 37 38 Diehl J. W. 385 Dienes A. 315 Dieterle W. 486 Di Giorgio J. B. 133 Dill D. R. 15 Dill K. 241 Dimmel D. R. 180 219 572 Dimroth K. 435 Dimtrienko G. I. 127 Diner U.E. 354 Dingwall J. G. 437 Dinner A. 240 Dirheimer G. 552 Dirlam J. P. 17I 297,305 393 Ditchfield R. 56 Dixie C. J. 136 Dixon J. E. 112 174 Dixon W. T. 198 Djerassi C. 14 84 529 Dmitrienko G. I. 252 Dobbs A. J. 212 D’Obrenau P.,553 Dobson C. M. 36 Dodd D. 285 Doddrell D. 31 Dodds A. J. 200 Dodson R. M. 130 Doering W. von E. 129. 402 Dohr M. 282 Doi Y.,358 Dolbier W.R. 124 128 131,374,420 Dolby L. J. 494 Dolhun J.J. 10 Dolphin D. 275 DoMinh T. 428 Done J. N. 534 Donelson J. 532 Donelson J. E. 558 Donewski A. R. 185 Donnelly W. J. 489 Donner W. 444 Donninger C. 151 152 155 Doomes E. 243 Doonan H. J. 478 Dopper J. H. 434 596 Dore M.,1I1 Dorman D. E. 30 Dorn H. C. 27 Doronzo S. 270 285 Dorschel C. A. 500 Doss S. H. 88 Dost F. 228 Dou H. M. J. 202 Dougan D. 533 Dougherty R. C. 16 121 Douglass I. B. 401 Doupeux H.,297 Dove D. 285 DOW L. 560 Dowd P. 251,424 Dowell R. 271 Downay R. H. 186 Doyle G. 279 Doyle M. J. 280 Doyle M. P.,340 Draeger B. 592 Draffan G. H. 15 Drake A. F. 376 Drakenberg T. 33 Dralants A. 595 Dravnieks F. 199 Dreiding A.S.. 212 410 482 Dromey R. G. 9 Druck S. J. 32 Dryhurst G. 3 12 Duax. W. 103 DuBois G. E. 523 Dubois J. E. 186 395 Duc D. K. M. 518 Dudley R.J. 84 Dudock B. 555 Duesberg P. H. 549 Duwel H. 461 Duff J. M. 276 Duffield A. M. 14 Duke R. E. 135 Dulber T. E. 172 Dulcere J. P.,335 Author Index 605 Du Manoir J. R. 579 Dumas L.B. 545 Dunbar R. C. 108 Dunkelblum E. 339,429 Dunlap L. H. 124 567 Dunlap R. P. 395 Dunn A. R. 437 Dunn B. M. 176 Dunn M. F. 149 Dunne K. 167,263 574 Dunning T. H. 56 Dunsmore G. 36 Duong K.N. V.,285 Duran N. 340 Durandetta J. 348 Durden D. A. 15 Durr H.,417 583 Duthie E. G. 452 Dutkey S. D. 185 DvlirAk V.,214 Dyall L.K.,577 Dzidic I. 11 Eaborn C. 111 117 5 70 Eachus S.W. 456 464 Eager R. G. 144 Early T. A. 36 Eastmond R. 373 Easton D. B. J. 217 Eaton D. F. 132,227 Eaton M. A. W. 546 Eaton P.E. 362 Ebel J.-P. 532 547 556 Eberbach W. 447 Eberhard P. 123 180 Eberhard R. 123 Eberhardt G. G. 274 282 Eberson L. 297 305 393 Eck C. 512 Eck D. 181 Eckert D. J. 528 Eckstein F. 545 546 Edagawa E. 36 Edge D. J. 191 Edmonds M. 549 Edmuston C. 51 Edward J. T. 249,438 Edwards A. J. 570 Edwards E. I. 221 Edwards J. A. 527 529 Edwards J. M. 86 Edwards J. O. 173 Edwards 0. E. 508 Effenberger F. 109 569 570 Efraty A. 284 Efremova L.A. 273 Efros L.S. 113 Egan B.Z. 534 Egan W. 391 Egger K.W. 128 Eggerer H. 142 151 152 Eglinton G. 14 522 Eguchi S. 136 247 Ehntholt D. J. 288 Ehrenson S. 64 Ehresmann C. 532 547 Ehrlich K. 288 Ehrlich M. 557 Eicher T. 585 Eidenschink R. 412 Eilers J. E. 44 Eimer J. 125,417 Eisenstein O. 394 Eisner T. 5 16 Eisner U.,265 449 Eiter K. 462 Ekeland T. 461 El Ghandour N. 132 El Ghariani M. A. 115 57 1 Eliel E. L. 357 439,440 Elliott R. L.,126 464 Elliot S.P. 381 Ellison F. O. 69 Ellison J. R. 559 Ellison R. A. 352 353 Ellred E. L. 132 Elmore N. F. 442 Elson I. M. 209 Emerson D. W. 353 Emerson G. F. 288 Ed T. 14 Empsall H. D. 276 Emsley J. W. 210 Enders D.341 Endo J. 500 Engelbrecht J. P. 529 Engelhard M.,416 Engelmore R. S.,14 Engemann G. 396 Engler E. M. 408 Englert M. 283,420 Engstrom L. 148 Engstrom N. 27 Ensminger A. 522 Enwall E. L. 103 Enzmann F. 16 Epiotis. N. D. 120 321 Epling G. A. 252 323 Epple G. 570 Epstein M. J. 125 Epstein W. W. 477 510 Ercoli R. 584 Erman W. F. 361 Ershov B. A. 238 Ershov V. V. 197 Eschenmoser A. 130 138 334,363 382 383 Essig T. R. 11 5 Eugster C. H. 520 Evans B. E.,94 Evans D. 271 Evans D. A. 237,333,346 380,415 506 Evans D. F. 36 Evans M. G. 184 Evans R. 472 Ewing D. F. 276 Ewing S.,170 Exner J. H. 160 Ezcurra P. 547 Faeber P. 546 Fagan F. J. 162 Fahnestock S.R.547 Fahrenholtz S.R. 21 Fairless B. 125 256 Fairwell T. 13 Fales H. M.,14 Falk J. C. 270 Falk W. R. 552 Fanelli R. 15 Fang-Yun Lew 145 Fanning A. T. 576 Fanning E. 532 Farber S. 559 Farcasiu D. 247 Farkas I. 89 Farnell L. F. 34 Farnham. W. B.,436 Farnsworth N. R. 487 Farnum D. G. 121 Farone F. 285 Farr F. R. 124 577 578 Farrant G. C. 288 Farrar T. C. 26,32 33 Fattorusso E. 521 Faulkner D. 417 Fauss H.,583 Favilla R. 149 Fayter R. G. 165 Feast W. J. 72 74 76 80 403 Fedoroff S.,559 Fedoryhski M. 359 Feeney J. 28 34,483 Fehtr F. 93 Fehn J. 452 Fehnel E. A. 260 568 Feigenbaum E. A. 14 Feiner S.,255 Feiring A. E. 243 Feit I.N. 183 Fel’dblyum V.Sh. 281 Feldmann R. 461 Felix D. 130 138 334 363,383 Felkin H. 133 379 Fellenberger K.,122 123 161 Fellmann P.,395 Fellner P.,532 547 Fellner-Feldegg H. 67 Felt C. R. 220 Fendley E. J. 114 571 Fendler J. H. 114 571 Fenical W. 125 515 Fenwick R. G. 596 Ferguson I. J. 108 Ferguson S. 123 Feriozi D. T. 431 Fernandez F.,89 Ferrari G. 270 496 Ferrari G. F. 286 Ferraris G. 284 Ferree W.I. 318 Ferreira N. P. 478 Ferry J. D. 264 Fersht A. R. 176 Fbtizon M.,353,450 518 FFutrill G. I. 339 Fiandanese V. 183 Fiaud J. C. 407 Field F. H.,11 Fiers W.,532 550 552 Fife T. H. 177 Figeys H. P.,564 595 Figuera 1. M. 178 Filardo G.584 Filippi A.,441 Filippini F. 119 174 Finch J. T.,555 Finder C. J. 563 Findlay D. M.,127,252 Findlay M.C. 186 Fink W.H.,64 Finkelhor R. S. 330 Finkenbine J. R. 340,427 Finlay T. H. 141 Finnegan R. A. 575 Finney C. D. 9 Fioshin M.Y.,295 Firestone R. A. 132 Firtel R.A 549 Firth P.A. 5 10 Fisch R. E. M.H.,525 Fischer E. O. 268 Fischer G. 398 Fischer N.,482 Fischer P.B. 11 1 570 Fischer R. D.,35,268,405 Fischer R. P.,333 Fischer S.,283 Fischer W. F. 118 Fish R. W.,288 Fishbein L. 15 Fisher R. T.,248 Fitzgerald R.. 215 Fitzky H.G. 66 Fiyita H. 69 Flament J.-P. 518 Flanagan K. J. 443 Fleischer. E. B. 272 Fleischhauer H. 119 169 Fleischhauer J. 137 Fleischmann M.,307 308 Fleischmann R.270 Fleming I. 122 161 228 Fleming R. 233 250 Fleming R. H. 134 25 1 Fleming W. J. 509 Flesch G. D. 9 Flesia E. 391 Fletcher S. R. 285 Flick B. H. 525 Flintoff W. F. 535 Flippen J. L. 97,436 Flood M. E. 481 Flood T. C. 332 377 Flores H. 1 16 Floriani C. 276 Floss H. G. 155 156 480 Flowers M. C. 252 Foa M.,287 Forsch M.,586 Foerster E. W. 326 Foglia T. A. 357 Foley G.E. 559 Folay R. T. 301 Folkers K. 16 Foltz R. L. 16 Fomicheva M.G. 303 Fong H.H. S.,487 Fontaine C. 285 Foote C. S. 127 133 327 376 Ford P. W.,136,255 Fordham W.D. 512 Forehand J. B. 10 Forrest T.P.,441 Forrester A. R. 210,219 Forrester J.M.,472 ForsCn S.,391 Forsyth D. A. 117 Forsythe J.-A. 354 Foster A. M. 233 249 335,386 Foster C. H.,416,426 568 Foster M.,74,403 Foster M.A. 141 Foulger. B. E.,325,573 Fowler F. W.,449,450 Franca N.C. 390 Franceschetti D. R. 56 224 Francis M. J. O. 467 Franck B. 484 Franck R. W.,563 Franck-Neumann M. 129 264 Frank G.W.,461 564 Frank J. K. 281 Franked E.N. 270 Frankowski A. 458 Author Index Frappier F. 525 Fraser R.R.,36 579 Fraser S.B. 497 Frazier J. 543 Frederick R. C. 248 571 Freedman A. N. 12 Freedman H. H. 169 592 Freeman J. P. 452 Freeman R.,27,30 33 Freemann B. H. 584 Freidlin A. Kh. 271 Freidlin L. Kh. 272 Freiesleben W. 268 376 Frenkel A.D. 391 Frensdorff H. K. 366,465 Frey H. M.,224,252 Frey J. P. 559 Frey T. G. 186 Fried J. H. 362 529 Friedman L. 218 576 Friedrich L. E. 322 Friend E. W. 579 Frigero A. 15 Fringuelli F. 89 117 435 Frohlich J. C. 15 Fronza G. 448 Frost A. A. 50 Frost D. C. 68 Frost D.J. 270 Frost K,A. 215 Frost L. N. 183 Froyshov 0.. 157 158 Fruchier A. 36 Fry A. 160,241,376 Fry A. J. 291 296 298 393 Fry J. L. 162 Fry K. 558 Frydman B. 483 Frydman R. B. 483 Frye C. L.,447 Fryer R. I. 462 Fuchs B.,93,447 Fuchs P.L. 334 362 Fueno T. 129,422 Fuganti C. 478,495 Fuhr H. 127,366 Fujimoto H. 224 225 Fujimoto T. T. 133 327 Fujio M..116 Fujisawa Y.,539 Fujita K.242 Fujita S.,462 581 Fujita T. 102,353 356 Fujita Y.,289 Fujiyama K. 453 Fukazawa S.,444 Fukui K. 224 225 588 589 Fukumoto K..325,491 Fukumoto T. 340 Fukunaga J. Y. 381 Author Index 607 Fukanaga M. 74 Fukuyama T. 340 522 Fukuzumi K.,275,279 Fuller D. L. 190 Funabiki T. 116,270 Funakura M. 131 393 Furimimsky C. 196 Furrer H. 124 450 Furuichi Y. 539 Furukawa J. 129,290,422 Furukawa N. 401 Furusato M. 352 Furutachi N. 135 Gabel C. 315 Gabel R. A.. 239 Gabrielson B. 165 Gacek M. 88 Gaertner K. 540 Gaeta F. 466 Gaffield W. 88 Gagnaire D. 439 Gaidis J. M. 592 Gainsford G. J. 275 Gait S. F. 454 458 Gajewski J. J. 251 Gakis N. 428 Gal A.173 Galbraith M. N. 512 Galibert F. 558 Gallagher P. E. 204 Gallegos E. J. 528 Gallo R. C. 549 560 Gallop P. M. 557 Gambino. S. 584 Gamboa J. M. 178 Ganem D. 532 Ganguly A. K. 536 Ganguly S. N. 516 Gansow 0. A. 27 Ganter C.,447 Gantz D. 484 Gardini G. P. 448 Gardner L. I. 559 Gardner R. J. 427 Gardner S.,280 Gariboldi P. 471 Garin D. L. 239 Garlaschelli G. 286 Garnett J. L. 273 274 329 569 Gamier F. 186 Garratt P. J. 432,584,589 593 Garrett E. R.,538 Garry A. B. 529 Garst J. F.,25 Gaskin P. 516 Gass J. D.,145 Gassen. H. G. 542 Gassman P. G. 233 236 248 249 258 277 354 417,419,430 571 Gastaminza A. 107 Gasteiger J. 171 565 Gatford C.285 Gaudemer. A. 285 Gavrilina L. Ya. 280 Gazit A. 587 Geertsema H. 390 Gefter M. L. 559 Gehrke C. W. 534 Gehrlein L. 428 Geiger W. E. jun. 297 Geise H. J. 407 Geisler N. 532 Geiss K.-H. 346 Gelius U. 68 Gellert R. W. 391 Gensin D. W.,50 Gender W. J. 171 Geoghegan P. J. 378 George A. D. 243 Georgian V. 567 Gerard G. F.,547 Gerlach H. 247 331 Gerlock G. L. 200 Germain A. 111 Gerson F. 204 212 410 588 Geske D. R. 210 Gesson J. P. 525 Ghambeer R. K. 144 Ghanborpour A. 165 Gharpure S. B. 180 Ghatak U. R. 516 519 Ghertner L.,533 Ghiringhelli D. 478 Ghosez L.,128 345,410 Ghosh S. 250 Giacometti G. 30 Giangrasso D. 478 Gianotti C. 285 Gibby M.G. 30 Gibson D. H.,288 Giering W. P. 288 332 377 Giessner B. G.,9 Giezendanner H.,428 Gilardi R. D. 96 100 Gil-av A. 278 Gilbert A. 325 573 Gilbert B. C. 196 200 206,212 Gilbert J. C.,135 Gilbert R.P.,172 Gilchrist A. B. 275 Gilchrist T. L. 122. 222 426 Gilgen P. 428 Gilham S. 544 Gilhuus-Moe C.,157 Gill G. B.,447 Gillard B. K. 427 Gillert R.W. 208 Gilles J. M. 204 292 589 Gillespie D. 550 Gillespie D. D. 549 Gillespie J. P. 380 592 Gillies C. W. 430 Gilmore C. J. 520 Ginanneschi M. 438 Ginnard C. R. 82 Ginsberg B. 559 Ginsburg D. 406 Ginsburg P. H. 315 Girard C. 330 Girijavallabhan M. 356 Girotra N. N. 446 Giumanini A. G. 218 Glasel J.A. 542 Glazer E. 428 Gleiter R. 212 230 410 437 Gless R. D. 505 Gloss G. L. 21 23 Glotfelty D. E. 327 Glotter E. 521 529 Glushko V. 31 Goad L. J. 477 Goddard J. P. 556 Goddard W. A. 56 61 120,224 Godel M.,116 Godfrey M. 117 Goe G. L. 127 Goh S. H.,225 Gokel G. W. 359 Gold A. 252 Gold E. H.,341 Goldberg B. J. 241 Goldberg I. 93 Goldberg N.L. 357 Goldsmith D. 509 Goldstein J. H.,28 Goldstein M. J. 120 127 136 172,254,257 566 Gollnick K.,130 133,319 327,451 Golloch A. 593 Golubtsov S. A. 273 Gonzalez A. G. 51 6 Goodall B. L.,275 Goodall D. M.,315 Goodchild J. B. 544 Goodfellow R. G. 243 Goodfellow R.J. 510,511 Goodings E.P.,436 595 Goodman P.567 Goodwin T. W.,477 Gordon A. E. 15 Gordon M. D. 435 Gordon-Gray C.G. 488 Gore J. 128 335 374 420 608 Gore P. H. 564 Gorter-La Roy G. M. 126 Gosavi R. K. 203 Gosselck J. 228,450 Gosteli J. 446 Goto K. 207 Goto T. 340 Gottarelli G. 87 Gotthardt H. 370 Gottleib 0. R. 390 Gottschalk G. 152 Goudie A. C. 516 Gould D. C. 142 Gould S. J. 471 Gourcy J. G. 302 Goutarel R. 525 528 Govindachari T. R. 490 503 Gowenlock B. G. 398 Grace D. S. B. 223 Graham J. C. 359 Graham J. D. 29 Graham W. D. 246 Grahe G. 538 Gramaccioli C. M. 95 Gramstad T. 439 Grandjean J. 35 Grant D. 409 Grant D. M. 24 30 31 32 Grantham R. 550 Gras J-L.128 374 420 Grasselli P. 478 Gravel D. 353 Gravestock M. B. 241 514 Grayson D. H. 484 Graziano M. L.,249 Greco C. V.,433,460 Grke R.,382 Greeling R. H. 170 Green A. 192 Green E. E. 425 Green M. 274 276 281 549 Green M. L. H. 281 Green R. J. S.,579 Greene A. E. 358 515 Greene J. C. 448 Greene R. N. 366,466 Greenspan C. M. 557 Greenwood G. 382 Gregonis D. E. 477 Gregorio G. 286 Gregory B. J. 160 Grellmann K. H. 326 Grethe G. 501 Grevasio G. 284 Grey A. A. 39 Grieco P.A. 237,330,332 333 358 513 515 Griffin C. E.,571 Griffin G. W. 227 Griffin R.C. 125 Grigg R. 138,457 Griller D. 195 Grimme W. 136 256 Grimmett M.R. 108 Grimshaw J. 132,293 Grindley T.B. 116 Grinham A. R. 214 Grins G. 449 Grishina A. D. 303 Grobel B-Th. 346 Groen A. 23 Groen M.B. 340 Granneberg T. 88,438 Grohman K. K. 593 Gromelski S. J. 334 Gromova E. V.,295 Gronenborn B. 532 Gronowitz S. 116 Gross H. J. 550 554 Gross M.A.. 169 Grosser J. 240 Grossert J. S.,509 Grossman N. 260 Grotch S. L.,13 Grovenstein E. 259 Groves J. K.,376 Groves J. T. 246 Grubbs R. H.,272 279 Gruetzmacher G. 236 Grundon M.F. 489 Grundy J. 357 Grunwald E. 162 Grutzner J. B. 178 566 Gschwend H. W. 442,581 Guainazzi M.,584 Gunther H. 461 588 Guest M. F. 68 71 Guilhem J. 104 Gulati S. C. 560 561 Gulick W. M.,jun. 206 Gunstone F. D. 399 Gunther H.39 125 136 256,417 Guss J. M. 275 Gust D. 563 Guthikonda R. N. 366 499 Guthrie D. J. S.,281 Guthrie R. D. 179 Gutowsky H. S.,37 Gutschow C. 15 1 Guttman L. J. 521 Guziec F. S.,jun. 341 Guzman A. 332 Gygax P. 130 363 383 Haake P. 241 Haas C.K.,227 Author Index Haase J. 369 Haberlield P.,130 Habersaat K.,131 Hachey D. 510 Haddadin M.J. 429 Haddon R. C. 132,588 Haeberlen U.,33 Haegeman G. 532 550 Hlinni R. 521 Hgnssle P.,345 Haeverten U.,32 Hagaman E.,133 379 Hagenmaier H.,16 Hagihara N. 269 Haginiwa J. 500 Hagishita S.,87 Hahn R. C. 38 Haiduc I. 284 Haidukewych D. 356 Haigh C. W. 38 Haines R. J. 279 Hair N. J. 91 Haisch D. 133 327 Hall C.M. 337 542 Hall D. M.,462 HaU D. T. 342 Hall J. H. 223 Hall L. D. 36 39 Hall R. E. 162 Hall S. F. 518 Hallak N. 488 Hallensleben M. L.,359 Halliday D. E. 289 Halpern B. 88 273 329 Halpern J. 173 388 Halpern Y. 167 168 Halsall T. G. 524 Halton B. 578 Haluska R. J. 265 423 456 567 Ham P. J. 528 Hamaguchi T. 279 Hamanaka T. 101 Hamberger H. 171 Hamer N. K. 253 Hamilton J. A. 142 Hamilton R. 532 Hammerich 0.. 264. 303 306,308,311,574 Hammon D. 67 Hammond G. 533 Hammond G. S. 132 193 227,262 3 15 326 Hampton A. 539 542 Hamrin K. 68 Hamuro J. 212 Hanack M. 241 Hancock M. 268 Hancock R. L. 533 Hands D. 447 Hanessian S.,536 Hanff S.577 Author Index Hann T. L.,285 Hansen E. R.,195 Hansen H.-J. 135 261 368,428,578 Hansen J. F. 250,452 Hansen L. D. 117 Hansen L.K. 96.436 Hanson A. W.,101 Hanson J. R. 472 473 513 Hanson K. R.. 151,481 Hanson S.W.,36 Hanstein W. 170 Hanyu Y.,36 Hapala J. 466 Happer D. A. R. 184 Hara A.,395 Hara H. 495 Harada F. 552 Harada K. 149 Harada N. 87 Harayama T. 493 Harding A. E. 515 Harding C. E. 241 Harding K. E.,415 513 Hardy A. D. U.,102 Harfast A. 15 Hargrave R. J. 172 Hargreaves R.,183 Hariharan P.C. 55,59 Harkness A. L. 33 405 519 Harley- Mason J. 5 16 Harper P.J. 542 Harrington C. K. 238 Harrington K. J. 233,250 Harris C. L. 118 Harris D.L. 171,288 Harris G. S.,584 Harris J. M. 162 166 Harris R. 541 Harris R. K. 31 32 Harris R. L.N. 441 Harrison A. G. 9 Harrison D. M. 489 5 17 Harrison J. M. 239 Harrison P. R.,560 Harrison P.W. 315 Harrit N. 326 460 Hart H. 592 Hartley F. R. 268 367 Hartman A. 69 Hartmann A. A. 357,440 Hartshorn S. R. 109 110 Harvey A. D. V.,288 Harvey G. R. 402 Hasegawa K. 348,443 Hasegawa T.,441 Haselbach E. 77 Hashimoto H. 227 282 Hashimoto I. 11 1 Hashimoto S. 429 Hashimoto T. 362 Hashmall J. A. 72 Hassall C. H.,479 Hasselmann D. 129,251 Hassid A. I. 340 Hassner A. 429 Hasty N. 133 327 Haszeldine R. N. 383 Hata G. 289 Hata N. 326 Hata T.,544 Hata Y.,229 236 Hattori M.546 Hauff S.,24 Hauptmann. H. 372,435 Hawser K. H. 32 Havew g. 586 Havinga E. 85 571 Havir E. A. 481 Hawker J. 473 Hawley D. M. 512 Hay P.J. 56 224 Hayakawa Y.,131 393 413,508 Hayashi H. 557 Hayashi J. 284 526 Hayashi K. 529 Hayashi M. 330 Hayashi S. 218 Hayashi Y.,221 Hayatsu H. 539 Hayes D. M. 64,216 224 Hayes E.F.,56,224 Hayes J. 24,25 Haymore B. L. 466 Hayward L. D. 89 Hayward R. J. 325 Heaney H. 161 216 362 563,576 577 581,589 Heathcock C. H. 415 Heatherly D. E. 534 Hecht S. M. 226,329,542 556 Heck R. F. 289 Heckel K. 447 Hedaya E. 368 Hedayatullah M. 569 Heden P. F. 68 Hedman J. 68 72 Hefelfinger D. T. 564 Heffron P.J. 222 Hegarty A. F. 183 Hegedus L. S.,289 579 Hehlmann R. 560 Hehre W. J. 42,43,47,64 65 66 109 393 401 Heiba E. I. 348 Heicklen J. 248 430 Heil G. 456 Heilbronner E. 404 Heimbach P. 268,280 Heimer E. P.,543 544 609 Heimgartner H. 135 261 428 Heinemann H. 290 Heinrich F. 423 Heinsohn G. E. 299,339 Heitz W.,331 Hekman M. 464 Helder R. 130 131 319 45 1 Hell A. 560 Heller S. R. 14 Helmchem. G. 565 Helmholdt R. B.. 441 Helmy E. 238 Hemidy J. F. 203 Hemingway J. C. 102 Hemingway R. J. 102 Hemmi K. 462 Henc B. 377,420 Henderson H. E. 390 Henderson W.,11 Henderson W. G. 396,439 Hendrick M. E. 225 402 Hendrickson D. N. 68 Hendriksen L.,391 Hengartner U.,339 523 Henning D.547 Hennis R. P. 125 316 Henrichs P. M. 38 Henrici-Olive G. 282 Henrick C. A. 513 Henriksson A. 77 Henri-Rousseau 0..132 Henry M. P. 385 Henry P.M. 386 Henry T. J. 368 Henson W.L.,176 Henzel R. P. 258 277 278,419 Henzi B. 384 Hepler L. G. 117 Herayama M. 36 Herberhold M. 267 Herbert A. J. 279 Herbert R. B. 481 Herbst M. M. 144 Hercher M.,315 Hercules D. M. 66 172 262,326 Herkenham M. A. 243 HtrmAnkovB V.,89 Herndon W. C. 122 377 420 546 Herout V. 512 Herr H. J. 587 Herring F. G. 68 Herrmann R. 560 Hershenson F. M.,371 Hershman A. 287 Hertz H. S.,13 Herz J. E. 37 Herz W. 517 610 Author Index Herzog H.395 Hesp B. 520 Hess B. A. 434 590 Hesse G. 573 Hesse M. 498 Hesse R. H. 337 353 526 536 571 Hetflejs J.. 272 273 Hetschko M. 450 Heu B. 417 Hevesi L. 538 Hewitt D. G. 323 Hewson A. T. 516 Hey D. H. 261 Hey H. J. 268 280 Heyden B. 558 Heyn J. 215 Heyre W. J. 170 Hiatt R. 376 Hibbert F. 119 179 Hiberty P. C. 64 Hickey M. J. 395 Hidai M. 272 279 Hieble J. P. 239 Higgins R. J. I1 1 Higuchi J. 196 Higuchi M. 444 Hiiragi M. 218 Hilbers C. W. 39 Hilgetag G. 213 Hill H. A. O. 141 Hill H. D. W. 27 30 33 Hill J. S. 502 Hill K. A. 357 Hill R. H. 132 Hillard T. A, 319 Hillier I. H. 68 71 82 Hindley J. 547 552 Hine J. 174 Hinshaw J.C. 132 186 340,427 Hintz P. J. 440 Hinze A. G. 270 Hirabayashi Y. 441 Hirai K. 336 Hirai R. 290 Hirano S.,581 Hirao K. 572 Hirata Y.,330 508 Hirayama K. 465 581 Hiriart J. M. 337 Hiroi K.,358 515 Hirooka S. 443 Hirose S.,560 Hirotsu T. 590 Hirsch R. 233 250 Hisatsune I. C. 248,430 Hites R.A. 13 384 Hjortkjaer J. 270 Ho C. K. 165 Ho,D. H. 406 Ho H. C. 352 353 356 Ho L. L. 241 Ho T.-L. 352 353 356 Hoas C. K. 337 Hobbs J.. 545 Hobbs J. B. 546 Hocker. H.. 279 Hocker J. 377 Hocks L. 279 Hodge E. B. 447 Hodge. P. 580 Hodge V. F. 174 Hodgkins T. 584 Hodson H. F. 487 495 Hofle G. 357 Hcjffman C. 355 Hoffman J. M. 136 166 246,410 Hoffmann H.M. R. 131 170 381 382 393 413 45 1 Hoffmann R.. 47 51 86 120 125 136 138 170 172 216 224 245 256 406 566 Hoffman R. W. 233 250 253 586 Hofmann H. 266,460 Hofmann J. Ch. 295 Hofmann P. 460 Hogenkamp H. P. C. 142 Hogeveen H. 167 171 373,423 567 Hogg A. M. 16 Hoggett J. C. I10 Hoinowski A. M. 446 Holah D. G. 272 Holcomb A. G. 175 Holkihar J. R. 199 Holland G. 199 Holliman F. G. 481 Hollstein U. 480 Hollyhead W. B. 178 179 Holm R. 66 Holman M. J. 543 Holman R. J. 207 Holmberg M. S. 33 Holmstedt B. I5 Holsboer D. H. 390 Holton R. A. 523 Holtz D. 396 439 Holy A. 539 540 Holyoke C. W. 434 Hong P. 269 Honma H. 421 588 Hoobler J. A.391 Hoogenboom B. E. 441 Hooper J. W. 523 Hooper M. L. 554 Hooz J. 345 357. 370 Hopf H. 254,376 579 Hopkinson A. C. 325 Hopla. R. E. 523 Hoppe D. 441 Horanyi G. 308 Hordvik A.. 96 97 436 43 7 Horgan S. W. 591 Horie Y.,477 Horn D. H. S. 512 Horn U. 138 334 Hornbeck C. L. 16 Horner L. 272 Hornish R. 361 Horowitz R. M. 88 Horrocks W. D. 36 Horsley J. A. 63 406 Horsley W. J.. 30 Horspool W. M. 170 Horstmann Chr. 88 Hortmann A. G. 427 Horton D. 539 Horwell D. C. 222 449 Hoshino 0.. 495 Hosokawa T. 284 Hotten T. M. 359 Houghton D. S. 312 Houghton R. P. 510 Houk K. N. 135,253 House H. 0..393 Housman D. E. 549 Howard F. B. 543 Howard J. A. 193 196 Howard P.H. 38 Howden M. E. H. 509 Howe I. 17 Howe R. F. 279 Howell J. A. S. 288 Howell J. M. 138 Howes P. D. 588 590 Howgate P. 539 Howley P. M. 225 Howman E. J. 378 Howsam R. W. 292 Hoyer G. A. 86 530 Hoyt E. B. 567 Hoz S. 182 Hrabak F. 281 Hrbek J. 88 Hruban L. 88 Hsu A. C. 594 Hsu I. N. 103 Hsu J. N. C. 127 Hsu K. 63 120 Huang E. 170,245 Huang F. 28 244 Huber L. E. 393 Hubert A. J. 228 330 Huche. M.,237,254 Hudlicky T.. 448 Hudnall P. M. 366 Hudson A. 191 Hudson B. 276 Hudson C.E. 205 Author Index Hudson R. F. 119 174 209 Huf J. 560 Huffman J. W. 215 514 Huffman W. F. 415 513 Hug R. 135 578 Hug W. 86 87 Hughes A.N. 272 Hughes R. P. 284 285 Hughes W. B. 268 376 Huguet J. 31 1 Hui B. C. 272 Hui M. H. 325 595 Huisgen R. 123 171 180 370,428,44 1 565 Hull L. A. 248 430 Hull S.E. 90 Humffray A. A. 312 Hummel K. 241 381 Hummel K. F. 225 Hunt D. F. 10 I I 288 Hunt E. 346 Hunt J. D. 423 Hunt W. J. 56 224 Hunter D. H. 28 124 Huong S. K. 161 169 Huong T. T. 331 Huppatz J. L. 441 Hurlbert R. B. 146 Hurnaus R. 584 Hursthouse M. B. 488 Hurwitz J. 559 561 Husson H.-P., 500 Hutchins R. O. 439,440 Hutchinson D. W. 537 546 Huttner G. 268 Huurdeman W. 353 Huynh C. 137 235 236 346 Huysmans W.G. B. 210 Hyatt J. A. 343 Ibarbia P.A. 192 Ibberson P.N. 481 Ibl N.295 Ibuka T. 492,493 508 Ichibori K.,137. 229 Ichikawa K. 570 Ichikawa M. 400 Ichikawa T. 555 Ichlov C. 254 Iddon B.,223 Ide J. 41 3 Iflah. S.,274 Ihrig A. M. 29 Iida H.,455 Iida K.. 286 312 Iida T.,512 Ikeda A. 307 Ikeda K. 342 Ikeda M. 452,453 Ikeda S.,271 Ikeda T. 541 Ikeda Y. 286. 570 Ikegami S.,529 Ikehara. M.,541. 544. 546 Ikekawa N. 477 Ikram M. 492 Il’ina G. P. 348 Illger W. 228 Imai I. 137 228 229 Imamura A. 69 Imamura K. 462 Imanari M. 207 Immirzi A. 495 Inglis R. P. 399 Inglis T. 269 Ingold C. K. 180 Ingold K. U. 193 196 Ingram V. M. 531 Ingrosso G. 407 Innorta G. 8 Inoue K. 469 Inoue S.,289 Inoue T. 262 Inoue Y.,282 Inouye H.469 Inque S.,340 Inubushi Y.,492,493 508 Ioda M. 589 Ioffe B. V. 219,250 Ionin B. I. 39 Ippen E. P.,3 15 Iqbal M. Z. 275 Ireland C. J. 333 Ireland P. R. 275 Ireland R. E. 253 339 355 523 Iriarte J.. 524 Irikawa H. 508 Irwin W. J. 444 Isaacs N. S. 166 183 336 Isaacs N. W. 105 Isagulyants G. V. 279 Isenhour T. L. 14 Isham K. R. 556 Ishida K. 69 Ishigami T. 275 352 526 Ishihara S.,137 237 445 455 Ishii F. 552 Ishikawa M.,326 460 Ishikawa N. 218 Ishitobi H. 163 Itaka Y.,520 Itakura K. 544 Ito G.,453 454 Ito M. 581 Ito S. 421 588 Ito T. 282 Itoh. K. 247 Itoh T. 455 541 611 Iwadare I. 529 Iwamoto N. 287 Iwamura H.74 Iwasaki T. 272 Iyodo M. 588 Izatt R. M. 466 Jablonski J. M. 216 Jachimowict F. 77 Jack J. J. 72 Jackman L. M. 178 Jackson B. 428 Jackson D. 15 Jackson D. A. 557 Jackson D. T. jun. 297 Jackson R.A. 191 Jackson W. M. 327 Jacob J. A. 16 Jacobs E. H. 340 Jacobs H. J. C. 85 Jacobs I. 388 Jacobs T. L. 92 375 Jacobsen A. 549 Jacobson H. L.,I19 Jacot-Guillarmod A. 357 Jacquesy J.-C. 525 526 Jacquesy R. 526 Jaffe M. H. 170 Jagur-Grodzinski J. 466 Jain T. C. 514 Jakobsen H. J. 435 Jakubowskh E. 203 Jalaty E. R. 201 James B. G. 357 James B. R. 270 271 272 James K. J. 484 James V. J. 407 Janda M. 291 Janik B. 545 Jankowski W. C. 26 Janot M.-M. 525 Janson T.R. 519 Jantzen R. 407 Janzen A. F. 236 Jaouen G.,290 Jaques B. 219 576 Jardetzkyh O. 150 Jardine I. 272 Jarreau F.-X. 525 Jarvis A. C. 284 Jarvis B. B.,185 Jarvis J. A. J. 520 Jae J. 89 Jatkowski M. 21 3 Jauffred R. 202 Jaz J. 428 Jean Y.,63,406 Jefford C. W. 243 Jeffrey A. M. 460 Jeffrey G. A. 105 Jeffs P.W. 104 612 Jehangir M. 564 Jones M. 122 125 248 Jelliner T.,320 256,403,566 Jeminet G. 302 Jones M.,jun. 225 402 Jemison R. W. 137 330 Jones N. D. 446 575 Jones P. F. 346 Jemson R. W. 237 Jones P. R. 129 Jenkins J. A. 137 255 Jones R. A. Y. 440 565 Jones R. H. 567 Jennings K.R. 17 Jones R. R. 214 254 368 Jennings P.W. 280 Jones W. B. G. 207 Jensen B.92 Jones W. M. 225,230,250 Jeppesen P.G. N. 552 Jones W. N Y. 173 Jerina D. M. 260 427 Joos R. 138 334 460,568 Jornvall H. 149 Jerussi R.A. 283 Jost F. L. 445 Jesson J. P. 271 Joseph-Nathan P. 37 Jetz W. 286 Joshi G. C. 227 329 337 Jewell C. L. 116 168 595 Jira R. 268 376 Josty P. L. 288 Johanson R. G. 167 Joule J. A. 502 Johansson G. 68 Joy D. R. 381 Johns E. W. 559 Jubault M. 299 300 Johns N. 481 Judewicz N. 547 Johnson A. 285 Julia S. 137 235 236 346 Johnson A. L. 28,241 Julshamn K. 97,437 Johnson A. W. 138,457 Junggren U. 366 Johnson B. F. G. 36,288 Junk G. A. 12 Johnson C. A. F. 398 Jurale C. 549 Johnson C. E. 38 Jurion M.,353 450 Johnson C. R. 401 Jussiaume A. 116 Johnson D. H. 440 Just G.250 Johnson G. A. 7 Justice J. B. 14 Johnson L. F. 26 Jutz C. 126 442 591 Johnson M.D. 179,285 Johnson P. L. 407 Johnson P. Y. 388 Kabuto C. 171 586 Johnson R. 396 Kacian D. L.,560 Johnson R. C. 362 Kaehler H. 396 Johnson R. W. 320 Kaeppeli F. 157 Johnson T. 3 17 Kirkkainen J. 16 Johnson T. R. 373 Kaeseberg C. 379 Johnson W. C. 84 Kagamanov V. N. 543 Johnson W. O. 432 Kagan H. B. 289,407 Johnson W. S. 241 514 Kagan I..242 Johnston D. E. 417 Kagawa T. 282 Johnston M. D. 36 37 Kageyama H. 272 Johnstone R. A. W. 8 9 Kahane S. 552 17 Kai Y.,283 Jolly P. W. 280 283,420 Kainosho M. 37,462 581 Jolly W. L. 68 Kajiwara M. 486 Joly G. 526 Kajtar M. 87 89 Jommi G. 471 Kakehi A. 453,454 JonCzyk A. 359 Kakoi H.340 Jones A. S. 556 Kakudo M. 101,283 Jones D. N. 238 Kalechits I. V. 279 Jones D. W. 221 222 Kalicky P. 527 439 Kalli M. 335 Jones E. R.H. (Sir) 530 Kalman J. R. 571 Jones F. M. 396 Kalmus C. E. 262 326 Jones F. R. 279 Kamemoto K. 450 Jones G. H. 261 Kameoka I. 290 Jones L. D. 494 Kamerling J. P. 16 Author Index Kametani T. 218 325 49 1 Kamitnski B. 116 Kamiya Y.,520 Kammerer R. C. 375 Kanai H. 277 Kanamori H. 455 Kaneda M. 520 Kaneko C. 122 326,460 54 1 Kanematsu K. 433 453 454 Kannan R. 11 3 Kantlehner W. 391 Kanzani Y. 303 Kapadi A. H. 507 Kapecki J. A. 380 592 Kaplan L. 264 Kaplan M.L. 23 Kaplan R.,537 Kapoor S.K. 518 Kappler F. E. 385 Kappus G.13 Kaptein R.,19 20 25 27 30 Karabatsos G. J. 29 Karady S. 16,446 Karasek F. W. 14 Karch N. J. 194 Karesch F. W. 13 Karimov K. K. 271 Kariv E. 294 Kari W. 318 Karle I. L. 100 102 Karle J. 97 100 436 Kasafirek E. 299 Kasai N. 283 Kasai P. H. 190 191 Kasal A. 530 Kascheres A. 429 Kascheres C. 247 Kashman Y. 447 527 Kasmai H. S. 456 Kasperek G. J. 260 427 568 Kaspi U. 172 Kastin A. J. 16 Kastner S. M.,226 Kasturi T. R. 525 Katagiri T. 280 Kates J. 549 Kato H.,69 Kato M. 126 Kato T. 512 Katoh F. 478 Katritzky A. R.,116 218 434,440 Katsuma T. 453 Katz J. J. 33 185 405 486 519 Katz L. 341 Katz M. 307 Author Index 613 Katz T.J. 258 280 281 439 586 Katzenellenbogen J. A. 362 363 Kaubisch N. 260 568 Kauffmann T. 131 412 465 Kaupp G. 134 325 595 Kawagita R. 595 Kawai T. 282 Kawakami K. 207 Kawamura T. 191 Kawamura Y.,556 Kawasaki A. 11 1 Kawazoe Y.,539 Kawazura H. 289 Kaye R. L. 129 Kazazian H. H. 549 Kazlauskas R. 523 Kazmaier P. 397 Kealde H. R. 269 Kean N. B. 408 Keana J. F. W. 342 Kearns D. R. 127 133 327 Keates R. A. B. 471 Keating M. 213 576 Kebarle P. 396 Keda M. I. 401 Keefer L. 88 Keehn P. M. 581 Keese R. 408 Keii T. 281 Keim W. 281 Keller K. 442 578 Kelley D. E. 549 Kelly C. F. 184 Kelly D. P. 167 168 259 263 569 574 Kelly K. W. 246 Kelly W.J.,-278 Kelmers A. D. 534 Kelsey D. R. 36 172 383 Kelso E. 93 Kelso P. A. 319 320 Kemball C. 279 Kemmerich T. 268 Kemmitt R. D. W. 284 289 Kemp T. J. 209 Kempe U. M. 130 363 383 Kemppainen A. E. 319 320 Kende A. S. 262 Kennard C. H. L. 105 Kennard O. 516 Kennedy B. W. 584 Kennedy G. J. 534 Kenney F. T. 547 Kenney M. E. 35 Kent M. 368 Kenyon G. L. 150,447 Kenyon R. S. 273,329 Kepler J. A. 504 Keppel R. A. 132,227 Kerber R. C. 222 288 Kermse W. 134 Kershner L. D. 160 592 Kersting G. F. 90 Keske R.G. 199 Keung E. C. H. 393 Khalaf H. 186 Khaleeluddin K. 164 Khalil M. H. 395 Khan H. A. 114 115 57 1 Khan M. K. A. 545 Khan N. H.,354 Khan S.A. 176 Khan W. A. 195 Kkeifets G. M.,438 Khetrapal C. L. 37 Khidekel M. L. 279 Khorana H. G. 532 543 544,545 558 Khun W. F. 10 Khuong-Huu Q.,528 Khwaja T. A. 541 Kidwai A. R. 354 Kiebania A.J. jun. 277 Kieboom A. P. G. 116 Kiefer G. F. 384 Kiehle L. H. 210 Kielbania A. J. 258 419 Kienzle F. 359 570 Kieslich K. 530 Kigasawa K. 218 Kikuchi T. 493 508 Kilcast D. 71 72 74 76 80,403 Kilner M. 269 Kim C. J. 165 175 Kim C. U.,333 336 342 Kim J. J. 555 Kim S. H. 555 Kimble B. J. 522 Kimling H. 44 369 583 Kimura B. Y . 284 Kimura J. 539 Kimura K. 31 1,455 King J. F. 579 King R. B. 284 Kinsel E. 355 Kinsky K. 85. 86 Kinugasa M.,429 Kipping F.B. 383 Kirby A. J. 176 385 Kirby G. W. 481 Kirk D. N. 85 86 89 399 Kirkpatrick D. 336 Kirmse W. 247 Kirson I. 529 Kis Z. 524 Kise H. 238 Kishi Y. 340 Kishida Y. 336 Kisilevsky R. 533 Kitagawa I. 51 1 514 Kitahara Y.,128 171,512 586 Kitamura T. 281 Kitchin J. 238 Kitching W. 418 Kitos P.A. 549 Klabunde K. J. 179 Klaentschi N. 270 Klaeren A. 93 Klar R. 573 Klarner F. G. 135 256 Klasek A. 88 Klasson M. 72 Kleier D. A. 125 Klein H. 86 Klein J. 173 339 Klein M. P. 30 Kleinberg J. 286 Kleinkauf H. 159 Klemm A. 532 Klemm L. H. 432 Kleppe R. 545 Kling T. A. 248 Klingsberg E. 458 Klinman J. P. 153 Kloosterziel H. 126 390 Klosowski J.M. 447 Klotz 1. M. 148 Klug A. 555 Kluge A. F. 362 Klumpp. G. W. 135 Klyne W. 84 85 86 Knaus E. E. 449 Knight A. R. 203 Knight J. 281 Knodgen B. 15 Knoppel H. 10 Knoth W. H. 271 Knowles J. R. 226 Knowles P.,150 Knowles W. S. 289 354 Knox J. H. 534 Knox S. A. R. 278 Kobari T. 491 Kobayashi R. 131 393 Kobayashi S. 112 Kobayashi Y. 449,453 Kober H. 417 Koblicova Z. 87 501 Kobrich G. 240 409 Kobuke Y. 129,422 Kochetkov N. K.,16 88 Kochi J. K. 191 195 Kodicek E. 272 Kobrich G. 226 Koenig T. 391 Konig W. A. 542 Kogwe T. 352 509 Kohler N. 290 Kohn H. 112,433 Kohn M. C. 44,64,401 Kohnstam G. 160 Kohoda H. 137,229 Kojo S.,212 Kokke W.C. M. C.,405 Kokubun H. 205 Kolc J. 214 Kolomnikov I. S.,275 Kolsayashi K. 279 Kolshorn H. 249 Kol’tsov A. I. 438 Komiya S. 271 Komornicki A. 44 Konakahara T. 455 Kondo K. 137 228 236 237 361 513 Kondo S.,137 229 Konig W. A. 16 Koninszy F. R. 16 Konishi S.,205 Konizumi M. 205 Konoshima T. 492 Konvicka. J.. 557 Konz W. E. 523 Kooistra D.-A. 340 Koos E. W. 425 Kooyman E. C. 134 386 Koppelmann E. 131 Kopyttsev Yu. A. 272 Koreeda M. 399 Korinek K. 308 Kormer V. A. 279 Kornberg A. 559 Kornberg T. 559 Kornblum N. 180 Korshak V. V. 192 Korte E. H.,84 Korth T. 503 Koshland D. E. 146 408 Koshmina N.V. 367 Kosman D. J. 143,208 Koso Y.,289 Kotani E.363 Kotick M. P. 545 Koudo Y.,323 Kouwenhoven C. G. 266 373,459 Kovacic P. 248 KovBcs K.,527 Kowerski R.C.,477 Kowert B. A. 205 Kowollik G. 540 Koyama T. 474 Koyama Y.,478 Kozarich J. W.,226,329 Kozlov I. A. 543 Krajca K. E. 230,250 Kramer B. D. 317 Kramer J. 215. 593 Krane J. 46 I Krantz A. 129,411 583 Kranz E. 444 Kraska A. R. 250 572 Krauss R. C. 257 Krebs A. 369 41 I 583 Krebs E. P. 408 Kreiser T. H. 545 Kreishman G. P. 535 Krentsel B. A. 281 Kresge A. J. 116 Kretchmer P. A. 338 Kreutzer P. 268 Kricheldorf H. R. 358 Kricka L. J. 431 Krishnamurthy M. 272 Krishnamurthy S. 338 423 Krishnamurthy T. 265 Krishtalik L. I. 303 KfiZ J. 389 Krohn K.495 Kroll W. R. 279 Kroposki L. M. 131 Kroszczynski W. 470 Krow G. R. 423 Krueger V. P. M. 542 Kruger C.. 280 283 Kruger T. L. 179 Krusic P. J. 195 211 404 Krygowski T. M. 116 Krystynak R. H. 38 Kubota T. 429 522 Kuc T. A. 274 281 Kucherov V. F. 510 Kuczkowski R. L. 430 Kudynowski J. 559 Kuehne M. E. 580 Kuempel P. L. 560 Kusters W. 365 Kufe D. 560 Kugel W. 391 Kuhlman K. F. 31 32 Kuhn H.J. 136 319,451 Kujama R.,529 Kukes S. G.,197 Kukhar V. P. 340 Kukolev V. P. 275 Kukolja S. 445. 446 Kulezycki A. jun. 225 Kulicki Z. 270 Kumada M. 269 363 Kumadaki I. 449 Kumagai Y.,283 Kumai S. 242 Kundsen T. P. 135 Kunesch N.,502 Kunstmann M.P.397 Kuntzel B.,552 KUO,Y.-N., 180,388 Author Index Kupchan S. M. 102 520 521 Kurabayashi K. 322 Kurbanov M. 510 Kuriyama K. 87 Kuroki Y. 348 Kurowsky S. R. 322 Kurtz D. W. 317 Kurz J. L. 427 444 Kushida K. 74 Kusuda K. 586 Kuthan J. 449 Kuwajima I. 358 Kuwano H.,137,445 Kuznetsov M. A. 219,250 Kvitko I. Y. 113 Kwan S.,549 Kwant. P. W. 423 Kwant R. W. 567 Kwart H. 116 134 135 252 386 392 Kyba E. P. 219 251 398 Laarhoven W. H. 325,592 Labinger J. A. 275 Labrot G. 391 Lacadie J. A. 401 Ladner J. E. 555 Lagodzinskaya G. V. 382 Lai K. H. 260 261 Lai M. M. C. 549 Laing D. G. 468 Laing M. 488 Laird T. 137 237 254 330 575 Lakings D. B. 534 Laland S.G.157 158 Lam L. K.M. 162 La-Mar G. N. 27 Lambert J. B. 175 457 440 Lambert J. L. 28 241 Lambert R. L.,jun. 227 Lambeth P. F. 324 Lamfrom H. 555 Lamm B. 366 Lammert S. R. 445 LaMontagne M.P. 344 Lancaster J. E.,426 568 Lancaster P. W. 176 385 Lancelot C. J. 162 Landesburg J. M.,341 Landgreke J. A. 286 Landis. R.T.,210 Landor P. D. 335 Landor S. R.,335 Lane C. D. 549 Lang S. A. 250,567 Langdon M.J. 397 Langen. P.,540 Author Index Langerman N. R. 148 Lee E.,480 Langlet J. 61 Lee E. K.C. 128 Langlois Y.,500 Lee G. C. Y. 439 535 Langone J. J. 171 Lee G. K.,497 Lanir A. 151 Lee H.L. 501 Lansbury P. T. 204 360 Lw K.-W.. 127 415,509 523 Lee L. 132 Lantos I.438 Lee S. Y.,549 550 Laonigro G. 517 Leete E.,488 Lapinski C. A. 117 LeFevre P.H. 176 Lapis S. 219 Lemer J. E. 194 Lapointe C. 161 Lefour J.-M. 394 Lapouyade P. 427 Leftin J. H. 278 Lappert M. F. 226 268 LeGoff E. 590 269,280 346,418 Lehman P.G. 264,440 Larcon L. L. 69 Lehn J. M. 51 465,466 Lark K. G. 560 Lehr R. E. 122 Larkin J. P. 196 206 Leibfritz D. 74 La Rose R. 242,409 Leichter L. M.,258 411 Larsen B. R.,477 583 Larsen D. L. 592 Leidhegener A. 228 Larsen E. R. 160 Leigh G. J. 279 Larsen J. W.,160 170 Leigh J. S.. 36 175,571 Leitereg T. J. 523 Larsen P. O. 480 Leonard I. E.,385 Latham D. W.S. 443 Leonard N.J. 534 535 Lathan W.A. 43,59 393 Leonard R. 524 La Torre J. 549 Leow H.M.,493 Lattes A.378 379 Leliveld C. G. 459 Latyaeva U.N.,268 Lemal D. M.,124,567 Lau R.,361 Lemieux R. U.,28 Lauer R. F.,377 LeNoble W.,165 Laurent A. 31 1 Lenoir D. 409 Laurent E. 31 1 Lenox R. S. 363 Laval J. P.,378 379 Lenz G. R.,528 Lavie D.,521 529 Lenz H.,152 Laviron E.,300 Le Patourel G. N.J. 468 Law P.Y.,142 Lepcska B. 128 186 Lawler R. G. 19 20 21 Lepley A. R.,21,24 Le Quesne P. W.,498 500 Lawlor J. M.,178 Lerch U.,236 Lawrence A. H.,427 -he J. P. 510 Lawson A. J. 111,209 Leshcheva A. I. 281 Lawson D. F.,200 Letsinger R. L. 545 Lawson G. 11 Leung F. 436 Layton R. B.. 357,370 Leung T.H.,210 Lazduncki M.,148 Le Van K.,564 Lazdunski C. 148 Levandos 0.S. 378 Lazutkima A. I. 280 Levek I. J. 384 La A.R.,232 Levene R. 173,339 Leander K.,508 hi A. 289 338 Leanza W. J. 446 Levin C. C. 86 Leaver D.,217 Levin G. 179,205 595 Lechtken P.,127 573 Levine B. A. 36 Leclerc G.,527 Levine S. G. 504 Leder P. 549 Levitzki A. 146 Lederbcrg f. 14 Levy A. B. 340,358 Ledger M.B. 324 Levy B. 41.56 Ledlit D.B. 242 Levy,G. C. 26 31,32 34 Lee C. 409 391 Lee C. V. 172 Levy M.N. 268 Lee,D.G. 342 Lewbart M.L. 527 615 Lewin A. H.,357 Lewis F. D. 319 320 Lewis G. J. 285 Lewis J. 36 288 Ley A. N. 553 Ley K. 443 Leznoff C. C. 325 Lhomme J. 164 Li K.L. 533 Liang G. 167 168,245 Liang J. H.,47 Liberles A. 44 Libert M.,311 Libman J. 325 595 Lichtenfeld A. 126,464 Lichtenthaler F.W.,389 Lichtenthaler R.G. 465 Lichter R. L. 34 Lieberman I. 146 Lien E. L. 142 Lightner D.A. 86 564 Ligon R. C. 517 Ligon W.V. jun. 224 Lijinsky W.,88 Likhosherstov A. M.,88 Liler M. 390 Lim P. K.K. 223 Limn W.,342 Lin C. Y.,41 1 583 Lin D. 541 Lin H.C. 167 260 Lin K.-T. 185 Lin S. 532 Linda P.,434 Linde H.,580 Lindgren J. E. 15 Ling D.,236 Ling V. 558 Lingrd J. B. 549 Linke K.-H. 93 Linke S. 220 Linnarsson A. 15 Liotta C. L. 118 Lipmann F. 157 159 Lipowitz J. 116 Lippmaa E.,23 Lipsky S. R.,36 Lisanti J. A. 559 Lisichkin G. V.,270 Liskow D. H.,59,64,401 Litt M.,557 Little R. D. 322 Littlecott G. W.,289 Littlejohn D.,12 Litvin E. F. 271,272 Liu C.-S.,522 Liu J.-C.,331 Liu K.-T.127 Liti S. Y.,527 Ljungdahl L. G. 144 Llaguno E.C. 97,437 Llewellyn P. 12 616 Author Index Lloyd D. 563 584 Lwowski W. 220 McKinney C. 13 Lloyd D. J. 181 182 Lyerla J. R. 32 McKornick M. J. 179 Lloyd R. V. 21 1 Lynen F. 142 McLafferty F. W. 17 Lloyd-Jones J. G. 477,526 Lythgoe B. 346 McLaughlin A. C. 150 Lo D. H. 55 57 MacLean C. 39 Lochmuller C. H. 21 MacLean D. B. 492 Lockard R. E. 549 Mabey W. R. 391 McLean S. 127 252 Lodish H. F. 549 McAllister T. 8 McLennon D. J. 183 Loeschen R. L. 325 595 McArdle P. 36 288 McLeod D. jun. 190 191 LiSsel W. 479 McBee E. T. 584 McMaster B. N. 9 Loewen P. C. 544 558 McBride J. M. 194 MacMillan J. 516 517 Logue. M. W. 341 McCarty C. T. 216 5 24 Logun A.A. 161 362 Macauley S. 523 McMillan R. S. 271 576 McCay I. W. 130 McMorris T. C. 529 Lohrmann R. 533 McCloskey J. A. 11 542 McNeel M. I. 37 Lohse C. 326 437 McCloskey J. E. 5 14 McOmie J. F. W. 117 Lok C. M. 571 McConnell H. M. 151 432 579 Lombardo L. 594 McConnell J. F. 407 McPhail A. T. 104 268 Londrigan M. E. 123 McCrae W. 527 McPherson A. 555 Long C. W. 146 McCullough J. D. 98 MacPherson C. A. 335 tong F. A. 119 179 McCullough J. J. 592 McQuarrie R. A. 179 Long M. A. 274,329,569 McDaniel D. M. 424 McQuillin F. J. 270 272 Long S.A. 423 McDonald E. 470 481 McShane T. 547 Long-Su Lin 224 483,484 Madden D. P. 289 Longworth S. W. 432 McDonald G. N. 33 405 Maddox M. L. 527 Loo S.N. 536 McDonald J. J. 542 Madison J. T. 552 Looker J.J. 596 Macdonald J. N. 398 Maeda T. 263 Loomis G. L. 515 McDonald R. A. 185 Mansson M. 400 Loomis W. D. 469 McDonald R. N. 587 Markl G. 372 434 435 Looney R. L. 142 McDowell B. L. 594 Marky M. 428 Lopez L. 343 McDowell C. A. 68 Magarity E. D. 315 Lorne R. 346 McElroy R. 37 Magnus P. D. 171 321 Louw R.C. 134 386 387 McFarland J. T. 149 353,527 Lovelock J. E. 13 McFarland P. E. 362 Mahler J. 297 Loven R. 259 McGahren W. J. 397 Mahler W. 195 Lovins R.E. 13 McGhie J. F. 475 Mahoney L. R. 197 Lowe G. 446 McGinnis J. 586 Maichuk D. T. 543 Lown E. M. 203 McGirk R H.,457 590 Maier C. A. 281 Lown J. W. 354,428,433 Machittkova O. 113 Maier G. 243 31 1 41 1 Lu S. H. 486 Machida Y. 472 Maithis P. M. 284 Lubinkowski J. 183 Maciel G. E. 27,29,30 35 Maitlis P.M.367 Luche M. J. 88 Mcllhenny H. M. 506 Majer J. R. 15 Luchter K. M. 397 McInnes A. G. 478 Majerski Z. 246,247 249 Lucken E. A. C. 209 McIntosh C. L. 451 Majumdar K. C. 369,442 Luckhurst G. R. 210 McIsaac J. E. 174 Majumdar S. P. 498 Luczak M. A. 143 McIver J. W. jun. 44 60 Makino S. 393 413 Lugtenburg J. 124 127 Makosza M. 359 Luhan P. A. 104 Mack H.,592 Malakhov V. V. 280 Lui J.-C. 430 464 Mack W. 441 Malament D. S. 225 Luisi P. L. 149 Mackay M. F. 95 455 Mallaby R. 152 154 155 Lukacs G. 525 McKellar J. F. 324 Mallion R. B. 38 Lukehardt C. M. 268 McKenna J. C. 175 Mallory T.P. 595 Lulav I. 537 McKenna W. G. 560 Malpass J. R.,429 Lumb J. T. 258,277 419 McKennis J. S. 41 1 584 Malrieu J. P. 61 Lunazzi L. 203 McKeough D. 432 Mamantov A.397 Lundgren J. O. 100 McKervey M. A. 409,417 Mandel M. 557 Lundin P. 100 Mackie R.K. 36 Mandella W. L. 563 Lunin V. V. 270 McKillop A. 335 423 Manger E. 186 Lustgarten R. K. 164,169 570 Mangini A, 203 Luthy J. 151 153 McKillop T. F. W. 512 Mango F. D. 279 378 Luttke W. 416,423 McKinley R.L. 15 Mangoni L. 517 Luzutkin A. M.. 280 McKinley S.V. 169 331 Manhas M. S.,446 Author Index 617 Maniscalco I. A. 455 Manisse N. 254 265 Manitto P. 496 Manmade A. 227 Mannassen J. 290 Manne R. 68 Manske R. H. F. 88 Maples P. K. 270 Marchand A. P. 122 Marchand-Brynaert J. 128 345,410 Marchese G. 183 Marchi P. 559 Marcoux L. 205 Marcus R. A. 118 Margaretha P.,251 Margolin Z. 172 410 566 Marhenke R.L. 361 Mariano P. S. 37 Maricich T. J. 238 Mar'in V. I. 279 Marino G. 117,438 Marino M. L. 516 Marinsky J. A. 115 Marioni F. 12 1 407 Markby J. L. 30 Markey S. P. 16 Marks P. A, 560 Markwell R. E. 518 Marmur J. 557 Marnett L. J. 21 Marples B. A. 526 528 Marquet A. 88 Marr D. H. 359 Marshal A. G. 36 Marshall D. R. 563 Marshall J. A. 376 415 512,513 Marshall J. C. 14 Marshall J. L. 29 Marshall L. G. 480 Marshall S. 549 550 Marsili A. 121 Martel B. 337 Martelli G. 448 Martens D. 123 412 Martin G. J. 39 Martin H.-D. 404 464 Martin J. C. 332 Martin M. L. 39 Martin N. H. 104 Martin R. A. 354 Martin R. B. 36 88 390 Martin R. H. 564 Martin S.F. 363,448 505 Martinego S. 286 Marty R. A. 586 Martz M. D. 451 Marumo S. 470 512 Maruya K.,281 Maruyama M. 102 Marx G. S. I16 Marx J. N. 510 Maryanoff B. E. 439 440 Maryott A. A. 33 Masamune S. 122 258 277 361 403 411 419 456 513 583 588 Mashio F.. 592 Maskasky J. E. 35 Maskornick M. J. 366 466 Mason R. 268 275 Mason S. F. 84 376 Mason T. J. 163 Maspero F. 270 Masser S. 118 Massey S. R. 481 Masters M. 560 Mateescu G. D. 78 80 167 169,259,404 569 Mateos J. L.,116 Mathew M. 284,415 Mathews D. A. 72 Math S. A. 232 249,426 Matson J. A. 575 Matsuda S. 279 Matsugashita S.,452 Matsui K. 361 513 Matsui M. 513 518 Matsumoto M. 270 Matsumoto N. 446 Matsuo T.446 Matthes D. 434 Mattocks A. R.,488 Matusak C. A. 593 Matyukhina L. G. 521 Mauger A. B. 16 Mauldin C. H. 338 Maurin R.,335 Maverick E. 92 Mawby R.J. 289 571 Maxwell J. R.,522 Mayall B. I. 126 Mayeda E. A. 3 10 3 13 Mayor C. 230 Mazur Y. 86 527 Meakin P. 191 271 Meakins G. D. 530 Means A. R. 549 Mebazaa M. H. 434 Mecca T. G. 160 242 Meck R. B. 385 Medete A. 355 Meeuwse J. 339 Mehta G. 357 518 Mehta P.J. 538 Meier H. 215 249 367 403 Meier H. P. 442 Meijer J. 254 Meindl H. 536 Meinwald J. 380 516 592 Meisels G. G. 9 Meisinger R.H. 239 Meister A. 145 146 Meister B. 377 420 Melli M. 549 Mellon F. A. 9 Meloche H.P. 143 Melquist J.L.,86 Melvin L.S. jun. 360 Menapace H. R.,279 Mendecki. J. 549 550 Mendicino F. D. 273 Mensel P.,569 Mente P. G. 426 Menzel P. 109 Menzelaar H. L.C. 10 Menzies I. D. 527 Meot-Ner M. 116 Merienne K. 285 Merigan J. C. 546 Merino M. A. 264 Merkel P. B. 127 133,327 Merkel W. 262,464 Merlini L.,497 Merten R. 377 Mestroni G. 270 Metafora S. 560 Metcalf A. R. 206 Metcalfe J. 128 Meth-Cohn O. 443 Metzger J. 202 376 Metzinger G. 10 Metzler M. 469 Metzner A. V. 175 Meyer A. 290 Meyer B.,266,460 Meyer D. 469 Meyer G. R. 176 258 277,419 Meyer J. W. 262 326 Meyers A. I. 347,348,356 449 Meyers C. Y.,241 Miana G. A. 492 Michejda C. J. 64 Michel U.,227 330 Michelot D.137 236 346 Michels R. 331 Michl J. 214 Midgley J. M. 529 Midland M. M. 340 358 Miginiac L. 235 Miginiac P. 362 Migita T.,137 228 229 Mihashi S. 512 Mii S. 550 Mijlhoff F. C. 407 Mijs W. J. 210 431 Miki Y.,452 Mikol G. J. 251 Mikolajczyk M. 89 Mikolajzak K. L. 493,495 Milborrow B. V. 470 618 Mildvan A. S.,150 Miles D.H.,353 518 Miles H.T.,543 Milje L.,96 Millar E. M. 118 119 Millar I. T.,462 Millard M. M. 82 Miller A. S.,429 Miller B. 260 261 Miller D.A.,559 Miller F.W.,173 Miller J. H.,532 Miller J. S.,270 Miller L. L. 306 310 313 Miller M. A.,395 407 Miller 0.J. 559 Miller S.I. 160,373 Millot F. 114 571 Milloy B. A. 432 Mills B.E.,72 Milne G.W. A, 14 Milner-White E.J. 152 Milowski K. 268 Minachev K.M. 279 Minale L.,521 529 Minami K.,338 Minamikawa J. 401,452 Minato I. 31 1 Minisci F. 448 Min Jon W.,532 550,552 Minns R.A. 381 Minot C.,394 Mirrington R.N.,339 Mishiguchi I. 242 Miskow M. H.,36,440 Mislow K.,435,436 563 Mistysyn J. 401 Misumi S.,581 595 Mitchard D.A.,436 595 Mitchard L. C.,281 Mitchell C.M. 285 Mitchell J. R.,213 Mitchell M. J. 490 Mitra S. K.,553 Mitsudo T.,286,287 Mitsuhashi H.,529 Mitsuhashi T.,230 250 Mitsui S.,272 Mitsui T.,101 Mitsunobu O.,341 363 539 Mitsuyasu T. 289 Mitteheijer M. C.,279 Miura I. 399 Mixan C.E.,440 Miyake A. 289 Miyamoto M. 446 Miyano S. 227 Miyawaki T.,446 Mizak S.A. 542 Mizogami S.,581 M[izuno H. 581 M[izuno Y.,342 541,556 MIlinaric K.,246 M[o F. 521 M[o Y.K.,167 168 175 245,259,260,263,569 MLock W.L.,409 M[odena G..289 338,426 M[odest E.F. 559 M[oe,N. S.,306 308 M[tiller F.,462 Mloerck R.E.,217 Mloesinger S.G.,510 M[offatt J. G.,236 Mloffitt W.,84 Mlogolesko P.D.,375 421 MIoinet G.,413 Mole T.,161,274,329,569 Mollier Y.,97,437 Mollov N.M. 491 M olloy G.R.,549 M.onastyrskaya G.,538 M ondelli R.,497 M ondon A.,495 Money T.,472 Moniot J. L.,88 490 492 Montagnier L.,549 Montforts P.-F. 484 M ontgomery F. C.,183 Montgomery P.D.,287 Monti S.A,. 248 M ontrasi G.,286 Moodie. R.B. 109 110 Mooney J. R.,35 Moore B.P.,520 Moore F.H.,407 Moore H.W.,374 420 580 Moore J. A. 463 Moore R.E.,401 Moore W.H.,128 M[oore W.R. 122 375 376,421 Mootz D.,103 More 1. R.,559 Moreau J. J. E.,273 Morel J. 114 Morelli,I. 121,407 Moreno-Manas M. 264 More O'Ferrall R.A. 116 Morgan A. R.,535 M organ D. D. 591 M organ T.D.B.,574 Mori E.,207 Mori K.,513 518 Moriarty R. M. 376 Moriconi E.J. 250,455 Morikawa M. 287 Morimoto A.,304 Morimoto N.,581 Morioka M. 590 Morioka S. 544 Author Index Morisaki M. 477 Morishima I. 207 Morita N.,128 586 Morita T.,591 Moritani I. 182 225 Morkved E.H.,194 Morley C.G.D. 144 Morokuma K.,64 Moron J. 483 Moro-oka Y.,281 Morris D E.,286 Morris D.G.,91 Morris H.R.,16 Morris J.I. 25 Moqrisett J. D..151 Morrison H.,322 Morrison J. 90 Momson J. D.,9 Morrison R.C.,25 Morselli P.L. 15 Morton J. R. 196 Mosbo J. A. 439 Moscowitz A. 84 Mose W. P.,85,86,89,399 Moser C.,63,406 Mosher H.S. 160 Moshuk G.,212,410 Moss G.P. 36 512 Moss,R.A. 226,228 397 Motroni G.,279 Motta L.,279 Moulijn J. A. 279 Mouzin G.,272 Mowery P.C.,177 Mozza M.,495 Muchmore D.C.. 339 Miillen K.,588 Miiller B.,583 Mueller D.C.,227 Mtiller E.,249,283 Mtiller G.,486 Milller J. 268 MUller K.,382 Milller M. 16 Mueller R. H. 253 355 362 Muller W. E. 530 Miiller-Hill B.,532 Milller-Westerhoff U.,587 Mugnoli A. 95 Muir D.M.,182 Mukai M.,276 Mukai T.,322 Mukaiyama T.,352 Mulder J.J. C. 61 120 Mulhausen €4. A.,174 Mulheirn L.J. 474 Mullen K. 204 Mullen P. W. 350 368 574 Muller J.-C. 358,515 Muller K.,20 23 Author Index 619 Muller R. K. 138 334 Muller W. 33 1 Mulligan P.J. 240 Mulvaney J. E. 123 Munavu R. 348 Munninger K. O. 552 Muquet M. 502 Murahashi S.4 225 Murai S. 131 348 393 Murao K.,552 Murase I. 357 Murata I. 590 595 Murayama K. 207 Murdoch J. R. 11 8 Murjahn K. 465 Murphy R. C. 16 Murray R. W. 298 Murray S. J. 264,463 Mush R.,279 Muscio F. 477 Muscio 0.J. 92,243,511 Musgrave W. K. R. 71,72 76,80 Mushina E. A. 281 Musker W. K. 35 Musser J. H. 514 Muthukrishnan R.,1 13 Muto A. 547 Mutterties E.L.,138 Muzychenko L. A.295 Myers H.K. 282 Myhre P.C. f 10,260 570 Nachtigall G. W.,163 Nagabhusan T. L.,28 Nagai S. 190 Nagai Y..273,352 Nagamachi T.,537 Nagaoka K. 563 Nagata C. 69 Nagebhwhan T. L.,16 Nagel D. W. 478 Nagpal K. L.,544 Naguse. H.,508 Nagy F. 308 Nagy J. B. 538 Nagy 0. B.. 538 Nagyvary J. 544 Nahlovska Z. 256 Nahlovsky B. D-, 256 Naik S. R. 536 537 Nair R. M.G. 16 Nair V.,25 1. 429 43 1 Naito S.,400 Nakadaira Y.,526 Nakagawa I. 544 Nakagawa K.,338 Nakagawa M. 588,589 Nakahara Y.,518 Nakai H. 462 Nakai T. 258 277 419 Nakaido S.,137 228 229 Nakamura A. 283 Nakamura G. R. 15 Nakamura H. 508 Nakamura N. 413 564 Nakanishi K. 87 88 135 399 526 557 Nakaniva M. 290 Nakans T. 519 Nakao R.340 Nakashima T. T. 30 Nakasone S.,477 Nakata T. 519 Nakatani Y.,524 Nakatsuji S.,588 Nakatsuyi H. 69 Nakayama E. 137 237 445 Nakayama K. 137,229 Nakazaki M.,581 Nakazato H. 549 Nakazawa K. 552 Nakazawa T. 595 Namiki M. 552 Napieralski J. 567 Napierski J. 124 423 Narang S. A. 544 Narango J. 498 Narasaka. K. 352 Narita S.,421 462 588 Nash W. D. 415 513 Nasini G. 497 Naso F. 183 Natusch D. F.S.,31 Navia M.A. 556 Navon G.,151 Nazarenko N.,348 Nazarova N.M. 272 Neff S. E.,516 Negishi A. 361 513 Negishi E. 185 350 Neidle S. 102 488 512 520 Neilson T. 545 Neisters A. 161 Nelke J. M. 354 503 Nelson A. J. 216 Nelson G. L.,26 32 391 Nelson J. L. 50 Nelson N. J.269 Nelson R. G. 84 Nelson S. F. 380 440 592 Nelson S. J. 494 Nelson S. M. 281 Ntmec M. 291 Nemoto H.,491 Nerdel F.,396 Netherton L.T. 160 Neu R. L.,559 Neubort S. 557 Neumaier. H.,396 516 Neumann P.,465,481 Neunhoffer H. 452 Newbold J. E. 549 Newburger M. R.,531 Newman M. S. 259 334 340 Newton M. D. 51,64,406 Newton M. G. 439,507 Ng F. T. T. 272 Nibbering N. M. 563 Nichols R. W. 117 Nickon A. 28 133 241 244 Nicolaides D. N. 432 Niederer P.,24 Niedererberger W. 38 Nieh M. T. 332 377 Nielsen S.D. 377 Nielsen S. F. 210 Nielson G. W. 208 Niemayer H. N. 179 Niemeyer H. M. 569 Nihonyahagi M. 273 Niizuma S.,205 Nikaido T. 517 Nikishin G. I. 348 Nikitina T. V.,268 Nikolaidis D.525 Nilsson R.,127 Ninomiya K.,358 Ninomya T. 289 Nir S.,69 Nir Z. 279 Nisato D. 88 Nishi N. 269 Nishida S. 226 Nishigaki S.,444 Nishiguchi I. 13 1 Nishiguchi K. 581 Nishiguchi T. 275 Nishimura S. 552 Nishino M. 225 Nishio T. 441 Nishiwaki T. 219 429 Nishiyama K. 582 Nissen A. 592 Nitta I. 190 Niwa H. 508 Nixon J. F. 276 Niznik G. E. 359 Noce P.,155 Noda H. 441 Noggle,J. H. 38 Noguchi T. T. 15 Nolley J. P.,289 Nomoto T. 588 589 Nomura A..556 Nomura M. 547 Nordblau G. D. 3 13 NordCn B. 84 Nordling C. 66 68 72 Noreen A. L. 163 620 Norman R. 0. C. 196 Ogunkoya L. 571 200,206,2 12 Ogura K.,344,474 Normant J. F. 240 344 Oguri T. 354 359 361 362,569 Oh S.K. 5 16 Norris R. K. 206 O’Hare M. J. 452 North A. C. T. 542 550 Ohasa S.,550 North P. P. 92 Ohashi Z. 552 Northington D. J. 135 Ohishi J. 478 253 Ohki M. 5 13 Norton D. A. 103 Ohmori T. 289 Norton J. R. 36 Ohnishi S. 190 Nour T. A. 393 Ohnishi Y. 126 592 Novak F. 315 Ohno K. 289 Novikov V. T. 295 Ohno M. 136 Nowoswiat E. F. 543 Ohrt D. 272 Noyce D. S. 117 Ohrt J. 407 Noyer E. 525 Ohtaka H. 477 Noyori R. 126 131 275 Ohtani H. 421 588 283 352 393,413 526 Ohtsuka E. 544 Nozaki H.,344,462,581 Oikawa Y. 541 Nozoe S. 470,472 Oishi T. 450 Niissbaum A. L. 543 544 Ojima I. 137 228 236 Niisslein C. 558 237 273 352 509 Niisslein V.,560 Okada K. 486 Numata T. 238 Okada T. 304 Nunn E. E. 425 Okajima T. 287 Nyberg K. 304 306 310 Okamoto S.,581 Nyburg S.C.436 Okamoto T. 443 Nye M. J. 438 Okamoto Y. 160 Nyholm R. S. 275 Okana M. 186 Okazaki R.,560 Okhlobystin 0.Y. 24 Oki M. 564 Oae S. 228 238 263 Okorie D. A. 241 514 40 1 Oku A. 592 O’Brien J. 339 Oku M. 241 365 Occhiucci G. 109 Okubayashi M. 471 Occolowitz J. L. 8 Okura I. 281 Ochiai E. 271 Olah G. A. 46 65 78 80 Ochiai M. 304 107 108 112 116 166 Ochiai S. 433 167 168 169 175 241 O’Connell E. L.,154 155 245 259 260 263 404 O’Conner T. 284 574 569 570 Oda M. 171,410 582 Oldenziel 0. H. 441 Oda O. 413,509 O’Leary B. 44 Odaira Y. 262 3 1 1 Olive S. 282 Odom H. C. 271 Oliver J. E. 97 436 O’Donnell G. M. 442 Olivera B. M. 560 Oediger H. 462 Ollis W. D. 137 237 254 Oehlschlager A. C. 5 18 330 390 575 Oele P.C. 134 387 Olofson R. A. 112 433 Oertel W. 558 Olsen C. 341 Ofstead E. A. 279 O’Malley B. W. 549 Oftedal P. 96 Omata T. 401 Ogata I. 286 Omelknczuk J. 89 Ogata Y. 11 1 195 248 Ona H. 41 1 583 Ogawa H. 461 Onderdelinden A. L. 270 Ogawa K. 552 Onderka D. K. 155 156 Ogawa O. 400 480 Ogilvie K. K. 541 O’Neal H. E. 430 Ogilvy M. M. 219 O’Neill P. P. 279 378 ogiso Y. 541 Ono I. 326 Author Index Oosterhoff L. J. 61 120 121,405 Opheim K. 516 Oppolzer W. 132 442 453,578 Orchin M. 286 591 Orgel L. E. 533 Oritani T. 512 Osaka N. 586 Osborn J. A. 271 275 Ota S. 289 Otani S. 157 Oth J. F. M. 204,292,456 589 Otocka E. P. 30 Otsubo T. 581 595 Otsuka S.,278 283 Otto B. 560 Otto E. 86 Ourisson G.358,s 15,52 1 522 524 525 Overath F. 142 Overberger C. G. 464 Overman L. E. 338 Overton K. H. 134 5 12 Owen G. 436 595 Owens P. H. 179 Owers R. J. 592 Oxenius R. 464 Ozaki A. 281 Ozaki S.,250 Ozeki H. 555 Pace N. R. 547 Pachler K. G. R. 28 36 Packard B. S.,246 Paddock G. 552 Paddon-Row M. N. 130 231,232,421 572 Padegimas S. J. 248 Padmanabhan R. 532,558 Padwa A. 132,264,428 Paetkau V. 535 Page S. M. 547 Page S. W. 507 Pais M. 525 Pal B. C. 556 Palenik G. J. 284 41 5 Paller R.C. 285 Pallister E. T. 104 Palmer D. A. 181 Palmer L. 15 Pancrazi A. 528 Pande L. M. 227 337 595 Pankova M. 184,466 Panov P. P. 491 Pantarotto C. 15 Panunzio M. 441 Author Index 621 Panzica R.P. 538 Paolillo L. 30 Paolucci G. 359 Paponchado L. 309 Paquette L. A. 125 239 247 250 256 257 258 265 277 278 292 419 423,456 567 Para M. 89 Pardee A. B. 146 Pardhasaradhi M. 271 Parham W. E. 247 Parish E. J. 353 518 Park C. H. 417 Park M. 535 Park Y. J. 105 Park Y. N. 433 Parker A. J. 181 182 184 Parker D. J. 144 Parker V. D. 202 253 264 303 305 306 308 31 1,437 574 Parker W. 512 Parkins A. W. 287 Parkinson B. 423 Parry D. R. 479 Parry R. J. 241 469 514 Partch R. 251 Partch R.E. 571 Parthasarathy. R. 407 Parton S. K. 218 Paschal P. W. 446 Pascucci V. L. 426 Passannanti S.,516 Pasternak V. I. 340 Pasto D. J. 128 186 Pastour P. 115 Patchornik A. 544 Patel D.J. 39 Patt S. L. 34 Pattabhiraman T. 103 Pattenden G. 357 Patterson J. M. 264 Pattnaik N. 5 18 Paudler W. W. 433 Paul B. 28 Paul I. C. 97 98 99 181 437,588 Paul J. 559 560 Paulik F. E. 286 Pauling H. 377 420 Paulissen R.,228 330 Paulmier C. 115 Paust J. 122 Pavez H. J. 117 Pavlick J. W. 264 Pawliczek J. B. 136 256 Peacock R. D. 84 Pearce B. W. 227 Pearson J. E. 154 Pearson R. G. 120 173 Pechet M. M. 337 353 526,536 571 Pecoraro J. 410 582 Pedersen C. J. 366 465 Pedersen C.L. 326,460 Pedersen C. T. 202 303 437 Peduli G. F. 203 Peek M. E. 213 458 576 Pegolotti J. A. 259 Pehk T. 23 Pelc B. 272 Pellegrini F. C. 433 460 Pelletier S.W. 507 Pelster D. 15 Peltier D.299 300 Pemberton R. E. 549 Pendygraft G. W. 179 Pennella F. 271 Penrose A. B. 512 Perevalova E. G. 268 Perez G. 108 Perie J. J. 378 379 Perkins M. J. 179 197 207,235,261 Perkins W. C. 410 Perrin C. L. 570 Perrotti E. 270 Perroud-Argiielles M.,447 Perry R. 15 Perry R. A. 391 Perry R. P. 549 Perry W. O. 563 Peruzzoti G. 362 Perveev F. Ya. 367 Pesce M. A. 460 Petcher T. J. 524 Pete W. 269 Peters J. W. 127 366 Peterson D. J. 330 347 410 Peterson E. R. 127 Peterson M. R. 35 Peterson. P. E. 175. 241 Peterson W. R. jun. 358 444 Petit M. A. 36 Petit R. 378 Petitclerc K. 148 Petrie G. 309 Pettersen R. C. 516 Pettiford L. R. 11 1 Pettit L. D. 367 376 Pettit R. 41 1 584 Pettus J.A. 401 Pevzner M. S.,113 Peyerimhofl S. D. 63 64 120 Pfahl M. 532 Pfeffer P. E. 355 357 Pfeifer W. D. 241 Pfister T. 585 Pflster-Guillonzo G. 437 Pfoertner K.,428 Pfuller H. 415 Philips B. A. 549 Philips J. C. 241 365 Philips S. 15 Phillips G. T. 154 Phillips J. N. 441 Phillips L. 117 Phillips R. P. 278 Piechucki C. 359 Pierre J.-L. 227 Pieterse M. J. 102 Pietra F. 37 113 Pietra S. 460 Pietropaulo R. 285 Piette L. H. 143 Pignataro S. 8 Pike D. 503 Pinar M. 498 Pincelli U. 41 Pincock J. A. 317 Pinder A. R. 271 Pine S.H. 19 Pinel R. 97 437 Pines A. 30 Pines S. H. 16,446 Pinhey J. T. 523 525 57 1 Pinkerton T. C. 552 Pinnick H. W. 180 Pino P. 286 Pinschmidt R.K.251,256 Pinson J. 450 Piozzi F. 5 16 Pirkle W. H. 37 Pitcher R. G. 478 Pitts J. N. jun. 127 366 Pizey J. S. 333 Placucci G 203 Platt T. 532 Plattner J. 505 Pletcher D. 306 307 308 Pletcher J. 101 Plevey R.G. 570 Plinke G. 456 Ploger W. 452 Plummer B. F. 318 Poe M. 142 Poisson J. 498 502 Pokorny S.,281 Polanyi M. 184 Poletayeva I. A. 279 Poljakova L. A. 24 Polonsky J. 474 Pommelet J. C. 254 265 Pommerenk U. 526 Ponpipom M. M. 536 Ponsinet G. 524 Poole A. J. 437 Poon R. 558 622 Poonian M.S.,543 Popjak G.,151 Popkie H.,40 67 Popkov K. K. 273 Pople J. A.,42 43 46 47 55 56 57 59 66 109 170,24 1,401,406,407 Popp G.,115,312 Porta O.,448 Porter A.,552 Porter G.,324 Porter N.A.,21 123 Porter R.D.,65 116 167 168,259 569 Porter S. K. 423 567 Posner G.H.,329 361 362,5 15 PospiSil J. 577 Postle M.J. I15 Postma H.J. 93 Potier P. 498 500 Potter D.E.,131 Potter S.E.,581 Potts K.T.,371 432 Poulter C. D.,38,243,510 51 I Poust J. 161 Poutsma M.L.,192 Povall T.J. 17 Powell J. 284 285 Powell R. G.,493,494,495 Powers H.O.,559 Powers T.W.,564 Prangova L.S. 113 Pregaglia G.F.,270 286 Pregosin P. S.,34 Prelog V.,565 Premuzic E.,509 Prescott D.M.,560 Prestegard J. H.,439,535 Preston N.W.,493 Preston W.E.,72 76 Price H.C.,87 Price P. 362 Priestley G. M.,431 Prinzbach H.,264 265 416,426 568 585 587 Pritchard G.O.,209 Prokof’ev A. P. 197 Prokofiev M.A.,543 Protiva J.530 Pruess D.L.,478 Pruss G.M.,184,466 Pryor W.A.,190,194 Pucci D.G.,464 Pucci P. 547 Pucci S.,286 Puddephatt R. J. 285 Pudjaatmaka A. H.,179 Puglisi V.J. 293 Pullman A.,45 Pwtley H.J. 68 Queen A. 160 Quigley G.J. 555 Quina F.H.,324 Quirk J. L.,285 Raab C. 554 Raab R. 428 Raber D. J. 162 166 Rabinowitz J. 125 Rabinowitz M.,587 Radlick P. 125 133 327 515 Radmer R. 483 Radom L. 42 43 46 47 57 170 241 401 406 407 Radunz H. 503 Ragle J. L.,210 Rahal S.,353 Rahimtula A. D.,157 Raich I. L.,165 Raj Bhandary U. L. 552 557 Rajeswari K. 245 Rakshys J. W.,jun. 169 33 1 Ramachandra R. 525 Ramage R. 468,481 Ramel A. 543 Ramm P. J. 474 Rance M.J.454 Randall E.W.,34 36 Randall G.L. P. 288 Randall P.J. 477 Rando R. R. 402 Ranganayakulu K. 170 245 Ranzi B. M.,470 Rao G.S.,506 Rao S.T.,96 Rapi G.,438 Rapoport H.,339 481 483,505,594 Rappoport Z.,172 173 182 Rasmussen P. W. 13 Rasuleva D. K.,197 Ratajczyk J. F. 385 Ratcliffe A. H.,501 RatclifTe. R. 415 Rathke M.W.,357 Rau H.,268 Raunio E.K..186 Rautenstrauch V. 137 235 237 Raven P. A. 279 Ravindran. N.,340 Rawlings T.J. 217 Rawlinson D.J. 390 Ray A. K..130 Author Index Rayner-Canham G. W. 275 Razuvaev G. A.. 268 Read L. K.,423 567 Redding T.W.,16 Reddy R. 547 Redmond J. W.,151 152 Redvanly C. S.,249 Reed G.H.,150 Reed L.L.,90 91 Reed R. G.,296 Reed R.L.,223 Reel H.,588 Rees C. W.,213 222 224 372 426 454 458 576 Rees H.H.,477 Reese C.B. 166 186 242 329,339,409 Reetz M.T.,121 233 250 251 Reeves P. C.,219 338 Regen S.L.,274 Regitz M.,226 228 Regulsti T.W.,186 Rehak V.,315 Rei M.-H., 378 Reich D.J. 160 Reich R. 342 Reid A. A, 264 463 Reid W.,262 464 Reilley C.N.,313 Reilly J. 423 567 Rein R. 69 Reinartz W. 447 Reineberg E.J. 567 Reinheimer H.,284 Reinhoudt D.N.,266,373 459 Reininger. W. 479 Reisdorf J. 590 Reitsma H.J. 279 Reitz D.C.,199 Reitz R. R.,587 Remaut E.,550 Remey P.,556 Remy D.E.,431 Renaud R. N.,310 Rennert J. 315 Rensing U.,552 Rmz P.,486 Reppaud K.D.,160 Restivo R. J. 521 Retey J. 151 153 156,157 Rettig M.F.,278 Rcttig T.A.,21 1 404 Reuben D.M.E.177,594 Reuben J. 36 Reusser F.E.,278 Reuvers A.J. M.,110 Reverman L. F. 545 Reynoldson T.,269 Rhee J. U.,259 Author Index Rhine W. 592 Ricard C. 202 Ricard D. 407 Ricci A. 107 108 Riccobono P. X.,563 Rich A. 555 Richards A. C. 440 Richards J. H. 144 Richards K. E. 110 Richardson C. C. 559 Richardson W. H. 174 430 Richie C. D. 169 Richter R. F. 186 Rick E. A. 273 Rickard R. C. 208 Ridard J. 56 Ridd J. H. 107 108 110 262 Ried D. H. 437 Ried W. 403 583 Riedenberg K. 51 Rieder W. 236 Riehl T. 397 Rieke R. D. 366 Rieker A. 24 577 Riemann J. M. 131 Riemenschneider J. L. 78,80 169,404 Riemenschneider P.307 Riesner H. 497 Riess J. G. 337 Rigau J. J. 401 Riggs A. D. 532 Riggs W. M. 82 Rilling H. C. 477 Rindone B.,219,470 Ringele P. 126 449 Ripperger H. 88 Risen W. M. 465 Rider H. 462 Ristagno C. V. 595 Ritchie C. D. 119 Ritchie G. L. D. 564 Riva,E. 15 Rizzardo E. 525 Robbins M. D. 330 410 Robert D. U. 337 Robert J. B. 439 Roberts B. P. 192 195 Roberts B. W. 594 Roberts D. B. 592 Roberts F. E. 446 Roberts G. C. K. 34 Roberts G. G. 281 Roberts J. D. 29 30 34 Roberts J. S.,89,252 440 Roberts M.,171 Roberts T. D. 342,576 Robertson A. K. 2 13 Robertson D. A. 427 Robertson H. B.,558 Robertson H. D. 552,554 Robertson. J. M. 512 Robertson P.M. 295 Robey R. L. 335 Robins M. J.536 537 Robins R. K. 538 541 Robinson K. K. 287 Robinson W. H. 243 51 1 Rocek J. 139 Rodeheaver G. T. 288 Rodmar S. 116 Rodriguez V. M. 37 Rodriquez O. 326 385 430 Rodulfo T. I6 1 Roe B. 555 Roedig A. 586 Roller H. 469 Roelofsen. D. P. 366 Rogers D. 102 512 Rogers M. T. 21 1 Rogers N. R. 254 322 351 Rogers P. A. 195 Rogers R. B. 449 Rogido R. J. 429 Rogne O. 118 Rohrer D. C. 105 Rojas C. I. 430 Roling P. V. 338 Ronchetti F. 496 Ronchi A. U. 340,441 Ronlan A. 308 Rooney J. J.,279,378,409 417 Roosevelt C. S. 247 Roozpeikar B. 329 Rosa J. J. 556 Rosa M. D. H. 556 Rosdal A. 563 Rose D. 289 Rose I. A. 153,154,155 Rosen U. 116 Rosenblatt D. H. 209 Rosenblum M. 288 332 377 Rosenfeld G.C. 549 Rosenfeld S.M. 22 Rosenheck K. 390 Rosenstein R. D. 501 Rosenthal I. 127 366 Roskoski R. jun. I59 Ross J. A. 317 Ross S. D. 112 Rossetti Z. L. 407 Rossi M. 285 Rossi R. A. 341 363 Roth H. D. 23 125 225 41 7 Roth J. F. 287 Roth R. J. 258 280 281 Roth R. W. 434,438 Rothenberger 0.S. 463 Rothman F. 148 Rotman A. 527 Rottele H. 456 Rottman F. 547 Rottman F. M. 545 Rouchetti F. 475 Rousseau R. J. 538 Roussel J. 378 379 Rousseluw B. A. C. 210 Rovbeek C. F. 171 Rowe W. B. 145 Rowland C. 56 224 Roy S.,543 Rozhdestvenskaya N. N. 279 Ruane M.. 18 1 Ruberstein P. A. 179 Rubinstein M. 544 Rubottom. G. M. 426 Ruccia M. A5 1 Ruckstaschel R. 326 385 430 Ruden R.A. 320 Ruedi P. 520 Ruelle J. J. 564 Rueppel M. L. 481 Ruge B. 41 7 Rummens F. H. A. 38 Rupilias W. 286 Russell G. A. 199 200 201,206,425 Russell H. F. 224 Russell J. H. 100 Russell L. W. 110 Russell R. K. 257 Russell R. L. 554 Russo G. 475,496 Ruth J. A. 415 513 Rutledge P.S. 521 Ryan J. A. 51 Ryan J. F. 10 11 Ryang M. 287 Ryashentseva M. A. 279 Ryback G. 15 1 5 12 Rycheck M. R. 271 Ryhage R. 12 Rykov S. V.,23 Ryles A. P.,481 Ryon A. D. 534 Rys P. 107 568 Sabacky M. J. 289 354 Sackman P. 264 Saegusa T. 357 362 Saenger W. 542 543 Saethre L.J. 96,436 Sagan C..533 Sagi N. 563 Sagiv J. 86 Saha M. 449 624 Said; M.R. 261 Sainsbury M. 309 Saito Y.,157 Saji I.493 508 Sajus L. 290 Sakai K. 41 3 509 Sakai M.,171 258 277 419 Sakai S. 500 Sakakibara T. 31 1 Sakakibara Y. 276 Sakata Y.,581 595 Sakimoto R.,I10 Sakurai H. 284,429 563 Saladin E.,336 Salaun J. R. 238 41 1 Salditt M.,550 Salem L. 47 56 61 63 170,224,25 1,406 Sales K. D. 36 Salih Z. S. 11 1 570 Sallomi I. J. 570 Salmond W. 529 Salamon R.G. 362 Salser W. 558 Saltiel J. 315 Saltikova L. A. 521 Salzer A. 268 Sam D. J. 66 383,466 Samarenko V. Y.,1 13 Samek Z. 512 Samman N. G. 409 Sammes P. G. 232 249 356,426 579 Samori B.,87 Sander E. G. 539 Sanderson A. P.,I1 1 570 Sandhu H. S. 203 Sandstrom J. 563 Sanger F. 552 Sano T. 341 Santacroce C. 521 Santaniello E.2 19 470 Santavy F. 88 Santos J. 178 Sanyal T. 5 16 Sam F. 435 Sarabhai A. 555 Sargent G. D. 226 Sartori P. 593 Sasaki K. 3 12 508 Sasaki O. 186 Sasaki T. 136 247 433 453,454 Sasakura K.,504 Sasse W. H. F.,592 Sasson Y.,274 Sato A. 5 13 Sato F. 286 Sato H. 135,449 526 Sato K. 141 289 462 Sato M. 286 Sato T. 58 1 582 591 Saucy G. 360 Sauer J. 125 Sauerbier M.,578 Sauers R. F. 130 Sauers R. R. 246 Saunders A. 462 Saunders J. R. M.,36 Saunders M.,168 170,244 Saunders W. H. 182 183 184 Sauter H. 585 Sauvage J. P. 466 Saveant J. M. 293 Savitzky M.,595 Sawa Y. 287 Sawada M. 116 117 Sawaki M.,110 Sawaki Y. 248 Sax M.,I01 Saxon G. 549 Sayer B. G.,28 Scanlan I. 72 Scannon P.J. 569 Scarpati R. 249 Scartazzini R. 446 Scattergood R. 440 Schaad L. J. 434 590 Schaal R. 115 571 Schaap A. P.,327 Schade G. 133 327 Schadt F. 183 Schadt F.L. 162 Schaefer A. D. 385 Schafer H. 307 Schaefer H. F. 56 59 64 70. 224 401 Schaefer J. 27 29 31 1 Schaefer J. P. 90 91 407 Schafer W. 435 586 Schaffner K. 22 Schakel M.,135 Schaller E. 318 Schaller H. 558 560 Schally A. V. 16 Scharf H. D. 137,365,573 Scharf K. H. 156 Schaub F. 513 Schear W. 215 Schechter H. 250 264 572 Scheffold R. 227 330 336 Scheidt F. 134 Scheit K.-H. 546 Schell K. R. 546 Scheppers G. 417 Scherer C. A. 500 Scherer K. V. 266 Scherrer R.A. 341 Scheutzow D. 586 Schevitz R. W. 556 Author Index Schiavelli M.D. 172 Schiess P. 126 449 Schildknecht H. 396 516 Schill G. 465 Schilling P. 570 Schindler N. 452 Schirmer R. E. 38 Schiruazi R. F. 309 Schleigh W. R. 124 450 Schlesinger M. J. 148 Schleyer P. von R. 46,47 57 122 123 161 162 166 170 172 211 241 246 383 404 406 407 408 Schlimme E. 556 Schlom J. 560 Schlosberg R. H. 167,259 5 69 Schmeltz I. 357 Schmid G. 269 Schmid G. H. 331 Schmid H. 261 368 428 498 578 Schmid U. 428 Schmidt A. H. 124 403 423 567 583 Schmidt C. F. 535 Schmidt E. A. 381 393 45 1 Schmidt F. J. 556 Schmidt H. 135 Schmidt J. 210 Schmidt P. 253 389 Schmidt R. R. 348 450 458 Schmidt W. 120 128 404 Schmidtchen F. 484 Schmiegel W. W.595 Schmitz A, 532 Schmitz F. J. 103 Schnabel I. 173 Schneider Gy. 527 Schneider 0. F. 390 Schneider W. P. 403 Schollkopf U. 122 123 161,227 345 353 Schoening C. E. 525 Schofield K. 108 109 110 Scholl R. L. 35 Scholz H.-U. 227 Schooley D. A. 399 Schott H. 533 Schott H. N. 320 Schrader B. 84 Schreiber J. 138 334 Schreiber K.,88 Schrivener F. E. jun. 194 Schroder G. 204,292,456 589 Author Index Schroder R. 353 Schroepfer G. J. 151 Schubert R. 129 Schubert W. M. 176 Schiittler R. 586 Schulman E. M. 24 Schulman J. M. 51 406 Schulman L. H. 556 Schulten H. R. 10 Schultz R. G. 287 Schultze P. 10 Schumacher E. 268 Schumacher H. 170 Schumann W. C. 317 Schurter J. J. 564 Schuster D.I. 135 Schuster G. B. 322 Schwalbe C. H. 542 Schwang H. 87 Schwartz J. 343 Schwartz J. H. 148 Schwartz L. H. 247 Schwartz M. A. 514 Schwartz M. E. 68 69 Schwarz V. 530 Schwarzel W. C. 523 Schweig A. 435 586 Schweiger J. R. 41 1 584 Schweitzer D. 32 33 Schwerin K. 396 Schwerzel R. E. 207 3 15 Schwesinger R. 265 416 426 568 Sciano J. C. 192 Scoggins R. 298 393 Scolastico C. 2 19 470 Scopes P. M. 89 399 Scorrano G. 289 338 Scott A. I. 480 486 502 Scott J. W. 360 Scott L. T. 122 248 403 566 Scott W. L. 415 506 Scriven E. F. V. 110 221 26l! Secrist J. A. 341 534 535 Sedat J. W. 558 Seebach D. 341 346 353 Seeley A. 3 18 Seeley D. A. 132 Seidl P. 171 Seidl R. 583 Seidner R.T. 456 Seiler M. P. 523 Seiler N. 15 Sekigawa K. 116 Sekine Y. 453 Sekiya M. 395 444 Selbeck H. 268 280 Selvarajan R. 392 Semenovsky A. V. 510 625 Semmelhack M. F. 172 Shimizu N. 226 298 299 329 339 410 Shimizu Y. 343 529 418,494 566 Shimojo N. 461 Sempuku C. 535 Shimura Y. 555 Senda Y. 272 Shine H. J. 202 525 595 Seng F. 443 Shine J. J. 202 Seshadri R. 529 Shinozaki K. 304 Senkler G. H. 563 Shioiri T. 354 358 Senkovich D. 494 Shirley D. A. 69 72 Seno T. 555 Shishido K.,491 Septe B. 285 Shmelev L. V. 510 Sergi S. 285 Shmueli U. 93 Seshadri R. 529 Shobataki M. 21 Sethi P. D. 529 Shoemaker G. R. 13 Setlow P. 559 Shoji E.. 137. 445 Seto S. 474 Shono T. 242 307 Seyferth D. 226 227 260 Short M. R.331,423 567 337,427 573 Shortland A. 268 285 Shabarova Z. A.. 543 Shoup R.R. 32 37 Shack P. 149 Shriver D. F. 269 Shaefer F. C. 370 Shu P. 426 568 Shalten J. P. 283 Shudo K. 248 Shamma M. 88,490,492 Shugar D. 546 Shamovsky G. C. 546 Shugart L. R. 556 Shank C. V. 315 Shushunov V. A. 194 Shannon T. W. 17 Sicher J. 376 Shapiro B. L. 36 37 Sickles B. R. 246 Shapiro R. 537 538 Sidani A. R. 443 Shapiro S. A. 115 Siderius H. 441 Sharma K. S. 130 Siddall J. B. 513 Sharma P. P. 576 Sidhu G. S. 271 Sharma R. P. 161 362 Siefert J. H.. 424 Sharma S. C. 432 Siefert. W. K. 528 Sharp J. T. 213 264 Siegbahn K. 67 68 463 Siegel H. 272 Sharples D. 482 Siegel S. 272 Sharpless K. B. 332 377 Siegfried R. 247 Sharpless T. W. 538 Siegl W. O.344 Sharts C. M. 381 Sievertsson H. 16 Shaw A. 186 Sigel C. W. 521 Shaw B. L. 275 276 Sigler P. B. 556 Shaw C. K. 185 Signor A. 88 Shaw J. T. 434 Sih C. J. 362 Shchori E. 466 Silbert L. S. 355 357 Shebaldova A. D. 279 Silinis H. 487 Shechter H. 217 Silverthorn W. E. 28 1 Sheehan J. C. 341 Silvestri G. 584 Shefter E. 94 264 Silvestro L. 285 Sheikh Y. M. 529 Sim G. A. 93 102 268 Sheldon R.,549 288 Shemin D. 486 Simalty M. 350 434 Shen C.-M. 342 Simes J. J. H. 523 Shen J. 108 Simmonds D. J. 51 1 Shepherd J. P. 339 383 Simmonds P. 13 Shepherd T. M. 36 Simmons H. E. 366 383 Shibata S. 517 520 41 7,466 Shibuya S. 102 Simonet J. 297 302 Shields J. E. 431 Simonetta M. 95 Shigematsu Y. 262 Simonetti F. 270 Shih H. 227 427 Simonsson E.559 Shih S. 64 Simpson R. T. 559 Shil’nikova L. N. 367 Simpson T. J. 524 Sims C. L. 237 333 380 Sims J. J. 515 Sims L. B. 160 Sims M. J. 94 Simsek M. 552 Singer C. E. 552 553 Singer H. 282 Singer L. A. 377 Singh B. 222 Singh J. M. 579 Singh N. 227 337 595 Singh P. 94 Singh S. P. 242 Singhal R. P. 533 Singler R. E. 581 Sinnema A. 110 Sinsheimer J. E. 506 Sipe J. P.,36 Sircar P. K. 5 16 Siu A. K. Q. 56 224 Sjith J. M. 327 Sjostrom M. 117 Skapski A. K. 285 Skare D. 247 Skell P. S. 224 Sklarz B. 219 250 398 Skrabal P. 107,568 Skramovoka J. 281 Sletten J. 97 Sletzinger M. 446 Slightom E. L. 11 8 Sliwinski W. F. 122 161 Slomp G. 542 Slotin L. 541 Slutsky J. 134 135 252 386 392 Smirnov V.D. 543 Smit W. A. 510 Smith A. R. H. 477 Smith C. J. 553 Smith C. R. 390 493 495 Smith D. G. 478 Smith D. H. 14 Smith D. L. 94 Smith D. M. 214 Smith D. S. H. 529 Smith D. W. 25 Smith E. M. 228,449 Smith G. 171 353 Smith G. A. 529 Smith G. D. 280 Smith G. F. 501 502 Smith G. N. 501 Smith H. R. 552 553 Smith J. D. 554 Smith J. L. 16 Smith K. R. 135 Smith L. D. 123 Smith M. 544 Smith M. R. 93 Smith R. G. 180 Smith R. H. 236 Smith R. J. 232 Smith R. M. 104 Smith S. L. 39 Smith S. M. 219 Smith T. N. 289 Smith W. E. 570 Smithers R. H. 131 170 381 393,413 Smolanoff J. 428 Smolenski S. J. 487 Smrt J. 545 Smyrl T. G. 236 Snatzke G. 85 86 87 88 89,405,447 Sneden D.555 Sneeden R.P. A. 284 Sneen R. A. 160 243 Snieckus V. 458 494 Snow J. T. 333 Snow R. A. 332 Snyder C. D. 339 Snyder E. I. 336 Snyder J. P. 132 137 224 Snyder R.V. 385 Sodano G. 529 SOH D. G. 552,554 555 Sogomonya B. M. 194 Sohn M. B. 125 225 256 402 Sohn W. H. 385 Sohn Y.S. 276 Sojka S. A. 29 Sokolov N. A. 194 Solar S.,251 Soll L. 559 Solladie G. 160 Solodovnikov S. P. 197 Soma N. 137,237,445 Sommer H. 546 Sommer L. H. 193 Sommer R.G. 545 Sommerfeld C. D. 265 4 16,426 568 Sommerville P. 488 Sondheimer F. 403 457 588 589 590 Sonnichsen G. 179 Sonoda N. 348 Sonogashira K. 269 Sood,R. 362 Sorensen T. S. 170 245 Sorm F. 512 Sorm M. 371 Sosin S.L.. 192 Sosnovsky G. 390 Souchay P.,450 Sousa L. R.,138,232.586 Soussan G.,394 Sowerby R.L. 331 Spadero J. J. 123 Spagnolo P. 203 448 A utkor Index Spahr P. F. 552 Spangler C. W. 125 316 Spanninger P. A. 262 Speckamp W. N. 259 Spek Th. G. 270 Spence J. M. 456 Spencer C. 268 Spencer J. H. 531 Spiegelman S. 560 561 Spies H. S. C. 390 Spiess H. W. 32 33 Spillner C. J. 243 51 1 Spoerri P. E. 116 Sporn M. B. 549 Spraggins R. L. 103 Sprague J. T. 407 Sprake J. M. 462 Sprecher M. 447 Sprecker M. A. 432 Spring D. J. 238 Spring M. S. 482 Sprinson D. B. 156 Sprinzl M. 556 Sprio V. 516 Spurlock L. A. 165 Spyckerelle C. 52 1 Spyropoulos C.G. 489 Sridhar R. 28 244 Srinivasan R. 127 316 324 325 Srinivasan V.130 Staab H.A. 592 Stadler P. A. 345 Stadtman E. R. 142 Stadtman T. C. 144 Stallcup W. B. 146 Stang P.J. 172 241 Stangl H. 428 Stanko J. A. 490 Stanley J. P. 190 Stanovnik B.,444 Stanton E. 222 Stanton J. 243 Stapleford K. S. J. 502 Staunton J. 151,481,484 Stead K.,109 Stearns R.W. 465 Stebles M. R. D. 242 409 Steckhan E.. 307 Stedman D. E. 118 Stedronsky E. R. 329 Steel G. 11 Stefanko B. D. 434 Steffens G. J. 447 Steglich W. 357 479 Steigel. A. 125 Steiner P.R.,39 Steinmetzer H. C. 430 Steinreich P. 48 1 Steitz J. A. 552 Stemniski M. A. 250 Step G. 409 41 7 Author Index 627 Stephani R. A. 145 146 Streitweiser A. 72 116 Suzaki Y. 285 Stephenson N.C. 104 177 178 179 569 594 Suzuki H. I10 Stephenson R. W. 372 Strickland R. C. 347 Suzuki J.. 228 444 Sterba V. I13 Strohmeier W. 270 Suzuki K. T. 470 Stern E. W. 270 Strome F. C. 315 Suzuki M. 508 Sternbach H. 545 546 Strong C. J. 238 Suzuki T. 343 512 556 Strong J. M. I5 Suzuki Y. 470 512 547 Sternerup H. 305 Strope D. 269 Svanholm U. 253 264 Sternhell S. 571 Stubbs M. E. 253,466 306 308 574 Stetter H. 447 Stucky G. D. 72 592 Svec H. J. 9 Stevens I. D. R. 181 182 Studier M. H. 519 Svec W. A. 519 Stevens J. D. 104 Stucheli N. 447 Svensson T. 163 Stevens J. I. 344 stutz P. 345 Sverolov E. 538 Stevens R. H. 549 Stulberg M. P. 556 Svoboda J. J. 80 169 Stevens R. M. 63,406 Sturm H. J. 428 Svoboda M. 184,466 Stevenson B. 160 Stusche D.264 426 Svoboda P.,272,273 Stevenson G. R.. 426 Su A. C. L. 282 Swain C. G. 11 1 Steward D. L. 546 Su,T. M. 122 161 Swaminathan S. 1 13 Steyn P. S. 478 Subbaraman J. C. 174 Swan C. G. 395 Stief L. J. 327 Subbaraman L. R. 174 Sweeney A. 243 Stiegler P. 532 547 Subramanian S. S. 529 Sweeting J. W. 579 Stilbs P. 390 Suck D. 543 Sweetman B. J. 15 Stille J. K. 425 Suda M. 41 1 583 Sweigart D. A. 439 Stirling C. J. M. 292 Suddath F. L. 555 Swern D. 221 238 396 Stock J.. 172 298 329 Suga K. 353 356 Swift H. E. 273 280 410 566 Sugasawa T. 504 Swift P. 279 Stock L. M. 205 Sugihashi M. 595 Swinehart J. 546 Stockert J. C. 559 Sugimoto T. 129 422 Switalski J. D.. 69 Stodola F. H. 392 Sugino A. 560 Sykes B. D. 34 Stober I. 219 Sugiura S. 340 Symons M. C.R. 208 Stockel K. 589 Sugiyama N. 441 Symons R. H. 557 Stocklin G. 109 Sugowdz G. 592 Syrdal D. D. 512 Stohrer W. D. 51 120. Sukai M.,276 Szabo W. 41 5 125 136 245 256 406 Sullivan D. 357 Szczepanski H. 447 Stoker J. R. 482 Sullivan D. E. 310 Szechner B. 133 Stokes B. 251 Sullivan T. F. 184 Szeimies G. I22 Stone F. G. A.. 275 276 Sultan M. K. 219,250,398 Szele I. 162 278 285 Sumida Y. 453 Szilagyi L. 89 Stone T. J. 209 Sumitani K. 363 Szilagyi P. 167 Stoodley R. J. 238 Summerhays K. D. 29 Szindely J. 261 Stoos F. 139 Summerville R. H. 172 Szwarc M. 179 205 595 Storer R. 489 383 Storey P. M. 196 Sumoto K. 401 Storey R. A. 210 Sundaralingam M. 96,555 Stork G. 366 499 Sundaresan T. 100 Taagepera M. 396 421 Storm C. B. 458 Sundberg R. J.223 224 439 Storm D. R. 408 Sundeen J. 529 Tabushi I. 212 421 Storr R.C. 122 213 372 Sundholm G. 308 Tack R. D. 434 454 458 576 Sunko D. C. 162 Tadros M. E. 274 Story P. R. 248 403 430 Surzur J. M. 391 Taft R. W. 396 439 Stothers,J. B. 28,241,244 Suschitzky H. 221 223. Tafuri D. 249 427 443 Taguchi. H. 344 Stotter P. L. 357 361 Sustmann R. 128 129 Tahara A. 5 19 Stout D. M.,449 132,428 Taimr L.. 577 Strach S. J. 207 Suter S. R.. 223 Tainturier G. 300 Strain H. H. 519 Sutherland D. S. 231 Tait B. S. 223 Strange P. G. 481 Sutherland 1. O. 136 565 Takabe K. 280 Strating J. 130,246,441 58I Takagi T. 279 Straus D. B.,546 Sutherland R.G. 220 Takahashi J. 181 182 Strausz 0.P. 203 Sutphen C. 179 205 595 Takahashi K. 289 586 Streckert G. 353 Sutton D.275 Takahashi R. 520 Streith. J. 458 459 Sutton W. D. 559 Takahashi Y..353 Takai Y.,116 Takami Y.,282 Takamuku S.,563 Takano T. 547 Takase K. 586 Takasuka T. 3 1 1 Takaya H.,131,283 Takaya M.,393 Takaya T. 221,449 Takebayashi N. 544 Takeda M.,333,336 Takeda R. 514 Takeda Y.,469 Takegami Y.,286,287 Takemura S. 552 Takeshima K. 493 Taketomi T. 278 Takeuchi Y.,218 Takiura K. 535 Takizawa T. 285 Talaty E. R. 425 Tamagaki S.,228 Tamao K. 363 Tamao Y.,142 Tamaru K. 400 Tamato H. 229 Tamm Ch. 521 Tamura S.. 529 Tamura Y.,401,452,453 Tan C. T. 28 244 Tan H.W. 439 Tanabe T. 552 Tanak S.,581 Tanaka A. 271 Tanaka J. 280 Tanaka M. 286,287 Tanaka O. 517 Tanaka R. 271 Tanaka T.508 Tancrede J. 332 377 Tancredi T. 30 Tang W. P. 438 Tangari N. 340,441 Tani K. 283 Tani T. 51 1 Tanida H.,163,421 Tanikaga R. 201 425 Tanino H. 340 Tarama K.,116,270 Tarpley A. R. 28 Tarzia G. 337 Tashiro M. 112 Tate S. S. 145 Taticchi A. 89 117 435 Tatlow J. C. 570 Tatsumi T. 279 Tatum C. M.,jun. 226 Taube H.,519 Taubenest R. 268 Taurand G. 459 Tauscher B. 396 5 16 Taylor A. J. 542 Taylor B. W. 273 Taylor C. W. 547 Taylor D. R. 522 Taylor D. S.,223 Taylor E.C. 94 335 363. 423,448 505 579 Taylor J. D..350 Taylor K. A. 287 Taylor K. G. 397 Taylor P.R. 29 Taylor R. 107 109 117 134 387,408 569 Taylor R. F. 323 Taylor R. T. 144,463 Taymaz K.,255 Tebby J.C. 462 Tee 0. S. 120 Teeter R. M.,528 Teetor G. H. 552 Teichmann Von H. 2 13 Teitel S. 339 Teklu Y.,458 Tel L. M.,47 Temple G. F. 549 Temussi P. A. 30 Tennant R.W. 547 Tennet H. G. 268 Terada M.,560 Terao S.,446 Terao T. 545 Terashima S.,350 Terrier F. 114 115 Tewson T. J. 117 Texier F. 428 Teyssik P. 228 279 330 Tezuka. S.,541 Thack E. 531 Thal C. 500 Thaynmanavan B. 16 Thedford R. 546 Thewalt U. 542 Thiele K. H.,268 Thielen D. R. 292 Thierry J. 525 Thijs L. 130 Thomalla M.,311 Thomas A. 190 Thomas A. F. 51 1 Thomas E. J. 122,161,228 Thomas F. 13 Thomas J. M. 82 Thomas M. T. 458 Thomas T. D. 72 Thomas W. 550 Thomassin R. 11 1 Thompson C. D. 301 Thompson M.,66 Thompson M.H.,596 Thompson M.J. 110 Thomson C. 89,440 Thomson J. B. 214,524 Thomson R. H. 219 Author Index Thornton E.R.,421 Thornton 1. M.S.,515 Thorwart W. 592 Thuan L.N. 491 Thuan S. L..395 Thuillier P.,533 Thummel R. P.,417 Thurber T. C. 542 Thyagarajan B. S. 369 442 Tichy M.,85 405 546 Tiecco M.,203,448 Tikhomirova-Sidorova N. S.,546 Timofeeva T. N. 39 Tinkelenberg A. 134 386 387 Tinker H.B. 286 TiSler M.,444 Titchmarsh D. M.,285 Tkatchenko I. 280 Tobinaga S.,363 Tobler H.,447 Toby F. S.,209 Toby S.,209 Tocanne J. F. 85 Toda M.,330,508 Toda T. 207 Todd J. F. J. 11 Todd M. 527 Todesco P. E. 343 Toh H. T. 337 536 Tokane K. 508 Tokoroyama T. 522 Tolman C. A.271.276 Tomao K. 289 Tomkiewicz M.,23 197 Tonelli A. E. 39 Tong C. 505 Toniolo C. 88 Tontapanish N. 327 Topal A. 172 Topsom R. D. 116 Topuvidze L. F. 272 Torchia D. A. 39 Tordo P. 391 Torii S.,312 Torrence P. F.,537 545 546 Torroni S.,8 Tortorella V. 88 Tom T. 247 Toube T. P.,488 Towns R. L.R. 37 96 Townsend C. A.. 486 Townsend L. B. 538 542 Toyama T. 228 Toyoda T. 504 581 Tozuka Z. 581 Tozune S.,228 Trachtenberg E. N. 396 Traeger J. C. 9 Author Index Traficante D. D. 375 421 Trahanovsky W. S. 350 368,574 Traylor T. G. 170 Trefonas L. M. 96 Treibs W. 433 Trenner N. R.,16 Triana J. 516 Tribble M. T. 395,407 Tribout J. 564 Trill H.,132 Trivellone E. 30 Trojanek J.87,487 501 Trojankova M. 487 Trost B. M. 185,243 360 41 5,427 Trozzolo A. M. 21 428 Trueblood. K. N.. 92 564 Trusdale L. K. 415 Truesdell D. 278 Truman D. E. S. 549 Trzupek L. S.,329 Tsatsas T. 465 Tsay Y.,283 Tsiyi J. 289 Tsuboyama S. 542 Tsuchida K. 342 Tsuchihashi G. 344 Tsuda T. 362 Tsuda Y.,146 Tsugita A. 550 Tsuji J. 287 Tsuji T. 163 Tsujimoto N. 453 Tsunetsugu J. 133 Tsuno Y.,116 117 Tsurugi J. 340 Tsushima T. 421 Tsutsui M.,268 Tsutsumi S. 13 I 287 348 393 Tuccio S.A. 315 Tufariello J. J. 123 Tundo A. 190 202,448 Tunemoto D. 361 513 Tuominen F. W. 547 Turchi I. J. 440 Turley J. W. 94 438 Turnblom E. W. 439 Turnbull K. W. 471 Turner A. B. 529 579 Turner D.W. 439 Turner K. 269 Turner L. 378 Turner L. M. 179 Turner P. H. 324 Turro N. J. 127 321 Tursch B. 529 Tursch B. M.,528 Tushima S. 446 Tweddle N. J. 429 Tycholitz D. R.,203 Tyler J. K.,398 Tyrlik S.,277 Tyssee D. A. 304 Uccella N. A. 17 Uchida A. 279 Uchida Y.,272 279 282 Uchine N. 276 Uda H.,271 Uebel J. J. 36 Ueda S.,469 Uemura S.,186 570 Uesugi S. 541 546 Uetrecht J. P. 593 Ugi I. K.,359 Ugo R.,270,290 Uh H.-S., 343 Uhmann R.,542 Ulland L. A. 193 Ullenius C. 136 255 Ulmen J. 136 256 Umbach W. 282 Umbreit M. A. 332 377 Umeda I. 275 283 352 526 Umen M. J. 393 Umezawa B. 495 Umpleby J. D. 133 379 Underwood G. R. 135 200 Undheim K. 88,438 Uneyama K.,312 Unni A.K. V. 220 Uno K.,462 581 Untch. K. G. 362 Urata K. 280 Uskokovic M. R.,501 Usova L.G. 194 Utakoji T. 559 Utley J. H.P. 291 Utter M. F. 155 Vahrenholt F. 128 Valasinas A. 483 Valentine D. 3 15 Valinsky J.,14 1 Valkanas G. 510 Valter K. 113 Van J. 415 Van Bekkum H.,270 366 Van Bolhuis F. 93 van Boom J. H.,339 van Dahn R.A. 433 Van Dam P.B. 279 Vandenberghe A. 552 Van der Heuvel W. J. A. 16 Van der Does L.,215 Van der Ent A. 270 van der Hart W. J. 61,120 van der Helm D.,103 Van der Hoek W. J. 210 Van der Kooi. J. P. 425 van der Lugt W. Th. Am. 121 van der Plas H.C. 216 van der Ploeg H.J. 283 Van der Stouw G. C. 250 572 van de Sande J. H.,558 van Deurson P. 339 Van Dine G.W. 122 161 Van Duyne R.P. 313 Vane F. M.,29 van Kamkamp M. 549 van Leeuwen F. F. 110 van Leusen A. M. 441 van Leusen D. 441 van Meerssche M.,37 van Melick J. E. W.,341 Van Rantwijk F.,270 Van Reijendam J. W.,464 van Remoortere F.P. 438 Vanstone A. E.,524 van Tamelen E. E. 122 170 259 270 423 523 566 Van Wazer J. R.,51 Varava T.I. 272 Vashi D. B.,317 Vasil’eva G. A. 268 Vaska L.,274 Vass A. 527 Vatter H. 458 Vaughan M. H.,549 Vaughan P. 567 Vaughan W.R.,384 Vaziri. C. 353 Vedejs E.,239 Vega E.,264 Veillard A. 64 Velarde E.. 376 Veldhuis R.G. M. 325 Venkateswarlu A. 339 Veracini C. A. 37 38 203 Verbjt L. 87 Verdini A. S. 30 Verkade J. G. 434 438 439 Vermeer H. 435 Vernin G.202 Vernon J. M. 431 Vertes. G. 308 Vialle J. 203 Vietmeyer N. D. 125 Vikane 0..439 Vilhuber H.G. 133 Villieras J. 240 344 Vincent A. T. 91 Vincenzi C. 203 Vineyard B. D. 289 354 630 Vining L. C. 478 Walba D. M. 336 Vining R. F. W. 274 329 Walborsky H. M. 179.359 569 Walden F. A. 162 Vink J. 16 Walder J. A. 407 Vink J. A. 571 Walinsky S. W. 365 Vinogradov M. G. 348 Walker J. A. 137 232, Vinokur E. 339 249 346 Viout P. 161 Walker P. J. C. 289 571 Virtanen P. 0. I. 119 169 Walker R. T. 536,556,557 Viswanathan N. 490 503 Walker R. W. 16 Vitali D. 113 Wall M. E. 504 Vitullo V. P. 260 Wallace R. G. 219 576 Vivona N. 451 Walling C. 21 24 192 Vliegenthart J. F. G. 16 Wallwork S. C. 100 Voecks G.E. 280 Walter T. J. 581 Vogtle F. 462 465 581 Walters J. A. 545 Voelter W. 542 Walton D. R. M. 11 1,373 Vogel E. 125 204 265 570 416 417 426 456 461 Wang H. C. 559 568 588 590 Wang J.-L. 279 Vogel P. 170 Wang J. T. 190 Voigt E. 215 Wani M. C. 504 VokaE K. 512 Ward H. R. 19 20 21 22 Volckaert G. 552 Ward J. S. 258 278 419 Vollhardt K. P. C. 432 Ward P. 179 235 584 593 Warneke J. 504 Vollman J. A. 16 Warner P. 35 171 242 Volod’kin A. A. 197 409 Vol’pin M. E. 275 Warnhoff E.W. 329 von Ammon R. 35,405 Warren F. L. 390 von der Haar F. 556 Warrener R. N. 130 421 Von Hinrichs E. 359 425,431 Vonnahme R. L. 288 Wasan M. T. 533 von Philipsborn W. 428 Washburn W. N. 527 Von Rosenberg J. L. 262 Washburne S. S. 358 444 von Straten J.W. 567 Wasserman E. 279 Vorbriiggen H. 541 543 Wasserman H. H. 581, Vos,A. 93 100 592 Vosa C. G. 559 Wasson J. R. 39 Voyakovskaya E.E. 3‘67 Wasylishen R. 29 Vuitel L. 357 Wat C.-K. 478 Vyshinskaya L. I. 268 Watanabe M. 229 236 Watanabe S. 353 356 Watanabe T. 242 Waali E. E. 225 Watanabe Y.,286,287 Wada M.,341 363 Watawa Y.,539 Wade K.,91 Waterman E. L. 289 579 Wade K.0..437 Waters J. A. 323 537 Wade-Jardetzky M. G. Waters W. L. 186 150 Watkinson I. A.. 157 Wadsworth D. H. 410 Watson J. T. 13 15 Wagenknecht J. H. 295 Watson M. B. 385 304,357 Watt D. S. 415 Wagh U.,559 Watts D. C. 150 Wagner H.U. 583 Watts G. B. 193 196 Wagner J. M. 591 Waugh J. S. 30 Wagner P. J. 319. 320 Webb H. M. 396 Wagner R. M. 126,442 Webb J.G. K. 114 Wagnihre G. 86 87 Weber H.,552 Wahl G. H. 35 Weber H.-P. 524 Wailes P. C. 285 Weber K.. 532 Wajer Th. A. J. W. 398 Weber W. P. 339,359,383 Author Index Webster D. E. 276 Webster 0.W. 392 Wedderburn J. H. M. 3 15 Wedler F. C. 146 Weeks P. D. 239 Weeren H. O. 534 Wege D. 594 Weglein R. 28 244 Wehinger E. 592 Wei C. C. 502 Weigert F. J. 29 Weigold M. 285 Wein R.H. 151 Weinberg R.A. 549 Weiner S.A. 193 197 Weinheimer A. J. 103 Weinreb S. M. 352 493 Weinshenker N. M. 342 Weinstock J. 184 Weinstock L. M. 446 Weinwurtzel D. H. 241 Weinzierl J. 555 Weisblum B. 559 Weise W. 268 Weisleder D. 495 Weiss C.. 178 Weiss C. H. 268 Weiss R. 112 Weiss U.,86 Weissbach H. 144 Weissenbach J.552 Weissmann C. 552 Weisz-Vincze I. 527 Weith H. L. 558 Wells D. 592 Wells P. B. 276 Wells R. B. 488 Wells R. D. 532 Welzel K. C. 259 Welzel P. 87 526 Wendisch D. 66 Wendler N. L. 446 Wendschuk P. H. 125 Wendt H. 307 Wenell C. 167 Wenger D. A. 16 Wenkert E. 133 335 379 474 Wentrup C. 230 Werme L. 0.. 68 Werner G. 452 Werner H. 268 Werner-Zamojska F. 405 Werstiuk E. 133 Werstiuk E. S. 545 Wuthemann D. 437 Wertz J. E. 199 Wesseler E. P. 584 West P. J. 321 West R. 236 584 Westcott N. D. 337 371 Westler W. M. 434 Author Index Westley J. W. 478 Westmore J. B. 541 Weston R. J. 524 Wetmore S. I. 428 Wetzel R. B. 447 Weyhenmeyer R. 486 Weyler W. 128 374 420 Whall T.J. 396 Whalley W. B. 529 Whan D. A. 279 Wharton E.J. 279 Wheatley P. J. 91 Wheeler J. W. 516 White A. F. 473 White A. I. 34 White A. M. 116 167 White D. H. 132 227 White D. L. 260 573 White D. M. 31 White D. V. 432 White E. 542 White E. H. 579 White R. E.,248 Whited E. A. 248,430 Whitehead M.A. 137,224 Whitehouse R. D. 238 Whitesides G. M. 274,329 Whitfield G. F. 238 396 Whiting A. 17 Whiting D. A. 99 510 51 1 528 Whitlock H. W. 456 Whitman D. R. 44 51 406 Whitman P. J. 486 Whitney C. C. 333 Whittaker D. 164 509 Whitten C. E.,362 Whitten J. L. 51 Whittle P. A. 199 Whyman R.,286 Wibberley D. G. 444 Wiberg K.B. 377 406 Wiberg N.,398 Wicha J. 526 Wicker K.,447 Wickner R.B. 559 Wickner S.,561 Wiedemann W. 125,417 Wiegers K.E. 184 466 Wieglepp H.,530 Wiemann J. 395 Wierenga W. 523 Wiersum U.E. 431 Wiese W. 280 Wiesner K.J. 480 Wife R. L. 439 Wigfield D. C. 255 Wigfield Y.Y..544 Wigger N.,447 Wightman R.H. 481,484 Wikel J. H. 180 Wikholm R. J. 580 Wikstrom S. 12 Wilcox C. F. 593 Wilcox C. F. jun. 510 Wilke G. 280 283 377 420 Wilkes J. S.,545 Wilkie C. A. 2 19 572 Wilkins B.,276 Wilkins B. J. 529 Wilkins B. T. 128 404 Wilkins C. L. 186 Wilkinson G. 268 271 285 Willard J. M. 155 Willi A. V. 165 Williams C. C. 353 Williams D. H. 16 17 36 529 Willimas D. L. H. 574 Williams F. 190 Williams F. J. 258 277 419 Williams F. M.15 Williams J. R. 450 Williams M. D. 449 Williams R. J. P. 36 141 542 Williams W. M . 124. 130. 429 Williamson A. R. 549 Williamson K.L. 118 Williamson R. 547 549 Wilson D. P. 545 Wilson G. E. 238 Wilson J. C. 160 Wilson. J. G. 579 Wilson L. A. 169 Wilson M.S. 11 Wilson S.E. 258,277,278 419 Wilt J. W. 259 595 Wilton D. C. 140 157 Wiltshire C. 353 526 Wiltshire H. R. 481 Wilzbach K.E. 264 Winfield M. E. 142 Wing R. M. 36 515 Wingard R. E. 239 257 Winkler H. W. 10 Winstein S. 38 136 162 163 164 165 169 171 181 182 207 510 565 566 577 Winter J. G. 262 Winter S. R. 287 344 Winter W. 283 Winterfeldt E. 497 503 504 Winters R. E. 9 Wirz J. 77 631 Wirz-Justice A. 467 478 .Wiseman J. R. 168 245 408 Wissner A. 594 Witiak J. L. 45 Witkop B. 323 374 537 545,546 Wittig G. 215 219 283 Wittstruck J. A. 36 Woessner W. D. 352 353 Wojcicki A. 286 Wojtkowski P. W. 326 385 430 Wold E. 207 Wold S.. 117 Wolf D. E. 16 Wolf F. J.,(16 Wolf H. 22 Wolf J. F. 310 350 Wolfe J. F.,448 Wolfe R. G. 149 Wolfe S.,47 Wolff G. 524 Wolff S. 322 Wolfram B. 447 Wolfson-Davidson E.,538 Wolinsky J. 361 Wolboff A. W. 331 Wolovski R. 279 Wolters E.T. M. 341 Wong C. M. 352,353,356 Wong R. J. 183 Wood G. 440 Wood H.G.. 144 155 Wood J. M. 142 Wood M. H.,82 Woodgate P.D. 530 Woodruff R.A, 227 Woods D. K.,510 Woodward R. B.. 84,446 Woolsey I. S.,68 Woolsey N.F. 395 Worsley M.,354 Wray V.117 Wren C. M. 134 387 Wren J. J. 383 Wright A. 236 Wright D. 280 Wright D. J. 169 Wright G. J. 110 Wright I. H. 507 Wright J. S. 61 63,460 Wu C. Y.,270 Wu R. 532. 558 Wu W. S.,592 Wudl F.,466 Wiiest H. 378 Wulfman D. S. 227 Wulfsberg G. 584 WunderwaId P.,152 Wurster J. M. 143 Wyatt M. 36 632 Wyatt P.A. H.,115 Wynberg H.,87 130 131 246 319 353 434 451 564.596 Xavier A. V. 36 542 Yagi H. 260 427 568 Yagihara T. 228 238 Yahner J. A. 180 Yakali E. 464 Yamabe S.,224,225 Yamada H.,443 Yamada K. 455 Yamada R.,142 Yamada S.,326 354 358 460 Yamada T.,508 Yamagata T.,283 Yamagishi T.,529 Yamaguchi H. 538 Yamaguchi T.,343 Yamaki N. 327 Yamamoto A.271 Yamamoto H.,344,456 Yamamoto K. 286 287 289,581,590 Yamamoto S. 595 Yamamoto Y. 286 Yamamura K. 421 Yamamura S.,330 508 Yamanaka E. 500 Yamashita J. 227 Yamashita K. 512 Yamashita M. 195 Yamato H. 137 Yamazaki A. 543 Yamazaki M. 478 Yamazaki T. 2 17 Yamazoe Y. 514 Yamadagni R. 396 Yamova M. S.,273 Yana J. 546 Yanagisawa I. 517 Yandovskii V. N.. 238 Yang N. C. 325 595 Yang S. K. 552,554 Yaniv M. 552 Yano T. 160 Yao S. Y. 490 492 Yarbrough L. 561 Yarrow D. 288 Yarus M. 556 Yasuda N. 283 Yasuoka N. 283 Yates K. 115 120 185 390 Yeboah S. K. 5~4 Yee K. C. 439 Yelland M. 224 Yeo A. 14 Yogev A. 86 Yokoyama K. 393,413 Yoneda F.,444 Yoneda S. 136 164 Yonemitsu O.426,572 Yonezawa T.,69,207 Yoo c. s.. 101 Yoshida Z. 136 164 212 42 1 Yoshikami D. 556 Yoshikoshi. A. 271 Yoshimoto M. 137 237 445 Yoshimura Y. 401 Yoshioko M.,523 Yosioka I. 51 1 Yosioka Y. 514 Young A. E. 169 Young A. T.,116 178 179 Young D. W. 489 Young M. R.,468 Young P.E. 205 Young R.H.,431 Young R. N.. 178 Young W. R. 177 Youngs V. 556 Youngson G. W. 385 Ysebaert M.,532 550 552 Yu C. Y.. 132 Yu S. H.,338 Yuan S. S. 248 Author Index Yufa T.L.,279 Yukawa Y. 116 117 Yuki H. 535 Zalkow. L. H. 132 Zaman Z. 484 Zamojska F. W. 85.87,89 Zanardi G. 448 Zaugg H.E. 385 Zavada J. 184,466 Zdunneck P. 268 Zecchi G. 441 Zech K. 542 Zeck L. 559 Zeiss H. H. 284 Zeller K.-P.249 Zenk M. H. 156 Zepp R.G. 319,320 Zey E. G. 415 Zeya M. 244 Zhidomirov F. M. 19 Ziegler G. R.,179 Ziff E. B. 558 Ziffer H.,86 Zika R. G. 451 Zimmer T. L. 157 158 Zimmerman E. 559 Zimmerman H. E. 138 232 252 317 322 323 564,586 Zimmermann R. A. 547 Ziolkowski F. 134 392 Zmudzkai B.,546 ZobhCovh A. 89 Zollinger H.,107,111,568 570 Zoltewicz J. A. 119 174 538 Zorina A. D. 521 Zundel J. L. 524 Zupan M. 444 Zurfluh R. 513 Zurr D. 171 353 Zwanenburg B. 130 Zweifel. G. 333

ISSN:0069-3030    

DOI:10.1039/OC9726900597

出版商:RSC    

年代:1972

数据来源: RSC