摘要:

8 Alicyclic Chemistry By S. A. MATLIN Chemistry Department The City University. Northampton Square London ECl V OHB 1 General The first quantitative study of the kinetics of SN2 closure of all-carbon 4-to 21-membered rings (Scheme 1) has been published.' The cyclization rates span nine orders of magnitude and show qualitatively the expected trends reflecting a combina- tion of ring-strain and distance factors. However an important feature of the results is that the transition-state strain-energies tend to parallel cycloalkane strain-energies for 7-membered and larger rings but not for the smaller rings. Me,N+ -/CozEt DMSO,25"C Br(CH,)_IC C0,Et Scheme 1 Cyclization of dibromides or ditosylates with methyl thiomethyl sulphoxide anion gives 3-to 6-membered rings in good yields the products with 4-to 6-membered rings being easily converted into ketones by acid hydrolysis.* Alkyl lithium species (1) cyclize efficiently to normal sized rings (2; n = 2-4) but (1 ;n = 5) fails to give the 8-membered ring.3 5-and 6- (but not 4-) membered rings are also formed in high yields by intramolecular cyclization of the Grignard reagents derived from trimethylsilylalkynyl halides (3) and the resulting Grignard reagents (4; n = 0,l) can be further alkylated Me,SiCrC -(CH,) -Br (3) (4) ' M.A. Casadei C. Galli and L. Mandolini J. Am. Chem. Soc. 1984 106 1051. ' K. Ogura M. Yamashita M. Suzuki S. Furukawa and G. Tsuchihashi Bull. Chem. Soc. Jpn. 1984,57 1637. A. R. Chamberlin and S. H. Bloom Tetrahedron Lerr.1984 25 4901. S. Fujikura M. Inoue K. Utimoto and H. Nozaki Tetrahedron Left.,1984,25 1999; see also Y. Okuda Y. Morizawa,K. Oshima and H. Nozaki. ibid. p. 2483. 153 154 S. A. Marlin Whereas the unsaturated diester (5; n = I) undergoes a vinylogous Dieckmann cyclization to (6) by a 6-(enolendo)-exo-trig process (‘favoured’ by the Baldwin Rules) the 5-(enolendo)-exo-trig reaction of (5; n = 0) is ‘disfavoured’ and does not occur. However the corresponding 5-(enolexo) processes from (7) and (8) are ‘favoured’ and proceed in reasonable yields.’ Me0 Me0,C / c+> & & @Me C0,Me C0,Me 6 The importance of stereoelectronic factors is also seen in cyclizations involving intramolecular attack of a carbanion on an oxetane ring that has now been examined for the first time? In the series (9; n = 1-4) only the cyclopropane (10; n = 1) is formed easily under forcing conditions (9; n = 3) will cyclize but even then the 4- and 6-membered rings are not-formed.However in the isomeric series (11; n = 0-3) 3-and 4-membered rings did not form but 5-and 6-membered rings (12; n = 2,3) were obtained in good yields. Catalysed Cope and Claisen reactions used in the synthesis of alicyclic compounds have been reviewed.’ M. Kodpinid and Y. Thebtaranonth Tetrahedron Lett. 1984 25. 2509. M. Yamaguchi and I. Hirao Tetrahedron Lett. 1984 25 4549. ’ R. P. Lutz Chern. Rev. 1984 84. 205. 155 Alicyclic Chemistry (9) 2 Three-membered 5-Bromo- and 5-iodo-pent-2-enes are cyclized in good yields to 1-cyclopropylethyl nitrite by passage through a column of silver nitrate on alumina.* A versatile synthesis of cyclopropyl phosphonates involves treatment of gem-dibromocyclopropanes with triethyl phosphite in the presence of Et,N and a control- led amount of water.' 2-Silyloxycyclopropanecarboxylicesters which are valuable building blocks in synthesis are prepared by diazoacetic ester addition to silyl enol ethers." Silylcyclopropanes (13) and (14) have been synthesized by addition of arsonium ylides to chalcones" and by modified Simmons-Smith cyclopropanation of vinyl-silanes,I2 the silicon function subsequently permitting a variety of functional group modifications to be made.I3 CH,I,-EtZnI ____, 4siMe3 &SiMe A CH,OH \ CHzOH :H,OH The cis-tributylstannylcyclopropyl methanol (15) available by Simmons-Smith rcaction on 3-tributylstannylprop-2-eno1, can be resolved as the 0-methylmandelyl ester.Replacement of the stannyl group by lithium using BuLi then affords the chiral cis-2-substituted cyclopropyl-lithium reagent for use in asymmetric ~yntheses.'~ R. T. Hrubiec and M. B. Smith J. Chem SOC.,Perkin Trans. 1 1984 107. T. Hirao M. Hagihara Y. Ohshiro and T.Agawa Synthesis 1984 60. 10 E. Kunkel I. Reichelt and H.-U. Reissig Annalen 1984,512; I. Reichelt and H.-U. Reissig ibid. p. 531. Y. Shen Z. Gu W. Ding and Y. Huang Tetrahedron Lett. 1984 25 4425. 12 G. J. Wells T.-H. Yan and L.A. Paquette J. Org. Chem 1984,49 3604. l3 L. A. Paquette T.-H. Yan and G.J. Wells J. Org. Chem 1984 49 3610; L. A. Paquette G. J. Wells and G. Wickham ibid. p. 3618; L. A. Paquette C. Blankenship and G. J. Wells J. Am. Chem SOC. 1984 106 6442. 14 E. J. Corey and T. M. Eckrich Tetrahedron Lett. 1984 25 2415. 156 S. A. Math Two new enantiospecific routes to chrysanthemic acid (17) derivatives have been described. One involves a microbiological reduction of the achiral diketone (16)15 and the other utilises the natural chirality of a supv derivative.16 0 0 Halogenovinyl cyclopropanes such as (18) have been synthesized via vinylcar-benoid additions following dehydrohalogenation of 3,3-dihalogenated propene~.'~ Passage of 3-chlorocyclopropene over AgF2-KF results in quantitative conversion into 3-fluoro~yclopropene.'~ The unusual reactivity of fluorinated cyclopropanes has been further examined." The first syntheses of methylenecyclopropene (20) leading to direct observation of this unstable species have been reported.20 The diene can be formed by elimination from 2-methylenecyclopropyl chloride bromide or phenylsulphoxide (19; X = C1 Br or SOPh) or by pyrolysis of diazoketone (21) and can be transferred in vacuo and frozen in a liquid nitrogen trap for spectroscopy.The 'Hn.m.r. spectrum at -90 "C displays two apparent triplets (3.60 and 8.18) suggesting a significant contribution from the resonance form (20b). Methylenecyclopropabenzene and methylenecyclopropa[b]naphthalene derivatives have also now been prepared and are stable solids.2' Is D.Buisson R. Azerad G. Revial and J. d'hgelo Tetrahedron Lett. 1984 25 6005. 16 B. F. Fitzsimmons and B. Fraser-Reid Tetrahedron 1984 40,1279. W. Gathling S. Keyaniyan and A. de Meijere Tetrahedron Lett. 1984 25 4101. 18 N. C. Craig K. L. Sloan J. R. Sprague and P. S. Stevens J. Org. Chem. 1984 49 3847. 19 S. F. Sellers W. R. Dolbier jun. H. Koroniak and D. M.Al-Fekri J. Org. Chem. 1984 49 1033. 2o W. E. Billups. L. J. Lin and E. W. Casserly 1. Am. Chem. SOC.,1984 106 3698 S. W. Staley and T. D. Norden ibid p. 3699; G. Maier M. Hoppe K. Lanz and H. P. Reisenauer Tetrahedron Lett. 1984 25 5645. 21 B. Halton C. J. Randall and P. J. Stang J. Am. Chem Soc. 1984 106 6108. Alicyclic Chemistry Unlike propadienone (22),22 which has a kinked ground-state structure (22b) cyclopropylidenemethanone (23) has a quasi-symmetrical structure according to microwave spectroscopy.CH,=C=C=O e* CH,=C- bC=O \+ (22a) (23) On treatment with MeLi gem-dibromocyclopropanes bearing a -C02H group directly attached to the ring undergo a stereospecific debromination leading to trans-2-bromocyclopropanecarboxylic The optically active truns-2,3-dicyanomethylenecyclopropane(24)undergoes an extremely rapid base-catalysed epimerization to the cis-i~omer.~~ A kinetic study" of the thermal stereomutations of deuterated phenylcyclopropanes has revealed unexpectedly large rate constants for the interconversion of the syn- and anti-isomers (25) and (26). The kinetics of reactions of cyclopropyl radicals with olefins have also been reported.26 Bromination of the trans-tetradeuteriocyclopropane(27)gave the dibromides (28) and (29) the latter being formed largely (>85%) as the erythro-product (29a).This is consistent only with corner bromination leading to inversion at both of the substituted carbon atoms.27 Pyridine attack on the spiro-activated cyclopropanes (30; R = H or Ph) is revers- ible and has been the subject of a kinetic study." Cuprates undergo homoallylic addition to the cyclopropylcarbinyl bromides (31 ;R = Bun Pr' or But) giving olefins as E/Z mixtures apparently viu rearrangement of a Cut radical intermediate rather than the previously postulated Cu" radical or Cut cation complex.29 The 22 R. D. Brown P. D. Godfrey B. Kleibomer R.Champion and P. S. Elmes J. Am. Chem. Soc. 1984 106 7715. 23 L. K. Sydnes and S. Skare Can. J. Chem. 1984,62 2073. 24 S. L. Buchwalter J. Org. Chem. 1984 49 4551. 25 J. E. Baldwin T. U. Patapoff and T.C. Barden 1.Am. Chem. Soc. 1984 106 1421. 26 L. J. Johnston J. C. Scaiano and K. U. Ingold J. Am. Chem. Soc. 1984 106 4877. 27 J. B. Lambert W. J. Schulz jun. P. H. Mueller and K. Kobayashi J. Am. Chem. Soc. 1984 106 792. 28 M. A. McKinney K. G. Kremer and T. Aicher Tetrahedron Lett. 1984 25 5477. 29 R. T. Hrubiec and M. B. Smith Tetrahedron 1984 40,1457; see also M. S. Alnajjar G. F. Smith and H. G. Kuivila J. Org. Chem. 1984,49 1271; S. H. Bertz G. Dabbagh J. M. Cook,and V. Honkan ibid. p. 1739. 158 S.A. Matlin R (31)&~ 0 2 ~ 'wMgBr ,CO,Me Me CuI.Me,S (32) Me cuprate-mediated homoconjugate addition of but-3-enylmagnesium bromide to bicyclohexanone (32) has been proved to proceed with inversion of configuration and furnishes a useful intermediate for natural product ~yntheses.~' The thermal ring-opening cycloadditions of cyclopropyl derivatives with activated olefins have been re~iewed.~' Vinylcyclopropanes undergo acid-catalysed ring open- ing uia cations,32 but thermal rearrangement to cyclopentenes uia biradical inter- mediate~.~~ An efficient synthesis of 1-vinylcyclopropanols has been developed and the thermal rearrangements of their silyl ethers provides a versatile route to siloxcyc- lopentenes as illustrated by the spirovetivane synthesis (Scheme 2).34 I +yiox I +& 0 +7ioP 0 d Me3si0& +$io Scheme 2 30 D.F. Taber K. R. Krewson K. Raman and A. L. Rheingold Tetrahedron Lett. 1984 25 5283. 31 T. Tsuji and S. Nishida Acc. Chem. Res. 1984 17 56. 32 Z. Goldschidt B. Crammer and R. Ikan J. Chem. SOC.Perkin Trans. 1 1984 2697; G. Suzukamo M. Fukao and M. Tamura Tetrahedron Lett. 1984 25 1595. 33 J. J. Gajewski and J. M. Warner J. Am. Chem SOC,1984 106 802. 34 J. Ollivier and J. Salaun. Tetrahedron Lett.. 1984. 25. 1269 J. P. Barnier and J. Salaun ibid. p. 1273. Alicyclic Chemistry The cis-1 -methylcyclopropylcarbinylcation has been prepared for the first time and undergoes facile interconversion with the 1-ethylallyl cation.35 The cation (33; R = H or Me) prefers substitution over ring-opening to an ally1 cation as a result of the influence of the ester In protic or strongly ionizing media the cyclopropenylcarbinols (34; R = Me or Et) rearrange to cyclobutenes and low- temperature n.m.r.studies suggest the intermediate to be a homoaromatic cyclo- butenyl cation.37 I C0,Et C0,Et (33) The heat of formation of diphenylcyclopropenone has been estimated38 by photo- acoustic calorimetry as 360 * 17 kJ mol-' indicating a resonance stabilization energy of 46 kJ mol-'. Whereas cyclopropenone ketals react with olefins bearing two electron-withdrawing groups to give cyclopentenes olefins bearing one electron- withdrawing group give cyclopropanes and addition to carbonyl groups leads to products uia butenolide ortho esters (Scheme 3; X = COzMe or CN).39 X Scheme 3 35 C.Falkenberg-Andersen K. Ranganayakulu L. R. Schmitz and T.S. Sorensen J. Am. Chem Soc. 1984 106 178. 36 R. Amaud A. Dussauge H. Faucher R. Subra M. Vidal and M. Vincens Tetrahedron 1984,40,315. 37 M. Vincens C. Dumont and M. Vidal Bull Soc Chim Fr. ZZ 1984 59. 38 J. J. Grabowski J. D. Simon and K. S. Peters J. Am Chem SOC 1984 106,4615. 39 D. L. Boger and C. E. Brotherton Tetrahedron Lett. 1984,25 5611:D. L. Boger C. E. Brotherton and G.1. Georp. ihid.. p. 5615. 160 S. A. Math Theoretical calculation^^^ predict a non-planar structure for a cyclopropenyl anion in agreement with the expected anti-aromatic character of this species. 3 Four-membered Rings Cyclobutanones have been prepared in high yields by lithiation of l-bromo-l-ethoxycyclopropane addition of an aldehyde or ketone and acid-catalysed rear- rangement of the product (Scheme 4).41A four-step procedure for the synthesis of cyclobutenediones has been described (Scheme 5).42 Reagents i Bu'Li Et20 -78 "C; ii R'R2CO; iii 48% aq.HBF Scheme 4 Reagents i PhSH; ii CI,C=C=O; iii Et3N; iv 3-ClC6H4C03H Scheme 5 Chloro(trimethylsilylmethy1)ketene [2 + 21 cycloaddition to olefins affords sub- stituted cyclobutanones from which methylenecyclobutanones and methylenecyc- lopentanones can be synthesized (Scheme 6).43 'so F-,R2Ra R2 0 Scheme 6 40 B.A. Hess jun. L. J. Schaad and P. Carsky Tetrahedron Lett. 1984 25 4721. 41 R. C. Gadwood Tetrahedron Lett.1984 25 5851. 42 L. S. Liebeskind and S. L. Baysdon Tetrahedron Lett. 1984 25 1747. 43 L. A. Paquette R. S. Valpey and G. D. Annis J. Org. Chem 1984 49 1317; see also G. Mehta and K. S. Rao Tetrahedron Lett. 1984 25 1839. Alicyclic Chemistry Reaction of cyclobutanone with the anion of dialkyl (diazomethy1)phosphonates yields cyclopentyne as an intermediate. This has been trapped by [2 + 21 cycloaddi-tion to cis-1 -methoxyprop-1-ene giving cyclobutene (35). The trapping product (36) with trans-1 -methoxyprop-1-ene cannot be isolated since it undergoes electrocyclic ring opening to diene (37) which has itself been trapped by Diels-Alder reaction.44 The first experimental evidence for a cyclobutyne intermediate has also been 0 II +(RO),PCHN -Beckmann fragmentation of the cyclobutanone oximes (38) has been useda for the stereoselective synthesis of the macrolide intermediates (39)..KH - RCOCl +cN EtO EtO (384 (39a) (61o/o ) RCOCl + +N EtOTo" EtO (38b) (39b) (64%) (9"/0) 44 J. C. Gilbert and M. E. Baze J. Am. Chem. SOC,1984 106 1885. 45 K.-D. Baumgart and G. Szeimies Tetrahedron Lett. 1984 25. 737. 46 G. Frater U. Muller and W. Gunther Terruhedron Lerr. 1984 25 1133. 162 S. A. Matlin A reinvestigation of the cycloaddition of dimethyl acetylenedicarboxylate to enamines has been reported?’ It now transpires that the immediate [2 + 21 cycloaddi-tion products 3-dialkylaminocyclobutenes,are isolable only when the enamine is derived from a 5-membered (or occasionally 6-membered) ring.In all other cases the cyclobutene opens to a cis-truns-cycloalka-1,3-dienewhich may further rearrange under the reaction conditions. 4 Five-membered Rings 3,CDisubstituted pent-2-enals are stereospecificallycyclized by Wilkinson’s catalyst to cis-3,4-disubstituted cyclopentanones which are useful in the preparation of prostaglandin^.^^ The synthesis of the latter from cyclopentane intermediates has been reviewed.49 Cyclopentanone annulation can be achieved by AlCl,-catalysed intramolecular acylation of an allyl~ilane.~~ In two further procedures using intramolecular cycliz-ations of allylsilanes to construct 5-membered rings the epoxy-allylsilane (40) gave mainly cis-l-hydroxymethyl-2-vinylcyclopentane,51 whilst the chiral allylsilane aldehyde (41) cyclized to cyclopentenol (42) in high optical yield.52 TiCI -OH Me,Si T~CI QIl Methylenecyclopentanes have been prepared by a one-pot synthesiss3involving 1,4-bis(bromomagnesio)butane addition to a-chloroesters (43) and by palladium-catalysed additions4 of the ally1 carbonates (44;X = p-MeC6H4S02or CN) to enones and acrylates (45 Y = alkyl or alkoxy).4’ BrMgnMgB, C0,Et + -8 (43) 47 D. N. Reinhoudt W. Verboom G. W. Visser W. P. Trompenaars S. Harkema and G.J. van Hummel J. Am Chem SOC 1984,106 1341. 48 K. Sakai Y. Ishiguro K. Funakoshi K. Ueno and H. Suemune Tetrahedron Lett. 1984 25 961. 49 V. A. Dombrovski D. Y. Fonskii V. A. Mironov and P. M. Kochergin Russ.Chem Rev. 1984,53,401. H. Urabe and I. Kuwajima J. Org. Chem 1984,49 1140. 51 T. S. Tan A. N. Mather G. Procter and A. H. Davidson J. Chem SOC.,Chem Commun 1984 585; see also D. Schinzer Angew. Chem Int. Ed. EngL 1984 23 308. 52 K. Mikami T. Maeda N. Kishi and T. Nakai Tetrahedron Lett. 1984 25 5151. 53 J. Barluenga M. Yus J. M. Concellon P. Bernad and F. Alvarez 1. Chem. Rex (S) 1984 122. 54 1. Shimizu Y. Ohashi and J. Tsuji. Tetrahedron Lett.. 1984. 25. 5183. Alicyclic Chemistry New routes to cyclopentenones include Claisen condensation of crotonates with dimethyl ~xalate,~' acylation of acetylenes with p,y-unsaturated acid chlorides,56 palladium-catalysed cyclization of 1-ethynylprop-2-enyl acetate^,^' the Ramberg- Backlund reaction5* of cyclic sulphones (46) conden~ation'~ of the dithiane anion (47) with methyl thiovinyl phosphonium salt (48) and intramolecular acylation6' of the sulphoxides (49; X = OMe or NMePh).In a modification of the latter method,61 the hydroxy-intermediate (50) is dehydrated alkylated and pyrolysed to give methylenecyclopentenones (Scheme 7). RbSOPh- R1&SOPh PhCH,NMe,+C,-1. Met NaOH R,& R1+ HO SOPh HO + 2. A (50) Scheme 7 55 R. T. Brown W. P. Blackstock and M. Wingfield Tetrahedron Lett. 1984 25 1831. 56 M. Karpf Helv. Chim Acta 1984 67 73. 57 V. Rauterstrauch J. Org. Chem. 1984,49,950. 58 H. Matsuyama Y. Miyazawa Y. Takei and M. Kobayashi Chem Lett. 1984 833. 59 A. G. Cameron A. T. Hewson and M. I. Osammor Tetrahedron Lett.1984 25 2267. 60 M. Pohmakotr and P. Phinyocheep Tetrahedron Lett. 1984 25 2249. 61 M. Pohmakotr and S. Chancharunee Tetrahedron Lett. 1984 25 4141. 164 S. A. Matlin Condensation of the dianion of di-isopropyl hex-3-enedioate with ethyl 3- bromopropionate leads to an exo-methylenecyclopentanone (Scheme 8) a con- venient intermediate for the synthesis of prostaglandins and sarkomycin (51).62 Other routes to this type of compound involve addition of ally1 iron complexes to 01efins~~ and cyclization of the allenic ethers (52).& n 1 n Scheme 8 OR 0 5 Six-membered Rings Brominative cyclization of polyenes in acetonitrile at low temperature6’ leads to capture of the intermediate as the ion (53) which eliminates MeCN at room temperature to give the olefin (54).Metal-catalysed cyclization66 of the dienes (55; n = 1;X and Y = H Me C02Et COR) gives mixtures with RhCl( PPh3)3 favouring the 5-em-trig product (56;n = 1) ‘R Br’x 62 A. Misurni K. Furuta and H. Yarnamoto Tetrahedron Lett. 1984 25 671; K. Furuta A. Misumi A. Mon N. Ikeda and H. Yamamoto ibid. p. 669. 63 R. Baker R. B. Keen M. D. Moms and R. W. Turner J. Chem. SOC.,Chem. Commun. 1984 987; J. C. Watkins and M. Rosenblurn Tetrahedron Lett. 1984 25 2097. 64 M. A. Tius and D. P. Astrab Tetrahedron Lett. 1984 25 1539. 6s T. Kato M. Mochizuki T. Hirano S. Fujiwara and T. Uyehara 1.Chem. SOC.,Chem. Commun. 1984 1077. 66 R. Gngg P. Stevenson and T. Worakun J. Chem. SOC.,Chem. Commun..1984. 1073. Alicyclic Chemistry R and Pdo the 6-endo-trig product (57; n = 1; R = H). Pdo-catalysed cyclization of (55; n = 2; X = Y = C02Et) gives mainly (56; n = 2) together with some (57; n = 1; R = Me). In the cyclization of allysilane-substituted ketals the presence of the silicon group provides a very effective means for controlling the final position of the double bond (Scheme 9),67 SiMe, 1 ZnBr SnC'4 CHSiMe -Me0 OMe OMe Me0 OMe OMe Scheme 9 Chiral cyclohexanones have been prepared by the rearrangement of a sugar derivative68 and by the palladium-catalysed cyclization of the sodium salt (58) which proceeds with complete retention at the original chiral centre.69 Na' eMe ee OC0,Me (58) Several new syntheses of shikimic acid (60) and its labelled derivatives7' have been published.Strategies devised include Diels- Alder addition of dimethyl acrylate to f~ran,~' iodolactonization of cyclohex-3-enecarboxylicacid72 and intramolecular Wadsworth-Emmons olefination in the sugar phosphonate (59).73 The cyclohexyne (62) has been observed spectroscopically in a frozen matrix following photolysis of the cyclopropenone (61) and cycloheptyne was similarly generated.74 67 H.-F. Chow and I. Fleming J. Chem. SOC,Perkin Trans. I 1984 1815. 68 F. Chretien and Y. Chapleur J. Chem. SOC.,Chem Commun. 1984 1268. 69 K. Yamamoto R. Deguchi Y. Ogimura and J. Tsuji Chem. Lett. 1984 1657. 70 L. 0.Zamir and C. Luthe Can. J. Chem 1984 62 1169. 71 M.M.Campbell A.D. Kaye M. Sainsbury and R. Yavarzadeh Tetrahedron 1984.49.2461 ;Tetrahedron Lett. 1984 25 1629; D. Rajapaksa B. A. Keay and R. Rodrigo Can. J. Chem. 1984 62 826. 72 P. A. Bartlett and L. A. McQuaid J. Am. Chem SOC,1984 106 7854. 73 G. W. J. Fleet T. K. M. Shing and S. M.Warr J. Chem SOC Perkins Trans. I 1984 905. 74 A. Krebs W. Cholcha M. Miller and T. Eicher Tetrahedron Left. 1984 25 5027. 166 S. A. Matlin CO Bu' I CO Bu' HO' OH (59) (60) A convenient new procedure for Birch reduction of benzenes to cyclohexadienes utilises a calcium-amine-t-butyl alcohol ~ystem.'~ Crystal structures of cis-and truns-cyclohexane-l,2-diolsshow both to be present in chair forms which are held together by pairs of intramolecular H-b~nds.~~ The conformational steric isotope effect for carbon in a methyl group in cis-1,Cdimethyl- cyclohexane (63) has been measured as 1.24 f 0.25J mol-' (13C preferring to be equatorial) a smaller difference than that estimated from force-field calculation^.^^ The 1,3-diaxial interaction of Me and Ph groups on a cyclohexane ring has been determined7' by 13C n.m.r.to be 14.2 * 0.4kJmol-' and the gauche Me-Me interaction in truns-1,2-dimethylcyclohexaneto be 3.1 kJ mol-'. A critical re-examination of Diels- Alder reactions has led Dewar and Pierir~i~~ to conclude that despite their concerted nature a very unsymmetrical transition- state close to a biradical or zwitterion is' involved and that these reactions are neoer synchronous. However Tolbert and AliSo take a different view and have presented evidence that the influence of an adjacent chiral centre in the dienophile on the degree of asymmetric induction observed in the product is in strict accord only with the transition state of a synchronous process.Addition of Lewis acids changes the transition state to a less symmetrical asynchronous one. 75 R. A. Benkeser J. A. Laugal and A. Rappa Tetrahedron Lett. 1984 25 2089. 76 S. Sillapnaa M. Leskela and L. Hiltunen Acta Chem. Scand. Ser. B 1984 38 249. 77 S. L. R. Ellison M. S. Fellows M. J. T. Robinson and M. J. Widgery J. Chem SOC.,Chem. Commun. 1984 1069. 78 M. Manoharan and E. L. Eliel J. Am. Chem. SOC.,1984 106 367. 79 M. J. S. Dewar and A. B. Pierini J. Am. Chem SOC.,1984 106 203.8o L. M.Tolbert and M. B. Ali. J. Am. Chem. Soc. 1984. 106 3806. Alicyclic Chemistry 167 The rates of Diels-Alder reactions are dramatically increased by the presence of AlC1 or of the clay Fe"'-doped K10 montmorillonite.81 Regioselectivity in metal- catalysed cycloadditons can be very solvent-dependent.82 New approaches to asymmetric induction in the Diels-Alder reaction include the use of chiral vinyls~lphoxides,~~ and chiral chiral a,P -unsaturated carbo~imides~~ acrylate esters of camphor derivatives8' as dienophiles. The addition of chiral a-chloro-a -nitroso compounds to cyclohexadiene gives a very high enantiomeric excess in the [4 + 21 cycloaddition product.86 6 Seven-membered Rings The cycloaddition of ally1 cations to 1,3-dienes as a general method for the synthesis of 7-membered rings has been re~iewed.~' 3-Methoxycycloheptatrienes are con- veniently prepared88 by the ring expansion of Birch reduction products derived from guaiacol silyl ethers (Scheme 10).OSiEt .,ooMe OSiEt Li-NH, R' R R CH,I IEt,Zn I R R Scheme 10 Substituted homotropylidenes have been synthesized from cycloheptatrienes by Diels- Alder reaction with 1 ,2,4-triazoline-3,5-diones,addition of diazoalkanes and removal of the heterocyclic bridge (Scheme ll) making possible a study of the effects of substituents on the Cope rearrangements of these divinylcyclopropane ana~ogues.'~ " P. Laszlo and J. Lucchetti Tetrahedron Lett. 1984 25 1567; 2147; 4387. 82 J.-L. Metral and P.Vogel Tetrahedron Lett. 1984 25 5387. 83 T. Koizumi I. Hakamada and E. Yoshii Tetrahedron Lett. 1984 25 87; C. Maignan A. Guessous and F. Roessac ibid. p. 1727; S. M. Proust and D. D. Ridley Aust. J. Chem 1984 37 1677. 84 D. A. Evans K. T. Chapman and J. Bisaha J. Am Chem SOC,1984 106,4261. 83 W. Oppolzer C. Chapuis and G. Bernardinelli Tetrahedron Lett. 1984 25 5885; W. Oppolzer and C. Chapuis ibid. p. 5383; W. Oppolzer M. J. Kelly and C. Chapuis ibid. p. 5889. M. Sabuni G. Kresze and H. Braun Tetrahedron Lett. 1984 25 5377; H. Felber G. Kresze H. Braun and A. Vasella ibid. p. 5381. 87 H. M. R. Hoffmann Angew. Chem. tnt. Ed. EngL 1984 23 1. 88 V. A. Roberts M. E. Garst and N. E. Torres J. Org. Chem 1984,49 1136. 89 J. K. Kettering and G.Maas Tetrahedron 1984 40,391. 168 S. A. Matlin Scheme 11 7 Medium and Large Rings Cyclonona- 1,2,3-triene has been synthesized and isolated for the first time by carbenoid ring-expansion of cyclo-octa- 1,2-diene and is calculated to have a bent cumulene structure with angles of around 162” at the allenic carbons.” The 9-membered rings of isocaryophyllene and caryophyllene have been construc- ted9’ by intramolecular acyl transfer reactions of the 13-membered lactam sulphoxide (64a) and its isomer (64b). LDA -.-0 0 (644 (64b) Cyclization by intramolecular alkylation of the a-phenylthio nitrile (65) gives a 10-membered ring and the method has been used in a new germacrene ~ynthesis.’~ Another simple and direct method93 of cyclization leading to a 10-membered ring involves intramolecular alkylation of the di-unsaturated malonates (66; X-X and Y-Y = cis or trans CH=CH or C-C).” R. 0. Angus jun. and R. P. Johnson J. Org. Chem. 1984,49 2880. 91 Y.Ohtsuka S. Niitsuma H. Tadokoro T. Hayashi and T. Oishi J. Org. Chem. 1984 49 2326. 92 T. Kitahara and K. Mori J. Org. Chem. 1984,49 3281. 93 P. Deslongchamps S. Larnothe and H.-S. Lin Con. J. Chem. 1984 62 2395. Alicyclic Chemistry Me0,C C0,Me Me0,C COzMe Y(5 A X II YX w Me0,C C0,Me 0 ph3fi+-Intramolecular Wittig reactions of the aldehydic phosphonium salts (67;n = 5-8) have provided access to macrocyclic die none^.^^ The transannular reactions accompanying electrophilic additions to double bonds in 8-membered rings continue to be ~tudied.~’ Whereas bromination of cyclo-octene gives small amounts of cis-and truns-1,4-dibromides as well as 1,2-dibromides bromination of 1-trimethylsilylcyclo-octene has now been shown96 to give 1-bromocyclo-oct-4-ene in high yield uiu desilylaltion of the lY4-dibromide I68).8 Bicyclic Compounds Ionic bicyclobutane (69)is an intermediate in the reactions of phenylthiolate with 3-halogenobicyclobutanecarbonitrile(70; X = C1 or Br).97 Spiroann~lation~~ of cyclic ketones with 2-chloroethyl dimethylsulphonium iodide occurs readily in the presence of base (Scheme 12; n = 1,2,3,7). The diazoacetic ester (71) cyclizes in high yield in the presence ofa soluble copper catal ys t.99 94 H. J.Bestmann and H. Lutke Tetrahedron Lett. 1984 25 1707. 95 J. E. Norlander K. D. Kotian D. E. Raff F. G. Njoroge and J. J. Winemiller J. Am. Chem. SOC.,1984 106 1427; G. Haufe and M. Muhlstadt Tetrahedron Lett. 1984 25 1777; G. Haufe zbid. p. 4365. 96 D. Dhanak C. B. Reese and D. E. Williams J. Chem. Soc. Chem. Commun. 1984 988. 91 S. Hoz and D. Aurbach J. Org. Chem. 1984,49 3285. 98 S. M. Ruder and R. C. Ronald Tetrahedron Lett. 1984 25 5501. 99 E. J. Corey and A. G. Myers Terrahedron Lett. 1984 25 3559. 170 S. A. Matlin PhsVcN xTN Scheme 12 The cyclization of y-stannyl alcohols to cyclopropanes has been further developed and extended to the synthesis of gem-substituted bicyclo[n.l.O]alkanes (Scheme 13 ; n = 1-3).'0° Whereas cis-1,2-diethylcyclopropaneis 4.6kJ mol-' less stable than the trans-isomer cis-and trans-bicyclo[6.1 .O]nonanes have the same enthalpies of formation.'" PhLi SOCI ___ (cza ___ (PPh SnBu3 SnBu Scheme 13 Bicyclic compounds with various ring-sizes can be obtained by the transmetalla- tion-cyclizations of the trimethylstannyl olefins (72) lo' and lanthanide-induced cyc- lizations of the iodo-ketones (73).'03 Copper( I)-catalysed intramolecular [2 + 21 photo-cyclization'@' of myrcene (74) afforded the bicyclo[3.1 .O]heptane (75) as well as the cyclobutene (76).Enantioselec-tion in [2 + 21 photo-cyclizations has not been extensively studied hitherto but it is now rep~rted"~ that the product (78) of addition of the (S)-enantiomer of the 100 J.F. Kadow and C. R. Johnson Tetrahedron Lett. 1984 25 5255. LO1 K. B. Wiberg E. C. Lupton jun. D. J. Wasserman A. de Meijere and S. R. Kass J. Am. Chem. Soc. 1984 106 1740. lo' E. Piers and H. L. A. Tse,Tetrahedron Lett. 1984 25 3155. 103 G. A. Molander and J. B. Etter Tetrahedron Lett. 1984 25 3281. 104 K. Avasthi S. R. Raychoudhun and R. G. Salomon J. 0%.Chem. 1984,49 4322. 105 K. Bruneel D. De Keukeleire and M.Vandewalle J. Chem. Soc. Perkin Trans. I 1984 1697. Alicyclic Chemistry SnMeJ H (73) ketene acetal (77) to cyclopentenone is formed with high intrinsic asymmetric induction. The regioselectivity of the ene reactionlM is affected by the presence of a TMS group,lo7 the diene (79; R = H) cyclizing to a mixture of (80; R = H) and (81) whereas the diene (79; R = SiMe,) cyclizes exclusively to (80; R = SiMe,).Several strategies have been reported for the synthesis of hydrindanes including the use of 9,10-dibromocamphor to construct the intermediate (82) from which methylenehydrindane (83) was obtained,'08 intramolecular acylations of the '06 F. E. Ziegler and J. J. Mencel Tetrahedron Lett. 1984 25 123. I07 F. E. Ziegler and K. Mikami Tetrahedron Lett. 1984 25 127. 108 J. H. Hutchinson T. Money and S. E. Piper 1. Chem. SOC.,Chem. Commun. 1984 455. 172 S. A. Matlin vinylsilane (84) and related intramolecular Diels- Alder reactions' lo such as the HF-catalysed cyclization of the chiral trienic ester (85) which furnishes the alcohol (86) after reduction but without asymmetric induction,"' and the Me,AlCl-catalysed intramolecular Diels- Alder reaction of (87 ; X = chiral oxazolidone) which affords hydrindane (88) with a high degree of asymmetric induction.ll2 Whilst these methods give trans-hydrindanes construction of the cis-hydrindane system is required for the synthesis of a number of classes of natural Br H (87) (88) 109 S.E. Denmark and J. P. Germanas Tetrahedron Lett. 1984,25 1231; K. Fukuzaki E. Nakamura and I. Kuwajima ibid. p. 3591. 110 M. Yoshioka H. Nakai and M. Ohno J. Am. Chem. SOC.,1984 106 1133; P. G. Gassman and D. A. Singleton ibid p. 6085; M. J. Kurth D. H. Bums,and M.J. OBrien J. Org. Chem. 1984,49,731; D. D. Sternbach D. M.Rossana and K.D.Onan ibid. p. 3427; S. D. Burke D. R. Magnin J. A. Oplinger J. P.Baker and A. Abdelmagid Tetrahedron Lett. 1984 25 19. 111 W. R. Roush H. R.Gillis and A. P.Essenfeld 1. Org. Chem 1984,49 4674. 112 D. A. Evans K. T. Chapman and J. Bisaha Tetrahedron Lett. 1984 25 4071. I13 S. Ohira Bull. Chem. SOC.Jpn. 1984 57 1902; H. Niwa K. Wakamatsu T. Hida K. Niiyama H. Kigoshi M. Yamada H. Nagase M.Suzuki and K. Ya'mada J. Am Chem SOC 1984 106,4547; M. E. Jung and L. A. Light ibid. p. 7614. Alicyclic Chemistry 173 Reagents i H2,Pd-C or Li-NH,-Bu'OH; ii LiAIH,; iii MeCOSH; iv; 3-CIC6H4C03H Scheme 14 and a strategy has been de~eloped"~ for the stereospecific conversion of hydrin- denones such as (89) into either type of product (Scheme 14).Approaches to the stereocontrolled synthesis of cis-and truns-bicyclo[6.3.0] and [5.3.01 systems are illustrated by the Al-catalysed cyclization"' of the keto-olefin (90) Ru04 oxidation116 of the triquinane olefin (91) to the diketone (92) use of boron hydride as a template for the carbonylation-cyclization"7 of the diene (93) to ketone (94) and conjugate addition-enolate trapping' '' to generate the intermedi- ate (95) which was cyclized to lactone (96; X = "Me or OCH2CH20) and this was converted by Claisen rearrangement of the silyl enolate of the ester into trans-hydrazulene (97). 6 0 1C12Me MeAICI H 114 E. J. Corey and T. A. Engler Tetrahedron Lett. 1984 25 149. B. B. Snider and C. P. Cartaya-Marin J. Org. Chem. 1984 49 153.116 G. Mehta and A. N. Murty J. Chem. Soc. Chem. Commun. 1984 1058. 117 J. W. S. Stevenson and T. A. Bryson Chem. Lett. 1984 5. 118 M. J. Begley A. G. Cameron and D. W. Knight 1. Chem. SOC.,Chem. Commun.,1984 827. + 9 '"> 1.BuLi S. A. Matlin 2. BrCH,CO,Et 0 OTHP OTHP (95) n I n I. LDA Bu'SiMe,CI t 2. A CO,Si+ I (97) (96) Silicon-directed N-acyliminium ion cycli~ation"~ of the ethoxylactam (98; R = H or CH2Ph) provides access to the trans-fused compound (99). Titanium-catalysed cyclization of the allylsilane (100; R = H Me) affords a cis- and trans-mixture (101) which is converted entirely into the trans-isomer with base.12* SiMe3 -0 0 Many additional strategies for obtaining the decalin system have been reported12' and some are depicted in Scheme 15.119 H. Hiemstra W. J. Klaver M. J. Moolenaar and W. N. Speckamp Tetrahedron Lett. 1984 25 5453. I2O T. Tokoroyama M. Tsukamoto and H. Iio Tetrahedron Lett. 1984 25 5067. 121 Y. L. Yang S. Manna and J. R. Falck J Am Chem SOC.,1984,106,3811; E. R. Koft and A. B. Smith ibid. p. 2115; W. G. Dauben and G. Shapiro J. Org. Chem. 1984 49 4252; C. Agami F. Maynier C. Puchot. J. Guilhem and C. Pascard Tetrahedron 1984 40,1031. Alicyclic Chemistry &:. (Ref 122) ~ wC02Et 0-O \ ( Ref 123) u- H H (Ref 124) Scheme 15 A new approach'*' to spirovetivanes is based on the fragmentation and recycliz- ation of Diels-Alder adducts (Scheme 16). An alternative route involves intramolecular cyclization of substituted cyclopentadienes.'26 $3 0 / Scheme 16 122 E.Piers and B. W. A. Yeung .I.Org. Chem. 1984 49 4567. P. R. Jenkins K. A. Menear P. Barraclough and M. S. Nobbs J. Chem SOC.,Chem. Commun. 1984 1423. 124 K. Mori and M. Waku Tetrahedron 1984,40 305. 125 A. Murai S. Sato and T. Masamune BulL Chem SOC.Jpn. 1984,57 2276; 2282; 2286; 2291. 126 K. Annak J. F. Kingston and A. G. Fallis Can. J. Chem. 1984 62 2451; see also K. Annak J. F. Kingston S. J. Alward and A. G. Fallis ibid. p. 829. 176 S. A. Matlin Ally1 cation cycloaddition to cyclopentadiene provides entry to the bicyclo[3.2.l]octane ~keleton,”~ whilst the bicyclo[4.1 .O] system is available by [6 + 21 cycloadditions of cycloheptatrienes.’28 The [6 + 41 cycloadditions of unsym-metrical tropolones with dienes have been shown’29 to proceed with ‘even’ selectivity faveunng the 1,6-product (Scheme 17).oo+& Q-) B Scheme 17 Bicyclic compounds with unusual geometries for which syntheses have been reported include the in,out-bicyclo[4.4.4]tetradecane (lO2),l3’ the bicyclo[5.3.2]- dodecane derivative (103) which contains a doubly orthogonal 1,3,5-triene unit,”’ and the chiral [10.10]- and [22.10]-betweenanes (104; n = 10 or 221 of (R)-configur-ation.13’ Analysis of c.d. spectra indicates that the bis-dienes (105; R = D Me) have eclipsed conformations whereas the structure of the alcohol (105; R = OH) is twisted.’33 2 (1 02) (1 03) TH(104))I0 (1 05) BH A a&.,.fi 9 Polycyclic Compounds A theoretical study’34 of the C(l)-C(3) bond in [l.l.l]propellanes in which the two bridgehead carbons have inverted configurations suggests a novel non-axial orbital arrangement termed ‘a-bridged T’.One-electron oxidation of tetra-t-butyltetrahedrane gives tetra-t-butylcyclo- butadiene radical cation.135 A one-step synthesis of tricyclo[3.2.1 .02*’]octan-6-ones has been developed’36 which involves vinylsulphone addition to a cyclohexenone anion by a combination of inter- and intra-molecular Michael reactions (Scheme 18). This type of combina-127 H. M. R. Hoffmann,A. Weber and R. J. Giguere Chem. Ber. 1984 117 3325. 128 K. Mach H.Antropiusova L. Petrusova V. Hanus and F. Turecek Tetrahedron 1984 40,3295.129 M. E. Garst and V. A. Roberts J. Am. Chem SOC 1984 106 3882. J. E. McMurry and C. N. Hodge J. Am. Chem. SOC.,1984 106 6450. 131 W. von E. Doering and J. C. Schmidhauser J. Am Chem SOC 1984 106 5025. 132 J. A. Marshall and K. E. Flynn J. Am Chem SOC.,1984,106,723; see also J. A. Marshall,J. C. Peterson and L. Lebioda ibid. p. 6006. 133 R Gabioud and P. Vogel Tetrahedron Lett. 1984 25 1729. 134 J. E. Jackson and L. C. Allen J. Am Chem. SOC.,1984 106 591. 135 H. Bock B. Roth and G. Maier Chem Ber. 1984 117 172. R. M. Cory and R. M. Renneboog J. Org. Chern. 1984,49 3898. 136 Alicyclic Chemistry SO,R Scheme 18 + w .m+ Scheme 19 tion has also been in a new strategy for the synthesis of cedrene (Scheme 19).The isomeric hydrocarbon clovene has been prepared'38 by application of the a-alkynone cyclization reaction (Scheme 20). The highly strained (247 kJ mol-' calculated) 1,7-cyclobutanonorbornanesystem has been synthesized for the first time by rearrangement of the propellane (106) followed by ring contraction. As expected the ketone (107) shows extreme reluctance to enolize towards the 2-position and undergoes acid-catalysed H-D exchange only slowly at the 4-po~ition.l~~ 137 M. Horton and G. Pattenden J. Chem. SOC.,Perkin Trans. I 1984 811. 138 J. Ackroyd M. Karpf and A. S. Dreiding Helv. Chim. Acta 1984 67 1963. 139 P. E. Eaton P. G. Jobe and I. D. Reingold J. Am. Chem. SOC., 1984 106 6437. 178 S. A. Matlin X-Ray studies have established that the double bond in norbornenes is not planar but bent towards the endo-face.Ia Two propellatrienones (109) and (1lo) have been prepared in nine steps from the diester (108) and their ring inversion dynamics studied by n.m.r.These studies led to the conclusion that energy barriers are not high enough to provide for the possibility of optical resol~tions.'~~ Conformational equilibria in perhydrophenalene isomers142 and in polyspirane (111)143 have also been examined and cascade rearrangements of the polyspiranes continue to be studied.14 0 C0,Me 140 A. A. Pinkerton D. Schwarzenbach J.-L. Birbaurn P.-A. Carrupt L. Schwager and P. Vogel Helv. Chim Actu 1984,67 1136. 141 H. Jendralla C. W. Doecke and L. A.Paquette J. Chem SOC Chem Commun 1984,942. 142 J. L. M. Dillen J. Org. Chem 1984,49 3800. 143 L. J. Fitjer U. Klages W. Kuhn D. S. Stephenson G. Binsch M. Noltemeyer E. Egert and G. M. Sheldrick Tetrahedron 1984 40,4337. 144 L. J. Fitjer D. Wehle M. Noltemeyer E. Egert and G. M. Sheldrick Chem Ber. 1984 117 203; L. J. Fitjer W. Kuhn U. Klages E. Egert W. Clcgg N. Schormann and G. M. Sheldrick ibid p. 3075. Alicyclic Chemistry 179 Dimerization of the strained olefin (1 12) takes place at room temperature in DMF and furnishes the 'superphane' (1 13).14' The homologous polyene (1 14) has also been prepared.'& All-cis-[5.5.5.5]fenestrane,containing a planoid tetraco-ordinate carbon atom has been ~ynthesized'~~ by two routes (Scheme 21) as well as the first derivative (115) of [4.4.4.5]fene~trane.'~~ Semi-empirical calculations predict orthogonene (1 16) to be an olefin with an orthogonal ground-state structure having singlet and triplet states close in energy.'49 0 Scheme 21 (1 17) The first synthesis of homoiceane (117) uses a homo-Diels-Alder reaction to assemble the frarnew~rk.'~' The intramolecular Diels- Alder reaction has been reviewed'" and applications demonstrated in the synthesis of a variety of polycyclic including anthra~yclines'~~ and atisane.lS4 145 K.B. Wiberg M. G. Matturro P.J. Okarma and M. E. Jason J. Am. Chem. SOC.,1984 106 2194; K. B. Wiberg R.D. Adams P. J. Okarma M. G. Matturro and B. Segmuller ibid. p. 2200. 146 J. E. McMurry G.J. Haley J. R.Matz J. C. Clardy G. Van Duyne R. Gleiter W. Schafer and D. H. White J. Am. Chem. SOC.,1984 106 5018. 147 M. Luyten and R.Keese Angew. Chem. Int. End. EngL 1984,23,390; Helv. Chin Actq 1984,67 2242. 148 V. B. Rao S. Wolff and W. C. Agosta J. Chem. SOC Chem. Commun. 1984 293. 149 D. A. Jeffrey and W. F. Maier Tetrahedron 1984 40,2799. 150 R. Yamaguchi M. Ban and M. Kawanisi J. Chem. SOC.,Chem. Commun. 1984 826. 151 A. G. Fallis Can. J. Chem. 1984 62 183. 152 G. Gallacher A. S. Ng S. K. Attah-Poku K. Antczak S. J. Alward 3. F. Kingston and A. G. Fallis Can. J. Chem. 1984 62 1709; B. M. Trost M. Lautens M.-H. Hung and C. S. Carmichael J. Am. Chem. SOC.,1984 106 7641. 153 J. Tamariz and P. Vogel Angew. Chem. Int. Ed. Engl.1984 23 74. 154 M. Ihara M. Toyota. K. Fukumoto T. Kametani and T. Honda J. Chem. Res. (S) 1984 252. 180 S. A. Matlin New approaches to the taxane carbon skeleton have been devel~ped'~~ and two are shown in Scheme 22. (Ref156) OH (Ref 157) Scheme 22 A polyene cyclization route to the androstane skeleton has been as well as intramolecular Diels- Alder routes to steroid^"^ and multi-step syntheses of gibberellic acid'60 and quassinoids161 have been developed. Antitumour sesquiter- penes such as quadrone (1 18) and coriolin16* continue to excite interest following 155 H. Nagaoka K. Ohsawa T. Takata and Y. Yamada Tetrahedron Letr. 1984 25 5389. 156 P. A. Brown P. R. Jenkins J. Fawcett and D. R. Russell J. Chem. SOC.,Chem.Commun.. 1984 253; see also K. Sakan and D. A. Smith Tetrahedron Lett. 1984 25 2081. 157 H. Neh S. Blechert W. Schnick and M. Jansen Angew. Chem. Znt. Ed. Engl. 1984 23 905. 158 J. R. Hwu and E. J. Leopold J. Chem. SOC.,Chem Commun. 1984 721. 159 M. E. Jung and K. M. Halweg Tetrahedron Lett. 1984 25 2121; G. Stork G. Clark and T. Waller ibid. p. 5367. 160 J. M. Hook,L. N. Mander. and R. Urech J. Org. Chem.. 1984 49 3250. 161 P.A. Grieco H. L. Sham J. Inanaga H. Kim and P. A. Tuthill J. Chem. SOC.,Chem. Commun. 1984 1345; D. G. Batt N. Takamura and B. Ganem J. Am. Chem. SOC.,1984,106,3353; G. Vidari. S. Femno and P.A. Grieco ibid. p. 3539. 162 M. Demuth P. Ritterskamp and K. Schaffner Helu. Chim Acra 1984,67,2023; S. Knapp A. F. Trope, M.S. Theodore N. Hirata and J. J. Barchi J. Org. Chem. 1984 49 608; T. Ito N. Tomiyoshi K. Nakamura S. Azuma M. Izawa F. Maruyama M.Yanagiya H.Shirahama and T. Matsumoto Tetrahedron 1984 40 241; P. F. Schuda and M. R. Heimann ibid. p. 2365. Alicyclic Chemistry 181 on from last year's reports of synthetic strategie~,'~~ new details of synthetic approaches to both compounds have appeared and the absolute configuration of the natural (-)-quadrone is now established as (1 18).'@ Among numerous reports dealing with routes to triq~inanes,'~' two groups'66 have independently described the transannular cyclization of a bicyclo[6.3.0]un- decane derivative as a method for constructing the ring system of pentalenene (120; Scheme 23).The related pentalenolactones have been appr~ached'~' through intramolecular carbenoid insertion in the diazoester (121). ' BF JU H' & OCOH Scheme 23 0 (121) The heat of formation of dodecahedrane is predicted'68 to be -20.9 kJ mol-' by ab initio MO calculations. A better synthesis of peristylane and as yet unsuccessful attempts to roof it to form dodecahedrane have been de~cribed.'~~ I63 S. A. Math Annu. Rep. hog. Chem. Sect. B 1983 83 189. 164 S. D. Burke C. W. Murtiashaw J. 0. Saunders J. A. Oplinger and M. S. Dike J. Am. Chem. Soc. 1984 106 4558; K. Cooper and G. Pattenden J. Chem. SOC.,Perkin Trans. 1 1984 799; A. B. Smith and J. P. Konopelski J. Org. Chem. 1984 49 4094; K. Kon K. Ito and S. Isoe Tetrahedron Lett. 1984 25 3739.I65 M. Dorsch V. Jager and W. Sponlein Angew. Chem. Int. Ed. Engl. 1984 23 798; S. J. Alward and A. G. Fallis Can. J. Chem. 1984 62 121; H. A. Patel and J. B. Stothers ibid. p. 1926; L. A. Paquette and K. E. Stevens ibid. p. 2415; B. A. Dawson A. K. Ghosh J. L. Jurlina A. J. Ragauskas and J. B. Stothers ibid. p. 2521; E.Carceller M.L. Garcia A. Moyano and F. Serratosa J. Chem. Soc. Chem. Commun. 1984 825; Y. Tobe S. Yamashita T. Yamashita K. Kakiuchi and Y. Odaira ibid. p. 1259; G. Mehta D. S. Reddy and A. V. Reddy Tetrahedron Lett. 1984,25,2275; D. Wilkening and B. P. Mundy ibid. p. 4619. 166 G. Pattenden and S. J. Teague Tetrahedron Lett. 1984 25 3021; G. Mehta and K. S. Rao' ibid. p. 3481; see also J. L. Jurlina H. A. Patel and J.B. Stothers Can. J. Chem. 1984 62 1159; E. Piers and V. Karunaratne J. Chem. SOC., Chem. Commun. 1984 959. 167 D. E. Cane and P. J. Thomas. J. Am. Chem SOC..1984. 106. 5295. 168 J. M. Schulrnan and R. L. Disch J. Am. Chem. SOC.,1984 106 1202. 169 P. E. Eaton A. Srikrishna and F. Uggeri J. Org. Chem. 1984,49 1728; P. E. Eaton W. H Bunnelle and P. Engel Can. J. Chem. 1984 62 2612.

ISSN:0069-3030    

DOI:10.1039/OC9848100153

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

9 Heterocyclic Compounds By E. H. SMITH Department of Chemistry Imperial College of Science and Technology London SW7 2AY 1 General Dedicated issues of two journals contain the reports of presentations at two inter- national meetings on heterocyclic chemistry held at Tokyo'" and Kaiserslautern.'b Two new books of general interest to heterocyclic chemists deal with 1,3-dipolar cycloadditions2 and with physical methods in heterocyclic chemi~try.~ Advances in Heterocyclic Chemistry continues to advance and a review on the photocyclization of stilbenes and related molecules contains some interesting heterocyclic example^.^ Two general procedures have been described for the N-methylation of benz-imidazoles indoles and benzotriazoles which involve heating these compounds with dimethylformamide dimethyl aceta16" or with dialkyl oxalates plus potassium alkoxides in dimethylformamide.6b Improvements over methods using methyl iodide or dimethyl sulphate are claimed.A sequence of reactions entailing o-thallation of an aromatic acid or amide followed by palladium-catalysed coupling with an olefin and concomitant cyclization forms the basis of a general synthesis of a range of benzo-fused heterocycles (Scheme l).' 2 Three-membered Rings Two new versions of the synthesis of epoxides from 2-hydroxyalkyl derivatives use dichlorocarbene to generate the leaving group and ostensibly the oxyanion in one step (Scheme 2).8 Both methods are stereoselective but the stereochemical results suggest that a cyclic mechanism intimated by Krief and his co-workers (depicted by the arrows) is not correct.A reaction between imines and the anions of chlorosulphones provides a route to aziridines analogous to the glycidic ester synthesis of epoxides (Scheme 3).9 The ' (a) 9th International Congress on Heterocyclic Chemistry Koshi University Tokyo August 1983 Heterocycles 1984,21; (b)10th European Colloquium on Heterocyclic Chemistry Kaiserslautern October 1983 Bull. SOC. Chim. Belg. 1984 93. 509605. * '1,3-Dipolar Cycloaddition Chemistry' ed. A. Padwa Wiley-Interscience New York 1984. 'Physical Methods in Heterocyclic Chemistry' ed. R. R. Gupta Wiley-Interscience New York 1984. Adu. Heterocycl. Chem. 1983 34; 1984 35 36. F. B. Mallory and C. W. Mallory Org. React. 1984 30,1. (a) R.W. Middleton H. Monney and J. Parrick Synthesis 1984 740; (b)J. Bergman and P. Sand Tetrahedron Letr. 1984 25 1957. ' R. C. Larock C.-L. Liu H. H. Lau and S. Varaprath Tetrahedron Lett. 1984 25 4459. (a) L. Castedo J. L. Castro and R. Riguerra Tetrahedron Letr. 1984 25 1205; (6) J. L. Laboureur W. Dumont and A. Krief ibid. 1984 25 4569. (a) V. Reutrakul V. Prapansiri and C. Panyachotipun Tetrahedron Lett. 1984,25 1949; (b)C. Mahidol V. Reutrakul V. Prapansiri. and C. Panyachotipun Chem. Lett. 1984 969. 183 184 E. H.Smith II 71% TI(02 C. C F3)2 Reagents i Tl(02C.CF3)3 CF,CO,H; ii Li2PdC14 MeCN base or heat Scheme 1 /Ref 8b It HO-C-C-X 1 II SMe2 /\ 0 Reagents i CHC13 50% NaOH Bun4N+CI-; ii TlOEt CHC13 Scheme 2 S02Ph Ar' 3Ar2 c1 N Ar2 N Ar2 Scheme 3 Heterocyclic Compounds Thai workers also show that the resultant sulphonyl aziridines can be readily alkylated?' In a potentially general approach to unstable methyl-substituted Dewar-furans a novel formal [2 + 21 cycloaddition forms the first step followed ultimately by a photoaromatization (Scheme 4)." In an adjacent paper," the authors report a successful trapping of the related species (1) by furan.(1) Reagents i DMSO; ii Zn-Ag dimer THF reflux; iii m-CPBA; iv diglyme reflux; v hv (254nm) -90°C Ph Scheme 4 Suitably mild methods for the deoxygenation of epoxides are sparse. It is now reported that a combination of dimethyl diazomalonate and catalytic quantities of rhodium(11) acetate in boiling benzene effects just such a process stereospecifically.12 An alternative stereospecific ring-opening occurs when thiiranes are heated with the benzyne precursor benzenediazonium-2-carboxylate(Scheme 5).13 Derivatives of thiiranes also prove to be of value in the synthesis of other heterocycles.Thus the allene episulphide (2) acts like the zwitterion (3) (Scheme 6) usually in the presence of Lewis acids,14 and the thiirene 1,l-dioxides (4) are more reactive equivalents of the corresponding acetylenes in their cycloadditions (Scheme 7)." lo R. N. Warrener I. G. Pitt and R. A. Russell J. Chem. SOC.,Chem. Commun. 1984 1464. 'I R.N. Warrener I. G. Pitt and R. A. Russell J. Chem. Soc. Chem. Commun. 1984 1466.12 M. G. Martin and B.Ganem Tetrahedron Lett. 1984,25 251. l3 J. Nakayama S.Takeue and M.Hoshino Tetrahedron Lett. 1984 25 2679. 14 W. Ando T. Furukata Y. Hanyu and T. Takata Tetrahedron Lett. 1984 25 4011. M.Komatsu Y.Yoshida M. Uesaka Y. Ohshiro and T. Agawa J. Org. Chem. 1984,49,1300. 186 E. H. Smith PhS PhvPh -h S Ph Ph T-7 PhN,+CI-. 0 reflux PhS)JPh phb-*Ph S Ph Scheme 5 R,C=O 48-70% -sxo RR Scheme 6 R R PhCzk-NPh phQphR R ArQPhH + HN \I R R R = Me Ph R = Ph Scheme 7 Heterocyclic Compounds Attempts to form oxirenes and reactions which possibly proceed through such species are the subject of a review16 and the family of electron-excessive irenes is extended by the synthesis of the phosphorus example (9.'' Ph vPh P I Ph (5) 3 Four-membered Rings In the presence of boron trifluoride etherate oxetanes can be opened by lithium ester or amide enolateslgn or acetylides,'8b the former reaction resulting in a sub- sequent closure to 6-lactones after acidification (Scheme 8).'GX R- 2 n R 3 - R 2 n 1 3 +\ R' 0- R1 0-0 x R' 0 Scheme 8 The bis-alkylidene-1,3-dithietane(6) has been shown to act as a stable form of the thioketene (7) in [3 +21-(with sodium azide) and [2 +21-(with an ynamine and an imine) cycloadditions across the C=S bond." In contrast the cyanoalkyl- idene- 1,3-dithietanones (8) react with imines to give the six-membered heterocycles (9) (Scheme 9) which eliminate COS to give thio-P-lactams only in sterically hindered cases (see P-lactam section).20 R' (9) Scheme 9 16 E.G. Lewars Chem. Rev. 1983,83 519. l7 A. Marinetti F. Mathey J. Fischer and A. Mitschler J. Chem. SOC..Chem. Commun. 1984 45. 18 (a) M. Yamaguchi K. Shibato and I. Hirao Tetrahedron Lett. 1984 25 1159; (b) M. Yamaguchi Y. Kobayashi and I. Hirao Tetrahedron 1984 40,4261. 19 G. L'Bbbe P. Vangheluwe S. Toppet G. S. D. King and L. van Meervelt Bull. SOC.Chim Belg. 1984 93 405. 20 E. Schaumann K. Wriede and G. Adiwidjaja Chem. Ber. 1984 117 2205. 188 E. H.Smith P-Lactams.-A number of phosphorus substituted P-lactams have been synthesized including the thienamycin phosphonate analogues ( which were stable to renal dehydropeptidase the cis-and trans-1-phosphacephalosporins (11),22a (12),22band (13),22cand the monocyclic p-lactam (14).23aIn the synthesis of the last compound OEt HO M eO 0&NyJ C0,Me (Scheme 10) the formation of only that stereoisomer indicated was claimed whereas the analogous synthesis starting from the cyano-amide (15) is reported to give a mixture of stereoisomers epimeric at C-4 (ratio = 51 :22).23bThe few data that are available suggest that the phosphorus groups have not enhanced the antibacterial activity.Scheme 10 Phosphorus reagents have proven to be eminent mediators in two p-lactam closures.24 Both research teams report that the unsubstituted phosphoramidate (PhO)P(Cl)NHPh is ineffective in the condensations (Scheme 11).A new route to carbapenams and carbacephams has been described in which the key steps are generation and ring-closure of a tricarbonyl intermediate (Scheme 21 A. Andrus B. G. Christensen and J. V. Heck Tetrahedron Lett. 1984 25 595. 22 (a) H. Satoh and T. Tsuji Tetrahedron Lett. 1984 25 1733; (b) H. Satoh and T. Tsuji ibid. 1984 25 1737; (c) M. M. Campbell M. C. Carruthers S. J. Michel and P. M. Winter J. Chem. SOC.,Chem. Commun. 1984 200. 23 (a) M. Shiozaki and H. Masuko Heterocycles 1984,22 1727; (b) M. Shiozaki H. Maruyama and N. Ishida ibid. 1984 22 1725. 24 (a)J. M. Aizpurua I. Ganboa F. P. Cossio A. Gonzalez A. Meta and C. Palomo Tetrahedron Lett. 1984 25 3905; (6) S. R. Shridhar B. Ram V. L. Narayana A. K. Awasthi and G. J. Reddy Synthesis 1984 846.Heterocyclic Compounds 0 CI R4XCH,C0,H COY K+ I1 Y I PhOPCl ? (PhO)P( NMePh) + + _____ 0Ei32 Et,N KR2 = NhOMe,XR4 0 Scheme 11 n = 1,2 1ii Reagents i Me2NCH(OMe), 25 "C; ii lo2;iii HF. pyridine MeCN Scheme 12 12).25"The method was used for the synthesis of the antibiotic (*)-PS-5 (16).25b A sulphoxide derivative of this antibiotic is reported to undergo displacement by two stabilized carbanions generated using the base tetramethylguanidine (Scheme 13).26 Other bases such as NaH NaOMe or KOBu' resulted in rupture of the 25 (a)H. H. Wasserman and T H. Han Tetrahedron Lett. 1984 25 3743; (b) H. H. Wasserman and T. H. Han ibid. 1984 25 3747. 26 T. Yoshioka K. Yamamoto Y. Shimauchi Y. Fukugawa and T.Ishikura J. Chem. Soc. Chem. Commun. 1984 1513. 190 E. H. Smith X = H,Y = NO X = CN,Y = C0,Me Scheme 13 p-lactam ring. A potential precursor (17; X = OAc) of the related asparenomycins (18)was prepared by the addition of chlorosulphonyl isocyanate to an allenyl acetate (Scheme 14).27Functionalization of the methyl groups could be achieved by allylic bromination in the more stable sulphone (17; X = S0,Ph). 07) Scheme 14 FN 20 "C, +=-s- 7 days ShoMe An X-ray structure determination of the thio-P-lactam (19) indicated a flatter N-pyramid and a shorter N-1 to C-7 distance implying a higher strain in the four-membered ring imposed by the thiocarbonyl group,28 a feature which must be reckoned with in future attempts at the synthesis of these analogues.A new N-protecting group for the synthesis of N-unsubstituted p-lactams is the formylmethyl group prepared from an ally1 or 2,2-dichloroethyl ~rogenitor.~~ A book on small ring heterocycles contains a section on p-lactarn~.~' 21 J. D. Buynak H. Pajouhesh D. L. Lively and Y. Ramalakshmi,J. Chem. Soc. Chem. Cornmun. 1984,948. 28 E. Schaumann W.-R. Forster and G. Adiwidjaja Angew. Chem Int. Ed. EngL 1984 23,439. 29 T. Fukuyama A. A. Laird and C. A. Schmidt Tetrahedron Len 1984 25 4709. 30 .G. A. Koppel in 'Small Ring Heterocycles. Part 2. Azetidines /3-Lactams Diazetidines and Diaziridines,' ed. A. Hassner J. Wiley New York 1983. Heterocyclic Compounds 4 Five-membered Rings A few rare 2-amino-5-sulphinylfuranscan be made by the reaction of alkynyl sulphones with ynamines (Scheme 15).31 The full scope of this reaction has yet to be realised.A new route (Scheme 16) to 2-substituted-4-trimethylsilylfurans involves epoxidation of the vinylsilane (20) followed by ring-opening and re-clos~re.~~ An alternative reaction of (Y -silylepoxides leads to 2,3-disubstituted furans (Scheme 17).33 Careful choice of the substituents allows predominant production of one regioisomer. R' ArSO,C=CH + R'-=-N(Ph)Me -* h MeN 0 SAr I I1 Ph 0 Scheme 15 JJR -Me,Si Me Si i Zn,ultrasound i m-CPRA RCN ii O.2M-HCI iii H,O' (20) iv molecular sieves Scheme 16 R2 R' R2 R' Scheme 17 Acid-catalysed isomerization of bis(pheny1thio)cyclopropane aldehydes provides a useful route to 2,3-dihydrofurans the starting materials being readily available.34 The amenable dichloropyran (21) acts as a useful precursor of the dithioacetals of tetrahydrofuran-2-carbaldehyde, which is much less ac~essible.~' The potential use of furans in synthesis is yet again underlined by the publication of an account of a convenient conversion of them into the ene-diones (22) using ceric ammonium nitrate.36 " G.Himbert. S. Kosach. and G. Maas Angew. Chem. Int. Ed. Engl. 1984 23 321. 32 P. Knochel and J. F. Normant Tetrahedron Lett. 1984 25 4383. 33 F. Sato H. Kankara and Y. Tanaka Tetrahedron Lett. 1984 25 5063. 34 0.G. Kulinkovich I. G. Tishchenko and N. A. Roslik J. Org. Chem. USSR (Engl. Transl.),1984,20,480.35 A. Mottoh and C. B. Reese J. Chem SOC.,Chem. Commun. 1984 1028. 36 L. Lepage and Y. Lepage Svnthesir 1983 1018. 192 E. H.Smith The effectiveness of trimethylsilyl and trimethylstannyl groups in promoting ipso-substitution is emphasized in the reported regiospecific C-2 acylation (SQ3'" and nitration [Sn using C( N02)4]37b of benzofurans. The ?r-complexed thiophene (23) suffers attack by a limited number of nucleophiles at the position indicated.38 The products of hydride attack can be protonated and decomplexed to give 2,3-dihydrothiophene. CF3S03-(23) Nu = -CN PBun3,BH,- HFe(CO),- HW(COb- Various new reductive routes to pyrroles have been described including the treatment of 4-alkoxy-A3-pyrrolin-2-ones(24)39 or succin~nitriles~~ with di-isobutyl- aluminium hydride and the reaction of 4-nitro-ketones with tributylphosphine and diphenyl disulphide mixture (Scheme 18).,l Di-isobutylaluminium hydride also reduces 2,2-disubstituted-4-halogenonitriles to A'-pyrrolines (25).42 The tetramic acid derivatives (24) required for the first method are simply available on treatment of the common 4-bromo-3-alkoxybut-2-enoates(26) with primary amines or ammonia.43 R' R30 RI R2 Dibal 0_Dibal X=CN NC x R2=H N No H H I";"~L,ci.cH,I (24) R2 (25) Scheme 18 I (26) R2 37 (a) M.Gill Tetrahedron 1984,40 621 ; (b)J. Einhorn P. Demerseman and R. Royer Synthesis 1984 978. 38 D. A. Lesch J. W. Richardson R. A. Jacobson and R. J. Angelici J. Am. Chem. SOC.,1984 106 2901.39 K. S. Kochhar and H. W. Pinnick J. Org. Chem. 1984,49 3222. 40 J. H. Babler and K. P. Spina Tetrahedron Lett. 1984 25 1659. 41 D. H. R. Barton W. B. Motherwell and S. Z. Zard Tetrahedron Lett. 1984 25 3707. 42 L. E. Overman and R. M. Burk. Tefrahedron Lett. 1984 25 5737. 43 K. S. Kochhar. H. J. Carson K. A. Clouser J. W. Elling. L. A. Gramens J. L. Parry H. L. Sherman K. Braat and H. W. Pinnick Tetrahedron Left. 1984 25 1871. Heterocyclic Compounds 193 1,3-Oxazines have served yet again as precursors to pyrroles this time as a result of attack by cyanide ion on the 2,4-dione derivative (Scheme 19).44Dilithiation and alkylation of pyrrole-2-acetic acids followed by decarboxylation provides 2-alkylpyr- roles effectively and simply (Scheme 20):' major minor Scheme 19 R' I i2 R' Scheme 20 A highly versatile one-pot synthesis of pyrroles derives from 1,Caddition of metallo-enamines to CY -aminoacrylonitriles alkylation of the intermediate CY -metal-lated nitrile and thermolysis in acetonitrile (Scheme 21)."6 Its major disadvantage stems from the lack of total control of regiochemistry in the formation of the metallo-enamines from the precursor imines (27) although this fault does not seriously detract from its usefulness.R' NR' R4 N' -b RaycN R'$ MeNPh R3 MeNPh R3 I NR' R4 R2w5cN 4 R' NRI ~5 MeCN R3 NPh Me Scheme 21 Two groups report that the deacylation and deformylation of pyrrole ketones and aldehydes occurs on attempted ketalization with ethylene glycol and toluene-p-sul- phonic acid in boiling benzene.Yields are best when one other electron-withdrawing group is present on the ring.47 It is already known that the use of large protecting groups on nitrogen enhances the amount of electrophilic attack at C-3 of pyrroles. 44 M. Yogo K. Hirota and Y. Maki J. Chem. SOC.,Chem. Commun. 1984 332. 45 J. M. Muchowski and D. R. Solas Synth. Commun. 1984 453. 46 H. Albrecht and A. von Daacke Synthesis 1984 610. 47 K. M. Smith M. Miura and H. D. Tabba 1. Org. Chem. 1983,48,4119; M. W. Moon and R. A. Wade ibid. 1984 49 2663. 194 E. H.Smith Now it has been demonstrated that trimethylsilylation using trimethylsilyl triflate and triethylamine occurs exclusively at C-3 and it is proposed that the size of the reagent complex accounts for this?* 3-Pyrrol-2-ones (28) can be made by the Wittig condensation of diethyl (diazomethy1)phosphonatewith pyruvamides followed by spontaneous decomposi- tion of the intermediate diazoalkene and indiscriminate C-H insertion of the resultant ~arbene.~' The use of 2,5-dimethylpyrroles as protected forms of primary amines has been advocated ;" the recovery of the amine using hydroxylamine hydrochloride is usually good.Two proponents of the use of hydroxamic acid derivatives for the synthesis of indoles in a mild relative of the Fischer synthesis have published their results (Scheme 22).'l The methods provide both 2-substituted and the less-common unsub- stituted indoles.I I co px NH R' f;]? R' I 1 ii ii -.-Reagents i 7x 0°C; ii A; iii ToAc Li2PdCl4,0 + 70°C Scheme 22 48 U. Frick and G. Simchen Synthesis 1984,929. 49 J. C. Gilbert and B. K. Blackburn Tetrahedron Lett. 1984 25 4067. so S. P. Bruekelman S. E. Leach G. D. Meakins and M. D. Tirel J. Chem. Soc. Perkin Trans. 1 1984,2801. 51 S. Blechert Tetrahedron Lett. 1984 25 1547 P. Martin Helv. Chim. Acta 1984 67 1647. Heterocyclic Compounds An intramolecular Diels-Alder reaction of an acetylenic 1,2-diazine is an interest- ing route to indolines the authors stressing the ability by this method to produce 4-substituted derivatives which are of potential use in natural product synthesis (Scheme 23).52 Acetylenes also feature in a rational synthesis of 2H-isoindoles (29) which proceeds through a combination of a retro-ene reaction and a [1,5-H]sigmatropic shift.53 A OMe X = C1,H R = H,Me CH,OTBDMS Scheme 23 R2 R3 R1M\ p R4 /\ Pr’,N NPr; (30) Phosphenium ions (R2P+) undergo cycloaddition with 1,3-dienes to give phos- pholes (30) much more rapidly than the dihalogenophosphines (RPC12).54 The reaction of oxazoles with amines to give imidazoles is a well established procedure which however has previously been found to fail with 5-acetyl-2,4- dimethyloxazole.The desirability of 1H-5-acetyl-2-aminoimidazoles from the phar- maceutical viewpoint has led to a reinvestigation of this reaction.55 It was found that the use of primary amines led to a preponderance of imidazole over pyrimidine whereas secondary amines gave comparable amounts of each.Apparently the dis- crepancy between these results and the earlier work arises from the use of the 2-amino-oxazoles (31) in the later work. 5-Acylimidazoles (32) are also available by the nitrosation of oxoketene-N,S-acetals followed by thermal elimination of water from the intermediate oximes (33).56 A similar procedure using the N-phenyl derivative (34) results in the formation of a thiazole. 52 D. L. Boger and R. S. Coleman J. Org. Chem. 1984,49 2240. 53 R. P. Kreher and N. Kohl Angew. Chem. Znt. Ed. Engl. 1984 23 517. 54 A. H.Cowley R.A. Kemp J. G. Lasch N. C. Norman and C. A. Stewart J. Am. Chem. SOC.,1983 105,7444. 5s J. L. LaMattina and C. J. Mularski Tetrahedron Lett.1984 25 2957. 56 A. Rahman. H. Ila. and H. Junjappa J. Chem. Soc. Chern. Cornrnun. 1984 430. 196 E. H.Smith 0 0 ?H H (33) I MeCN A 5-Acylamino-oxazoles57" and trisubstituted imidazoles5'' are capable of acting as masked dipeptides the unmasking being achieved by very different procedures (Scheme 24). The requirement for 2,4(5)-dialkyl imidazoles led the same research group to investigate the reduction of the easily obtainable N-hydroxyimidazoles (35). It was found that titanium trichloride in aqueous methanol was admirably suited for this purpose.58 iii H, Pd/C Scheme 24 N N /= Me< +R Tic'3' Me< *R R MeCN aq. MeOH N .. N I H OH (35) A simple synthesis of 5-aminopyrazoles (36) results from attack of hydrazine hydrate on the p-chloroacrylonitrile (37).59The 2-trimethylsilyloxazole (38) acts as an equivalent of the corresponding carbanion in reactions with some electrophiles 57 (a) B.H. Lipshutz R. W. Hungate and K. E. McCarthy J. Am. Chem SOC.,1983 105,7703; (b) B. H. Lipshutz and M. C. Morey ibid. 1984 106 457. 58 B. H. Lipshutz and M. C. Morey Tetrahedron Lett. 1984 25 1319. 59 H. Hartmann and J. Liesbcher Synthesis 1984 276. Heterocyclic Compounds Ar i DMF POCI, Ary ii. NH,OH . HCI* H OSiMe thus behaving exactly analogously to the thiazole derivative.60 However in contrast to oxazoles thiazoles are well known for their reluctance to behave as 1,3-dienes in Diels-Alder reactions. Even in the first recorded example of such a process intramolecularity is insufficient inducement and the substitution pattern appears to be critical (Scheme 25).61 The reduction of 4-cyanoisoxazoles (39) leads unexpectedly and expeditiously to the 5-aminoisoxazoles (40).62 EtO4% Lok3-R=CO,Mei X,Y = OH H or 0 s -R = Mc;X,Y = 0 Scheme 25 A.Dondoni T. Dall'Occo G. Fantin M. Fogagnolo A. Medici and P. Pedrini J. Chem SOC. Chem. Commun. 1984 258. 6' P. Jacobi K. Weiss and M. Egbertson Heterocycles 1984 22 281. '* A. Alberola A. M. Gonzalez M. A. Laguna and F. J. Pulido J. Org. Chem. 1984 49 3423. 198 E. H. Smith Japanese chemists have shown that heating a primary nitroalkane with a catalytic quantity of toluene-p-sulphonic acid in boiling mesitylene generates a nitrile oxide which can be trapped.63 This method provides a simple albeit hot and acid alternative to the use of isocyanates for the dehydration of nitro-compounds.Oximes which have already shown their versatility as precursors to imidazoles can also serve for the preparation of isothiazoles (41).64 Thiazoles are a minor side-product both heterocycles apparently deriving from sulphur extrusion by two possible modes from an intermediate dithiazine cation (42). A novel route to benzoisothiazoles (43) involves insertion of an amine into the aliphatic C-S bond of a benzothiete (44). The thermal reaction probably results in production and trapping of a o-thioquinone methide.65 A new approach to benzisoxazoles (45) results in ultimate formation of the 2-3 bond and allows the synthesis of 3-phenyl derivatives bearing bulky substituents at the ortho-position of the phenyl group (which proved impossible to make by classical methods).66 (45) 63 T.Shimizu Y. Hayashi and K. Teramura Bull. Chem. SOC.Jpn. 1984 57 2531. 64 M. Ishida H. Nakanishi and S. Kato Chem. Lett. 1984 1691. 65 K. Kankarajan and H. Meier Angew. Chem. Znt. Ed. Engl. 1984 23 244. 66 G. M. Shutske J. Org. Chem. 1984 49. 180. Heterocyclic Compounds The formation of Reissert compounds from five-membered heterocycles is nor- mally excluded by the more facile ring-opening reactions caused by the aqueous conditions of the classical route. However the use of trimethylsilyl cyanide as a non-aqueous source of cyanide allows ready formation of the first Reissert com- pounds (46; X = 0 S) from benzoxazoles and benzothia~oles.~~ 0 In the area of meso-ionic compounds two reports are interesting.1,3-Oxazolium-4- olates (47) much rarer than their Solate counterparts are available by deoxygena- tion of the phenylglyoxylic imides (48).68 The very few stable derivatives of this ring type were those which precipitated rapidly from solution and these were sufficiently long-lived to allow reaction with N-phenylmaleimide. The second report of more general interest described the production of the carba-analogue (49) of ~ydnone.~~ Compound (49) represents one of a range of possible carba-analogues of meso-ionic and betaine compounds whose reactions particularly cycloadditions could prove fascinating.0 (48) Ph Ph +-Bu'CZSP + XGY-Z -Finally in this section 1,3-dipolar cycloaddition to the C=P bond provides some triaza- oxaza- and diaza-phospholes (50).70 67 B. C. Uff S. L. A. A. Chen Y.-P. 30,F. D. Popp and J. Kant J. Chem. Soc. Chem. Commun. 1984,1245. 68 M. J. Haddadin and H. T. Tannes Heterocycles 1984 22 773. 69 S. Araki J. Mizuya and Y. Batsuyan Chem. Lett. 1984 1045 70 Y. Y. C. Y. L. KO R. Came A. Muench and G. Becker J. Chem. Soc. Chern. Commun. 1984 1634; see also Y. Y. C. Y. L. KOand R. Came J. Chem. Soc. Chem. Commun. 1984 1640. 200 E. H. Smith 5 Six-membered Rings The Diels-Alder approach to pyrans was highlighted in these reports in 1982 (Annu. Rep. Progr.Chem. Sect. B 1982,79,228-229). A new variant of this method using a phosphacumuleneylide as the dienophile leads to a-pyrones (Scheme 26) through R' R' + It X ___,THF reflux R' 0 X- THF PhC0,H. reflux R' X (51) the intermediacy of the somewhat unstable ylides (51).7' hbPh3 0 X = NPh Scheme 26 The lure of tetrahydropyran-containingnatural products has led to the develop- ment of a new general route to 5,6-dihydropyrans which can be hydrogenated to the saturated derivatives (Scheme 27).72 The reaction did not work with two starting materials containing double bonds in which the alkyl substituents were in a trans-relationship. However the known good stereoselectivity of the Ireland-Claisen rearrangement was maintained in this new application.CdR3 dR1fJ OSiMe, i,ii iii-v Pr' Pr' C0,Me -Pr'RiiR3 Reagents i LDA -78°C; ii Me3SiCI Et3N; iii PhMe 105-110°C; iv H,O+; v CH2N Scheme 27 As the ability to form and utiiise a-lithiopyrans would also be of interest in the same synthetic context the report on the generation of these species by reductive desulphurization is timely.73 Experiments using the bicyclic congeners (52) estab-lished that the derivatives are configurationally stable at the temperature of gener- ation (-78 "C) and that the metal is directed axially but the equatorial orientation is preferred at -30°C. Although the authors correctly state that production of the lithio-species by deprotonation was not a serious alternative to their method a contemporaneous report on the deprotonation of saturated ethers including tetrahy- dropyrans using lithium-free butylpotassium suggests that this may not be the case in the future.74 71 H.J.Bestmann and G. Schmid Tetrahedron Lett. 1984 25 1441. 72 S. D. Burke D. M. Armistead and F. J. Schoenen J. 0%.Chem. 1984,49 4320. 73 T. Cohen and M.-T. Liu J Am. Chem. SOC.,1984 106 1130. 74 R.Lehmann and M. Schlosser. Tetrahedron Lett. 1984 25 745. Heterocyclic Compounds 201 Me OH A novel procedure for the synthesis of the tricarbonyliron complexes of some 6-ethoxy-a-pyrones (53) results from the addition of an alkyne to the iron carbene complex (54) and subsequent incorporation of two molecules of carbon monoxide (Scheme 28).75 On continued heating rearrangement of the complexes (53) to the isomers (55) occurs.(54) (53) (55) Scheme 28 A well established route to hydro-furans or -pyrans involves intramolecular alkoxymetallation of alkenes and alkynes. Two groups of workers have shown that the scope of this method can be increased by the utilisation of the intermediate metallated species to introduce further functionality in the resultant chrom~nes~~~ and tetrahydr~pyrans~~' (Scheme 29). A related process involves ortho-thallation of an aromatic acid and Heck olefination with concomitant oxypalladation (Scheme 30).77The latter process is applicable to simple olefins vinyl bromides 1,2- 1,3- and l,4-dienes as well as vinyl cyclopropanes (with opening of the three-membered ring). The Claisen rearrangement previously used to good effect in the synthesis of precursors to coumarins (Annu.Rep. Prog. Chem. Sect. B 1982 79 230) has provided the basis of two one-pot procedures to benzopyrans. Thus Lewis acid catalysed rearrangement of the (a-aryloxymethyl)acrylates (56) gives the methylene coumarins (57),7*awhereas thermolysis of the y-chloroallyl phenyl ethers (58) gives the chromenes (59).78b 7s M. F. Semmelhack R. Temura W. Schnatter and J. Springer J. Am. Chem. SOC.,1984 106 5363. 76 (a) R. C. Larock and W. L. Hamson J. Am. Chem. SOC.,1984 106 4218; (b) M. F. Semmelhack and C. Bodurow ibid. 1984 106 1496. 77 R. C. Larock S. Varaprath H. H. Lau and C. A. Fellows J. Am. Chem. Soc. 1984 106 5274. 78 (a) K. Sunitha K. K. Balasabramanian and K.Rajagopalan Tetrahedron Lett. 1984 25 3125; (b) N. A. Andreev V. I. Levashova and L. I. Bunina-Krivorakova J. Org. Chem. USSR (Engl. Trans/.) 1984 20. 331. 202 E. H.Smith trans 87 10 0 cis 0 0 97 Reagents i Hg(OAc), AcOH; ii aq .NaCI; iii CuCI, cat. PdCI, CO MeOH Scheme 29 -+x 4 R2 + X R2 R' Reagents i Tl(OCOCFs)3 CF3C02H; ii hRI PdC12 MeCN 25 "C; iii 2 Na,C03 2 Et,N A Scheme 30 0 (56) (57) CI R' '0-a 190"C undecane R' Heterocyclic Compounds 203 3-Nitrobenzopyrans have come to the fore during the year. The conversion of 2-hydroxy-a-nitroacetophenones (60) into their magnesium enolates and condensa- tion with aroyl chlorides provides a simple route to 3-nitro-2-aryl chromones (61).'9" The use of magnesium enolates is essential for the success of the reaction.Conditions are also critical in the synthesis of 3-nitrochromenes where the use of the indicated amine hydrochloride and ester solvent is important (Scheme 3 l).79bThe application of 3-nitro-2-aryl chromenes to the synthesis of flavonols has been highlighted in three papers from the same group,8o the method involving basic peroxide having been used to prepare the previously unknown 6-methoxy-flavonols (Scheme 32). R2wNo2 R' 0 R3R2@;H+ OHi"' i-C,H,,OAc A+ R3 BU"~NH,+CI- R4 R4 Scheme 31 NaOH H,O, MeOH R' OR CrCI, aq. HCI THF OH 0 Scheme 32 Most synthetic work during the year on pyridines has been directed towards dihydro- and tetrahydro-derivatives.Thus reduction of 4-pyridones gives rise to 5,6-dihydro-4-pyridones (62),81whereas the parent molecule (63) is obtainable by two methods and proves to be very unstable polymerizing above -80 "Cin solution.82 Lewis acid mediated transfer of carbon groups from silanes or silyl enol ethers to (a) M. Cushman and A. Abbaspour J. Org. Chem. 1984 49 1280; (b) D. Dauzonne and R. Royes Synthesis 1984 348. T. S. Rao A. K. Singh and G. K. Trivedi Heterocycles 1984 22 1377; T. S. Rao S. Deshpande H. H. Mathur and G. K. Trivedi ibid. 1984,22 1943; T. S. Rao H. H. Mathur and G. K. Trivedi Tetrahedron Lett. 1984 25 5561. P. Guerry and R. Meier Synthesis 1984 485. M.-C. Lame J.-L. Ripoli J.-C. Guillemin and J.-M. Denis Tetrahedron Lett.1984 25 3847. 204 E. H.Smith K R N N R I I C0,Et C0,Et (44) (65) R = 6, CN,O% 5,6-dihydro-4-pyridinols (64) gives A3-piperidines (65) with ally1 migration.83 Finally a totally new approach to tetrahydropyridines which is an adaptation of a process recently introduced in carbocyclic chemistry derives from a ring contraction of a macrocyclic azalactone by means of the Ireland-Claisen rearrangement (Scheme 33y4 + --70°C &3- A N Ph ‘0 Ph Scheme 33 A useful means of introducing an alkyl group at C-3 of pyridines involves initial Birch reduction to the bis-silylated 1,4-dihydropyridines (66) followed by fluoride- induced electrophilic attack by aldehydes (mainly) and ketones.” An alternative homolytic alkylation of pyridinium and quinolinium trifluoroacetates with an excess of primary or secondary iodides provides the 2-alkyl derivatives selectively (Scheme 34).86 83 A.P. Kozikowski and P. Park J. Org. Chem. 1984 49 1676. 84 R. I. Funk and J. D. Munger J. Org. Chem. 1984,49 4319. 85 0. Tsuge S. Kanemasa T. Naritomi and J. Tanaka Chem. Lett. 1984 1255. C. Castaldi F. Minisci V. Tortelli and E. Vismara Tetruhedron Lett. 1984 25 3897. 86 Heterocyclic Compounds SiMe 'N' TH F 'N-' I SiMe Scheme 34 The chemistry of pyridinium methylides has been prominent this year. Two new ways of generating the ylides have been described and reaction with dimethyl acetylenedicarboxylate proceeds normally to give an indolizidine (Scheme 35)87a-c In contrast in reactions with olefins the parent ylide acts as a methylene transfer reagent.87 'vd Re1 87a K,CO,/AI20 R2 = H n: / I R2 = SiMe Me02C.C-C . C02Me + R' = H R3+3 ,EWG N+ A / R1 C0,Me CsFRe187b7c or Bu,N+F-I! R2 R1 \ EWG R2 = SiMe,,R' = H EWG = Electron-withdrawing group Scheme 35 Just as pyrroles may act as masked primary amines (see earlier section) so can the dinitro-4-pyridones (67). Protection and deprotection occur under exceptionally mild conditions with no racemization in the amino-acids used as substrates.88 Two ncw approaches to quinolines involve the reaction of arylimidoyl radicals with alkyne~~~ and the cyclodehydration of o-hydroxyalkyl anilides (Scheme 36):' The use of the MeS group in place of the Me0 group as the aryl activating moiety in standard acid-catalysed isoquinoline syntheses has been advocated on the grounds that it is readily removed by hydrogenolysis to give the unsubstituted derivatives which are otherwise difficult to make by these procedures." 87 (a)J.Alvarez-Builla M. G. Quintinilla C. Abril and M. T. Gandesequi J. Chem. Res. (S) 1984 202; (6) 0. Tsuge S. Kanemasa S. Kuraoka and S. Takanaka Chem Lett. 1984 279; (c) Y. Miki H. Hachiken S. Takemura and M. Ikeda Heterocycles 1984 22 701; (d) 0. Tsuge S. Kanemasa S. Takenaka and S. Kuraoka Chem. Lea 1984 465. 88 E. Matsumura H. Kobayashi T. Nishikawa A. Ariga Y.Tokida and T. Kawashima Bull. Chem. SOC. Jpn. 1984 57 1961. 89 R.Leardini G.F. Pedulli A. Tundo and G. Zanardi J. Chem. SOC.,Chem Commun.,1984 1320. 90 P. D. Curran and S.-C. Kuo J. Org. Chem. 1984,49 2063. 91 M. R. Euerly and R. D. Waigh J. Chem. SOC.,Chem. Commun. 1984 127. 206 E. H. Smith aq. pyridine 02NfYNo2 + R'\C02H 7 02NhNo2 N NH2 N A. R CO,H NO 02NfiNo2+ y12 N R C02H I n-c,,H1 3 R aNJ*$2 60 "C C,H DPDC = di-isopropyl peroxydicarbonate H Scheme 36 Vinyl isocyanates generated by Curtius rearrangement have proven to be versatile starting materials for the synthesis of polyhydro-phenanthridinonesor -(iso)quino- lines (Scheme 37).92 Chloro-iminium salts continue to play an important role in the synthesis of heterocycles as shown this year by the development of the 2-azapropenylium salts (68) as precursors to a number of ring types (Scheme 38)930 and the use of phosgene-iminium salts (69) in the syntheses of q~inazolines~~ and benzo(naphth0)- 1,3-0xazines~~~ the former process allowing specific production of the less accessible 2-alkylamino-4-chloro derivatives.92 J. H. Rigby and N. Balasubramanian J. Org. Chem. 1984 49 4569. 93 (a) G. V. Boyd P. F. Lindley and G. A. Nicolaou J. Chem. SOC.,Chem. Commun. 1984 1105; (b) B. Kokel G. Menidi and M. Hubert-Habart Tetrahedron Lett. 1984 25 1557 (c) B. Kokel G. Menidi and M. Hubert-Habart ibid. 1984 25 3837. Heterocyclic Compounds 207 H PhCH, reflux 61% Scheme 37 (68) KSCN R5 R5= H,02N Me R3 + R4 = H,Ar Scheme 38 CI XH R ' d I 4 X=NH + = N NR2R3 CI R2 )+ CI ~3~1- (69) 208 E.H.Smith Pyridazinones of two different substitution patterns are obtainable by the treatment of A2-oxazolin-5-ones with aldazine~~~ or by ring-opening of 2-trimethylsilyloxy-cyclopropanecarboxylates with hydrazine hydrate (Scheme 39).95 R R R4 C0,Me H H2NNH,. H,O Me,SiO R' R2 R' R2 R3 Scheme 39 A general route to the rare 6H-1,3-oxazin-6-ones (70) uses a retro-Diels-Alder cycloaddition a now common tactic?6 Two new groups of heterocyclic compound are the 1,4,2,5-dithiadiazines (71)97 and the blue crystalline betaine (72).98 0- 6 Seven-membered Rings It has been shown that the chloroazirines (73) react with o-aminobenzylamines to give 5 H-1 ,Cbenzodiazepines (74) ." Although yields are only moderate the reaction works in those cases where the alternative use of an a-diketone fails indicating the potential use of (73) as bifunctional reagents.94 D. Konwar D. Prajapati J. S. Sandhu T. Kametani and T. Honda Heterocycles 1984 22 2483. 95 J. Reichert and H.-U. Reissig Synthesis 1984 786. % G. Stajer A. E. Szabq F. Fulop and G. Bernath Synthesis 1984 345. 97 B. G. Lenz and B. Zwanenburg J. Chem. SOC,Chem Commun. 1984 1386. 98 F. A. Neugebauer H. Fischer and C. Krieger Tetrahedron Lett. 1984 25 629. 99 K. R. Randles and R. C. Storr. J. Chem. SOC..Chem. Commun.. 1984 1485. Heterocyclic Compounds Two routes to oxocenones from six-membered rings have been published.The first case uses simple 8-lactones the two extra carbons being provided by the addition of an acetylide anion to the carbonyl group,1oou whereas the second proceeds through the base-catalysed ring expansion of a-pyrone-chloroalkene photoadducts (Scheme 40).loob 0 ii HMPA Et,N ___ -HCI R2RjJ 1.1. 0 X = H Me SMe R' = C1,H R2 = R3 = C1,CN Scheme 40 The X-ray structure of the stable oxazocine (75) establishes that unlike its precursor (76) .it is planar with much less marked bond length alternation in the eight-membered ring strongly suggesting that 1 0.n-delocalization is present."' F OaTS i,K/NH it (MeO),C,H,CH,CI ' 0~N7c6H2(0Me)3 (76) (75) 7 Fused and Bridged Systems The fluorine atoms in the derivative (77) of the 2,6-dioxabicyclo[3.1.llheptane type which is believed to be present in thromboxane-A* confer considerable stability towards acid hydrolysis the rate of reaction being approximately 100-times slower than that for acetaldehyde diethyl acetal."' OBn pH 1.27 .qJB* Fql 0 OBn HO OBn (77) 100 (a) S. L. Schreiber and S. E. Kelly Tetrahedron Lett. 1984,25 1757; (6)T.Shimo K. Somekawa J. Kuwakino H. Uemura S. Kunamoto 0. Tsuge and S. Kanemasa Chem Lett. 1984 1503. I01 B.Zipperer D.Hunkler H. Fritz G. Rihs and H. Prinzbach Angew. Chem. Inf.Ed. Engf. 1984,U,309. 102 J. Fried E. A. Hallinan and M. J. Szwedo J. Am. Chem. Soc. 1984,106. 3871. 210 E. H. Smith Two new heterocyclic systems of some theoretical and practical interest are the highly coloured betaines (78)'03 and the fascinating and exceptionally stable free- radical (79).'04 0 R = Ph,CN X = 0 S NTs C(CN)-Finally the synthesis of the hexa-azaoctadecahydrocoronene (80) pursued for its oxidation to a potential ferromagnetic organic salt involved multiple closures of the hexa-amide (81) which because of the high yield (80%) and absence of side products must have occurred in the same direction for each closure.'05 CI 0 N N 0 CI lo3 K.T. Potts and W. R. Kuehnling J. Org. Chem 1984 49 3672. A. Albini. G. F. Bettinetti G. Minoli and T. F. Soldi Chem. Lett. 1984 1197. I05 R. Breslow P. Maslak and J. S. Thomaides J. Am. Chem. SOC.,1984 106 6453.

ISSN:0069-3030    

DOI:10.1039/OC9848100183

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

10 Organometallic Chemistry Part (i)The Transition Elements By D. PARKER Department of Chemistry University of Durham South Road Durham DH13LE 1 Introduction 1984 was a year in which organotransition metal chemistry was applied successfully to several synthetic problems notably asymmetric carbon-carbon bond forming reactions. Several useful texts and reviews appeared including Volume 2 of the Patai series on the metal-carbon bond,’ a summary of leading developments in homogeneous catalysis and another monograph on the application of transition metals to organic synthesis3 Leading reviews appeared on the use of metal carbenes in synthesis the photochemistry of transition metal alkyls,’ aspects of organocopper cobalt mediated cycloadditions,8 palladium-assisted reactions of mono- olefins,’ palladium and mercury catalysed sigmatropic rearrangements,” and transi- tion metal trialkylsilane complexes.’ A timely text discussed olefin metathesis and ring-opening polymerization of cyclo-olefins,12 topics which were also Notable articles appeared lying outside the scope of this report on carbon-carbon bond activation in unstrained alkanes,” the catalytic chlorination of methane,16 the mechanism of nickel catalysed HCN addition to alkenes,”-19 and the development of a modified flash chromatography procedure for the purification of air-sensitive organometallics.20 ‘The Chemistry of the Metal-Carbon Bond’ ed.F. R. Hartley and S. Patai Vol. 2 John Wiley New York 1984. ‘Fundamental Research in Homogeneous Catalysis’ ed.M. Graziani and M. Giongo Vol. 4 Plenum New York 1984. ‘New Pathways for Organic Synthesis. Practical Applications of Transition Metals’ H. M. Colquhoun Plenum New York 1984. K. H. Dotz Angew. Chem. Znr. Ed. Engl 1984 23,587. ’ H. G. Alt Angew. Chem. Znf. Ed. Engl. 1984 23,766. J. Lindley Tetrahedron 1984 40 1433. ’ B. H. Lipshutz R. S. Wilhelm and J. A. Kozlowski Tetrahedron 1984.40 5005. * K. P. C. Vollhardt Angew. Chem. Inr. Ed. Engl. 1984 23,539. L. S. Hegedus Tetrahedron 1984. 40,2415. lo L. E. Overman Angew. Chem. Int. Ed. Engl. 1984 23,579. ‘I J. A. Gladysz Acc. Chem. Res. 1984 17 326. 12 ‘Olefin Metathesis and Ring Opening Polymerisation of Cyclo-Olefins’ V. Dragutan A. T. Balaban and M. Dimonie John Wiley Chichester 1984.I’ B. A. Dolgoplask and E. I. Tinyakova Usp. Khim. 1984 53,40. 14 B. A. Dolgoplask and Y. V. Korshak Usp. Khim. 1984 53,65. R. H.Crabtree and R. P. Diou J. Chem. SOC. Chem. Commun. 1984 1260. 16 N. Kitajima and J. Schwartz J. Am. Chem. SOC. 1984 106 2220. 17 C. A. Tolman W. C. Seidel J. D. Druliner. and P. J. Domaille Organornetallics 1984 3,33. 18 J. D. Druliner Organornetallics 1984 3,205. 19 R.J. McKinney and D. C. Roe J. Am. Chem. SOC. 1985 107 261. 20 K. A. M.Kremer and P.Helquist Organomerallics 1984 3,1743. 211 212 D. Parker 2 Metal-promoted Alkylations Acylations and Vinglations Iron acyl complexes have long been recognized as useful in synthesis because of the range of mild decomplexation methods permitting their conversion into a variety of carbonyl functionalities.A series of articles has reported diastereoselective carbon-carbon bond formation based on elaboration of the acyl ligand of (1). Treatment of (1) with base followed by alkylation leads to the diastereoisomeric acyl (2) while reaction of the methoxycarbene (3) with base gives a methoxyvinyl complex which may be alkylated to give the opposite diastereoisomer (4) (Scheme 1).21*22 Similar methods permit the stereoselective synthesis of quaternary carbon i. BuLi i. BuLi ii. PhCH,Br ii. PhCH,Br I I Scheme 1 atoms leading to chiral 2,2-dialkylb~tyrolactones.~~ More significantly this methodology has led to the development of a chiral acetate enolate equivalent for the synthesis of P-hydroxy acids with 3200 :1 diastereoselectivity ! Condensation of the dialkylaluminium enolate of (5) with carbonyls at low temperature gives rise to the P-hydroxyacyl complex (6) (3100 l) with the P-alkyl group preferring the least hindered position in the transition state and in the initial aluminium chelated product directed away from the phenyl group of the PPh3 ligand.Further elaboration of the acyl permits the synthesis of the erythro disastereoisomer (7) with 3200 1 diastereoselectivity (Scheme 2) .24*25 Imines also condense stereoselectively with (5) to give P-aminoacyl iron complexes which may be oxidatively cyclized to p-~actams.~~.~~ 21 G. J. Baird J. A. Bandy S. G. Davies and K. Rout J. Chem. Soc. Chem. Commun. 1983 1202. 22 G.J. Baird S. G. Davies R. H. Jones K. Prout and P. Warner J. Chem. SOC.,Chem. Cornmun. 1984,745. 23 P. J. Curtis and S. G. Davies J. Chem. Soc. Chem Commun. 1984 747. 24 S. G. Davies I. M. Dordor and P. Warner J. Chem. SOC.,Chem. Commun. 1984 956. 2s S. G. Davies I. M. Dordor J. C. Walker and P. Warner Tetrahedron Lett. 1984 25 2709. 26 L. S. Liebeskind M. E. Welker and V. Goedken J. Am. Chem. SOC.,1984 106 441. 27 K. Broadley and S. G. Davies Tetrahedron Lett. 1984 25 1743. 213 Organometallic Chemistry -Part (i) The Transition Elements i. BuLi ii. Me1 Ph,P iii. HIO iv. BrJH,O H OH (6) (7) Scheme 2 The regio- and stereo-controlled functionalization of cycloheptadiene~~~*~~ and cyclohexene~~~ using organoiron organomanganese and organomolybdenum car- bony1 complexes has been reported.Reaction of (8) with stabilized enolate nucleophiles gives an intermediate .rr-allyl (9) which was converted into the lactone (10) using a modified iodolactonization demetallation procedure;l (Scheme 3). MO(CO),CP C0,Me ,cp -CH(CO,Me), 0 o:yob _____* ii.yH/MeOH /M? (CO,Me),HC” iii. H,O+ ‘I oc co (8) (9) (10) Scheme 3 A highly enantioselective homoaldol addition reaction with chiral N-allylureas mediated by organotitanium species has facilitated the synthesis of a series of chiral y-lactone~.~~ Reaction of (1 1) with base followed by TiCl( NEt,) gave the stabilized titanium alkyl (12) which condensed stereoselectively with a series of carbonyls to give the enamide (13) which may be readily converted into the desired lactone (14) (Scheme 4).The reaction of 1,3-dialkyl-substituted ally1 anions with aldehydes is mediated by v3-allyltitanium compounds facilitating a synthesis of hydroxy- substituted cy~loalkanes.~~ Similarly the allylmetallation of alkynes has been shown to assist the synthesis of various cycloalkenes in the presence of C1,ZrCp2. Reaction of allyldi-isobutylalane with terminal alkynes mediated by Cp2ZrC12 gives the cis monoallylation product as two constitutional isomers permitting a general method for converting terminal alkynes into various penta-l,4-diene derivative^,^^ (Scheme 5). A convergent approach has joined a masked conjugated diene with a potential dienophile in a metal-catalysed alkylation reaction.Each partner may be readily assembled individually and the sensitive intermediate is generated under very mild alkylation conditions immediately prior to intramolecular cycloaddition. The nature of the Diels-Alder reaction is governed by the regioselectivity of the alkylation which depends upon the choice of the metal template. Thus alkylation of (15) with 28 A. J. Pearson S. L. Kole and T. Ray J. Am. Chem. SOC.,1984 106 6060. 29 A. J. Pearson P. Bruhn and I. C. Richards Tetrahedron Lett. 1984 25 387. 30 A. J. Pearson M. Khan and I. Nazrul Tetrahedron Lett. 1984 25 3507. 31 A. J. Pearson M.Khan and I. Nazrul,J. Am. Chem. SOC.,1984 106 1872. 32 H. Roder G. Helmchen E. M.Peters K. Peters and H. G. Van Schnering Angew. Chem Znt. Ed.Engl. 1984 23 898. 33 Y. Kobayashi K. Umeyama and F. Sato J. Chem. Soc. Chem Commun. 1984 621. 34 J. A. Miller and E. Negishi Tetrahedron Lett. 1984 25 5863. 214 D. Parker 0 __--Ti( NEt,) i. BuLi -b MeN ii. (NEt,),TiCI ,\ Me Ph Me I. Ph (1 1) (12) R*R~CO x MeOH MeN NCH=CHCH,-C--R' R2-&Lo I 4 LJ ii. BFJMCPBA R' Me Ph (14) (13) Scheme 4 major minor Scheme 5 the stabilized carbanion (16) is mediated by Mo(CO) to give after hydrolysis the aldehyde (17) which may be cyclized under Lewis acid catalysis to give the tricyclic pyran (18) (Scheme 6). Similarly reaction of (19) with the carbanion (20) in the presence of (MeCN) W(CO)3 proceeds uia exclusive internal attack on the inter- mediate wallyl to give (21) which is readily cyclized to (22) (Scheme 7).35 Metal alkyls and aryls are usually extremely sensitive to moisture but the chromium alkyls such as (THF),Cl,Cr-R (R = Me Bun allyl) permit the alkylation of carbonyls under mild conditions in protic media to give the corresponding 1-Bromoallenes may be converted into phenyl-substituted allenes with inversion of configuration in the allenyl moiety by reaction with diphenylzinc in the presence of Pdo(PPh3),;37 reaction of (R)-(23) generates (S)-(24).A series of heterocycles may be synthesized via a stepwise thallation and palladium-promoted vinylation sequence; reaction of (25) gives (26) in high yield while (27) gave the benzopyran (28) ~electively.~~ 2-Bromo-l,6-dienes are catalytically cyclized to give conjugated five-membered bis-exocyclic dienes and six-membered mono-exocyclic dienes under 35 B.M. Trost M.Lautens M. Lautens M. H.Hung and C. S. Carmichael J. Am. Chem SOC.,1984 106 7641. 36 T. Kauffmann R. Abeln and D. Wingbermuhle Angew. Chem. Int. Ed. Engl 1984 23 729. 37 C. J. Elsevier H. H. Mooiweer H. Kleijn and P. Vermeer Tetrahedron Lett. 1984 25 5571. 38 R. C. Larock C. L. Liu H. H. Lau. and S. Varaprath Terrahedron Lett. 1984 25 4459. Organometallic Chemistry -Part (i) The Transition Elements MeAICI CH,CI i (18) Scheme 6 Scheme 7 rhodium and palladium catalysis (Scheme 8). RhCl(PPh3)3 catalyses formation of the 5-exo-trigonal product while Pd( PPh3)4 favours the 6-endo ring-clo~ure.~~ The bis-exocyclic dienes undergo Diels- Alder reactions in high yield so that the attractive combination of consecutive metal-catalysed creation of Diels- Alder precursors with Diels-Alder cycloadditions is partially realised (uiz.Schemes 6 and 7). In a related reaction RuC12( PPh3) catalyses cyclization of N-allyltrichloroacetamides to give the corresponding y-butyrolactams in good yield:’ (29) -+ (30). Copper( I) chemistry continues to attract considerable interest and the alkenyl copper reagents have again proved remarkably versatile. The carbocupration of acetylenic acetals and ketals has facilitated synthesis of geranial and 2,4-(E,Z)-diena1s;l while the amidomethylation of alkenylcopper reagents permits the syn- thesis of various allylic amides?2 Thus reaction of (31) with the formamide deriva- tives (32) generates the allylic amide (33) which may be readily converted into the corresponding amine.The chiral epoxide (34) reacts stereospecifically with the 39 R. Grigg P.Stevenson and T. Worakun J. Chem. SOC.,Chem Commun. 1984 1072. 40 H. Nagashima H. Wakamatsu and K. Itoh J. Chem. SOC.,Chem. Commun. 1984 652. 41 A. Alexakis A. Commercon C. Coulentoanos and J. F. Normant Tetrahedron 1984,40 715. 42 G. Germon A. Alexakis and J. F. Normant Svnthesis 1984 40. 216 D. Parker R,. H -Ph / Ph,Zn R. / H/c=c=c \Br Pd(PPh3) )'='=' \ H H u Li PdCl /MeCN aco2,& H,C=CHR ' 'R T 1 (CF,C02)2 X=Y=H X = Y = CO,Et X = Y = COMe X = Me,Y = COPh xy xy xy Scheme 8 CI,CCONHCH,CH=CH2 (29) H H xR2 -HR2 + CICH,NMeCHO ~1 CuLi R' CH,NMeCHO (32) (31) (33) alkenylcopper reagent (35) to generate the allylic alcohol (36).Repeating such reactions in sequence has permitted the synthesis of chiral all syn 1,3-p0lyols.~~ Nuclear magnetic resonance and X-ray crystallographic studies have revealed that the Reformatsky reagent exists as a dimer in both solution and in the solid-state and dissociates into a monomer only in very polar solvents such as DMSO.@Finally 43 B. H. Lipshutz and J. A. Koslowski J. Org. Chern. 1984,49 1147. 44 J. Boersma G. J. M. Van der Kerk and A. J. Spek Organornerallics 1984 3 1403. Organometallic Chemistry -Part (i) The Transition Elements 217 PhCH,OCH P (H2C=CH)2Cu(CN)Li2 PhCH20CH2CH(OH)CH2CH=CH2 (34) (3 5) (36) in contrast to the highly diastereoselective stoicheiometric carbon-carbon bond- forming reactions discussed earlier in this section a highly promising enantioselec- tive catalytic carbon-carbon bond-forming reaction has been de~cribed.~' The pres- ence of a cobalt(I1) diamine complex of (S,S)-(+)-1,2-diphenyl-l,2-ethanediamine catalyses the Michael addition of methyl vinyl ketone with P-keto esters.Reaction of (37) with (38) at -50 "C generates the corresponding 1,5-dicarbonyl (39) with 66% enantiomeric excess. 3 Nucleophilic Attack on Co-ordinated n-Ligands The enhanced susceptibility to nucleophilic attack of co-ordinated digands has once more facilitated many important syntheses.The anti-tumour agent 1 1 -deoxyan- thracyclinone (40) has been synthesized via a method involving ex0 nucleophilic attack of the stabilized enolate (41) on the (q6-arene)tricarbonylchromium complex of the hydronaphthalene derivative (42).& The thienamycin precursor (43) has been prepared with the key step involving insertion of (-)-PhCH( Me)NH2 into the .Ir-allyltricarbonyliron complex (44) in the presence of ZnCl,.TMEDA to give diastereoisomeric lactone complexes (45) and (46) in 60% yield.47 The separated CN Me II 45 H. Brunner and B. Hammer Angew. Chem. Int. Ed. Engl. 1984 23 312. 46 M. Uernura T. Minarni and Y. Hayashi 1.Chem. Soc. Chem. Commun. 1984 1193. 47 S. T. Hodgson D. M.Hollinshead and S. V. Ley J. Chem. Soc.Chem. Commun. 1984,494. 218 D. Parker lactam (45) was oxidized with Ce’” to give the p-lactam (47) which may be readily transformed into (43). Nucleophilic attack on the ex0 isomer of the chiral allylmolyb- denum complex [R(CO)( NO)MoL]+ (R = neomenthylcyclopentadienyl L = 7’-cyclo-octenyl) has provided a simple route to enantiomerically pure allylically substituted alkenes e.g. (48) The configuration at the metal centre controls the configuration at the generated chiral allylic centre owing to preferential attack cis to the NO ligand in the ex0 i~omer.~~.~’ An enantiospecific synthesis of (+)-gabaculine (49) involves amination of the resolved q4-dienetricarbonyliron com- plex (50)” (Scheme 9). Various new organoiron synthons have been developed51i52 including some vinyl ether iron complexes as vinyl cation equivalents.Reaction of (51) with the lithium enolate (52) generates the a-methylene lactone (53).52 R = neomenthylcyclopentadienyl W L = ~3-cyclooctenyl C0,Me i. Ph3C+ ii. H,N-C0,Bu‘ Hunig’s base (CO),Fe -6 (48) C0,Me 1,0)&--6H i. Me,NO ii. -OH/MeOH ~ iii. H30+ CO,Me& (50) NHC0,Bu‘ (49) NH Scheme 9 Nickel(I1) complexes have been used to catalyse the synthesis qf conjugated dienes from various 5-ring aromatic heterocycles,s3 and amination of but-2-yne in the presence of (Et,NH),NiBr under a CO atmosphere generates the unsaturated 48 J. W. Faller K. H. Chao and H. H. Murray Organometaffics 1984 3 1231. 49 J. W. Faller and K. H. Chao Organometallics 1984 3 927. 5o R.B. M. Bandara A. J. Birch and L. F. Kelly J. Org. Chem. 1984 49 2496. 51 M. Marsi and M. Rosenblum J. Am. Chem. SOC. 1984 106 7264. 52 T. C. T. Chang and M. Rosenblum Isr. J. Chem. 1984 24 99. 53 E. Wenkert H. M. Leftin and E. L. Michelotti J. Chem. SOC.,Chem. Commun. 1984 617. 219 Organometallic Chemistry -Part (i) The Transition Elements lactone (54) in 91% yield.’4 In an interesting application of porphyrin complexes N-substituted aziridines e.g. (55) are formed stereospecifically by reaction of PhI=NR (R = OTs) with stilbene in the presence of iron(Ir1) or manganese TPP.” The nature and synthetic utility of nucleophilic attack on q3-allylpalladium complexes continues to be explored. Using a chiral ?r-allyl (56) it was found that attack by malonates and amines proceeded with inoersion of configuration with the nucleophile attacking the ?r-ally1 directly from the side opposite the metal.With Grignard reagents as nucleophiles retention of configuration occurred with the ?r-ally1 being attacked from the same side as the palladium in a two-step proce~s.’~ Such experiments neatly confirmed the stereochemical course of these two generally accepted reaction pathways. In a separate study the mechanism of the palladium- assisted olefin animation was examined with the reaction sequence varying with the nature of the amine.” Efficient intramolecular chirality-transfer has been observed in reactions of E and 2 ally1 carbonates using Pdo catalysts with phosphine or phosphite ligands.” Thus cyclization of (57) in the presence of a phosphine- palladium complex stereoselectively generated the chiral lactone (58).The synthesis of various bicyclic and tricyclic 7-oxaprostaglandin endoperoxide analogues has been devised uia oxypalladation of norbornadiene. Alkoxylation of dichloro(norbor- nadiene)palladium with OH(CH2)5C02B~‘,followed by in situ hydroformylation gave (59).59 The stereoselective palladium-catalysed 1 ,Cdiacetoxylation of 1,3-dienes 0 0),,C02Me Pd,(dba),.CHCI Me0,CO A H m 5 C0,Me (58) (57) (59) 54 H. Hoberg and J. F. Fananas J. Organomet. Chem. 1984 262 C24. 55 D. Mansuy J.-P. Mahy A. Dureault G. Bedi and P. Battioni J. Chem. SOC.,Chem. Commun. 1984 1161. 56 T. Hayashi M. Konishi and M. Kumada J. Chem. SOC.,Chem Commun.1984 107. 57 L. S. Hegedus B. Altermark K. Zetterberg and L. F. Olsson 1. Am Chem Soc. 1984 106 7122. 58 T. Takahashi Y. Jinbo K. Kitamura and J. Tsuji Tetrahedron Left. 1984 25 5921. 59 R. C. Larock and D.R. Loach 1. Org. Chem. 1984.49. 2144. 220 D. Parker permits the synthesis of 1,4-diacetoxy-2-alkenes under ambient conditions,6' and this route has been applied to the preparation of a key intermediate in the synthesis of racemic shikimic acid.6l A palladium-promoted synthesis of 5-dialkylamino-1,3-pentadienes (as found in the antibiotic griseoviridin) has also been described (Scheme - -/ 0 It LiCI/LiOAc C1 P(OEt),/Nal P(OEt) Pd(OAc),/HOAc ' AcO-R,NH/Pd(PPh,)4+ R,N i. ~NP~JTHF ii. R'CHO Scheme 10 4 Use of Metal Carbenes The potential of Fischer carbene complexes as olefinating agents has long been realised but despite the earlier work on tantalum ~arbenes~~ and the introduction of the Tebbe developments have been surprisingly slow.A series of papers however has described tandem and concurrent cycloaddition-annulation reactions of chromium alkynyl carbene The Diels-Alder reaction of a,P -acetylenic chromium carbene complexes (60) with dienes proceeds smoothly at 20°C and the resultant carbenes are of high synthetic value by virtue of their annulation reactions with alkynes to give the chromium complexed phenols (R2 = H) or cyclohexadienones (R2= Me) (Scheme 11). The cycloaddition and annula- tion reactions may also be carried out concurrently with the carbene complex the diene and the alkyne in one pot.The concurrent reaction (Scheme 12) of (61) (2-trimethylsi1oxy)butadiene and the alkyne (62) gives after ketalization the phenol (63) which is a key intermediate in the synthesis of the anti-tumour agent daunomy- cinone. Carbonyl olefinations may be carried out in protic media using methyl- enemolybdenum reagents such as (64). Aldehydes are selectively olefinated over ketones and the reagent is clearly of value for hydrophilic substrates.68 Some control of olefination stereochemistry has been achieved with long-chain zirconium alkylidene analogues of the Tebbe reagent such as (65).69The photolysis of chromium carbenes with azobenzenes gives rise to azo-metathetical products ;photo-lysis of azobenzene with (66) gives rise to monomeric (67) and dimeric products 60 J.E. Baeckvall J. Vaagberg and R. E. Nordberg Tetrahedron Lett. 1984 25 2717. 61 J. E. Baeckvall E. S. Bystroem and R. E. Nordberg J. Org. Chem. 1984,49 4619. M. Nikaido R.Aslanian F. Scavo P. Helquist B. Aakermark and J. E. Baeckvall J. Org. Chem. 1984 49 4738. 63 R. R. Schrock J. Am. Chem. SOC.,1976,98 5399. 64 F. N. Tebbe G. W. Parshall and G. S. Reddy J. Am. Chem. SOC., 1978 100 3611. 65 W. D. Wulff and C. D. Jung J. Am. Chem. SOC.,1984 106 7565. 66 W. D. Wulff and P. C. Tang J. Am. Chem. SOC.,1984 106 434. 67 W. D. Wulff and P. C. Tang J. Am. Chem. SOC.,1984 106 1132. T. Kauffmann P. Fiegenbaum and R. Wieschdlek Angew. Chem. In?.Ed. Engl. 1984 23 531.69 S. M. Clift and J. Schwartz J. Am. Chem. Soc. 1984 106 8300. Organometallic Chemistry -Part (i) The Transition Efements 221 (C0),Cr<OMe*R2 + R1f -+ ~1% /cr(CO)5 (60) OMe R2=$c-cH 1 RC=CHR2 = Me 1 OH Scheme I1 Ill Me3S10h + @ 1. 0 (62) OMe k <OH ,Me,SiCI ' OH (63) Scheme 12 0 II CIMo=CH LCP2Zr-IR L = PPh, R = But (64) (65) (68) and (69)." Rh,(OAc) has been used to catalyse cyclization of a-diazoketones derived from 3-arylpropanoic acids for the synthesis of bicyclo[5.3.0]decatrienones and tetra lone^.^^ Thus reaction of (70) proceeds to give the trienone (71) in 99% yield at 40 "C. 70 L. S. Hegedus and A. Kramer Organornetailics 1984 3 1263. 71 A. M. McKervey S. M.Tuladhar and F. M. Twohig 1. Chem. SOC.,Chern. Cornrnun. 1984. 129. 222 D. Parker Me PhNf -OMe PhCH,CH,COCHN J-NPh 0 The asymmetric cylopropanation of styrene with 2-diazodimedone (72) is cata- lysed by copper complexes of 3-trifluoroacetyl-( +)-camphor and an immobilized analogue on silica to give product (73) with high enantiomeric purity." 5 Oxidation and Reduction The synthetic application of catalytic homogeneous hydrogenation and oxidation has been a major triumph for organotransition metal chemistry over the past decade. Further progress has been made in the stereoselective hydrogenation of cyclic and acyclic olefinic alcohols. Using Crabtree's cationic iridium complex [Ir(COD)py.( PCy3)]+PF, or the Schrock and Osborn cationic rhodium diene [Rh(nbd)Ph,P(CH,),PPh,]+ the hydroxy-group directs the stereochemical course of the hydrogenation of various allylic alcohols.Reduction of (74) using the rhodium catalyst gives (75) with 2290 :1 diastereo~electivity,'~while the related methyl- enecyclohexanol (76) may be reduced using the same catalyst with 398% selectivity go Me6 Me,.J 0Ph (73) (74) (75) Q""' oMe OH OH (76) (77) in aprotic solvents to give the alcohol (77).74 In the latter case the axial hydroxy- group binds to the rhodium preferentially stabilizing formation of the shown transition-state (78). Such diastereoselective reductions are apparently sensitive to the catalyst to substrate stoicheiometry and the reduction of acyclic olefinic alcohols generally proceeds with lower ~electivity.'~ The mechanism of homogeneous hydro- gentation continues to arouse debate and interest.'H and "P magnetization transfer experiments have suggested a cis (PPh3),Rh arrangement during the course of alkene 72 S. A. Math W. J. Lough L. Chan D. M. H. Abram and 2.Zhou J. Chem. Soc. Chem. Commun. 1984 1038. l3 D.A. Evans and M. M. Morrissey Tetrahedron Lett. 1984 25 4637. 74 J. M. Brown and S. A. Hall Tetrahedron Lett. 1984 25 1393. 75 D. A. Evans and M. M. Momssey J. Am. Chem. Soc. 1984 106 3866. Organometallic Chemistry -Part (i) The Transition Elements hydrogenation using RhC1( PPh3)3 rather than the putative trans arrangement previously accepted.76 Further information pertinent to Sharpless' asymmetric epoxidation procedure has been divulged.Two new catalysts have been reported using Ti(OPri)4 with chiral tartramides the epoxidation of allylic alcohols with Me3C02H gives chiral epoxides with the opposite enantioselectivity from that reported using standard diester tartrates ;using TiCl,(OPr') instead of Ti( OPr'), chlorodiols are produced consistent with regiospecific opening of the intermediate epoxy alcohols.77 The crystal structures of two titanium tartrate asymmetric epoxidation catalysts have been determined (79) and (80).78 The catalysts have a dinuclear structure with the tartrate oxygens bridging the two titanium atoms to form a Ti202 rhombus. In (79) the weak co-ordination of the amide carbonyl oxygens implies facile dissociation and reco-ordination in solution.This feature may facilitate exchange of the alkoxide ligands for the substrate molecules Me3C02H and allylic alcohol via an intermedi- ate in which one or both titanium atoms are pentaco-ordinate. The Sharpless catalyst has been used for the asymmetric oxidation of aryl alkyl sulphides (81) to give Ti (OPr),/ Me,CO,H S . Ar/ 'R HO..JCO E I R = Me Pr Bu Ar = Np Ph the chiral sulphoxides (82) in up to 95% enantiomeric purity. Optimal results were obtained with R = Me in the prochiral sulphide (81) and operating with a closely defined water content at -20 0C.79 The stereochemical course of the osmium tetroxide oxidation of allylic alcohols has been examined in detail and it was found that the relative stereochemistry between the pre-existing hydroxy- or alkoxy-group and the adjacent newly introduced hydroxy-group of the major product is erythro in all cases.8o Alkenes may be epoxidized by iodosylbenzene in the presence of Cu2+ in organic solvents such as acetonitrile.Contrary to some previous suppositions it is apparent that porphyrin ligands are not required for the metal-ion activation of iodosylbenzene.*' 76 A. R. Lucy and J. M. Brown J. Chem. SOC.,Chem. Commun. 1984,914. 71 L. D. Lu R. A. Johnson M. G. Finn and K. B. Sharpless J. Org. Chem. 1984,49 728. 78 I. D. Williams S. F. Pedersen K. B. Sharpless and S. J. Lippard J. Am. Chem. Soc. 1984 106 6430. 79 H. B. Kagan and P. Pitchen Tetrahedron Lett. 1984 25 1049. 80 J. K. Cha W. J. Christ and Y.Kishi Tetrahedron 1984,40 2247. C. C. Franklin R. B. Van Atta A. Fan Tai and J. S. Valentine J. Am. Chem. Soc. 1984 106. 814. 224 D. Parker 6 Other Cycloadditions Isomerizations Carbonylations and Carboxylations In a further development of cobalt-catalysed cycloadditions an intramolecular [2 + 2 + 21 cycloaddition of linear enediynes has been reported in the presence of C~CO(CO)~.~~ Cyclization of (83) for example leads to formation of the tricyclic ring (84). Thermal non-catalysed [6 + 21 cycloadditions are symmetry forbidden (CH2L-2 H2C=CH(CH2),CrCCH2XCH2CECR x@ (83) X = O,CH,CH cpco R = SiMe R (84) but in the presence of TiCl4-Et2A1Cl or ( ~6-C6H6)Ti"(AlC14)2 the reaction proceeds to give mainly the bicyclic diene,83 (Scheme 13).The reaction of cycloheptatriene with dienes and alkynes is presumably facilitated by co-ordination of the triene and modification of its HOMO.Low-valent titanium (TiC13 Zn-Cu) also catalyses the retro-Diels-Alder reaction converting 1,4-endoperoxides into the corresponding 78% 8 Yo 5 yo Scheme 13 1,3-dienes in moderate yield.84 Copper( I) catalysts are useful for [2 + 21 photocyclo- additions and have been used to catalyse the [2 + 21 addition of alkenes with conjugated dienes," and also have facilitated the synthesis of bicyclic pyrrolidines via photobicyclization of ethyl N,N'-diallylcarbonates,86 (Scheme 14). Scheme 14 82 E. D. Sternberg and K.P. C. Vollhardt 1. Org. Chem. 1984 49 1564. 83 K. Mach H. Anttopiusova L. Petrusova V.Hanus and F. Turecek Tetrahedron 1984 40,3295. 84 R. Riguera E. Quinoa and L. Castedo J. Chem. SOC. Chem. Commun. 1984 1120. 85 K. Avasthi S. R. Raychaudhun and R. G. Salomon 1. Org. Chem. 1984 49 4322. 86 R. G. Salomon S. Ghosh S. R. Raychaudhun and T. S. Miranti Tetrahedron Lett. 1984. 25 3167. Organometallic Chemistry -Part (i) The Transition Elements An important step forward in asymmetric catalysis has been the report of the highly enantioselective preparation of chiral E-enamines by isomerization of pro- chiral allylamines catalysed by a chiral rhodium biphosphine comple~.~~-~~ Using the cationic complex (85) isomerization of (86) gives (87) in 100°/~ yield with at least 96% enantiomeric purity. The catalyst is stable for more than 7000 turnovers over a range of reaction temperatures and is tolerant of other functionalities including hydroxyl.The system thus presents a convenient and practical route to chiral aldehydes. For example the catalysed isomerization of (88) gives (+)-7-hydroxydihydrocitronellal,(89) following hydrolysis of the intermediate enamine. Compound (89) is responsible for the fragrance odour of lily of the valley. i. (85) F +HO ii. H,O+ The palladium( 11)-catalysed concurrent decarboxylation-decarbonylation of ally- lic carbones yields P,y-unsaturated esters in good yields” and the total synthesis of the tricyclic hetereocycle (90) involves a palladium-catalysed intramolecular carbonylationof the intermediate (91)?‘ The PdC1,-catalysed intramolecular alkoxy- palladation-carbonylation of the chiral alcohol (92) gives the cis-pyran (93) in high yield and high dia~tereoselectivity.~~ a-Lactams such as (94) may be converted into 87 K.Toni T. Yamagata S. Akutagawa H. Kumobayashi T. Taketomi H. Takaya A. Miyashita R. Nayori and S. Otsuka J. Am. Chem. Soc. 1984 106 5208. 88 S. Otsuka Fund. Res. Homog. Catal. 1984 4 145. 89 H. J. Hansen and R. Schmid Eur. Pat. Appl. EP 104 375; Chem Abstr. 1984 101 111196. 90 J. Tsuji K. Sato and H. Oknmoto J. Org. Chem. 1984 49 1341. 91 M. Mori M. Ishikura T. Ikeda and Y. Bou Heterocycles 1984 22 253. 92 M. F. Semmelhack and C. Bodurow J. Am. Chem. SOC.,1984 106 1496. 226 D. Parker azetidine-2,4-diones (95),by reaction with CO and Rh2C12(CO)4.93 Finally nickel(o) diene complexes catalyse the carboxylation of alkynes and 1,3-dienes to give a$? -unsaturated acids and a,o-diacids H CH,Ph 1 Me0 Hoq,-& CHMe Me0 0 (90) Me O C H CO H (93) 0 (94) (95) 93 D.Roberto and H. Alper Organornetallics 1984 3 1767. 94 H. Hoberg D. Schaefer,G. Durkhart,C. Krueger and M. J. Romas J. Organornet. Chern. 1984,266,203. 95 H. Hoberg and B. Apotecher J. Organornet. Chern. 1984 270 C15.

ISSN:0069-3030    

DOI:10.1039/OC9848100211

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

10 Organometallic Chemistry Part (ii) The Main-Group Elements By John D. KENNEDY Department of Inorganic and Structural Chemistry University of Leeds Leeds LS2 9JT 1 Introduction and General Considerations A very useful three-volume 3232-page reference work entitled Dictionary of Organornetallic Compounds has been published this year.* This is an extensive compilation of those organometallic compounds deemed by the Editors and their advisors to be important and for each compound details of structure physical and chemical properties reactions and selected references are given. There are some 7650 entries for main-group compounds (Li Na K Rb Cs; Be Mg Ca Sr Ba; B Al Ga In,TI; Si Ge Sn Pb; As Sb Bi; Zn Cd Hg) and the book (and its readers) are well served by four different complementary indexes.Some readers will find that a quick flick through reveals a number of gaps where they would expect to find compounds which they would consider to be quite important. However selection is always difficult and it is planned to have annual supplements each containing some 2000 entries to abstract the recent literature and to extend the field of coverage the Editors state that they are always pleased to receive suggestions for compounds or groups of compounds to be included and so the project will develop into an even more valuable ‘information resource’ as they say nowadays. The publication of these volumes together with the major work Comprehensive Organometallic Chemistry mentioned in the 1982 report,2 does however introduce a disturbing consideration that this reporter has now heard aired increasingly over the past year or so.This is that for three or four years now the mean annual amount of compilatory review literature in organometallic chemistry has approached and probably exceeded the amount of published original research in the area! With other encyclopaedic compilations also currently in preparation and with the usual run of annual surveys reviews periodical reports etc. etc. this peculiar situation seems likely to continue for some time yet. As with the choice of direction of experimental work mentioned previously,2 it is again up to the organometallic chemists themselves to consider whether the advancement of their sub-discipline would not perhaps be better served by adopting other approaches.Perhaps because of this diversion of a substantial proportion of available organometallic talent from creative experimentation to compilatory literature abstraction the character of much of the new main-group organometallic chemistry ‘ Dictionary of Organometallic Compounds’. ed. J. Buckingham Chapman and Hall 1984 (3 vols.) J. D. Kennedy Annu. Rep. hog. Chem. Sect. B 1982 79 257 and 1983 80 293. 227 J. D. Kennedy reported in 1984 is again one of shall we say steady progress and consolidation rather than one of a general burgeoning of innovative chemistry. In this regard it may be relevant to note that feelings of dijh vu professed last year by this reporter were also experienced by the corresponding reporter of a decade ago.3 Fortunately many sparks of creativity still glow however and encouraging flames are still often seen.Organosilicon chemistry in particular remains a lively area. Of the two complementary structural tools that have become much more generally available in recent years viz. single-crystal X-ray diffraction analysis and versatile multielement n.m.r. spectroscopy the latter does not yet seem to be exploited to its full potential in more general aspects of main-group organometallic chemistry and so there are probably many interesting applications still to come in the near future. There is however once more a high incidence of single-crystal X-ray work reported in both older and newer areas of the sub-discipline and cyclopentadienyl and other arene complexes of the main-group metals seem to be well represented this year.In some areas the use of X-ray diffractometry is becoming quite routine and it is being applied increasingly to examine the more subtle variations in molecular dimensions rather than to elucidate new structural types and behaviour. In this context it must however be evident that (to take but one example) the collection of sorhe 45 000 X-ray data to determine the molecular structures of Ph,MSMe (where M = C Si Ge Sn or Pb)? although excellent systematic work will bring tears to the eyes of those organometallic chemists with real structural mysteries to solve but who have limited or zero access to diffractometer facilities. 2 Group I Again the bulk of the reported work for this Group is in organolithium chemistry.There is however an interesting report that unsolvated aryl alkali-metal reagents ArM where M = Na or K as well as Li can be made to be soluble in aromatic solvents by the use of the magnesium P-alkoxyoxide [Mg(OCH2CH20Et),] so that sodiation and kaliation of organic compounds under homogeneous conditions is now possible.' This has obvisus synthetic potential. The solution species are believed to have formulations such as [Na2MgPh2(OCH2CH20Et)2]n. There is continuing interest in the solution equilibria of more straightforward organolithium reagents and in the relationship of these to reactivity and product distribution. PhLi has been examined in solution by n.m.r. chemical shift and relaxation studies and has been found to be tetrameric in cyclohexane/diethyl ether solution with the same geometry as in the solid state.6 In dilute diethyl ether however dimer and tetramer coexist and in THF the species is dimeric even at -120 "C.The isomerization of vinyllithium species continues to 'attract attention from the schools involved (ref. 7 and other refs. cited therein) the equilibrium of equation (1) and its variation with solvents substituents etc. has been examined and is of interest in connection with the use of these species for stereospecific syntheses. Various isomerization mechanisms are considered. K. Smith Annu. Rep. hog. Chem. Sect. B 1975 72 136. G. D. Andreeti G. Bocelli G. Calestani and P. Sgarabotto,J. Organomet. Chem. 1984 273 31. C. G. Screttas and M.Micha-Screttas Organometallics 1984 3 904. L. M. Jackman and L. M. Scarmoutzos J. Am. Chem. SOC.,1984 106 4627. Organometallic Chemistry -Part (ii) Main-Group Elements R' Li H\ H\ / L ,c=c\ /-c=c /\ R2 Li R2 R' N.m.r. studies now including 6Li as well as 13C data have revealed two previously undefined 'dilithium semibullvalenides' prepared in dimethyl ether or THF solution from the reduction of sernibullvalene by metallic lithium.8 These two species are identified as the achiral meso-C, and chiral (*)-D2 diastereoisomers of bis(bicyclo[3.3.0]octa-3,7-diene-2,6-diyl)tetralithium [Li4(C8H&] the first charac- terized pair of diastereoisomeric organolithium compounds [structures (1) and (2) respectively] the system also displays interesting inter- and intramolecular intercon- version processes both within and between the two isomeric forms.The use of co-ordinating ligands to increase the effective bulk about the Li atom (see later) thereby inducing lower states of aggregation in organolithium compounds has its complement in the use of bulky substituents on the organic residue. This aspect of organolithiurn chemistry is still receiving some attention. For example it has been found that [LiCH(SiMe,),] is a monomer in the gas phase at 413 K with the distance Li-C about 203pm whereas in the solid it is a polymer with a -Li-C-Li-C-Li-C-backbone with angles at both Li and C each averaging about 150" and with the distances Li-C in the range 213(9)-227(2) ~m.~ This behaviour contrasts with the isoelectronic but ostensibly less bulky [LiN(SiMe,),] which is a cyclic dimer in the gas phase and a cyclic trimer in the solid.However aggregation in the amide does not require electron-deficient bonding and the 2 x (2e 2c) Li-N-Li linkages are therefore significantly shorter than the 2e 3c Li-C-Li units. The 'simplest metallocene' [Li(C5H5)] [structure (3)] has been approached yet more closely the latest report in this area containing X-ray structural work on [(tmeda)LiC5H4(SiMe3)] [structure (4)I.l' This is made in a straightforward manner by the treatment of [Me3SiC5H5] with Bu"Li in tmeda solution. The Li-C distances are not surprisingly somewhat longer than those previously calculated for [Li(C,H,)] by those chemists (commonly known as theoretical chemists) who do quantum mechanical calculations and who thereby tend not to be constrained by what may be experimentally achievable (e.g.,ref.11);the reasons for the discrepancy R. Knorr and T. von Roman Angew. Chem. Int. Ed. Engl. 1984 23 366 and other refs. cited therein. M. J. Goldstein and T. T. Wenzel J. Chem. Soc. Chem. Commun. 1984 1655. J. L. Atwood T. Fjeldberg M. F. Lappert N. T. Luong-Thi R. Shakir and A. J. "'home J. Chem SOC. Chem. Commun. 1984 1163. M. F. Lappert A. Singh. L. M. Engelhardt and A. H. White J. Orgonomet. Chem. 1984 262. 271. 230 J. D. Kennedy n are discussed.” A comparative perusal of references such as 10 and 11 in fact indicates that this is one of several areas in which there are compatibility problems between useful working approaches adopted by experimental chemists and useful working treatments adopted by the theoreticians particularly with regard to assump- tions about the orbital availability of the metal atom and the nature of the organometallic bond.Similar considerations apply for example to some cyclo- pentadienylberyllium species and to various related six-vertex beryllaboranes.’* Another area of apparent dichotomy between theory and fact arises from the experimentally determined structure of dilithium tribenzylidenemethane-2tmeda which has a gross geometry as represented in (5).13 Although it is pointed out that the geometry differs from the threefold anticipated from calculations for the free 2-anion (6)’ it should be noted that in practice the lithium counter-ions are of course required for stability and their presence contributes to the geometry.Whether this demonstrates an essential futility of performing calculations on species that are not experimentally observable or whether it should be regarded as a valid way of examining their ‘chemistry’ precisely because they are not experimentally observable is of course a moot point. The (polymeric) ‘polylithiated methanes’ {CLi H4-,}, continue to be examined from various points of view,”’-’’ and an overview of some of the philosophy behind E. D. Jemmis and P. von R. Schleyer J. Am. Chem. SOC. 1982 104 4781. 12 J. D. Kennedy hog. Inorg. Chem. 1984 32,pp. 625-627 and refs. cited therein. l3 D. Wilhelm H. Dietrich T.Clark W. Mahdi A. J. Kos and P. von R. Schleyer J. Am. Chem. Soc. 1984 106 7279. 14 A. Maercker and M. Theis Angew. Chem. Int. Ed. Engl. 1984 23,995. j5 J. A. Gurak J. W. Chinn R. J. Lagow H. Steinfink and C. S. Yannoni Inorg. Chem. 1984 23,3717. 16 J. A. Gurak J. W. Chinn R. J. Lagow R. D. Kendrick and C. S. Yannoni Inorg. Chim. Acta 1985 % L75. ” H. Kawa J. W. Chinn and R. J. Lagow 1. Chem. Soc. Chem. Commun. 1984 1665. Organometallic Chemistry -Part (ii) Main-Group Elements 231 the work has appeared.18 Two new approaches have been established for the synthesis of these species.’ These involve an initial treatment of [C(B(OMe),),] with [Hg(OAc),] followed by NaCl to give [C(HgCl),] [equation (2)] or treatment with [HgEt(OAc)] to give [C(HgEt),] [equation (3)].Treatment of either [C(HgCl),] or [C(HgEt),] with an excess of Bu‘Li or with Li dust in diethyl ether then results in the formation of CLi,. The halide reaction gives a solid that contains LiCl whereas [C(HgEt),] in cyclohexane yields a red-brown solution from which a deep red- brown pyrophoric solid may be obtained.’ The precise nature of the polylithiated methanes in the solid state remains an intriguing mystery however and 1984 has seen the application of solid-state CP- MAS 13C n.m.r. spectroscopy to the problem for which interestingly the use of 6Li isotopomers was found to be This is in principle a very suitable probe but unfortunately in this case the results were not too informative. This did not dampen the enthusiasm of the research team involved however who are obviously so proud of the work that they tell us about it twice.The interested punter therefore has the unaccustomed luxury of being able to choose to read an account of the n.m.r. work printed either on thinner shiny paper (ref 15) or thicker matt paper (ref 16). The synthetically useful lithium organocuprates or ‘Gilman Reagents’ which are usually held to be dimeric in solution have received increased attention in 1984. Structural work has shown that the yellow crystalline species [Li2CU3Ph&[ Li,C1,(OEt2),,] has a {Li2Cu3} core structure based on a trigonal bipyramid (7),19 and that a gold species [Li2A~2(2-C6H4CH2NMe2)4], used as a ‘model for the organocuprates’ has a virtually planar {Li2Au2[ C( ipso)],} entity with C(ipso) showing interaction with both Li and Au [schematic structure (8)].,’ As with straightforward alkyllithiums the use of bulky groups on C or Li in these species tends to reduce the state of aggregation which will obviously influence the nature of their reactivity.The species [LiCu{C(SiMe,),},(thf),] has been shown by (7) l8 R. J. Lagow and J. A. Gurak in ‘Chemistry for the Future’ ed. H. Griinewald Pergamon Oxford 1984 pp. 107-1 13. 19 H. Hope D. Oram and P. P. Power J. Am. Chem. Soc. 1984 106 1149. 20 G. van Koten and J. Jastnebski J. Am. Chem Soc. 1984 106 1880. 232 J. D. Kennedy crystallography to have cationic [Li(thf),]+ and anionic [CU{C(S~M~~)~}~]-moieties,2' the compound being isomorphous with the corresponding lithium 'ate' complex [Li(thf),][ Li{C(SiMe,),},] mentioned in last year's report.Another inter- esting incidence of steric bulk is in the lithiated carbaborane [(pmdeta)LiC2B,oHloMe] obtained from Bu"Li and [C2B,oH,lMe] in hexane fol- lowed by the addition of pmdeta (N,N,N',N",N"-pentamethyldiethyl-enetriamine).22 In this compound the Li atom is bound to six-co-ordinate carbon [schematic structure (9)]. The Li-C distance is short at 218(1) pm possibly due to the high carbon s-character in the bond although the correlation of bond-order with bond-length is far from clear-cut in this area.22 3 Group I1 In Group I1 nothing in organoberyllium or organocadmium chemistry has attracted this reporter's attention in 1984 although some interesting chemistry for the other elements has been published.In organomagnesium chemistry it has been found that Mg n.m.r. spectroscopy (25 MHz at 9.4 Tesla) is a surprisingly good method of investigating Schlenk equilibria et~.,~ There is a large chemical shift range of some 200 p.p.m. which is held to facilitate clarification of controversial bonding behaviour and in the investigation of the Schlenk equilibrium the method has the advantage that all three species can be identified directly. Although large linewidths are associated with bis( a-bonded-alkyl)magnesiums,it is nevertheless found to be much more useful than 13C or 'H n.m.r. spectroscopy. In the example given [Mg(C,H,),] it is concluded that predominantly covalent bonds are present.23 Magnesium compounds involving the anthracene skeleton mentioned briefly in last year's report,2 have been the subject of further interesting work.The orange magnesium-anthracene 1:l adduct in THF has been found to be an effective electron-transfer reagent in the generation of Grignard reagents such as (10) and (thf)CIMg M gCI (t hf) MgCl(thf) 21 C. Eaborn P. B. Hitchcock J. D. Smith and A. C. Sullivan J. Organornet. Chem. 1984 263 C23. 22 W. Clegg D. A. Brown S. J. Bryan and K. Wade Polyhedron 1984 3 307. 23 R. Benn H. Lehmkuhl K. Mehler and A. Rufinska. Angew. Chem. Int. Ed. Engl. 1984 23 534. Organometallic Chemistry -Part ( ii) Main-Group Elements 233 (11) from the corresponding halides.24 These two species are formed in >90% yield when stoicheiometric quantities of [Mg(C14Hlo)] are used and are not easily accessible if at all using other forms of magne~ium.,~ Further work on the characterization of the magnesium-anthracene complex itself has been reported and the work includes a study of the kinetics of f~rmation.~’ The species [ Mg(C,,Hlo)(thf),] can be recrystallized from THF solution as orange needles which are sparingly soluble.N.m.r. spectroscopy indicates that the strongest metal interaction occurs with the 9,10-positions and it is concluded that the com- pound can be best regarded either as an ion pair with strong interaction at C-9,lO or as a covalent compound with a large polar contribution [schematic structure (l2)].,’ This structure is to be compared with that of the magnesium-aluminium compounds [ (thf),MgHAlR,( C14H,0)] the magnesium dihydroanthrylene dialkyl- hydroaluminates [schematic structure (13)] which are formed by the reaction of the relatively insoluble magnesium anthracene ( 12) with R2AlH in THF solution.26 H :‘ \ (thf)3Mg AIR2 Y \I Other work on mixed-metal species containing magnesium includes the solid-state structure of lithium magnesates such as [Li,(PhC~C)~Mg(trneda),]and [ Li(tmeda) ][ (tmeda)LiBz,MgBz,] ;27 the configuration of the latter is represented in structure (14).The solid-state structure of the first organogermylmagnesium compound [ (dme)2Mg(GeMe3)2] (1 5) has been established.28 Its preparation from [Hg(GeMe,),] with Mg in 1,2-dimethoxyethane (dme) was reported initially in 1981 previous to which organogermylmagnesium compounds had been postulated A GeMe 24 C.L Raston and G. Salem J. Chem. SOC.,Chem Commun. 1984 1702. 25 B. Bogdanovik S.-T.Liao R. Mynott K. Schlichte and U. Westeppe Chem. Ber. 1984 117 1378. 26 H. Lehmkuhl K. Mehler R. Benn A. Rufinska G. Schroth and C. Kriiger Chem. Ber. 1984,117,389. 27 B. Schubert and E. Weiss Chem Ber. 1984 117 366. 28 L. Rosch C. Kruger and A.-P. Chiang 2. Naturforwh.. Ted B. 1984. 39. 855. 234 J. D. Kennedy to exist only as unstable short-lived intermediates. The compound has an approxi- mately octahedral cis-{Ge20,} configuration about the Mg centre with the mean Ge-Mg distance 271.9(6) pm.28 The renaissance of organozinc chemistry continues and developments include a study of fluxional 2-alkenylzinc compounds by i.r.Raman 'H n.m.r. and 13C n.m.r. ~pectroscopies,~~ and the generation of [ZnBr(CH,Br)] from Zn and CH2Br2 in THF,30 which is claimed to be a useful inexpensive alternative to the more usual use of CH212in Simmons-Smith-type processes for methylene generation. The Reformatsky reaction has been the subject of some attenti~n,~'-~~ and ultrasound has been found to be useful for the generation of the Reformatsky reagents from metallic Thus for example the ultrasound-promoted reaction between ethyl bromoacetate zinc and Schiff's bases gives excellent yields of p-lactams -90% after a few hours with activated zinc granules and SO-70% with presumbably pure zinc The Reformatsky reaction first described nearly a century ago is still one of the best methods for preparing P-hydroxy acids via their esters (Scheme 1),33 but as with many very well-studied organometallic reactions (I):c=o BrCH,COOR + Zn -+ BrZnCH2COOR -:C(OH)CH,COOR -:C(OH)CH,COOH (ii) HzO Scheme 1 the lack of knowledge about the actual reagent in solution inhibits the emergence of a clear picture of the mechanism.In this regard some work on the nature of the Reformatsky reagents that are derived from the ethyl and t-butyl esters of bromoacetic acid is of interest.33 The dimeric structure (16) found in the crystal persists in solution but the solution behaviour is complicated by Schlenk-type equilibria [equations (4) and (S)] and in very polar solvents such as Me,SO the reagents are monomeric C-metallated species; the consequences of these findings for the mechan- ism of the Reformatsky reaction in commonly used solvents are also discussed in the which also serves to re-emphasize the important general point that the 2[BrZnCH2COOR] ZnBr + [Zn(CH,COOR),] (4) [BrZnCH,COOR] ZnBr + l/n[Zn(CH,COOR),] (5) (16) 29 E.G. Hoffman H. Nehl H. Lehmkuhl K. Seevogel and W. Stempfle Chem. Ber. 1984 117 1364. 30 B. Fabisch and T. N. Mitchell 1. Organornet. Chem. 1984 269 219. 3' B. H. Han and P. Boudjouk J. Org. Chem. 1982 47 5030. 32 A. K. Bose K. Gupta and M. S. Manhas J. Chem SOC.,Chem Cornmun. 1984 86. 33 J. Dekker P. H. M. Budzelaar J. Boersma G. J. M. van der Kerk and A. L. Spek Organomefalfics 1984 3 1403. Organometallic Chemistry -Part (ii) Main-Group Elements 235 aggregation state of a typical early main-group organometallic reagent has critical mechanistic implications for its reactions with organic substrates.In view of the structural diversity of Group I1 organometallic compounds the amount of crystallographic work is still rather scant and it is always of interest to see new work. Structural reports this year include an acetoximate complex [Zn,Me,( Me2CN0)4] based on a Zn tetrahedron with an oxime group bound above each Zn3 face in such a way that all the Zn atoms are different.34 Another interesting compound is the colourless species [(p-CSH5)(p-N{SiMe,),)-(Zn-o-C,H,),] [schematic structure (17)] made by the reaction between [Zn(C,H,),] and [Zn{N(SiMe,),},].The bridging C5Hs is asymmetrically bound (Zn-C ca. 210 and 250 pm) and the compound is fluxional (AG ca. 70 kJ mol-') with respect to exchange of the organic groups via scission of a Zn-p-(C5H5) link and rotation about Zn-N.35 Me3Si \\\ Pi"" Alongside interesting new chemistry such as this it is always nice to see the elucidation of old problems. One of these concerns the constitution of 'mercuretin' a compound with a long history which was first obtained in 1809 by melting mercuric acetate and which may well have been the first organometallic compound to be discovered. It has now been identified as the condensation polymer of tris(acetoxy-mercuri)acetic acid (AcOHg),CCOOH with the formulation [AcO{HgC(HgOAc)2C0.0}nH] where n -The compound has a ...OHgC.CO.OHgC.CO.OHgC.CO...backbone and hydrolysis in dilute HC1 gives (ClHg),CCOOH as the only Hg-containing product (identified by X-ray diffraction as its DMSO solvate). Treatment with AcOH yields (AcOHg),CCOOH which reverts to mercuretin by AcOH Other C-metallations involving mercury carboxylates include the quantitative mercurations of bis(dipheny1phosphino)methane with [Hg(OAc),] [equation (6) where n = 2 or 3],,' and the mercuration of 1-OMe-2-NO2-C6H4 with [Hg(OCOF3),] in CF,COOH solution.38 The former reaction is thought to be of interest in that previous examples of C-mercuration in aliphatic compounds were limited to sites with more classically acidic H atoms and the second because the product [structure 34 N.A. Bell H. M. M. Shearer and C. B. Spencer Acta Crystallogr. Sect. C 1984 40,613. 35 P. H. M. Budzelaar J. Boersma G. J. M. van der Kerk and A. L. Spek Organornerallics 1984 3 1187. 36 D. GrdeniC B. Korpar-colig and M. Sikirica J. Organornet. Chern. 1984 276 1. 37 M. Lusser and P. Peringer Organornetallics 1984 3 1916. 38 G. B. Deacon G. N. Stretton and M. J. O'Connor J. Organornet. Chern. 1984. 277 C1. J. D. Kennedy (lS)] exhibits the rather large nuclear spin-state energy difference ,J( 199Hg-’99Hg) of 2163 Hz. Ph2PCH2PPh2+ n[Hg(OAc),] + [Hg(drn~o),][CF~S0,]~ __* [H,-,(AcOH~),-,C(PP~~H~OAC)~][CF,S~~~~ + (n-1)AcOH (6) Other mercury work has been mentioned above [equations (2) (3) and structure (1511. 4 Group I11 It has long been known that gallium halides of empirical formula GaX are freely soluble in benzene and can be precipitated from solution as solids containing ‘crystal benzene’ (see also 1983’s report).2 In this area details of the bis(mesity1ene)gal- lium( I)-gallium( 111) halide complex [Ga(C,H3Me3)2][GaC1,] have been reported.39 The compound is prepared by the dissolution of GaC12 (i.e.Ga[GaCl,]) in hot mesitylene followed by cooling to precipitate the product and the synthesis has also been extended to the indium analogue [In(C,H3Me3)2][InBr4].40 The latter compound is sensitive to heat and light and readily loses mesitylene. The cations of both species have the ‘bent sandwich’ structure (19) with the distances from the metal to the centre of the {c,} plane being CQ.267 and 289 pm respectively. In the indium compound the metal is also bound to three co-planar bromine atoms at 248-250 pm forming a co-ordinate polymer whereas the [Ga(C6H3Me3)2]+ cation is more chemically discrete the interionic Ga ...Cl distances being >325 pm.39*40 More novel is the ‘naked’ mono-organogallium cation [Ga(C,Me,)]+ in [Ga(C,Me,)][GaBr,] [schematic structure (20)],4’ in which although there are again longer-range interactions with nearest-neighbour bromine atoms these are weak at >320 pm and the gallium centre is bonded principally to the hydrocarbon at 252 pm 39 H. Schmidbauer V. Thewalt and T. Zafiropoulos Chern. Ber. 1984 117 3381. 40 J. Ebenhoch G. Miiller J. Riede and H. Schmidbauer Angew. Chern. Inr. Ed.Engl. 1984 23 386. 41 H. Schmidbauer U. Thewalt. and T. Zafiropoulos Angew. Chem. Int. Ed. EngL 1984 23. 76. Organometallic Chemistry -Part (ii) Main-Group Elements above the (c6) centroid i.e. much more strongly than in the [Ga(Ar),]+ species. In this general area it may be noted that there has been a theoretical analysis of the related (neutral) species [M(C5H5)] where M = In or Tl.42 Other gallium work reported in 1984 includes the potentially interesting species K[GaH2(CH2SiMe3)2] prepared from [Ga(CH2SiMe3)2Br] and 2KH in DME at 25°C.43 The compound was synthesized in the hope that reaction with [Ga(CH2SiMe3)2Br] would yield [Ga(CH2SiMe3)2H] which would then reductively eliminate TMS to give the gallium( I) species. In the event and perhaps not surpris-ingly Ga metal [Ga(CH2SiMe3)3] and H2 were formed instead.Apart from the aluminium-magnesium-anthracenespecies mentioned in Section 3 above [structure ( 13)],26 aluminium work noted in 1984 has included the formation of an unusually stable aluminium-alkyl bond in the species [EtAl( N4C22H22)] [schematic structure (21)].44 Reaction of &Et6 in hexane with the precursor [N4C22H24] but heating [schematic structure (22)] yields initially [Al( N4C22H23)Et2] of the latter in the solid state at 100°C results in the quantitative elimination of more ethane to give the product (21) which can be crystallized from hydroxyl- containing solvents such as water. Acid conditions e.g. HCl (immediately) and PhOH (much less readily) cleave the Al-C bond as does photolysis but perchloric acid protonates the methine carbons leaving the Al-C bond intact this last may therefore be a step in the HC1 acidolysis.44 Other Al-C bonds stable to thermolysis (though not now to air and moisture) are known to result from the complexing of aluminium alkyls with oxyanions.A 1984 example is K2[A14Me,2S04] formed by the stoicheiometric reaction between 4AlMe3 and a K2S04 suspension in aromatic solvents.45 The [S(0AlMe3),l2- anion has a straightforward tetrahedral configuration about sulphur and the compound interestingly forms a p-xylene clathrate K4[Al4Mel2S0412[C6H4Me2l- 5 Group IV Once again the organometallic chemistry of Group IV is the best represented of the main-group metals organosilicon chemistry in particular reseiving most attention.Again areas of new behaviour which figure largely are those of small ‘strained’ ring compounds multiple bonds to metals the metal( 11) valency state the consequences 42 E. Canadell 0. Eisenstein and J. Rubio Organometallics 1984 3 759. 43 0. T. Beachly and R. B. Hallock Organornetaflics 1984 3 199. 44 V. L. Goedken H. Ito and T. Ito J. Chem. SOC. Chem. Commun. 1984 1453. 45 R.D. Rogers and J. L. Atwood Organometallics 1984 3. 271. J. D. Kennedy of bulky substituents on the metal and the reaction chemistry involving supposed or real reactive intermediates such as free radicals and monometallenes. The interest in these types of behaviour is of course independent of general reaction chemistry and in this context the book Carbon-Functional Organosilicon Compounds46 will be of interest to chemists who are concerned with organic syntheses based .on organosilicon chemistry.The study of multiple bonds between Group IV metals is now approaching maturity; there are two review articles in the area,47,48 a very efficient concise survey of many of the salient points? and there is continued structural The species [Ge{CH(SiMe,),},] now made in improved yield from [GeCl,(dioxane)] and the new Grignard reagent [MgC1{CH(SiMe,),}(OEt2)] is monomeric in the orange-red gas phase with Ge-C 204(2) pm and the angle C-Ge-C 107(2)" but in the solid phase it is a bright yellow dimer m.p. 182"C with a Ge-Ge distance of 234.7(2) pm.49*52 The structural characterization of the dimer now permits the com- parison of M=M 'double' bonds in four periods of Group IV (Table 1).All have Table 1 Some structural parameters for crystalline Group IV dimetallenes M2Ria M C Si Ge Sn R' Sum of angles Z at M/" Ph 360 C,H2Me3-2,4,6 355.3 CH( SiMe3)2 348.5 CH(SiMe3)2 342 Fold angle O/" Twist angle /" (C(sp2 or sp3)-M)/A M-M In tetrahedral M,/A M-MIA 0 8.4 1.494 1.356 1.545 18 5 1.88 2.160 2.352 32 0 2.00 2.347( 2) 2.445 41 0 2.28 2.764( 2) 2.810 M-M Bond shortening in M,R compared with M, % 12 8 4 2 (a)Data from ref. 49 and other refs. cited therein. the trans-folded configuration [structure (23)] and it can be seen that there is a general decrease in formal double-bond character down the sequence C + Si -+ Ge -+ Sn accompanied by an increase in the folding angle 8.It will be interesting to see structural work on the lead compound first reported as a purple solid nearly a decade ago.53 It is appropriate to note here that there is an error associated with 46 'Carbon-Functional Organosilicon Compounds' ed. V. Chvalovski and J. M. Bellama Plenum 1984. 47 A. H. Cowley Polyhedron 1984 3 389. 48 A. H. Cowley. Acc. Chem. Res. 1984 17. 386. 49 P. B. Hitchcock Michael F. Lappert S. J. Miles and A. J. Thorne J. Chem Soc. Chem. Commun. 1984 480. S. Masamune S. Murakami J. T. Snow H. Tobita and D. J. Williams Organometallics 1984 3 333. 51 M. J. Fink J. Michalczyk K. J. Haller R. West and J. Michl Organometallics 1984 3 793. 52 T. Fjeldberg A. Haaland B. E. R. Schilling H.V. Volden M. F. Lappert and A. J. Thorne J. Organomel. Chem. 1984 276 C1. 53 P. J. Davidson D. H. Harris and M. F. Lappert 1. Chem. Soc. Dalton Trans. 1976. 2268. Organometallic Chemistry -Part ( ii) Main-Group Elements work reported in this area in 1983 (see footnote 2 in ref. 49); this reporter confesses to not spotting this in last year's report and also therein of wrongly transcribing the formula [Sn{N(SiMe3)2)21.54 The dissociation of the {Ge,} and {Sn,} species to their respective monomers is mirrored somewhat in the sterically hindered but otherwise conventionally singly bonded hexamesityldisilane and he~arnesityldigermane.~~ In these the M- M bonds dissociate homolytically and reversibly between -60 and -32 "C for Si(AHdiss ca.79kJmol-') and between -12 and +53"C for Ge (AHdissca.86kJmol-'). The radicals that are generated react irreversibly for example by substitution of aromatic species or by abstracting hydrogen.,' thf O+ The chemistry of compounds with multiple bonds from silicon to other elements continues to progress steadily and a review of unsaturated Si and Ge compounds of the type R2M=C(SiR3)* and R,M=N(SiR,) has been published.56 The structure of the silaethene species [Me,Si=C( SiMe,)( SiMeBu',)(thf)] has been determined [schematic drawing (24)]. The carbon is planar but there is some pyramidalization at silicon and a zwitterionic contribution to the bonding has been postulated [structures (25)].,' Unsubstituted silaethene H2Si=CH2 has been isolated at low temperatures in an argon matrix and its interconversion with methylsilylene via a photochemically induced 1 + 2 shift [equation (7)] has been studied.'8p59 In related argon matrix work silabenzene [HSiC5H5] has also been isolated.60 Other compounds with a formal metal(I1) valency state are the metallocene species which also attract steadily progressing experimentation.Monomeric germanocene [Ge(C5HJ2] previously thought to be polymeric in the solid state has now been prepared in pure form from [Na( C'H,)] and [GeCl,( dioxane)] in THF solution in 60% yield.61 The compound is stable for weeks at -30 "C and has the open sandwich structure also exhibited by [Sn(C,H,),]. The angle between the rings at 50.4" is somewhat larger than in [SII(C,H,)~] even though the Ge atom is the smaller and 54 M.F. Lappert personal communication 1985. The reporter thanks Professor Lappert for drawing his attention to this matter. 55 W. P. Neumann K.-D. Schultz and R. Vieler J. Organornet. Chem 1984,264 179. 56 N. Wiberg J. Organornet. Chern. 1984 273 141. 57 N. Wiberg G. Wagner G. Muller and J. Riede J. Organornet. Chern. 1984 271 381. 58 G. Maier G. Mihm and H. P. Reisenauer Chem Ber. 1984 117 2351. 59 G. Maier G. Mihm H. P. Reisenauer and D. Littman Chem Ber. 1984 117 2369. 60 G. Maier G. Mihm R. 0. W. Baumgartner and H. P. Reisenauer Chem Ber. 1984 117 2337. 61 M. Grew E. Hahm W.-W. duhlont and J. Pickardt Angew. Chern. Znt. Ed. EngL 1984 23 61. J. D. Kennedy the divergence among the Ge-C distances (235-273 pm) is also more pronounced than the corresponding ones in the tin compound.61 Sterically bulky substituents on the C5 rings tend to reduce these angles; [Sn(C,Me,),] has a similar angle to [Sn(C5H5)2] but in [Sn{C5H2(SiMe3)3}2] made according to Scheme 2 the angle is reduced to 18°,62 and in [Sn(C5Ph5),] the two planes are parallel even though the (mean) Sn-C distance of 269.2(8) pm is very similar to the more open species.63 The perphenylated compound is made in 56% yield in a straightforward manner by the treatment of C5Ph5Br with BuLi followed by SnC12.63 Associated with this compound are a number of ‘Zuckerman Claims’ (without which over the years the literature of organometallic chemistry would be much the Of these ‘the first symmetrical main-group sandwich com- pound’ is of course reasonable but ‘the first example of a molecular main-group species in which the lone pair is stereochemically inert’ and ‘the first molecule to violate decisively the VSEPR theory’ will presumably run into flak.(27) (26) Scheme 3 Related to these metallocenes and to some of the lithium zinc and gallium work cited above are the closo cluster stannacarboranes of general configuration (26) which can be made by the bridge-deprotonation of the nido precursor (27) in THF followed by addition of SnC1 (Scheme 3).65*66 In some related polyhedral carborane chemistry use is made of {SiMe3} as a leaving group well known in organic synthesis to generate the nido twelve-vertex species [(Me3Si)2C4BsH10] oia the thermal elimi-nation of Me3SiH from nido-[(Me3Si)2C2B4H6].67 It is a healthy sign to see links such as this between the organometallic and polyhedral sub-disciplines of main-group chemistry and it is obviously an area of good potential for new chemistry not only with Group IV organometallics.62 A. H. Cowley P. Jutzi F. X. Kohl J. G. Lasch N. C. Norman and E. Schliiter Angew. Chem. Int. Ed. Engl. 1984 23 616. 63 M. J. Heeg C. Janiak and J. J. Zuckerman J. Am. Chem. SOC.,1984 106 4259. J. J. Zuckerman as quoted in Chem. Eng. News 1984 62,‘20. 65 A. H. Cowley P. Galow N. S. Hosmane P. Jutzi and N. C. Norman J. Chem. SOC.,Chem. Commun. 1984 1564. 66 N. S. Hosmane. N. N. Sirmokadam and R. H. Herber Organomerallics 1984 3 1665. 61 N.S. Hosmane M. Dehghan and S. Davies J. Am. Chem. Soc.. 1984 106 6435. Organometallic Chemistry -Part (ii) Main-Group Elements 24 1 The more straightforward divalent and/or multiply bonded Group IV organometallic species are often invoked as reaction intermediates. Interesting 1984 examples include an unusual silanediyl-germanediyl exchange.68 In this process photochemically generated Me2% is reported to react quantitatively with the germole (28) to give the corresponding dole (29) and polygermanes (Me,Ge), with n =4 as the major polygermane product (Scheme 4). The reaction is thought to go via an initial addition to a germole double bond followed by equilibration of an intermediate such as (30).68 A second 1984 example is the generation of the true silicones R2Si=0 (known as silanones) by thermolysis of the 6-oxa-3-silabicyclo[ 3.1 .O]hexanes (3 1) in a flow system at 460 "C (Scheme 5).69The reaction also works for the corresponding germanones.The transient silanones polymerize to cyclic siloxanes (61-70%) or by using a 1,3,2-disilaoxapentane as a trap the corresponding dioxatrisilacycloheptanes may be obtained in 41 O/O yield. Me Me Me Me \/ Ge \si/ jjph -Me,Si + ;)ph +(Me,Ge), I I Mc Me Me Me Me Me \/ \/ Gi Ph,&Ph / Ph / Me I Ph (30) Scheme4 75-80% Scheme 5 An interesting extension of this is to start with the spiro compound (32) which results in a 60% yield of the spirosiloxane of configuration (33) when the cyclo- trisiloxane (Me2SiO) is used as a trapping agent.It would be nice to think of monomeric silica O=Si=O as the intermediate but reality will probably assert that the reactive >Si=O units are generated ~tepwise.~~ 68 J. A. Hawari and D. Griller J. Chem. Soc. Chem. Commun. 1984 1160, 69 G. Manuel G. Bertrand W. P. Weber and S. A. Kazoura Organometallics 1984 3 1340. rcsi3Me J. D. Kennedy 0-Si-0 0-Si-0 / \/ \ 490°C 0-(Me,SiO) Si\ Si /Si 0-si-0' \o-si -0 (32) (33) As usual there h'as been much small-ring chemistry reported either incorporating silicon as one of the ring members or as a substituent; sometimes bulky organic groups are used for stability and sometimes the organosilicon group itself constitutes the stabilizing substituent. Examples include the first single-crystal X-ray structural analysis of a silacyclobutene (34),70the first isolated siloxetane (35),71octamethyl-spiropentasilane of configuration (36),72 and the boron-containing heterocycles (37),73(38),74 and (39).75The last species (39) is of interest because it is believed to topomerize as indicated (AG* CQ.48 kJ mol-') but calculations suggest that structures such as (40) may be the most stable and that topomerization may occur via structures such as (39) and (41) as intermediate^.^^ Somewhat in accord with this in its reaction chemistry the compound behaves as if it is of configuration (41) and undergoes a number of carbene-like reactions.77 Bu'Me,Si /SiMe,Bu' \ Me,Si SiMe, N-N \/ \/ c=c B \/ I B N I SiPh, Me,Si /\SiMe (38) (37) 70 M.Ishikawa S. Matsuzawa K. Hirotsu S. Kamitori and T. Higuchi Organometallics 1984 3 1930. 71 A. Sekiguchi and W. Ando J. Am. Chem. Soc. 1984 106 1486. 72 P. Boudjouk and R. Sooriyakumaran 1. Chem. SOC.,Chem. Commun.,1984 777. 73 U. Klingebiel Angew Chem. Znf. Ed. Engl. 1984 23 815. 74 B. Pachaly and R. West Angew. Chem. Znt. Ed. Engl. 1984 23 454. 75 H. Klusik and A. Berndt Angew. Chem. Int. Ed. Engl. 1983 22 877. ?6 B. H. M. Budzelaar P. von R. Schleyer and K. Krogh-Jespersen Angew. Chem. Znt. Ed. Engl. 1984 23 825. 77 R. Wehrmann H. Klusik and A. Berndt Angew. Chem. Znt. Ed. Engl. 1984.23 826. Organometallic Chemistry -Part ( ii) Main-Group Elements 243 A large amount of the chemistry of the silacyclopropanes and silacyclopropenes first reported in a preliminary fashion in 1977 has now been reported in some The silacyclopropenes are much more reactive than the silacyclopropanes and reactions with aldehydes ketones styrenes conjugated terminal acetylenes benzyne terminal 1,3-dienes and a conjugated imine are reported.These reactions generally give five-membered cyclic organosilicon products in which the C=O C=C CEC or C=N bonds of the organic reagents have inserted into the Si-C bond of the silirene ring. C-C insertions and acyclic products isomeric with the cyclic ones are also observed and the available evidence is taken to suggest that a radical mechanism is operative.79 Apart from the aspects mentioned abo~e,~~~~*~~*~~*~~ organogermanium chemistry is not well represented this year.A review of structural organogermanium chemistry may be noted,80 and also the start of the use of 73Ge n.m.r spectroscopy in this INEPT n.m.r. techniques are found to be helpful,82 and there is a confirmation of the linear relationship between the chemical shifts S(29Si) and 6 (73Ge) for equivalent organosilicon and organogermanium species.83 In organotin chemistry too there is little novel to note. Again some developments have been dealt with above.62d6 There is the hardy perennial interest in the auto-associaton of organotin oxides and alkoxides but this now appears to be on the wane. In this area the solid-state structure of the simple 2,2-dibutyl-1,3,2- dioxastannolane has been found to be an infinite ribbon of six-co-ordinate tin atoms in highly distorted octahedral sites.84 This result indicates that conclusions arising from Mossbauer data on the same compoundss need to be re-examined.More complete details on the initial work on the ‘Lewis acid crowns’ mentioned in last year’s report,2 have been published,86 and a potential ‘Lewis acid cryptand’ PhSn((CH,),},SnPh has been reported by the same Unfortunately in this compound the potentially cryptating cavity appears to be already full of hydrogen atoms from the polymethylene chains. Since the discovery in the early 1970s of the interesting variety of stereospecificity in reactions between organostannylalkali reagents such as Me,SnNa and organic halide substrate^,^^^^^ there has been a lot of careful experimentation in the area which has not been without controversy and the papers in the field often make interesting reading.Reference 90 is a good lead-in to this literature but it mainly deals with a meticulous examination of the reaction between Me3SnM (where M = Li Na or K) with organic bromides in various solvent systems and with the establishment of the relative contributions of electron-transfer and SN2 mechanisms 78 D. Seyferth D. P. Duncan M. L. Shannon and E. W. Goldman Organometallics 1984 3 574. 79 D. Seyferth S. C. Vick and M. L. Shannon Organometallics 1984 3 1897. 80 K. C. Molloy and J. J. Zuckerman Adu. Inorg. Chem. Radiochem. 1983 27 113. 81 I. P.Sekatsis E. Liepins I. A. Zicmane and E. Lukevits Zh. Obshch. Khim. 1983 53 2064.82 K. M. Mackay P. J. Watkinson and A. L. Wilkins J. Chem SOC. Dalton Trans. 1984 133. 83 Y. Takeuchi T. Harazono and N. Kakimoto Inorg. Chem. 1984 23,3835. 84 A. G.Davies A. J. Price H. M. Dawes and M. B. Hursthouse J. Organomet. Chem. 1984 270 C1. 85 R. H. Herber A. Shanzer and J. Libman Organometallics 1984 3 586. 86 Y. Azuma and M. Newcomb Organornetallics 1984 3 9. 87 . M. Newcomb M. T. Blanda Y. Azuma and T. J. Delord J. Chem. SOC. Chem. Commun. 1984 1159. 88 G. S. Koermer M. L. Hall and T. G. Traylor J. Am. Chem. SOC.,1972 94 7205. 89 H. G. Kuivila J. L. Considine and J. D. Kennedy J. Am. Chem. SOC., 1972 94 7206. 244 J. D. Kennedy to the reaction.” Contributions identified in other systems also include metal- halogen exchange processes and it is apparent that the balance between these three mechanisms depends intimately on the nature of the organostannylalkali species in solution (compare Sections 2 and 3 above).Preliminary multielement n.m.r. work has shown large changes of n.m.r. parameters with solution conditions,” and further n.m.r. work allied with solid-state structural investigations will be particularly valuable. Other mechanistic work includes a study of the reaction between organotin hydrides and acid chlorides to give aldehydes and esters as summarized in equation (8).92Long believed to be a free-radical process this is now thought o be a non-radical mechanism in which the initial products are RCHO and RGSnCI the remaining products being formed by subsequent reaction of the aldehyde.For example R$SnOCH,R will be formed from the aldehyde and the tin hydride and can then react further with RCOCl to give RC0.0CH2R with RCHO to give R;SnOCHROCH,R and with RiSnH to give RCH20H?2 RCOCl + RjSnH -RjSnCI + RCHO + RCO.OCH,R (8) It has been found that the reaction between SnS and Me1 in H20 yields MeSnI in 33% yield it is reasonably claimed that this may bear on the ubiquitous occurrence of methylstannanes in the environment and also that it represents a convenient one-step synthesis of MeSn13.93 The implication that previously reported syntheses are much less simple or much more inconvenient is less reasonable however. For example it is very easy to devise a reaction between Me1 and the perhaps more realistic starting material SnC12 to give an 87% yield of MeSnI in a one-pot process:4 which may be compared to the overall yield of 25% in a two-step process from the same starting materials that is implicit in the more recent report.93 Theoretical studies do not usually come within the scope of this report but organotin chemists will be interested to note that MNDO parameters are now available for tin and MNDO treatments have been applied,(with some success it is claimed) to four topics of current interest in organotin chemistry?’ This has led to satisfactory interpretations of the mechanism of hydrostannylation structures of the sandwich and half-sandwich cyclopentadienyltin compounds the possibility of multiple bonding by tin in distannene and dimethylmethylenestannene,and the geometry of the trimethylstannyl radical?’ 6 Groups V and VI Organometallic compounds of these later main-group metals and metalloids continue to be a happy hunting ground for transition-metal chemists in their insatiable search for ligands.Even the heavier elements are now no longer immune 1984 examples M. S. Alnajjar and H. G. Kuivila J. Am. Chem. SOC.,1985 107 416. 91 J. D. Kennedy and W. McFarlane J. Chem. SOC.,Chem. Commun. 1974 983; J. Chem SOC.,Dalton Trans. 1976 1219. 92 L. Lusztyk E. Lusztyk B. Maillard and K. U. Ingold J. Am. Chem. SOC.,1984 106 2923. 93 W. F. Manders G. J. Olson F. E. Brinckman and J. M. Bellama 1. Chem. SOC.,Chem. Commun. 1984 538. 94 J. D. Kennedy J. Labelled Compd. 1975 11 285.95 M. J. S. Dewar G. L. Grady D. R. Kuhn and K. M. Men. J. Am. Chem. Soc. 1984 106 6773. Organometallic Chemistry -Part (ii) Main-Group Elements including the use of Sb2Ph2 as a bridging ligand between two rhenium centres96 and a kinetic study of the oxidative addition of Te2Ar2 to the iridium(1) complex [Ir(CO)Cl(PPh3),].97 Another in the same area is the reaction of Bi,Ph4 with [co,(co)g] to give [CO(B~P~,)(CO)~].~~ The study of these metal-metal bonded species such as the distibines and dibis- muthines in a non-transition-metal context continues to be an area of progress. The molecular structure of Sb2Me2 a pale yellow liquid which freezes at +17 "C to give a bright red solid has been determined at -160"C.99 The structure consists of essentially collinear chains of Sb atoms with alternating short and long inter- antimony distances of 286.2(2) and 364.5(1) pm similar to those of the higher (bistibole) homologues mentioned in previous reports2 A new thermochromic dibismuthine 2,2',5,5'-tetramethylbibismole (42) which is red in solution but black with a greenish-blue lustre in the solid state has been made.'" The synthesis from 1,4-dilithiobutadiene is given in equations (9) and (lo) and proceeds uia the potentially aromatic bismolyl anion (43).The compound (42) is air-sensitive but can be stored at room temperature as the solid m.p. 95 "C. The crystal packing is also believed to be similar to the thermochromic bistibole mentioned in the 1982 report2 The corresponding biarsole is non-thermochromic.'Oo In these general areas the main-group o-framework permutational chemists are just as voracious as the transition-metal chemists mentioned in the first paragraph of this Section and in accord with this it appears that the derivative chemistry of these M-M species may also now be receiving increasing attenti~n.'~'-'~~ Thus for example Sb,Me4 and Sb2Et4 have been found to react with elemental Se or Te to give compounds of the general formulation R2Sb-E-SbR2 where E = Se or Te,"' and Bi2Me4 reacts with PhEEPh where E = S Se or Te to give compounds of general formula Me2BiEPh.lo2 Similarly Bi2Me4 reacts with stoicheiometric amounts of O2or sg to give essentially quantitative yields of yellow [(Me,Bi),S] and colourless explosion-prone [( Me2Bi)20],'03 and the reaction of PhLi with either Bi2Me4 or 96 1.Bernal J. D. Korp F. Calderazzo R. Poli and D. Vitali J. Chem. SOC.,Dalton Trans. 1984 1945. 97 R. T. Mehdi and J. D. Miller J. Chem. SOC.,Dalton Trans. 1984 1065. 98 F. Calderazzo R. Poli and G. Pelizzi J. Chem. Soc. Dalton Trans. 1984 2535. 99 A. J. Ashe E. G. Ludwig J. Oleksyszyn and J. C. Huffman Organometallics 1984 3 337. 100 A. J. Ashe and F. J. Drone Organometallics 1984 3 495. 101 H. J. Breunig and H. Jawad J. Organomet. Chem. 1984 277 257. 102 M. Wieber and I. Sauer 2. Naturforsch. Teil B 1984 39 1668. 103 M. Wieber and 1. Sauer Z. Naturforsch. Teil B 1984 39 887. J. D. Kennedy Me2BiBr gives good yields of BiMe2Ph as a colourless very oxygen-sensitive 1iq~id.l'~ Other insertions into the Bi-Bi bond include the reaction of Bi2Ph2 with p-benzoquinone to give pale-yellow [Ph2Bi-OC6H40-BiPh2] in 87% yield and with diazomethane to give [(Ph2Bi)2CH2] in 49% yield.lo4 In a related area yellow unstable [S(NBiBu:),] is made from BuiBiBr and K2SN2in CH3CN solution and the yellow-orange {BuiSb} and yellow {Ph2As} derivatives which are more stable are made ~imilarly.''~ In addition to these singly-bound Group V M-M species there is a continuing development in the chemistry of the multiply bound species RM=MR.This area has been and a comprehensive experimental account has also been presented.lo6 The final compound in this year's report is the dark-red mouldy-smelling orange solid As4Bui which is unstable even at -78 OC.'07 It is made from Bu'AsC12 according to equation (11) and is believed to have the butterfly 2,4-di-t-butyl-bicyclo[l.l.O]tetraarsane structure (44).It is a member of the set of compounds which also includes As,Bu\ [structure (45)] and As,Buk [structure (46)] previously reported by the same school in 1981. 2ButAsC1 + 2AsC1 + lOLiH- As,Bu + lOLiCl + 5H (11) Bu' But Bu' Bu'A s I ,AsBu' /AS.As-AS \ \As/As-As Bu' Bu' 104 F. Calderazzo R. Poli and G. Pelizzi J. Chem. SOC.,Dalton Trans. 1984 2365. 105 M. Herberhold W. Ehrenreich and K. Guldner Chem. Ber. 1984 117 1999. 106 A. H. Cowley J. E. Kilduff J. G. Lasch S. K. Mehrotra N. C. Norman M. Pakulski B. R. Whittlesey J. L. Atwood and W. E. Hunter Inorg. Chem. 1984 23 2582.107 M. Baudler and S. Wietfeldt-Haltenhoff Angew. Chem. Znt. Ed. Engl. 1984 23 379.

ISSN:0069-3030    

DOI:10.1039/OC9848100227

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

11 Synthetic Methods By A. P. DAVIS Department of Chemistry Trinity College Dublin 2 Ireland 1 Introduction This report is presented in almost exactly the same format as last year’s. A major division is made between methods for the construction or alteration of the carbon skeleton of a molecule and methods for the introduction and modification of functional groups. These sections are then systematically subdivided the former according to topology (connection of separate fragments cyclization etc.) and the latter into oxidations reductions and non-redox conversions. The coverage is intended to reflect the interests and concerns of those chemists who are involved in synthetic methodology in general as opposed to those who are concentrating on a particular area.Even with this limitation it has been necessary to exclude a great deal of material which was well-qualified for inclusion and it is probably vain to hope that the result will not appear biased to a large number of readers. 2 C-C Connection and Disconnection Connection of Separate Fragments.-Enolates and their Equivalents. The intensive investigation of enolate chemistry which has been pursued over the past few years shows no sign of abating. Significant advances in the regio- and stereo-selective formation of enolates have been made by two groups who have discovered conditions under which carbonyl compounds may be deprotonated and immediately trapped in situ. Thus the treatment of a range of ketones with potassium hydride in the presence of t-butyldimethylsilyl chloride gave enol silyl ethers derived from the more stable (‘thermodynamic’) enolate.Selectivity was improved by the addition of HMPA. In this way 2-enol ether (1) and its stereoisomer were formed from pentan-3-one in the ratio 97 :3.’ OSiMe, + ’ J. Orban T. Turner and B. Twitchin Tetrahedron Lett. 1984 25 5099. 247 248 A. P. Davis On the other hand it has been found that at -78 “Cin THF trimethylsilyl chloride can be used to trap ‘kinetic’ enolates generated from ketones and esters by lithium di-isopropylamide (LDA). The selectivity was invariably greater than that obtained via the usual two-step procedure. A further improvement was made by replacing the LDA with lithium t-octyl-t-butylamide a new highly hindered amide base.These conditions allowed the preparation from pentan-3-one of E-enol ether (2) and its stereoisomer in the ratio 98:2.’ QSiMe R4SiMe Reagents i CO(1 atm.) Et20 15 “C; ii Me3SiC1 Scheme 1 A new synthesis of acylsilane enolates is shown in Scheme 1. An a-lithiosilane adds to carbon monoxide to give an intermediate acyl-lithium which rearranges to give specificially the E-enolate (3).3 The ‘simple diastereosel’ectivity’ of the aldol reaction (the relative configurations of the two newly formed chiral centres) has most often been discussed in terms of the Zimmerman-Traxler ‘chair’ transition-states? The general tendencies predicted and observed are that 2-enolates give syn aldols while E-enolates give anti aldols. However in a few cases this rule is broken by enolates which give syn aldols irrespective of their geometry.Recently two groups have independently reported that enolborates react in this fa~hion.’.~ Thus enolborates (4) and (5) both react with benzaldehyde to give the syn aldol (6) after decomplexation with triethanolamine. In each case the diastereomeric excess (d.e.) was 90% or greater.’ E. J. Corey and A. Gross Tetrahedron Lett. 1984 25 495. S. Murai I. Ryu J. Iriguchi and N. Sonoda J. Am. Chem. SOC.,1984 106 2440. D. A. Evans Top. Stereochem 192 13 1. R. W. Hoffmann and K. Ditrich Tetrahedron Lett. 1984 25 1781. C. Gennari L. Colombo and G. Poli Tetrahedron Lett. 984 25 2279; C. Gennari S. Cardani L. Colombo and C. Scolastico Tetrahedron Lett. 1984 25 2283. Synthetic Met hods This result is all the more remarkable because E-enolboranes are particularly successful in anti-selective ald01s.~ The Mukaiyama addition of enol silanes to aldehydes catalysed by Lewis acids has been reported to give poor simple diastereoselectivity (a result confirmed recently in a systematic study by Heathcock7).However Reetz and co-workers have recently found that for Mukaiyama reactions with a-and /I-alkoxyaldehydes catalysed by TiC14 a good diastereofacial selectivity ('chelation-controlled') is accompanied by good simple diastereoselectivity. Thus the complex (7) reacted with enolsilane (8) to give virtually exclusively the diastereomer (9) (Scheme 2).* It was proposed that Ph' (7) (9) Scheme 2 the position of the Ti atom forced by chelation to co-ordinate anti to the aldehyde H was the crucial factor.This is supported by the fact that analogous BF,.Et,O- catalysed reactions show poor simple diastereoselectivity. The latter Lewis acid is incapable of chelation and is thought to form complexes such as (10) with a-alkoxyaldehydes. In accord with this (10) gives 'non-chelation-controlled'products of the form (11) with nucleophiles N such as enolsilanes.' Tetra-substituted enolates of defined stereochemistry are quite rare in acyclic systems. Scheme 3 shows how such a species may be formed from an unsaturated thioamide and how it may be used in a diastereoselective aldol condensation." The stereochemical control in the first step is presumably due to co-cordination of the thioamide sulphur atom to the magnesium in the Grignard reagent.Remarkable simple diastereoselectivity has been observed in Michael reactions of lithium ester enolates under certain conditions. Examples are given in Scheme 4 showing how variations in solvent and in the enolate ester group R lead to dramatically different stereochemical results.' 'C. H. Heathcock K. T. Hug and L. A. Flippin Tetrahedron Lett. 1984 25 5973. M. T. Reetz K. Kesseler and A. Jung Tetrahedron 1984 40,4327. M. T. Reetz and K. Kesseler J. Chem. Soc. Chem. Commun. 1984 1079. Y.Tamaru T. Hioki S.4. Kawamura H. Satomi and Z.4. Yoshida J. Am. Chem Soc. 1984 106,3876. 'I M. Yarnaguchi M. Tsukamoto S. Tanaka and 1. Hirao Tetrahedron Lett. 1984 25. 5661. 250 A. €? Davis Reagents i EtMgBr; ii EtCHO Scheme 3 I R 0.A \ /C=CHMe + %-I 1 + Y-7 LiO CO,Et RO2C CO,Et R02C C0,Et R = Et reagents i ;>20 1 R = Bu' reagents ii; 1 >20 Reagents i THF. HMPA -78 "C ii THF. -78 "C Scheme 4 Very high stereoselectivity has been reported for the alkylation of enolates sub- stituted in the /3 position by a dimethylphenylsilyl group. Scheme 5 shows how the P-silylester (12) (94% d.e.) could be formed in two steps from methyl cinnamate,12 then oxidized stereospecifically to the P-hydroxyester (13).13 For the alkylation of the intermediate enolate the authors suggest a transition state (14) in which the P-H eclipses the enolate C=C and attack by iodomethane occurs anti to the silicon. PhMezSi uoMe . .. I I1 iii,iv ---+ PhdOMe Ph UOMe Ph Reagents i.(PhMe,Si),CuLi; ii Mel; iii HBF, iv m-CPBA Scheme 5 There continue to be many reports concerning enolates containing removable chiral auxiliaries. A lot of attention has been paid to enolates derived from acyl iron complexes such as (15). For example Scheme 6 shows how (15) can undergo two highly diastereoselective C-C bond-forming reactions to give the erythro 12 W. Bernhard 1. Fleming and D. Waterson J. Chem. Soc. Chem. Commun. 1984 28. 13 . 1. Fleming R. Henning and H. Plaut J. Chem. Soc. Chem. Commun. 1984. 29. Synthetic Methods 25 1 P-hydroxyacid ( 17).14For the second of these steps the enolate (16) is thought to take up the conformation shown and to be alkylated from the face opposite to the bulky Ph3P ligand.Assuming that this sequence can be conveniently carried out with chiral starting material it amounts to an enantioselective synthesis of (17). /vi iv vii if’ Me w I ,HEtJ. Reagents i BuLi THF -78 “C; ii Et,AICl -40 “C 45 min.; iii EtCHO; iv work-up; v BuLi (2 equiv.); vi MeI; vii Br, H20 Scheme 6 Another ‘chiral acetate enolate’ is the ester enolate (18) which reacts with a variety of aldehydes to give hydroxyesters (19) in approximately 90% d.e. The chiral auxiliary is derived from R-mandelic acid; the S enantiomer is also a~ailab1e.l~ Enolates derived from the amides (20) can be alkylated16 or acylated” with extremely high diastereoselectivities (Scheme 7). For a range of R’ and R2 and with few exceptions the products (21) and (22) were formed with d.e.’s of 98% or better.As shown the acylation can be followed by a stereoselective reduction analogous to one reported earlier by the same group. A number of publications this year have demonstrated that a chiral alkoxy-group on a nucleophilic ,sp2-hybridized carbon atom can exert stereocontrol in carbonyl 14 S. G. Davies 1. M. Dordor and P. Warner J. Chem. Soc. Chem. Commun. 1984 956. Is M. Braun and R. Devant Tetrahedron Lett. 1984 25 5031. 16 Y. Kawanami Y. Ito T. Kitagawa Y. Taniguchi T. Katsuki and M. Yamaguchi Tetrahedron Lett. 1984 25 857. l7 Y. Ito T. Katsuki and M. Yamaguchi Tetrahedron Lett. 1984. 25. 6015. 252 A. P. Davis MOMO MOMO . .. I I1 111 L RZ R ' y0 -0MOM 0 0 MOMO I Reagents i LDA; ii R21;iii HCI aq.; iv BuLi; v R'COCI; vi Zn(BH,) Scheme 7 addition reactions.An example within enolate chemistry is the addition of the lithium enolate of alkoxyester (23) to acetone giving preferentially one diastereomer of ester (24) in 89% d.e.'* Further examples will be discussed in the section on ally1 anions (p. 254). The phase-transfer-catalysed alkylation of enolates presumably occurs tria quater-nary ammonium enolates. If a chiral ammonium ion is used it is possible that a chiral product may result. Early attempts at putting this into practice met with limited success but a recent report shows how careful optimization of a particular system can lead to satisfactory results. Thus N-benzylchinchonium chloride (25) catalysed the alkylation of indanone (26) with chloromethane to give (27) in up to 96% e.e.19 Two new reagents have been described which are unusual in that they will act as carbon electrophiles towards the a-carbons of ketones without requiring acid or base catalysis.The first is l,l,-bis(benzenesulphony1)ethene (28) which will react with neat butanone under reflux for example to give the ketone (29) quite regioselec- l8 J. d'hgelo 0. Pages J. Maddaluno F. Dumas and G. Revial Terrahedron Lett. 1984 25 5869. U.-H.Dolling P. Davis and E. Grabowski. J. Am. Chem. Soc.. 1984 106 446. Synthetic Methods (25) S0,Ph tively and in 75% yield.20 The second is the thiourea derivative (30),which efficiently carboxylates ketones in the a-position at room temperature in DMF.” Enol ethers may react as enolate equivalents albeit unreactive ones.Recently it has been shown that they can be alkylated not by the usual electrophilic reagents but by a free-radical reagent (e.g. Scheme 8).22 The reaction is performed by thermolysis of an a-hydroperoxydiazene such as (31) dissolved in the enol ether. The main limitation of the method may well be the highly explosive nature of the reagents. ,--Me + Me2C0 +N 52% Scheme 8 AZZyZ Anions and their Equivalents. As for the aldol reaction the questions of simple diastereoselectivity and diastereofacial selectivity are of particular concern in the reactions of ally1 organometallics with carbonyl compounds. Keck and co-workers 2o 0.de Lucchi L. Pasquato and G.Modena Tetrahedron Letr. 1984 25 3647. 21 N. Matsumura N. Asai and S. Yoneda J. Chem. Soc. Chem. Commun. 1984 1487. 22 E. Y. Osei-Twun D. McCallion A. S. Nazran R. Panicucci P. A. Risbood and J. Warkentin J. Org. Chem. 1984.49 336. 254 A. P. Davis have embraced both issues in a systematic study of the Lewis acid catalysed reactions of allyl- and crotyl-stannanes with aldehydes of the form (32) and (33).23With CH2CI2 as solvent they found that a combination of R = PhCH2 and a chelating Lewis acid (MgBr, SnCI etc.) maximized ‘chelation control’ to give (34)and (35) respectively (R’= CH2CH=CH or CHMeCH=CH,). The opposite diastereofacial selectivity (‘Felkin-Anh’ or ‘non-chelation’ control) was maximal with R = SiMe,Bu‘ and BF3.Et20 as the Lewis acid.Good simple diastereoselec- tivity could also be obtained; thus treatment of (32; R = PhCH,) with crotyltributylstannane and MgBr gave (36)in 85% d.e. Me IH 4e OR OH OH (35) (36) It has been reported by two groups that the tetrahydropyranyl group in allylboron- ates such as (38)can direct the stereochemistry of the two new chiral centres formed on additions to aldehydes.24v25 Scheme 9 shows how this was employed in an enantioselective synthesis of ( -)-exo-brevicomin (40).,’ The allyl tetrahydro- pyranyl ether (37)used as starting material was derived from dihydrocarvone. Out of 3 diastereomers formed in the aldehyde addition the desired compound (39) comprised 89% of the total. It is notable that this selectivity is paralleled in the enolate addition discussed earlier (p.252). Hoppe and his group have previously shown that aluminium derivatives of E-2-butenyl carbamates will add to aldehydes giving anti stereochemistry about the new C-C bond. They have now shown that the 2-analogue (41) will give the corresponding syn diastereomers [e.g. (42)in Scheme In both stereochemical series an interaction between the aluminium and the carbamoyl oxygen is thought to control the regiochemistry of the addition. The addition product (42) can be hydrolysed to the y-lactol derivative (43) so that the reaction is effectively a ‘homo-aldol’ reaction. Hoppe has published a review of this class of reaction^.^' 23 G. E. Keck and E. Boden Tetrahedron Lett 1984 25 265; G. E. Keck and E.Boden Tetrahedron Lett 1984 25 1879; G. E. Keck and D. E. Abbott Tetrahedron Lett. 25 1883. 24 R. Metternich and R. W. Hoffmann Tetrahedron Lett. 1984 25 4095. 25 P. Wuts and S. Bigelow J. Chem. SOC.,Chem. Commun. 1984 736. 26 D. Hoppe and F. Lichtenberg Angew. Chem. Int. Ed. Engl. 1984 23 239. 27 a.Hoppe Angew. Chem.. In?. Ed. Engl. 1984 23 932. Synthetic Methods \ (40) Reagents i Bu'Li; ii ;iv H,/Pd; v H30+ Scheme 9 (42) (d.e.80%) Reagents i BuLi pentane TMEDA -78°C; ii Bu;AIOSO2Me; iii MeCHO; iv AcOH; v MeOH MeS03H Hg(OAc) Scheme 10 An enantioselective homo-aldol reaction has been described employing the allyltitanium (44) as a reagent. With aldehydes RCHO adducts (45) are formed with ca. 90% d.e.28 H.Roder G. Helmchen E.-M. Peters K. Peters and H. von Schnering Angew. Chem. Int. Ed. Engl. 1984 23 898. 256 A. P. Davis According to a report by Yamamoto et al. ally1 organometallics can add to imines to give homoallylic amines. An interesting feature of the reaction is the remarkably high diastereofacial selectivity shown. Thus 9-allyl-9-borabicyclononanereacts with the irnine (46) to give exclusively the amine (47) as predicted by Cram's rule.29 The corresponding reaction of 2-phenylpropanal is only slightly stereoselective. The results can be rationalized with reference to the transition state (48). The trans configuration of the imine forces the chiral centre into an axial position where it will interact strongly with the alkyl substituents on the boron.In the case of the aldehyde there is nothing to prevent the chiral carbon occupying an equatorial position in the corresponding transition state. Me Me 1 A versatile synthesis of 2,E-dienes based on an allyltitanium species is shown in Scheme 11. In the resulting mixture of dienes the isomer (49)generally formed 95% of the total.30 R' SiMe,\MBu' S 1.. II.. Bu'S ?SiMe iii Ti(OPr'), I/ iv I Reagents i Bu'Li pentane THF; ii Ti(OPr'),; iii R'CHO; iv R'Mgl Ni" catalyst Scheme 11 29 Y. Yamarnoto T. Kornatsu and K. Maruyama J. Am. Chem. SOC.,1984 106 5031. 30 J. Ukai. Y. Ikeda N. Ikeda. and H. Yarnamoto. TefruhedronLeu. 1984 25. 5173. Synthetic Methods 257 Allyboronates feature reguarly as allyl anion equivalents (see above for examples).They may be synthesized stereoselectivity by a simple new procedure based on the reaction of vinyl-lithium reagents with the chloromethylboronate (50).31Finally it has been shown that the allyl anions derived from alkenes (51) can be alkylated specifically a to the stabilizing substituents. Scheme 12 shows how this can be utilized in a synthesis of a$-unsaturated ketones.32 (51) Ts = Me em,-Reagents i TsCH2NC KOBU'; ii POCI, Et3N; iii KOBU'; iv R3X (X = C1 Br I); v H30+ Scheme 12 Miscellaneous. The importance of diastereofacial selectivity in carbonyl addition reactions is not restricted to enolates and allyl anions of course. Reetz has reviewed the operation of chelation and non-chelation control in a range of additions to a-and P-alkoxycarbonyl compounds.33 A further type of nucleophile for which simple diastereoselectivity is conceivable is an allenyl organometallic.Reagents of this type have indeed been shown to add highly stereoselectively to both aldehydes and aldimines. Thus allenylzincs (52) added to aldehydes giving alcohols (53) in around 90% d.e. (Scheme 13).34 The selectivity is readily explained by invoking the transition state (54) ;analogous attack on the other face of the aldehyde would involve steric interference between R' and R2. A variety of reagents (55) were similarly successful in additions to aldimine~.~' R' (52) (53) Reagents i Bu'Li THF,-90°C; ii ZnC1,; iii R'CHO; iv H30+ Scheme 13 31 P. Wuts P. Thompson and G. Callen J. Org. Chem.1984 49 5398. 32 J. Moskal and A. van Leusen Tetrahedron Lerr. 1984 25 2585. 33 M. T. Reetz Angew. Chem. Int. Ed. Engi. 1984 23 556. 34 G. Zweifel and G. Hahn J. Org. Chem. 1984 49 4565. 35 Y. Yamamoto W. Ito and K. Maruyama J. Chem. SOC.,Chem. Commun. 1984 1004. 258 A. P. Davis Zn I.+SiMe3 M A great deal of interest was shown this year in synthons behaving effectively as (56). For example the silylated amine (57) was investigated by two groups,36 and shown to alkylate Grignard reagents organolithiums and silyl ketene acetals with loss of the methoxy-group. Also a review was published on ‘a-amidoalkylation’ synthons (58).3’ A complementary survey dealt with a-metalloamine synthetic equivalents (59).38 \/ I \“ N -4 M Several papers have appeared on the use of a-metallated organosilicon compounds as equivalents of a-metallated alcohols.39 This has been made possible by the recent discovery that an organosilicon compound with at least one acid-labile group can be oxidatively decomposed so that RSi is replaced by ROH.Another application was discussed A versatile ‘vinylene dication’ equivalent has been reported by Rosenblum.4’ The complex (60) will react with a variety of carbon nucleophiles to give adducts from which ethanol can be eliminated stereospecifically. The result is a displacement of ethoxide by the nucleophile with net inversion giving a trans alkenyl complex e.g. (61) in Scheme 14. Repetition of the sequence with a second nucleophile followed by decomplexation gives a cis alkene such as (63).Usefully the trans complexes such as (61) are usually less stable than their cis analogues; thus thermal isomeriza- tion of (61) gives (62),which can be transformed ultimately to the trans alkene (64). There have been some interesting developments in the area of carbonyl olefination. One long-standing problem has been the lack of stereoselectivity in Wittig olefinations with ylids Ph,=CHR where R = aryl or alkenyl. Recently it was reported that replacement of one of the phenyl groups on phosphorus improved matters considerably (e.g. Scheme 15).41 The best E-selectivity was generally achieved using ‘salt-free’ conditions. 36 H. J. Bestmann and C. Wolfel Angew. Chem. Int. Ed. Engl. 1984,23 53; T. Morimoto T. Takahashi and M.Sekiya J. Chem. Soc. Chem. Commun. 1984 794; K. Okano T. Morimoto and M. Sekiya J. Chem. SOC.,Chem. Commun. 1984 883. 37 H. Zaugg Synthesis 1984 85 and 181. 38 P.Beak W. Zajdel and D. Reitz Chem. Rev. 1984 84 471. 39 K. Tamao T. Iwahara R. Kanatani and M. Kumada Tetrahedron Lett. 1984,25 1909; K. Tamao and N. Ishida Tetrahedron Lett. 1984 25 4245; ibid. 4259. 40 M. Marsi and M. Rosenblum J. Am. Chem SOC 1984 106,1264. 41 E. Vedejs and H. W. Fang J. Org. Chem. 1984,49 210. Synthetic Methods (61) (62) Fp = q5-C,H,Fe(CO) (63) 52% (64) 38% Reagents i Me2CuLi THF -78 "C; ii HBF4.Et,0 -78 "C; iii r.t. 30 min.; iv -78 "C; v Nal Me2C0 25 "C Scheme 14 R = Ph; 1:l R = crotyl; 14:l Reagents i BuLi; ii Scheme 15 The anion derived from the chiral phosphonamide (65) was found to olefinate 4-t-butylcyclohexanone to give one enantiomer of the product alkene in 90% e.e?2 It has been discovered that the organomolybdenum reagents (66) and (67) can be used in the presence of water and ethanol.43 The Peterson olefination has been reviewed.44 Me 42 S.Hanessian D. Delorme S. Beaudoin and Y.Leblanc J. Am. Chem. SOC 1984 106 5754. 43 T.Kauffmann P. Fiegenbaum and R. Wieschollek Angew. Chem. Int. Ed. En& 1984 23 531. 44 D. J. Ager Synthesis 1984 384. 260 A. P. Davis Many of the most powerful and versatile stereospecific olefin syntheses rely on additions to acetylenes. A valuable new development is exemplified in Scheme 16.45 The first step carbotitanation of an alkynylsilane was known previously but stereospecific oxidative cleavage to give halogeno-alkenes such as (68) had not been achieved before.The products should serve as intermediates in the stereoselective synthesis of tetra-substituted olefins. Reagents i Et,AICI CpzTiC12 CH,Cl2 6 h 25 "C; ii N-iodosuccinimide CH,CI, 2 h -78 "C Scheme 16 Vinyl halides are often useful intermediates in olefin synthesis particularly in transition-metal-catalysed coupling reactions. It has recently been shown that vinyl trifluoromethanesulphonates (vinyl triflates) (69) can substitute for the halides in certain of these reactions. Thus the triflates which are readily available from ketones alkenylated alkenes (70) to give dienes (71) under palladium catalysis (Scheme 17).46 The reaction was most efficient with cyclic triflates derived from steroids.Alkenes containing no electron-withdrawing group could also be alkenylated but the reactions were not generally regioselective. -"+O,f+ R3 i R1-)qo R' R3 (69) (70) (71) Tf = CF3S02 Reagents Et3N Pd(OAc)z Ph3P Scheme 17 A more versatile (but more elaborate) relative of the above reaction involved coupling of the triflates with a variety of stannanes R3SnR3 (R3=alkenyl allyl alkynyl alkyl or H) giving alkenes (72):' It was also shown that carbon monoxide 4s R. Miller and M. Al-Hassan J. Org. Chem 1984 49 725. 46 S. Cacchi E. Morera and G. Ortar Tetrahedron Lett. 1984 25 2271. 47 W.Scott G. Crisp and J. K. Stille J. Am.Chem. Soc.. 1984 106 4630. Synthetic Methods 26 1 could be incorporated in the products of this type of reaction (Scheme 18). This was demonstrated both for X = I R3 = alkenyl alkynyl ary1,48 and for X = OTf R3 = alkenyl allyl alkynyl alkyl a1yl.4~ The yields were generally good and it is notable that pressures of only 1-3 atmospheres of CO were required. Reagents i Pd" catalyst (2 mol. O/O) CO (1-3 atm.) THF; ii Pd(PPh,) (3 mol. O/O) CO (1-3 atm.) THF Scheme 18 Several other transition-metal-catalysed carbonylations have been reported. One example is the reaction of halides R'Br with borates B(OR2) and carbon monoxide to give esters R'C02R2. When [hexa-1,5-diene RhC1I2 was used as catalyst the reaction was useful only for benzylic halides but the addition of Pd(PPh3)4 to the system broadened the scope considerably so that good yields were obtained for R' = alkyl vinyl and aryL5' Scheme 19shows an example of another useful carbony- lation.An important advantage of this reaction is that the conditions are compatible with a variety of functional groups. Ring-opening occurs selectively at the primary carbon of the epoxide but will also occur at a secondary centre if there is no choice. In such cases inversion of configuration is observed." i MeO-OSiEt ,Me Meopo -0 OSiEtzMe Reagents i HSiEt2Me CO~(CO)~ cat. CO (1 atm.) CH2Cl2 25 "C Scheme 19 Evidence is emerging that a variety of organometallic reagents can be used in the presence of Lewis acids which considerably moderate their reactivity.A particularly useful combination appears to be that of BF3.Et20 with an organocopper reagent. Thus it has recently been reported that R2CuLi/BF3*Et20 reacts rapidly and cleanly with epoxides acetals and or tho ester^.^^ The reaction with acetals does not occur at all in the absence of BF, and is perhaps particularly useful because chirality may be transferred from the acetal moiety to the new asymmetric centre formed (e.g. Scheme 20). The same reagent has also been found to add quite cleanly to imines a reaction which is complicated by side reactions for most other organometal- lic reagents.53 BF3 may also be used to increase the potency of 'higher-order' cuprates. For example Ph,Cu(CN)Li will react with isophorone (73) to give adduct (74) in the presence of BF3-Et20.Without the Lewis acid no adduct is formed.54 48 W. Goure M. Wright P.Davis S. Labadie and J. K. Stille X Am. Chem. SOC. 1984 106 6417. 49 G. Crisp W. Scott and J. K. Stille J. Am. Chem. SOC.,1984 106 7500. 50 K. Hashem J. Woell and H. Alper Tetrahedron Lett. 1984 25 4879. " T. Murai S. Kato S. Murai T. Toki S. Suzuki and N. Sonoda J. Am. Chem. Soc. 1984 106 6093. 52 A. Ghribi A. Alexakis and J. F. Normant Tetrahedron Lett. 1984 25 3075 and 3083. 53 M. Wada Y. Sakuri and K.-y. Akiba Tetrahedron Lett. 1984 25 1079. 54 B. Lipshutz D. Parker J. Kozlowski and S. Nguyen Tetrahedron Lett. 1984 25 5959. 262 A. P. Davis 100°/~d.e. Reagents i Me2CuLi BF,.Et,O Et20 -78 "C to -50 "C Scheme 20 Remarkably it appears that even the highly reactive organolithium reagents can be used with BF3 at low temperatures.An example is shown in Scheme 21. Without the BF, the organolithium desilylated (75) in preference to opening the epoxide. A number of control experiments suggested strongly that the organolithium and the Lewis acid were acting separately within the reaction mixture.55 (75) Li Reagents i EtO < BF,.0Et2 THF -78 "C Scheme 21 Organometallic reagents derived from Lewis acidic metals might be expected to show quite similar reactivity to the systems discussed above. Indeed it has been shown that MeTiC1 will react with acetal (76) to give (77) in 88% d.e. (cJ Scheme 20). It is notable that this reagent is virtually unreactive towards nonan-5-one under the same condition^.'^ (76) (77) 55 M.Eis J. Wrobel and B. Ganem J. Am. Chem. SOC.,1984 106 3693. 56 A. Mori K. Maruoka and H. Yamamoto Tetrahedron Lett.. 1984. 25. 4421. Synthetic Methods There has been a quite intensive search for organocuprates RCuXLi which will efficiently transfer the alkyl group R without wastage. Recently it has been suggested that the ligand X of choice should be dicyclohexylphosphide and that LiBr should be present in the reaction mixture for maximum effecti~eness.~’ The use of Cu’ compounds as catalysts in the reactions of organolithiums and Grignard reagents has been reviewed.58 It is likely that the highly reactive sodium and potassium organometallics could be useful in carbon-carbon bond formation if they were not insoluble in the few solvents to which they are stable.It has now been reported that phenylsodium and phenylpotassium can be solubilized in benzene by Mg(OCH2CH,0Et),. The solu- tions are shelf-stable at 20°C or below and behave as expected for organo- alkali-metal reagents (i.e. the phenyl group is apparently not transferred to the magne~iurn).~~ Finally the following reviews contain material pertinent to this section; ‘Car- bometallation; addition of organometallic compounds to isolated multiple bonds in functionally substituted compounds’,60 ‘Carbene complexes in organic syn- thesis*,6’ ‘Three-carbon homologating agents*,62 ‘Organo-iron complexes of aromatic compounds-applications in ~ynthesis’,~~ ‘Palladium(1 ])-assisted reactions of mono- olefin~’,~~ and ‘Copper-assisted nucleophilic substitution of aryl halogen’.65 Cyclization.-Two new cyclization reactions show familiar functional groups behav- ing in rather unusual ways.The first is exemplified in Scheme 22.66 It is well- established that a sulphonyl group attached to an sp3-hybridized carbon atom will stabilize a negative charge on the carbon allowing it to react with an electrophile. However it is unusual for the sulphonyl to act as a leaving group allowing the carbon atom to react with a nucleophile. Last year a rearrangement was reported in which a sulphonyl group was induced to leave by a Lewis acid and Scheme 22 shows how the same principle has recently been employed in a cyclization. This development allows sulphones to be considered potentially as ‘1-1 dipoles’ R‘R’c+-.Reagents i AICI, ether Scheme 22 57 S. Bertz and G. Dabbagh J. Org. Chem. 1984.49 1 119. 58 E. Erdik Tetrahedron 1984 40,641. 59 C. Screttas and M. Micha-Screttas Organometallics 1984 3 904. 60 J. Vara Prasad and C. Pillai J. Organomef.Chem. 1983 259 1. 61 K. Dotz Angew. Chem. Inf. Ed. Engl. 1984 23 587. 62 J. Stowel Chem. Rev. 1984 84 409. 63 D. Astruc Tetrahedron 1983 39 4027. 64 L. S. Hegedus Tetrahedron 1984 40,2415. 65 J. Lindley Tefrahedron,1984 40 1433. 66 B. Trost and M. Ghadiri J. Am. Chem. Soc. 1984 106 7260. 264 A. P. Davis Similarly while a trimethylsilyl group is known in many circumstances to act as an electrofugal leaving group and thus a source of nucleophilic carbon it is not generally perceived to be of use if it is remote from any other functionality.The cyclization shown in Scheme 23 proves that this need not be the case.67 The example chosen demonstrates that the conditions required are not so vigorous as to preclude the presence of other functional groups. Reagents i LDA HMPA THF; ii J.,+,-SiMe.3 ; iii (COCI), C6H6; iv AICI, CH,CI Scheme 23 Another new cyclopentanone synthesis is the rhodium-catalysed cyclization of 3,4-disubstituted enals such as (78) to give cis-disubstituted products in good yields (Scheme 24). Again an example has been chosen to demonstrate that a high degree of functionality can be tolerated. The reaction is a development of earlier work which showed that analogous 2,3-disubstituted enals gave much poorer results.The authors postulate that the stereoselectivity arises from intramolecular H-transfer within an intermediate (79) in which steric interactions between R' and R2 are minimized.68 0 0 .c1 Reagents i (Ph,P),RhCI CH2C12,r.t. 4 h Scheme 24 H (79) 67 H. Urabe and I. Kuwajima 1. Org. Chem. 1984 49 1140. 68 K. Sakai Y.Ishiguro K. Funakoshi K. Ueno and H. Suemune Tetrahedron Lett. 1984. 25,961 Synthetic Methods 265 A convenient synthesis of cyclopentanones is the cyclization of enynes (80) with PdCl,(MeCN)2 as catalyst. The products (81) were shown to arise uia cyclopen-tadienes (82) by trapping experiments using the powerful dienophile N-phenyl- maleimide.69 0 OAc Scheme 25 shows a new synthesis of 1,2-bisalkylidenecyclohexanes(83) clearly of potential use in the construction of polycyclic compounds.The E,E isomers were formed selectively. Analogous cyclizations to give 5-and 7-membered rings were also successfu~.~~ R' =-. @ R' i,ii 4 -R2 (83) Reagents i Cp,TiC12 Ph2PMe Na-Hg THF; ii H30+ Scheme 25 Although benzenoid aromatics are more usually synthesized by substitution reac- tions a route involving the cyclization of an acyclic precursor may in many cases be more efficient. The latter approach is surveyed in a recent review.71 Cycloadditions and Annu1ations.-Diels- Alder Reactions. Interest continues in Diels- Alder reactions of dienophiles with removable chiral auxiliaries.Among recent publications in the area are a review by Oppol~er,'~ and reports on the highly stereoselective Lewis acid-catalysed Diels-Alder reactions of (84),73 (85),73 and (86).74The first two give complementary product stereochemistries while the latter 00 00 RdNAO RdNAO &NL L-J / R Me Ph (84)(R = H,Me) (85) (R = H Me) (86)(R = H,Me) 69 V. Rautenstrauch J. Org. Chem. 1984 49 950. 70 W. Nugent and J. Calabrese J. Am. Chem. SOC.,1984 106 6422. 71 P. Bamfield and P. F. Gordon. Chem. SOC.Rev.. 1984 13. 441. 72 W. Oppolzer Angew. Chem. ini. Ed. Engl. 1984 23 876. 73 D. A. Evans K. Chapman and J. Bisaha J. Am. Chem. SOC.,1984 106 4261. 74 W. Oppolzer C. Chapuis and G. Bernardinelli Helv. Chim. Acfa 1984 67 1397.266 A. P. Davis is available in both enantiomers. These dienophiles are all notable for their crystal- linity and high reactivity; in many earlier procedures the chiral auxiliary could only be used with an acryloyl moiety and not with the less reactive crotonyl group. Sustained interest has also been shown in the development of dienophiles which will act as 'acetylene-equivalents' in Diels-Alder reactions. In the past year a review has appeared,75 as well as a new solution to the problem which is represented in Scheme 26.76 In the example shown the key electrolytic elimination step occurred in 83% yield. Reagents i 60 "C 18 h ii hydrolysis iii electrolysis in MeCN-EtOH-KOH Scheme 26 It has been reported that Diels-Alder reactions can be induced to occur under very mild conditions when catalysed by K10 montmorillonite clay doped with Fe3+ or A13+.For example the adduct between furan and acrolein was formed in 65% yield after 15 minutes at -43 0C.77Previously this addition had been successfully accomplished only at very high pressures. It is possible that Lewis acidic centres and 'pools' of water within the clay may jointly be responsible for the catalysis. In reactions between cyclopentadiene and butenone employing a variety of solvents stereoselectivities were observed which were very similar to those obtained earlier in aqueous solution.78 Two comprehensive reviews have appeared on the intramolecular Diels- Alder reaction.79 Other Reactions Forming 6-Membered Rings. The cyclocondensation of 1,3-dioxyge- nated dienes with carbonyl compounds has received further investigation.It has been reported that whereas the diene (87) reacted with simple aldehydes to give the cis-disubstituted dihydropyrones (88) alkoxyaldehyde (90) reacted to give the trans isomer. Furthermore only one face of the aldehyde was attacked resulting in control'of the relative stereochemistry in all three asymmetric centres of the product (89) (Scheme 27).*' These results were rationalized by reference to transition states (91) and (92). In the former the metal and its ligand sphere are co-ordinated anti to R in the aldehyde and are supposed to be sterically dominant. In the latter chelation to the a-alkoxy substituent in the aldehyde holds the metal syn to the bulk of the aldehyde.Chelation control also appeared to be effective in the Eu"'-catalysed reaction of diene (93) with a-alkoxyhexanals. Again the products (94) had the threo 75 0.De Lucchi and G. Modena Tetrahedron 1984 40 2585. 76 D. Hermeling and H. Schafer Angew. Chem. Int. Ed. EngL 1984 23 233. 77 P. Laszlo and J. Lucchetti Tetrahedron Lett. 1984 25 4387. P. Laszlo and J. Lucchetti Tetrahedron Lett. 1984 25 2147. 79 E. Ciganek Org. React. 1984 32 1; A. G. Fallis Can. J. Chem. 1984 62 183. 8o S. Danishefsky W. Pearson and D. Harvey. J. Am. Chem. SOC.,1984 106 2456. Synthetic Methods OMe < iii ii , 2 Me Me-;.:”R OCH2Ph 0 Me3Si0 Me Me Me Et (88) (87) (89) Reagents i RCHO Lewis Acid; ii AcOH; iii E:(90) MgBr, THF Et Scheme 27 Me OMe H Et (92) 0 OSiMe FOMe Me0 HI Me0& Bu (93) (94) stereochemistry.This diene is unusual in that it is reactive enough to undergo cyclocondensation with ketones as well as aldehydes.81 Until recently nitrosoalkenes have appeared to be of only limited use as ‘heterodienes’. However a new study has appeared in which these reactive intermedi- ates were successfully trapped in a stereoselective intramolecular [4 + 21 cycloaddi-tion (Scheme 28). The most successful reaction conditions were those which gave very slow generation of the nitrosoalkene.82 Reagents i CsF MeCN 20 h (for R = Me); KF MeCN 336 h (for R = H) Scheme 28 81 M. Midland and R. Graham J. Am.Chem. SOC.,1984 106 4294. 82 S.Denmark M. Dappen and J. Sternberg J. Org. Chem. 1984 49 4741. 268 A. P. Davis A highly versatile new heteroannulation method is illustrated in Scheme 29.83As shown the sequence allows the addition of a C2X or a C3X component to one double bond of a conjugated diene or vinylcyclopropane; an example was also reported of a [3 + 31 annulation involving a 1,4-diene and a C2X unit. In general the first step proceeds via transmetallation of the mercurial to give an organopal- ladium species which then adds to the olefinic component to give a (?r-allyl) palladium intermediate (e.g. Scheme 30). In the second step the palladium is displaced by intramolecular nucleophilic attack of the heteroatom X. c140zH HgCl + 0-c1 p O H Me c1’ Reagents i LiPdCI,; ii K,CO,; iii NaH Scheme 29 PdCl XH __* + LiPdCI3 + 0-& 0 base Scheme 30 An annulation reaction in which an alkene is converted into a cyclohexadienone is shown in Scheme 31.This conversion is an extension of earlier benzannulation reactions which were analogous except in that the final products could tautomerize to phenols. The addition is regioselective with the substituent on the acetylene ending up (Y to the carbonyl and is also quite stereoselective; for R = Bu the product (95) was formed in 80% d.e.84 83 R. C. Larock L. Harrison and M. Hsu 1. Org. Chem. 1984 49 3662. 84 P.-C. Tang and W. Wulff 1. Am. Chem. SOC.,1984 106 1132. Synthetic Methods -+ R-=-H Me Me OMe Reagents i THF 45 "C 24 h; ii air (95) Scheme 31 The last ten years have seen sustained development in the application of cobalt- catalysed [2 + 2 + 23 cycloaddition reactions to organic synthesis.Most of this has been due to Vollhardt and he has recently published a review of the area.85 Other Ring Sizes. An area which has been widely researched over the past decade is the addition of a three-carbon unit to two adjacent carbon atoms to create a new cyclopentane ring. Such 'cyclopenta-annellation' reactions have been reviewed sys- tematically,86 and two new examples of interest have been reported. (99) (98) Reagents i THF catalyst from Pd,(dba),CHC13 + dppe Scheme 32 Firstly ally1 carbonates (96) (El = Ts or CN) were found to react with electron- deficient alkenes (97) (E2 = COR or C02R) under Pdo catalysis to give cyclopen- tanoids (Scheme 32).For E' = Ts the reaction stopped at the methylenecyclopen- tanes (98) but for E' = CN these initial products generally isomerized to the cyclopentenes (99).87 Secondly highly electron-deficient olefins such as (100)reacted thermally with cyclopropene (101) to give cycloadducts such as (103) (Scheme 33). This reaction is unusual in being a single-step cyclopenta-annellation requiring no transition-metal catalysis. It was presumed to occur via dipolar intermediates such as (102)." 85 K. P. C. Vollhardt Angew. Chem. Int. Ed. Engf. 1984 23 539. 86 M. Ramaiah Synthesis 1984 529. 87 I. Shimizu Y. Ohashi and J. Tsuji Tetrahedron Lett. 1984 25 5183. 88 D. Boger and C.Brotherton J. Am. Chem. Soc. 1984 106 805. 270 A. P. Davis n EtO,C + EtOZC&' Me Me 57% Reagent i C6H6 75 "c 15 h Scheme 33 A few years ago Marino reported that dichloroketene reacted with 1-alkenyl sulphoxides to give y-butyrolactones. He has now published a study of the same synthesis with single enantiomers of the sulphoxides and has found that the stereochemical information is transferred completely from the sulphur to the new bonds in the product. Furthermore it has been shown that the reaction can be extended to monochloroketene and that the extra asymmetric centre in the resulting products is also formed in one sense only. Thus optically pure (104) was converted to optically pure (105) in a reaction which generated three new chiral centres stereospecifically (Scheme 34).89 Reagents i HCCl,COCI Zn Et,O Scheme 34 Although ketenes do not readily cycloadd to simple alkynes it has been known for some time that tetramethylketeniminium salts (106) (R' R2 = Me) will do so successfully.The reaction has now been extended to the less-substituted examples having R' R2 = H Me and R' R2 = H.90The salts can be obtained by dehydration of amides (107) with trifluoromethanesulphonic anhydride and collidine. The cyclo- butenones resulting from the cycloadditions (followed by aqueous work up) undergo a number of useful further transformations. 89 J. P. Marino and A. Perez 1.Am. Chem. SOC.,1984 106 7643. 90 C. Schmidt S. Sahraoui-Taleb E. Differding C. Dehasse-De Lombaert and L.Ghosez Tetrahedron Lett. 1984 25 5043. Synthetic Methods 27 1 The cycloaddition of allyl cations to 1,3-dienes has been developed into a useful synthesis of 7-membered carbocyclic rings. The area has been reviewed by Hoffmann.” Rearrangements-A number of noteworthy publications concerned the Claisen rear- rangement. In general the widely used modifications of this reaction give products at the carboxylic acid oxidation level. In order to obtain aldehydes directly it is necessary to start with allyl vinyl ethers and the syntheses of such compounds can be problematical. Scheme 35 outlines a new modification which gives acceptable yields and appears to be quite ~onvenient.~~ The reagent (108) is obtained from trimethylamine and ethyl propiolate.‘R3 1 R2 Reagents i (108); ii H,O+;iii 150-200 “C hydroquinone (trace) Scheme 35 The stereochemical influence of neighbouring hydroxyl or alkoxyl groups in the Claisen ester-enolate rearrangement has been in~estigated.9~ In one example rear- rangement of the silyl ketene acetal derived from (109) led predominantly to the diastereomer (110). The other three diastereomers comprised only ca. 10% of the mixture. OMe Reviews have appeared on catalysis of the Cope and Claisen rearrangement^,^^ and on mercury(r1)- and palladium(I1)-catalysed [3,3]-sigmatropic rearrangement^.^^ As a further development in the exploration of the Wittig [2,3]-rearrangement as a stereoselective synthetic method attention has been directed towards the enantiospecificity of the reaction.In particular two groups have observed that 91 H. M. R. Hoffmann Angew. Chem Int. Ed. EngL 1984,23 1. 92 G. Buchi and D. Vogel J. Org. Chem. 1983,48 5406. 93 J. Cha and S. Lewis Tetrahedron Left. 1984,25,5263 ;M.Kurth and C.-M. Yu Tetrahedron Lett. 1984 25 5003. 94 R. P.Lutz Chem. Rev. 1984,84 205. 95 L. E. Overman Angew. Chem. Inr. Ed. Engl. 1984 23 579. 272 A. P. Davis 07Me Me * ""r*, HO' SiMe3 SiMe3 optically enriched ally1 propargyl ethers (111) give alcohols (1 12) with virtually complete stereospecificity on rearrangement with butyl-lithi~m.~~ The thermal rearrangement of isonitriles to nitriles has attracted considerable theoretical interest for many years but because it has been difficult to perform cleanly it has not proved to be of great use in synthesis.Now largely as a result of the mechanistic studies it has been discovered that under conditions of flash vacuum pyrolysis ( Torr ca. 500 "C) the reaction occurs cleanly in excellent yield and with retention of configuration in the migrating group. In suitable cases the conver- sion R*NH2 to R*C02H is thus now po~sible.~' 0 Bu i ii iii Me Ph ___. OH Bu Reagents i Bu-E-Li THF -78 "C; ii LiAIH4 THF; iii pyH+TsO- EtOH; iv MsCI Et,N CH2CI2 0"C;v Et3AI hexane -42 "C Scheme 36 Pinacol-type rearrangements in acyclic systems generally suffer from a lack of stereospecificity due to the involvement of carbonium ion intermediates. Recently mild conditions have been found which allow the stereospecific migration of alkenyl and aryl groups in mesylates.One example is shown in Scheme 36.98 The chiral ketone (113) used as a starting point was made from a lactic acid derivative. Not only is there complete inversion of configuration at the migration terminus but also the migrating alkenyl group retains its configuration. A similar rearrangement is observed on reduction of ketones (114) (R = aryl alkenyl) with di-isobutyl- aluminium hydride leading to aldehydes which are further reduced to primary alcohols (115).99 96 D. Tsai and M. Midland J. Org. Chem. 1984 49 1842; N. Sayo K.4. Azuma K. Mikami and T. Nakai Tetrahedron Lett. 1984 25 565. 97 M. Meier and C. Ruchardt Tetrahedron Lett. 1984 25 3441.98 K. Suzuki E. Katayama and G.-i. Tsuchihashi Tetrahedron Lett. 1984 25 1817. 99 K. Suzuki E. Katayama T. Matsumoto and G.4. Tsuchihashi Tetrahedron Lett. 1984 25 3715. Synthetic Methods 0 Me+ R OMS Me Finally Vedejs has published a great deal of elegant work developing synthetic applications of sulphur-mediated 2,3-sigmatropic ring expansions. A recent review outlines the progress of this research.lW Fragmentations.-Barton and co-workers have continued to develop their decarboxy- lative functionalization method based on thiohydroxamic acid esters such as (1 16). According to recent publications these intermediates can now be converted into hydroperoxides R-0-OH sulphides selenides and tellurides R-X-R' and alkene addition or substitution products."' Scheme 37 shows one of these reactions the substitution of an allylic alkylthio-group by the radical R.40 0 R-C + \ c1 coz + T 1 Scheme 37 Two groups have discovered that the treatment of cyclic y-hydroxyalkyl stannanes with oxidizing agents results in fragmentation to give acylic enones or enals. Nakatani and Isoe used lead tetra-acetate as the oxidant with 5-and 6-membered carbocyclic stannanes.lo2 The reaction was shown to be stereospecific; a trans relationship between the tin and a P-alkyl substituent resulted in a trans-alkene as in the example in Scheme 38. The corresponding cis relationship led to a cis alkene. Fujita and co-workers used a combination of iodosylbenzene boron trifluoride etherate and dicyclohexylcarbodi-imideto accomplish similar transformation^.'^^ Their examples included the seven-membered carbocycle (1 17) which led to enal (118) on fragmentation.100 E. Vedejs Acc. Chem. Res. 1984 17 358. 101 D. H. R. Barton D. Crich and W. B. Motherwell J. Chem Soc. Chem. Commun. 1984. 242; D. H. R. Barton D. Bridon and S. Zard Tetrahedron Lett. 1984 25 5777; D. H. R. Barton D. Crich and G. Kretzschmar Tetrahedron Lett. 1984,25 1055; D. H. R. Barton and D. Crich Tetrahedron Lett. 1984 25 2787. lo' K. Nakatani and S. Isoe Tetrahedron Lett. 1984 25 5335. 103 M. Ochiai T. Ukita Y. Nagao and E. Fujita; J. Chem. Soc. Chem. Commun. 1984 1007. 274 A. €? Davis Reagents i Pb( OAc), benzene Scheme 38 0H An apparently useful y- ketoaldehyde synthesis has been reported based on the methoxide-catalysed fragmentation of gem-dichlorocyclopropyl ketones ( 1 19) (Scheme 39).As shown the second reductive step may be followed by acid work-up to give the y-ketoaldehyde directly or by basic work-up to give a protected a1 ternative. lo4 Reagents i MeONa MeOH; ii LiAIH4 p-dioxan; iii HCI aq. iv NaOH aq. Scheme 39 3 Functional Group Modifications Oxidation.-Additions to C=C. It is well-established that the halogenolactonization of 3-substituted pent-4-enoic acids can be achieved with excellent stereoselectivity (1,2-asymmetric induction). In contrast 1,3-asyrnmetric induction in this reaction (i.e. the stereoselective halogenolactonization of 2-substituted pent-4-enoic acids) has not been attained.However Yoshida and co-workers have observed almost complete stereoselectivity in an analogous cyclization performed on the related amides and thioamide~.'~~ For example the pentenamide (120) gave the trans-bromolactone (121) in 98% d.e. as shown in Scheme 40. The corresponding 104 0. G. Kulinkovitch I. G. Tischenko and N. V. Masalov Synthesis 1984 886. 105 Y. Tamaru M. Mizutani Y. Furukawa S.-i. Kawamura Z.-i. Yoshida K. Yanagi and M. Minobe J. Am. Chem. SOC.,1984 106 1079. Synthetic Methods thioamide cyclized similarly to a thiolactone. Unlike many of the more selective iodolactonizations these reactions take place under kinetic control ; equilibration of (121) with its cis-isomer gave a mixture in which the latter comprised 55% of the total.Reagents i N-bromosuccinimide DME,H,O; ii NaHCO aq. Scheme 40 Again unlike the earlier thermodynamically controlled iodolactonizations 1,2- asymmetric induction in this system was very poor. The cyclization of pentenamide (122) gave a ca. 1:1 mixture of diastereomers. The 1,3-asymmetric induction was rationalized in terms of a transition state (123). Transposition of substituent R and the C(2)-H would introduce a destabilizing interaction between R and one of the NMe groups. R Me -Me2NA0 Me' The iodocyclization of homoallylic carbamates has been used in a stereoselective 1,3-diol synthesis. It has now been shown that the introduction of a sulphonyl group on the carbamate nitrogen allows cyclization to take place through nitrogen instead of oxygen under appropriate conditions.The result is a moderately stereoselective synthesis of protected 1,3-arninoalcohols exemplified in Scheme 41.lo6 Analogous reactions on allylic carbonate derivatives gave protected anti-1,2-aminoalcohols but with rather lower stereoselectivity. II I 6.2 1 Reagents i I, K2CO3 Et,O Scheme 41 M. Hirarna M. Iwashita Y. Yarnazaki. and S. It6 Tetrahedron Lett. 1984 25 4963. 276 A. I? Davis The iodocyclization of allylic carbonate anions has been developed as a 1,2-diol synthesis. An extension now allows it to be used to make P-hydroxyketones (Scheme 42).'07 I Reagents i BuLi; ii CO,; iii I,; iv Amberlyst A26 F-form C6H6 reflux Scheme 42 Chamberlin et al.have studied iodohydrin formation from allylic alcohols and their derivatives."' When the double bond in the substrate is 1,2-disubstituted the reaction is generally regio- and stereo-selective. Addition to the double bond is trans with the iodine ending up on the carbon adjacent to the oxygen substituent and syn to it. For example treatment of alcohol (124) with iodine and an aqueous phosphate buffer gave almost exclusively the iododiol (125). 0-Alkylated or -silylated derivatives of ( 124) reacted similarly but with slightly lower selectivity. The stereochemical result can be rationalized by invoking a transition state (126) in accordance with the recent calculations of Houk et allo9 1 , I 4e A Bu 1 1 An interesting.new synthesis of optically pure dihydroxycycloalkanones is exemp- lified in Scheme 43.The stereochemistry of the osmylation of (127) is thought to be influenced both by the hydroxyl group (anti-directing) and the sulphoximino nitrogen (co-ordinating to osmium and thus syn-directing)."' Ph Ph I* I* 0 =ST= N Me 0=S,= N Me 127) Reagents i S-PhSO( NMe)CH2Li; ii separation of diastereomers by chromatography on silica gel; iii Me,N+-O- OsO cat.; iv heat Scheme 43 107 G. Cardillo M. Orena G. Porzi S. Sandri and C. Tomasini J. Org. Chem. 1984 49 701. 108 A. R. Chamberlin and R. Mulholland Jr. Tetrahedron 1984 40 2297. I09 K. N. Houk N. Rondan Y.-D. Wu J. Metz and M. Paddon-Row Tetrahedron 1984,40,2257. 110 C. R. Johnson and M. Barbachyn. J. Am. Chem.Soc. 1984 106 2459. Synthetic Methods The trans-addition of phenylselenenyl chloride to alkenes is well-known. Recently it was reported that the phenylseleno group in the product could be displaced by oxidation with chlorine followed by nucleophilic attack by chloride ion in a 'one-pot' operation. The net result is a convenient and apparently general syn-addition of chlorine to alkenes (Scheme 44)."' c1 I c1 c1 I c1- R'eR2 SePh Se+ /\Ph c1 Cl Reagents i PhSeCI; ii CI2; iii Bu,N+CI- Scheme 44 The epoxidation of alkenes is generally insensitive to steric hindrance. Rebek and co-workers have now synthesized the peracid ( 128) designed selectively to epoxidize less hindered alkenes.Il2 Whereas rn-CPBA shows very little selectivity between cis and trans alkenes (128) was found to epoxidize cis-2-octene 7.7-times faster than the trans isomer.Other Oxidations. A remarkably selective oxidation of alkenes to enones has been reported by Pearson and co-worker~."~ Scheme 45 shows an example in which a secondary alcohol in the substrate was unaffected. The catalytic species is thought to be Cr(C0)3(MeCN), formed from the chromium hexacarbonyl in situ. OH OH 60% Reagents i Bu'OOH (1.2 eq.) Cr(CO) (0.5 eq.) MeCN reflux Scheme 45 A. Morella and A. D. Ward Tetrahedron Leu. 1984 25 1197. 112 J. Rebek Jr. L. Marshall R. Wolak and J. McManis J. Am. Chem. Soc. 1984 106 1170. 113 A. J. Pearson Y.-S.Chen S.-Y. Hsu and T. Ray Tetruhedron Lett. 1984 25 1235. 278 A.P. Davis Two new methods have appeared for the oxidative functionalization of a carbon a to a carbonyl group. The oxaziridine (129) will oxidize enolates derived from ketones or esters and KHMDS to give a-hydroxycarbonyl compounds. This reagent is claimed to give cleaner conversion and greater stereoselectivity than the established alternatives; for example the enolate derived from lactone (130) was hydroxylated exclusively on the upper face to give alcohol (131).'14 A convenient method for brominating aldehydes and ketones employs a mixture of t-butyl bromide and DMSO. Carboxylic acids and esters do not react and ketones are selectively brominated at the more-substituted position. The active brominating agent is thought to be Me2SBr+Br-."5 r? r-? Ogo 0 8 Ph PhS02' H H The following sets of conditions have been reported to oxidize allylic alcohols selectively to enals or enones in the presence of saturated alcohols (i) K2Fe04 and PhCH,N( Et),'Cl- in benzene and aqueous sodium hydroxide;"' (ii) molecular oxygen with catalytic amounts of hydrated Ru02 in 1,2-di~hloroethane;"~ (iii) molecular oxygen with catalytic amounts of nitroxyl (132) and CuCl in DMF.Il8 In the last of these the active oxidant is thought to be the nitrosonium ion (133).All three methods preferentially oxidize primary allylic alcohols particularly (iii) which is completely ineffective with secondary analogues. In a modification of (iii) a stoicheiometric amount of CuC12 is used to generate the nitrosonium ion. These conditions will oxidize saturated primary alcohols fairly selectively in the presence of secondary alkanols.A method has been reported for the 'one-pot' conversion of primary alcohols to t-butyl esters (Scheme 46).'19 As indicated the reaction is presumed to proceed via the formation and oxidation of hemi-acetals ( 134) within the reaction mixture. 114 F. A. Davis L. Vishwakama J. Billmers and J. Finn J. Org. Chem. 1984 49 3241. 'Is E. Armani A. Dossena R. Marchelli and G. Casnati Tetrahedron 1984 40,2035. K. Kim Y. Chang S. Bae and C. Hahn Synthesis 1984 866. 117 M. Matsumoto and N. Watanabe J. Org. Chem 1984 49 3435. 118 M. F. Semmelhack C. Schmid D. Cortes and C. Chou J. Am. Chem. SOC 1984 106,3374. 119 E. J. Corey and B. Samuelsson J. Org.Chem. 1984,49 4735. Synthetic Methods ii[ R-CH,OH -[R-CHO] -R-C-OH ] -R-C0,Bu' 0But Reagents i py.Cr03(4eq.) CH2C12,DMF 15 min; ii AczO (10 eq.) Bu'OH (20 eq.) 16 h Scheme 46 A clean conversion of thiols to carbonyl compounds is shown in Scheme 47.12* The photochemical cleavage of phenacyl derivatives (135) to thiocarbonyl com-pounds (136) and the trapping of the latter by silyl nitronate (137) was previously established. The new development is the cleavage of adducts (138) to carbonyl compounds. OSiMe,Bu' (138) Reagents i PhCOCH,CI Et3N THF; ii hv (sunlamp). benzene (137) iii Bu,N+F- THF Scheme 47 A new conversion likely to prove particularly useful is the direct oxidation of secondary amines to nitrones by hydrogen peroxide catalysed by sodium tung- state.l2* When there is a choice of regiochemistry the method appears to give the more thermodynamically stable nitrone ; for example 2-methylpiperidine (139) is oxidized to the more substituted isomer (140) in 68% yield.E. Vedejs and D. Perry 1. Org. Chern 1984,49 573. I21 H. Mitsui S.-i. Zenki T. Shiota and S.4. Murahashi 1. Chem. SOC.,Chem. Commun. 1984,874. 280 A. P. Davis Optically pure sulphoxides are increasingly used in synthetic methodology. They have usually been prepared via a procedure involving the separation of diastereomeric menthyl sulphinates but it has long been recognized that a preferable route would be an efficient asymmetric oxidation of sulphides. Kagan and co-workers have come very close to this goal with a modification of the Sharpless conditions for asymmetric epoxidation.'22 In their best example treatment of p-tolyl methyl sulphide with a mixture of Ti(O'Pr), (R,R)-diethyl tartrate Bu'OOH and (critically) water in the ratio 1 :2 2 1 at -40 "C rising to -24 "C gave the R-sulphoxide in 95% yield and 93% e.e.It has been recognized for some time that a carbonyl carbon may be rendered nucleophilic by conversion to a hydrazone. It has now been shown that a vinylogous extension of this principle is possible. Thus electrophiles such as chlorine bromine iodine sulphenyl chlorides and sulphinyl chlorides react with crotonaldehyde hydrazone (141) to give substitution at C-3.'23 Scheme 48 shows bromination as an example and also demonstrates that the carbonyl group may be regenerated at the end of the sequence.I ii Mee/O 2Me+ ,,N-NMe2 Br Br Reagents i Me2N-NH,; ii Br, Et3N; iii H2C0 aq. HCI aq. Scheme 48 Finally reviews have been published on synthetic applications of (i) the palladium- catalysed oxidation of olefins to ketones (Wacker process)'24 and (ii) polyvalent iodine compounds (PhIC12 PhIO PhI02 etc).12' Reduction.-Hydrogenation of Carbon-Carbon Multiple Bonds. The homogeneous hydrogenation catalysts [Ir(cod)(py)(PCy,)]PF and [Rh(NBD)(DIPHOS-4)]BF4 (142) were both known to induce highly stereoselective hydrogenations of alkenes controlled by neighbouring hydroxyl groups. However neither had been tried on a broad range of acyclic alkenols. Employing hydrogen at one atmosphere pressure + BF,-122 P.Pitchen and H. Kagan Tetrahedron Lett. 1984,25 1049; P. Pitchen E. Dunach M. Deshmukh and H. Kagan J. Am. Chem. SOC.,1984 106 8188. lZ3 T. Severin G. Wanninger and H. Lerche Chem. Ber. 1984 117 2875. 124 J. Tsuji Synthesis 1984 369. 12' A. Varvoglis. Synthesis 1984 709. Synthetic Methods 281 Evans and Morrissey tested both catalysts on (143) (144) and a number of related alkenes. The results were disappointing until the pressure of hydrogen was raised to cu. 50 atmospheres; although the iridium catalyst was no more effective the rhodium catalyst gave very good selectivity as exemplified in Scheme 49. Under these conditions the rhodium catalyst was found stereoselectively to hydrogenate a wide range of cyclic and acyclic alkeno1s.126 Me+NRlaA M e Y N R M e wI NI R Me Me Me Me Me 93 7 9 91 Reagents i CH2CI, H (640 p.s.i.) (142) Scheme 49 A recent paper is claimed to give the best method yet reported for the selective cis-semihydrogenation of acetylenes.The reaction is performed under one atmo- sphere of hydrogen in a solvent mixture containing quinoline using a catalyst prepared from Pd(OAc), sodium hydride and t-amyl alcohol. Under these condi- tions 'self-terminating' semihydrogenation is possible.'27 An apparently convenient new method for simple hydrogenations and hydrogenolyses is the use of palladium on charcoal with sodium hypophosphite as a hydrogen source.128 Curbonyl Reductions. As usual there have been a large number of papers on the asymmetric reduction of ketones.Two of the more effective reagents were (i) the hydroaluminate (149 which reduces acetophenenone to give the S-alcohol in 97% e.e.,129 and (ii) a combination of [Rh(cod)Cl], Ph2SiH2 and the ligand (146) which hydrosilylates acetophenone to give the R-siloxane in up to 97.6% e.e.l3' Both reagents were much less selective with dialkyl ketones. Sih and Chen have reviewed the microbial reduction of ketones,131 often the best way of preparing simple alcohols enantioselectively. One of the more important examples is the reduction of P-ketoesters (147) by baker's yeast. The configuration and optical purity of the product appear to depend on the relative sizes of the two groups on either side of the carbonyl.Thus for R'=Me R2=Et the S-alcohol can be obtained in 97% e.e. while for R' R2=Et the R-isomer is produced in much 126 D. A. Evans and M. Momssey J. Am. Chem. SOC. 1984 106 3866. 127 J.-J. Brunet and P. Caubere J. Org. Chem. 1984 49 4058. 128 R. Sala G. Dona and C. Passarotti Tetrahedron Lett. 1984 25 4565. I29 K. Yamamoto H. Fukushima and M. Nakazaki J. Chem. SOC.,Chem. Commun. 1984 1490. 130 H. Brunner R. Becker and G. Riepl Organometallics 1984 3 1354. 131 C. J. Sih and C.-S. Chen Angew. Chem. Inr. Ed. Engl. 1984 23 570. 282 A. P. Davis lower optical purity. An elegant modification which considerably broadens the scope of the method is outlined in Scheme 50. An alkylthio group introduced at C-2 of the substrate ensures that this carbon will appear bulkier to the enzyme.The resulting alcohols have the S-configuration at C-3 both diastereomers being produced in 96% e.e. for a range of R' R2 and R3. Straightforward removal of the alkylthio group completes the sequence.'32 c SR2 sRZ SRZ Reagents:i baker's yeast preparation; ii m-CPBA; iii AI-Hg Scheme 50 There is great potential in many areas of natural-product synthesis for carbonyl reductions which are stereodirected by a pre-existing centre in the substrate. Oishi and Nakata have played an important part in developing such methods and have now reviewed their Recently it has been reported that bulky organosilanes can act as highly stereoselective reducing agents. Notably derivatives of a-hydroxy- and a-amino-ketones can be reduced to either erythru or threo products depending on the conditions (e.g.Scheme 51).'34 Brown continues to explore the use of boranes and hydridoborates as reducing agents for carbonyl compounds. Recent developments include the use of chloroborane complex (148) to reduce carboxylic acids to aldehyde^,'^^ said to be the first convenient method for accomplishing this conversion directly and the use of (149) in the stereoselective reduction of cyclic ketones.'36 The latter reagent is similar in selectivity to L~(BU')~BH ('L-selectride') but is advantageous in that it requires only a hydrolytic work-up as opposed to an oxidative one. 13* T. Fujisawa T. Itoh and T. Sato Tetrahedron Leu. 1984 25 5083. 133 T. Oishi and T. Nakata Acc.Chem. Res. 1984 17 338. 134 M. Fujita and T. Hiyama J. Am. Chem. SOC. 1984 106 4629. 135 H. C. Brown J. Cha B. Nazer and N. Yoon,J. Am. Chem. Soc. 1984 106 8001. 136 H. C. Brown J. Cha and B. Nazer J. Org. Chem. 1984 49 2073. Synthetic Met hods OH OH phQCHIPn ph*OCH,Ph + phsOCH2Ph Me Me Me Reagent i 96 4 Reagent ii 7 93 0 OH >98% d.e. >98% d.e. Reagents i PhMe2SiH Bu,N+F- cat. HMPA; ii PhMe2SiH CF3C02H Scheme 51 c1 K+ H Othe, Reductions. The reduction of aliphatic nitro-compounds to imines has generally been effected under conditions which immediately hydrolyse the imines to ketones. It is now reported that a combination of tributylphosphine and diphenyl disulphide will accomplish the reduction under conditions which are not only anhydrous but ~e1f-drying.l~' This allows the trapping of the imine in a number of ways for example by HCN addition to give an a-aminonitrile as in Scheme 52.A possible mechanism involves the interaction of the aci-form of the nitro-compound with an adduct (150) formed reversibly from the phosphine and the disulphide. (Scheme 53). Adduct . .. I II ph-om NOz -NH2 Reagents i (PhS), Bu3P,NaCN THF:ii AcOH Scheme 52 D. H. R. Barton W. Motherwell. and S. Zard Tetrahedron Lett. 1984. 25 3707. 284 A. P. Davis OH R' (150) >NH c--R'>-N' + Bu3P=0 + PHSjz R2 RZ Scheme 53 (150) also reacts rapidly with water to give tributylphosphine oxide and thiophenol. As implied in Scheme 53,the same conditions will also reduce oximes to imines.13* The Bamford-Stevens procedure for reducing ketones to alkenes has many poten- tial applications but is somewhat limited by the strongly basic conditions required.This year two methods have been reported which allow the same conversion to be accomplished under different and in some respects milder conditions. In one case the ketone was converted into a phenylaziridine hydrazone such as (151) which on thermolysis in decalin at 160 "C for 2 hours gave alkene (152) in 92% yield.'39 In the second method the ketone was converted into a vinyl triflate such as (153; X = OTf) which could be reduced to alkene (153; X = H) in 85% yield by tributylammonium formate in DMF with Pd(OAc)*( PPh3)* as ~atalyst.'~' n X NC 'Y Ph (151) Finally a paper by Zimmerman and Breslow describes a reaction which is unusual in that it was conceived out of an interest in enzyme mimicry but may form the basis for a general synthetic method of genuine usefulness.In nature the enzymatic interconversion of a-amino acids and a-keto acids is mediated by the coenzyme pair of pyridoxal (154) and pyridoxamine (155). In the presence of metal ions pyridoxamine itself may be used for the conversion of a-keto acids to a-amino acids but without (of course) the enantiospecificity of the enzymatic reaction. The analogue (156) was designed to remedy this deficiency. As shown in Scheme 54 the reaction requires the interconversion of two isomeric imines via a proton transfer. I38 D.H. R. Barton W. Mothewell E. Simon and S. Zard J. Chem. SOC.,Chem. Commun. 1984 337. I39 F. Mohamadi and D. Collum Tetrahedron Lett. 1984 25 271. 140 S. Cacchi E. Morera and G. Ortar Tetrahedron Lett. 1984 25 4821. Synthetic Methods (156) contains an amino group placed so that this may be accomplished intramolecularly on one face only of the intermediate. Hydrolysis of the products (157) gave amino acids of up to 90% e.e. and the authors point out that the possibility that (156) was not optically pure implies that the true enantioselectivity may be even greater.I4' NMe2 H (157) Scheme 54 Non-Redox Conversions.-Substitution at sp3-Hybridized Carbon. While it is generally fairly easy to induce an sp3 C-0 bond to cleave heterolytically few ways are known for cleavage of sp3 C -N.One well-established option is the conversion of a primary amine into a pyridinium compound followed by nucleophilic substitution in which the nitrogen leaves as part of the pyridine nucleus. Katritzky and his group have explored this area in depth and a review has appeared on their progress over the last four years.14* 141 S. Zimmerman and R. Breslow J. Am. Chem. SOC.,1984 106 1490. 142 A. R. Katritzky and C. Marson Angew. Chem. Inf. Ed. Engl. 1984 23. 420. 286 A. P. Davis A new method for C-N cleavage is exemplified in Scheme 55. The reagent (159) has a number of advantages over vinyl chloroformate used in an earlier version of the method; in particular decomposition of the initial products (160) occurs readily under neutral conditions.In general the order of ease of cleavage of alkyl groups is tertiary >> secondary > methyl > primary >> piperidine ring residue. As implied in Scheme 55 this allows substituted piperidines (158) to serve as a fairly general source of chlorides ( 161).'43 I Me OMe cAHzCl-+ C02 + Me-( -CN-.('-(cl + R-Cl OMe (161) Reagent i MeOH Scheme 55 The Cs' ion has been shown to be particularly useful as counterion for an anionic nucleophile in a number of SN2 macrocyclizations. As shown in Scheme 56 this has now been extended to the synthesis of azamacrocycles.'44 Ts Iiii H N Reagents i Cs2C03 DMF; ii Br-(CH2),6-Br; iii Na-Hg Na2HP0, MeOH Scheme 56 143 R.A. Olofson J. Martz J.-P. Senet M. Piteau and T. Malfroot J. Org. Chem. 1984 49 2081; R. A. Olofson and D. Abbott J. Org. Chem.. 1984,49 2795. 144 B. Vnesma J. Buter and R. M. Kellogg 1. Org. Chem. 1984 49 110. Synthetic Methods 287 The ring-opening of epoxides by attack of bromide ion at the less-substituted carbon requires essentially ‘non-electrophilic’ conditions. Obvious reagents to choose might be tetra-alkylammonium bromides or alkali metal bromides in dipolar aprotic solvents. However the ‘naked’ bromide ions provided by these sources seem to be relatively ‘hard’ inducing base-catalysed side-reactions in some substrates. It is reported that these difficulties can be avoided by using Li,NiBr, which appears to function as a source of unusually ‘soft’ Br-.*45 Substitution at spZ-Hybtidized Carbon.The macrolactonization of a complex hydroxyacid is a crucial step in many natural product syntheses. A new method outlined in Scheme 57 gave excellent yields for a number of 13- 14- and 16- membered macrocycles.’46 0 r Me \OH Me Me NMe2 Reagents i THF -60 to 0 “C; ii; CH,C12 or toluene 10-camphorsulphonic acid cat. Scheme 57 The conversion of an acid halide or ester into the corresponding carboxylate salt would generally be accomplished uia the acid itself and would probably involve an aqueous step. It is reported that a direct conversion which could be quite valuable in some circumstances can be accomplished by alkali-metal trimethylsilanolates (Me,SiO-M’) which thus act as anhydrous ‘0,-equivalent^'.'^' Alkyl diaryl sulphonium salts are of pivotal importance in sulphonium ylide chemistry because they offer only one site for deprotonation.Usually they must be made by the alkylation of diaryl sulphides and there is a clear need for practical methods for arylating alkyl aryl sulphides. A new procedure reported by Garst and co-workers is shown in Scheme 58. The sulphonium salts (162) are formed in acceptable yields and can be used in standard sulphonium ylid reactions such as cyclopropanation and epoxide f~rmation.’~~ 145 R. Dawe T. Molinski and J. V. Turner Tetrahedron Lett. 1984 25 2061. 146 H.-J. Gais Tetrahedron Lett. 1984 25 273. 147 E. Laganis and B. Chenard Tetrahedron Lett. 1984 25 5831. 14* B.McBride M. E. Garst and M. Hopkins J. Org. Chem. 1984 49 1824. 288 A. P. Davis 0 OH OMe Ar-S I i_ / BF, + 0 ;@/ BF A io R Ar -S Ar-S 0 R OH R OMe Reagents i CH2CI2 HBF,; ii CH2N2 Scheme 58 It has been known for some while that the reagent (163) will react with aromatic aldehydes to give the corresponding iminium salts. The reaction has now been generalized to aliphatic aldehydes. For example 4,4,4-trichlorocrotonaldehydecould be converted into the iminium fluoroborate (164) shown to be a powerful dienop hile. 149 Me Addition to C-C Multiple Bonds. The oxymercuration of a,P-unsaturated carbonyl compounds is known to be regiospecific placing the oxygen nucleophile in the P-position. It has now been shown that when applied to a-alkyl-8-oxygenated substrates such as (165) it is stereoselective as well (Scheme 59).lS0 The stereochemistry appears to be determined by the configuration at the y-carbon the new alkoxy group appearing anti to the alkyl substituent as in the example shown.The reaction should be generally useful in the synthesis of the 1,3-dioxygenated systems so common in natural products. A I,. II ..&yo .. I Me04 0 OEt t> OEt Me0 I/ bPh ( 165) > 90% d.e. Reagents i Hg(OAc), PhCH,OH CH2C12 HC10 aq.; ii NaBH, THF H,O Scheme 59 TeCl is known to add syn Markovnikov to simple alkenes. However it has recently been reported that with allylic esters rather different behaviour is observed. As shown in Scheme 60 addition is syn and 1,3 with stereospecific migration of the acyloxy group.The tellurium may be removed reductively to give chloroesters ( 166).”’ 149 A. Schwobel and G. Kresze Synthesis 1984 944. 1so S. Thaisrivongs and D. Seebach J. Am. Chem. Soc. 1983 105 7407. 151 L. Engman J. Am. Chem. SOC.,1984 106 3977. Synthetic Methods R' R3 R 1 q R 2 oAo ii 0'0 "YoR3 -+ RI&R? I R]&R' I Tea3Cl CI ( 166) Reagents i TeCI,; ii Raney Ni EtOH reflux Scheme 60 Miscellaneous. Conditions have been reported for the conversion of allylic selenides into a variety of protected allylic amines. Examples are shown in Scheme 61 chosen to illustrate the stereoselectivity of these reactions which presumably proceed via the [2,3]-sigmatropic rearrangement of selenimides ( 167).lS2 OH I UePh '3 HNTs 0 Reagents i ROANH2 (R = Bu' PhCH2) PrkNEt N-chlorosuccinimide MeOH; ii TsNCINa MeOH Scheme 61 R' I I52 J.Frankhauser R. Peevey and P. Hopkins Tetrahedron Lett. 1984 25 15; R. Shea J. Fitzner J. Fankhauser and P. Hopkins J. Org. Chem. 1984;49 3647. 290 A. P. Davis Esters of the form (168) have been proposed as useful protected carboxylic acids. As shown in Scheme 62 cleavage occurs under very mild conditions with Pdo catalysis giving the highly labile trimethylsilyl esters (169).lS3 + Me3Si-0 kR 0 Reagents i CH2C12 Pd(PPh,) (0.02eq.) Scheme 62 Acetal formation can be accomplished efficiently and conveniently with a new heterogeneous catalyst formed by derivatizing silica gel with alkoxysilane (170) and neutralizing the amino groups with hydrochloric acid.As it is only mildly acidic the catalyst is especially useful with substrates containing acid-sensitive Finally a new synthesis of nitro compounds employs the well-known reaction of azides RN3 with phosphines RiP to give iminophosphines RN=PRi which is then followed by cleavage with ozone to give RN02.155 (EtO),Si &NH 153 H. Mastalerz J. Org. Chem. 1984 49 4092. I54 F. Gasparrini M. Giovannoli D. Misiti and G. Palmieri Tetrahedron 1984 40,1491. 155 E. J. Corey B. Samuelsson and F. Luzzio J. Am. Chem. SOC.,1984 106 3682.

ISSN:0069-3030    

DOI:10.1039/OC9848100247

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

12 Alkaloids By D. J. ROBINS Department of Chemistry University of Glasgow Glasgow G12 800 1 Introduction A colossal amount of new work has been reported in the five years since alkaloids were last reviewed in Annual Reports.’ Three more volumes of Specialist Periodical Reports on the alkaloids are available,24 which cover the period July 1979-June 1982. The biosynthesis of alkaloids is included in these Reports and in Volume 7 of the Specialist Periodical Report on biosynthesis which covers a three year period 1979-198 1.5More recent aspects of alkaloid chemistry and biochemistry are treated in the journal Natural Product Reports which has superseded the Specialist Periodical Reports on alkaloids and biosynthesis and which began in 1984. Several new monographs on alkaloid chemistry have appeared.68 The period covered by this selective review is 1980-1984 inclusive.Two particular themes that have become increasingly apparent over the past five years merit special attention. One is the use of chiral starting materials to synthesize alkaloids in optically active form and the other is the shift towards the utilization of stable isotopes and cell-free preparations to elucidate details of biosynthetic pathways to alkaloids. 2 Pyrrolidine Alkaloids The biosynthesis of nicotine continues to generate much attention. The pyrrolidine ring is known to be derived from ornithine. Leete and Yu9 fed DL-[2,3-’3c2,5-’4c]-ornithine (1) to Nicotiana glutinosa plants. The I3C n.m.r. spectrum of the biosyn- thetically derived nicotine (3) exhibited satellites of equal intensity at C-2’ C-3’ and C-4’ C-5’ due to contiguous I3C atoms (Scheme 1).This result confirmed the D. G. Buckley Annu. Rep. hog. Chem. Sect B 1979 76 382. * ‘The Alkaloids’ ed. M. F. Grundon A Specialist Periodical Report The Royal Society‘of Chemistry London 1981 Vol. 11. ‘The Alkaloids’ ed. M. F. Grundon A Specialist Periodical Report The Royal Society of Chemistry London 1982 Vol. 12. ‘The Alkaloids’ ed. M. F. Grundon A Specialist Periodical Report The Royal Society of Chemistry London 1983 Vol. 13. E. Leete in ‘Biosynthesis’ ed. R. B. Herbert and T. J. Simpson A Specialist Periodical Report The Royal Society of Chemistry London 1983 Vol. 7 chapter 4. D. R. Dalton. ‘The Alkaloids. The Fundamental Chemistry.A Biogenetic Approach’ Marcel Dekker New York and Basel 1979. ’ M. Hesse ‘Alkaloid Chemistry’ Wiley-Interscience Somerset New Jersey 1981. G. A. Cordell ‘Introduction to Alkaloids. A Biogenetic Approach’ Wiley-Interscience Somerset New Jersey 1981. E. Leete and M.-L. Yu Phyrochemistry 1980 19 1093. 29 1 292 D. J. Robins Scheme 1 symmetrical labelling of the pyrrolidine ring from ornithine probably via putrescine (2). Furthermore when [ l-I3C methylamino-'5N]-N-methylputrescine(4) was fed by Leete and McDonell to N. tabacum only C-5' of nicotine (6) showed a satellite in its 13C n.m.r. spectrum due to an adjacent '*N (J15N-~3c4.2 Hz)." This labelling pattern is consistent with the incorporation of the precursor (4) into nicotine via the N-methyl-1-pyrrolinium ion (5) formed after oxidation of the primary amine of (4) to the aldehyde (Scheme 2).The stereochemistry of the enzymic processes Scheme 2 involved in transforming putrescine into nicotine has been deduced by Wigle et al." (R)-[l-2H]Putrescine (7) was incorporated into nicotine and the labelling pattern (8) was evident from the 2H n.m.r. spectrum. The presence of 2H at the 2'-and 5'4 R) positions indicates that the pro-S hydrogen is stereospecifically lost from C-1 when N-methylputrescine is oxidized to 4-methylaminobutanal. This stereochemistry is in accord with other reactions catalysed by diamine oxidase. Attack of the pyridine-ring precursor on the N-methyl-1-pyrrolinium ion (5) takes place on the l-si,2-re face to yield (S)-nicotine (8).(7) An unusual feeding technique whereby aqueous solutions of the precursors containing a detergent were painted on the leaves of Erythroxylon coca had to be used to obtain reasonable incorporations of precursors into cocaine (9). The label from DL-[5-'4C]ornithine [cf (l)] was shown by Leete to be equally distributed between the two bridgehead carbons C-1 and C-5 in cocaine (9).12 Thus cocaine is derived from ornithine again via the symmetrical intermediate putrescine (2). It should be noted that the biosynthesis of some other structurally related tropane alkaloids derived from ornithine does not involve any symmetrical intermediates. 10 E. Leete and J. A. McDonell J. Am. Chem. Soc. 1981 103 658. 1. D. Wigle L.J. J. Mestichelli and I. D. Spenser J. Chem. Soc. Chem. Commun. 1982 662. 12 E. Leete J. Chem. Soc. Chem. Cornmun. 1980,1170; J. Am. Chem. Soc. 1982 104 1403. Alkaloids 293 Leete has also demonstrated that C-2 C-3 C-4 and C-9 of cocaine (9) are derived as expected from acetic acid.13 After feeding [l-'4C]acetic acid 48% of the 14C label was found to be located at C-3 and 38% was at C-9. The higher activity at C-3 is attributed to C-4 and C-3 constituting the starter unit and therefore containing a higher level of activity than the second unit (C-2 and C-9) which is added via malonate. [4-3H]Phenylalanine was also incorporated specifically into the benzoic acid moiety of cocaine (9) confirming previous res~1ts.l~ A tropane alkaloid subhirsine with a most unusual structure (10) has been isolated by Russian workers from Convoluulus ~ubhirsutus.'~ 3 Piperidine and mridine Alkaloids A novel sulphur-containing monoterpenoid glucosidic alkaloid xylostosidine (1 1 ) has been isolated from aqueous extracts of Loniceru xylosteum L." Lysine is known to be a specific precursor for the piperidine ring of anabasine (12).Leete has confirmed these findings by feeding ~~-[4,5-'~C,,6-'~C]lysine (13) to Nicotiana glauca.I6 Satellites for contiguous I3C atoms at (2-4' and C-5' in anabasine (12) were observed in its I3C n.m.r. spectrum. The 14C radioactivity was located almost entirely (98% ) at C-6' of anabasine. Lysine is therefore incorporated into anabasine without going through a symmetrical intermediate such as cadaverine (14) ( CJ nicotine and cocaine biosynthesis).(1 1) (12) (13) (14) Muscopyridine (16) is one of the rare mammalian alkaloids known. It is present in the musk deer and plays a role in communication when used for territorial marking. Two syntheses of (R)-(+):muscopyridine (16) have been reported." In one shown in Scheme 3 the desired enantiomer was formed by reduction of the double bond in (15) using a chiral borane reagent derived from (-)-a-pinene. l3 E. Leete Phytochemistry 1983 22 699. 14 S. F. Aripova E. G. Sharova and S. Yu. Yunusov Khim. Prir. Soedin. 1982 640 (Chem. Abstr. 1983 98 160979). l5 R. K. Chaudhuri 0. Sticker and T. Winkler Helu. Chim. Actu 1980 63 1045. 16 E. Leete J. Nut. Rod. 1982 45 197. 17 K.Utimoto S. Kato M.Tanaka. Y.Hoshino S. Fujikura and H. Nozaki Heterocycles 1982 18 149. 294 D. J. Robins / iii J *-(16) (15) Reagents i AIC13 high dilution; ii NH,; iii tetrachloro-o-benzoquinone;iv MeLi Scheme 3 4 Pyrrolizidine Alkaloids Significant progress has been made in the study of the synthesis and the biosynthesis of pyrrolizidine alkaloids in the past five years. In particular the synthesis of a few natural macrocyclic pyrrolizidine alkaloids has been accomplished and the biosyn- thetic pathway to retronecine (17) has been clarified by use of I3C- I5N- and 'H-labelled precursors. The structures of the 200+ known pyrrolizidine alkaloids are depicted in a review.'* Macrocyclic diester pyrrolizidine alkaloids occur with 1 1- 12- or 13-membered rings.Five new alkaloids which are triesters each containing a 14-membered ring have been isolated by Edgar et all9 from Parsonsia species (fam. Apocynaceae). The novel structure (18) proposed for one of these compounds parsonsine has been confirmed by X-ray diffraction studies on two crystalline modifications of (18) which exhibit different folding patterns for the macrocyclic portion of the molecule.20 HO H 6H20H (17) (18) (19) '' D. J. Robins Forschr. Chem. Org. Natursr. 1982 41 115. I9 J. A. Edgar N. J. Eggers A. J. Jones and G. B. Russell Tetrahedron Lett. 1980 21 2657. N. J. Eggers and G. J. Gainsford Cryst. Struct. Commun. 1979 8 597; 1980. 9 173. Alkaloids 295 The synthesis of natural macrocyclic alkaloids has been a long-standing challenge in this area.The first step forward was taken by Robins and co-workers when they achieved the preparation of unnatural 11 -membered macrocyclic pyrrolizidine diesters exemplified by (19).21 Treatment of (+)-retronecine (17) with 3,3-dimethyl- glutaric anhydride gave a mixture of the 7-and 9-monoesters. These were lactonized uia their corresponding pyridine-2-thiolesters to give the pyrrolizidine aikaloid analogue (19) in 75% yield. The large difference in chemical shift of 1.24 p.p.m. for the C-9 protons of (19) supports the formation of a macrocycle and suggests that the conformation of (19) may be different from those of 1 1-membered macrocyclic pyrrolizidine alkaloids where lower values have been observed." The hydrobromide of (19) was readily metabolized by liver oxidase enzymes to the corresponding toxic pyrrole derivative and showed hepatotoxic effects similar to those of the common macrocyclic pyrrolizidine alkaloid monocrotaline.22 Similar strategy was used by Robins and co-workers to prepare (+)-dicrotaline (20) and its C-13 e~imer.~~ One of the separated products was identical with natural dicrotaline isolated from Crotalaria dura seeds.The absolute configuration at C-13 in both compounds was established by a series of selective reactions on each epimer to yield optically active mevalonolactone (21) (Scheme 4). Dicrotaline (20) has the largest value so far recorded (1.24 p.p.m.) for the chemical shift difference between the C-9 protons for an 11-membered pyrrolizidine alkaloid containing retronecine.HO Me I 11 + t-lo (20) Reagents i H2/Pt02 AcOH; ii Na liq.NH3 Scheme 4 A total synthesis of the 1 1-membered macrocyclic alkaloids (*)-crispathe (27) and (*)-fulvine has been achieved by Vedejs and Lar~en.~~ Crispatic anhydride was prepared and the tertiary hydroxy function was protected as its methoxymethyl ether (22) (Scheme 5). Coupling of the mixed phosphoric anhydride (23) was carried out with the lithium alkoxide of protected (*)-retronecine (24)2' to afford (25) and a diastereoisomer. Lactonization was effected by displacement of the methanesul- phonate group in (26) with the liberated carboxylate anion. The diastereoisomeric products were separated to yield (*)-crispathe (27).An analogous series of reactions " D. J. Robins and S. Sakdarat J. Chem. SOC.,Chem. Commun. 1980 282; J. A. Devlin D. J. Robins and S. Sakdarat J. Chem. SOC. Perkin Trans. I 1982 1117. 22 A. R. Mattocks Chem.-Biol. Interact. 1981 35 301. 23 J. A. Devlin and D. J. Robins J. Chem. SOC. Chem. Commun. 1982 1272; K. Brown J. A. Devlin and D. J. Robins 1. Chem. SOC. Perkin Trans. I 1983 1819. 24 E. Vedejs and S. D. Larsen J. Am. Chem. SOC.,1984 106 3030. 25 E. Vedejs and G. R. Martinez J. Am. Chem. SOC. 1980 102 7993. 296 D. J. Robins M eMe A,OCH,OMe..Me "08 ,OSiMe,Bu' d i ii 0 + 0 (EtO),PO CO,CH,CH,SiMe N Me ?CH20Me M~ OCH,OMe iv e-- Me* 0 v1 VII \ 0 ($ Reagents i Me2A10CH2CH,SiMe3 ; ii ( Et+02POCl; iii Bu"Li 4-dimethylaminopyridine; iv HF; v MeS02CI Et3N vi MeCN.Bu",NF vii BF3.Et20,EtSH Scheme 5 from fulvinic anhydride yielded (*)-fulvine [(27) with opposite stereochemistry at c-131. The first synthesis of a 12-membered pyrrolizidine alkaloid was carried out by Japanese workers.26 They started with a stereoselective synthesis of (*)-integerrinecic acid (28).27A series of steps was necessary to protect the free carboxyl group in (28) cleave the &lactone protect the tertiary hydroxy group and form the linear anhydride (29). This anhydride was coupled with the lithium alkoxide of protected (*)-retronecine (24) to produce a monoester mixture (30). Lactonization was achieved by nucleophilic displacement of the methanesulphonylmethyl group by alkoxide to yield the cyclized product and a diastereoisomer (Scheme 6).These products were separated and removal of the protecting group from one racemate under acidic conditions afforded (*)-integertimine (31). K. Narasaka T. Sakakura T. Uchimaru K. Monmoto and T. Mukaiyama Chem. Lett. 1982 445. 2'7 K. Narasaka and T. Uchimaru Chem. Lett. 1982 57. Alkaloids 297 Y li CO,CH,SMe ll-v -(31) (30) Reagents i Bu"Li 4-dimethylaminopyridine; ii hH,F; iii H202 (NH4)6M~7024; iv Bu"Li; V Zn H2S04 Scheme 6 Retronecine (17) was first synthesized by Geissman and Waiss in 1962.28There has been a long gap until further syntheses have been reported.29 Rueger and Benn3' have made the (+)-lactone (32) from natural (-)-4-hydroxy-~-proline in 12 steps.This is an intermediate in the original route to (*)-retronecine,28 and has been converted into (+)-retronecine by an improved pr0cedu1-e.~~ (+)-Croalbinecine (33) and (-)-platynecine (34) were also produced.31 An alternative route to the (+)-lactone (32) has been reported by Buchanan et al?2 from a carbohydrate precursor. Synthetic routes to optically active pyrrolizidine bases have blossomed and a further selection includes (-)-hastanecine (35) from (R)-malic (+)-heliotridine (36) from (S)-malic acid,34 and (-)-rosmarinecine (37) from D-glUCOSamine.35 H@ 0 'KHHw20H .-H OH NH N N 28 T. A. Geissman and A. C. Waiss 1. Org. Chem. 1962 27 139. 29 J. J. Tufariello and G. E. Lee J. Am. Chem. Soc. 1980 102 373; G. E. Keck and D.G. Nickell ibid. p. 3634; T. Ohsawa M. Ihara K. Fukumoto and T. Kametani Heterocycles 1982 19 2075; H. Niwa A. Kuroda and K. Yamada Chem. Leu. 1983 125. 30 H. Riieger and M. Benn Heterocycles 1982 19 23. 31 H. Riieger and M. Benn Heterocycles 1983 20 1331. 32 J. G. Buchanan G. Singh and R. H. Wightman J. Chem. SOC. Chem. Commun.,1984 1299. 33 D. J. Hart and T.-K. Yang J. Chem Soc. Chem. Commun. 1983 135. 34 A. R. Charnberlin and J. Y. L. Chung J. Am. Chem. SOC.,1983 105 3653. 35 K. Tatsuta H. Takahashi Y. Arnerniya and M. Kinoshita J. Am. Chem. SOC. 1983 105 4096. 298 D. J. Robins Significant progress has been made in the past few years in the understanding of the biosynthesis of retronecine (17) chiefly by use of precursors containing stable isotopes.This work began with the demonstration by Khan and Robins of the first complete labelling patterns in retronecine by I3C n.m.r. spectroscopy after feeding [1 ,4-13C2]- and [2,3-13C2]-putrescine.36The labelling pattern obtained with [1,2-CJputrescine is illustrated (38).3' These results confirmed that retronecine is derived from two molecules of putrescine. Evidence for the involvement of a later symmetrical C4- N-C4 intermediate in the biosynthetic pathway to retronecine was provided by the use of a l3C-I5N doubly labelled precursor. Retronecine derived from [l-amin~-'~N,l-~~C]purescine (39) showed enhanced 13C signals for the peaks due to C-3 -5 -8 and -9 in the I3C n.m.r. spectrum.38s39 In addition the signals for C-3 and C-5 of retronecine showed satellites due to 13C-15N coupling.The presence of equal amounts of the two labelled species (40) and (41) indicates that a later symmetrical intermediate is involved in retronecine biosynthesis. This intermediate was shown to be homospermidine by use of 14C-38 and I3C-labelled h~mospermidine.~' Thus [1 ,9-13C2]homospermidine (42) was fed to Senecioisatideus plants and the I3C n.m.r. spectrum of the derived retronecine displayed doublets around the natural abundance signals for C-8 and C-9 with a geminal coupling constant of ca. 6 Hz,indicating that homospermidine is incorporated intact into retr~necine.~' Further support for the role of homospermidine in pyrrolizidine alkaloid biosynthesis was provided by Robins.41 [1 ,9-14C]Homospermidine (42) was converted into [''C]-trachelanthamidine (44) using enzymes under physiological conditions.Treatment of homospermidine with diamine oxidase and reduction of the cyclized aldehyde (43) with a dehydrogenase gave the saturated pyrrolizidine base (44). Degradation of the ''C-labelled base (44)yielded methylamine (Scheme 7) containing 51 % of the total activity of the base indicating that homospermidine is not broken down (e.g. to putrescine) before formation of trachelanthamidine. 36 H. A. Khan and D. J. Robins J. Chem. SOC. Chem. Commun. 1981 146; J. Chem. Soc. Perkin Trans. I 1985 101. 37 D. J. Robins J. Chem. Res. (S) 1983 326. 38 H. A. Khan and D. J. Robins J. Chem. SOC.,Chem. Commun. 1981 554. 39 G. Grue-Sorensen and I.D. Spenser 1.Am. Chem. Soc. 1981 103 3208. 40 J. Rana and D. J. Robins J. Chem. Res. (S),1983 146. 4' D. J. Robins J. Chem. SOC.,Chem. Commun. 1982. 1289. Alkaloids 299 (43) (44) iii iv I Reagents i pea seedling diamine oxidase + catalase; ii liver alcohol dehydrogenase; iii SOCl,; iv LiAIH,; v CrO, H,S04; vi NaN3 H2S04 Scheme 7 Information about the stereochemistry of the enzymic processes involved in retronecine biosynthesis has been obtained using ’H-labelled precursors. The label- ling patterns in retrorsine (49) derived biosynthetically from [1 ,4-’H4]- and [2,3-’H4]- putrescine were established by ’H n.m.r. spectro~copy.~’ The formation of (9S)-[9- ’Hlretrorsine from the former precursor is consistent with stereospecific reduction of an aldehyde precursor as for a normal coupled dehydrogenase enzyme system.This work has been extended by the use of chiral [l-’H]putres~ine~~*~ to establish a number of the stereochemical details in retronecine biosynthesis (Scheme 8). Initial &:+7 __* H2NLNJNH2 NH OHC (45) /CHO CHO 1 (47) CHzOH 1 do N (48) Scheme 8 42 J. Rana and D. J. Robins J. Chem. SOC.,Chem. Commun. 1983 1222. 43 G. Grue-Sorensen and 1. D. Spenser J. Am. Chem SOC.,1983 105 7401. 44 J. Rana and D. J. Robins J. Chem. Soc. Chem. Commun. 1984 517. 300 D. J. Robins oxidation of putrescine to 4-aminobutanal takes place with loss of the pro-S hydro-gen. Reduction of the imine (49 formed by coupling of putrescine with 4-aminobutanal occurs by hydride attack on the si-face of the imine to yield homosper- midine (42).Two further oxidation steps each take place with removal of the pro-S hydrogens to afford a dialdehyde (46). Cyclization of the corresponding iminium ion (47) occurs by attack on its re-face to give the 8a-pyrrolizidine (48). Reduction of the aldehyde takes place on the re-face of the carbonyl group. Further insight into the stereochemistry of pyrrolizidine alkaloid biosynthesis is likely to result from the use of other 2H-labelled precursors. 5 Indolizidine Alkaloids The occurrence and synthesis of indolizidine alkaloids has been re~iewed.~’ Swain-sonine (57) has been isolated from Swainsona canescens,46 the spotted locoweed (AstragaZus lentiginosus),4’ and the fungus Rhizoctonia Zeguminicol~.~~ It is a potent inhibitor of the enzyme a-mannosidase.This disruption of the processing of gly- coproteins may. cause locoism a chronic neurological disorder of grazing animals. Three syntheses of (-) -swainsonine from carbohydrate precursors have been recently The route developed by Richardson and co-workers is out- lined in Scheme 9.49Selective protection of the 3-amino-3-deoxy-a-~-mannopyrano-side (50) gave the crystalline diol (51). The free amine formed on hydrogenolysis of (51) cyclized when heated at reflux in ethanol containing sodium acetate. The product was isolated as its N-benzyloxycarbonyl derivative (52). Acid hydrolysis of (52) yielded the furanose (53) which was condensed with ethanethiol under acidic conditions to give the protected aldehyde (54).The aldehyde group was liberated from the corresponding triacetate and condensation with ethoxycarbonylmethyl- enetriphenylphosphorane in a Wittig reaction yielded the a,@-unsaturated ester (55). Hydrogenation of the double bond in (55) also removed the protecting group and generated the indolizidinone (56).Reduction of the lactam with borane and deacetyl- ation with sodium methoxide afforded (-) -swainsonine (57) identical with natural material and obtained in 2.7% overall yield from (50). All of the chiral centres of the aminohexose (50) are incorporated intact into swainsonine (57). Slaframine (61) is another toxin produced by Rhizoctonia Zeguminicola. Swain- sonine and slaframine are both formed from L-lysine via pipecolic acid (58) and the remaining two carbon atoms are derived from mal~nate.’~ The indolizidinone (59) has been shown to be an intermediate in the biosynthetic pathway to sla- frami~~e.’~ In further studies [2,3,4,5,6-2H9]pipecolic acid was incorporated into slaframine (61) with the loss of two deuterium atoms from C-6 suggesting that the ketone (60) is involved in the biosynthetic pathway (Scheme The same feeding 45 E.Gellert J. Not. Prod. 1982 45 50. 46 S. M. Colegate P. R. Dorling and C. R.Huxtable Aust. J. Chem. 1979 32 2257. 47 R.J. Molyneux and L. F. James Science 1982 216 190. 48 M. J. Schneider F. S. Ungemach H. P. Broquist and T. M. Harris Tetrahedron 1983 39 29. 49 M. H. Mi L. Hough and A. C. Richardson J.Chem. SOC.,Chem. Commr:n. 1984,447. so G. W.J. Fleet M. J. Gough and P. W. Smith Tetrahedron Lett. 1984 25 1853. 51 T. Suami K. Tadano and Y.Iimura Chem. Lett. 1984 513. 52 E. C. Clevenstine H. P.Broquist and T. M. Hams Biochemistry 1979 18 3659. 53 F. P. Guengerich S. J. DiMari and H. P. Broquist J. Am. Chem. SOC.,1973 95 2055. 54 M. J. Schneider F. S. Ungemach H.P. Broquist and T. M. Hams J. Am. Chem. SOC.,1982 104,6863. Alkaloids 301 "O? Tso> HoI OH -ZN*OH t (54) (53) 1 Et0,CCH =Ckts AcO--OAcAcO 0 (55) 2 =COOCHzPh (56) Scheme 9 Scheme 10 experiment yielded swainsonine (57) which had lost two deuterium atoms from C-8 and C-8a. The hydroxylation at C-8 accounts for the loss of one of these atoms; loss of the other (from C-8a) can be attributed to the formation of an iminium ion (62).Hydride attack on this iminium ion would then lead to the inversion of configuration at C-8a necessary in the formation of swainsonine (57). 302 D. J. Robins Castanospermine (63) is a toxic alkaloid isolated from seeds of the Australian legume Castanosperrnurn austr~le.~~ The structure and relative configuration of castanospermine were deduced from an X-ray crystal determination. 6 Quinolizidine Alkaloids A short stereoselective route to a-isosparteine (65) involving nitrones as intermedi- ates has been developed by Oinuma et al. (Scheme 11).56Sequential reaction of two molecules of 1-piperideine 1-oxide with pyran gave the intermediate (64).Reductive cleavage of the N-0 bonds in (64) followed by iminium ion formation and reduction of the iminium ions led to a-isosparteine (65). H H iii c- (64) 1 Reagents i 140 "C; ii 190 "C iii H2 PdO.H,O MeOH Scheme 11 Major contributions have been made to our understanding of the biosynthesis of quinolizidine alkaloids. The biosynthetic pathway to these alkaloids is known to proceed from L-lysine via cadaverine (66). Crude enzyme preparations from cell 55 L. D. Hohenschutz E. A. Bell P. J. Jewess D. P. Leworthy R. J. Pryce E. Arnold and P. J. Clardy Phytochemistry 1981 20 811. 56 H. Oinuma S. Dan and H. Kakisawa J. Chem. Soc. Chem. Commun. 1983 654. Alkaloids 303 suspension cultures of Lupinus polyphyllus have been shown to catalyse the conver- sion of cadaverine into 17-oxosparteine (67) in the presence of pyruvic acid.s7 This suggests that transamination reactions are occurring with the pyruvic acid acting as a receptor for the amino groups in cadaverine.Since no intermediates were detected during the biosynthetic process a series of enzyme-linked intermediates on an enzyme complex was postulated by Wink et uZ.,~~and 17-oxosparteine (67) was proposed as a key intermediate in the biosynthesis of tetracyclic quinolizidine alkaloids. Further evidence has been provided by the use of stable isotopes. Three [l-arnino-”N l-’3C]cadaverine units (68) are incorporated to about the same extent into sparteine (69).58,59 Two 13C-”N doublets were observed in the 13C n.m.r.spectrum of sparteine indicating that two of these units are incorporated into the outer rings of sparteine in a specific fashion (69) (Scheme 12). In a similar manner two Scheme 12 cadaverine units (68) were shown to be incorporated into the bicyclic alkaloid lupinine (70) in L. luteus but only one 13C-”N doublet was observed in the I3C n.m.r. spectrum.59B60 This finding demonstrates that a later C5-N-C5 symmetrical intermediate is not involved in lupinine biosynthesis and thus provides an interesting contrast to pyrrolizidine alkaloid biosynthesis. The stereochemical courses of a number of the enzymic reactions involved in lupinine biosynthesis have been established by feeding chiral [1 -2H]cadaverines to 57 M. Wink T. Hartmann and H.-M.Schiebel Z. Naturforsch. Teil C 1979 34 704. 58 J. Rana and D. J. Robins J. Chem. Soc. Chem. Commun. 1983 1335. 59 W. M. Golebiewski and I. D. Spenser J. Chem. SOC.,Chem. Commun. 1983 1509. 60 J. Rana and D. J. Robins J. Chem. Soc. Chem. Commun.. 1984 81. 304 D. J. Robins L. For example formation of (1 1 S)-lupinine from (I?)-[ l-2H]cadaverine is consistent with attack of hydride at the re-face of the carbonyl of an aldehyde intermediate in the biosynthetic pathway. This result is analogous to that obtained in retronecine biosynthesis. Complete labelling patterns in sparteine and other tetracyclic quinolizidine alkaloids derived from (R)-and (S)-[l-2H]cadaverines have been establi~hed.6~~~~ In particular the presence of 2H at C-17 in all the alkaloids derived from (R)-[1 -2H]cadaverine clearly demonstrates that 17-oxosparteine cannot be an intermediate in the biosynthesis of the tetracyclic quinolizidine alkaloids as suggested by Wink et aLS7 7 p-Phenylethylamine Alkaloids A number of new alkaloids with unusual structural features have been discovered.Bharatamine (72) isolated from Alangium Zamarckii has a novel substitution pat- tern.64 The structure of bharatamine was confirmed by its synthesis from the enamine (71) involving cyclization and debenzylation. Karachine (73) is present in Berberis aristata and has a more typical substitution pattern on both aromatic rings but somewhat strangely appears to incorporate two acetone residues6’ Another new alkaloid (*)-chilenine (79 was isolated from a different species in the same genus 61 W.M. Golebiewski and I. D. Spenser J. Am. Chem. SOC,1984 106 1441. 62 A. M. Fraser and D. J. Robins J. Chem. SOC.,Chem. Commun. 1984 1477. 63 W. M. Golebiewski and I. D. Spenser J. Am. Chem. SOC.,1984 106 7925. 64 S. C. Pakrashi R. Mukhopadhyay P. P. G. Dastidar A. Bhattacharya and E. Mi Tetrahedron Lett 1983 24 291. 65 G. Blasko N. Murugesan A. J. Freyer M. Shamma A. A. Ansari and Atta-ur-Rahman J. Am. Chem. SOC.,1982 104 2039. Alkaloids 305 B. empetrifoZia.66Spectroscopic studies showed that (*)-chilenine is an isoindolo- benzazepine; this is a ring system that has not previously been encountered in Nature. The alkaloid (75)was identical to material that had been prepared earlier by oxidation of berberine to the hydroxyketone (74)followed by rearrangement of (74)in base.67 Norlaudanosoline (79)is widely believed to be derived biosynthetically from dopamine (76)and 3,4-dihydroxyphenylpyruvicacid (77)by condensation to give (78),followed by decarboxylation and reduction of the imine produced.68 Some data that contradict these findings have been presented by Zenk and co-~orkers.~~ They isolated an enzyme that catalyses the formation of laudanosoline from several plant species that are known to produce isoquinoline alkaloids.The substrates for the enzyme were dopamine and 3,4-dihydroxyphenylacetaldehyde. 3,4-Dihy-droxyphenylpyruvic acid was not a substrate. The product from a large scale incubation with the enzyme from Eschscholtzia tenufolia was (S)-norlaudanosoline (79),but the material isolated had only 25% optical purity.The racemic material is presumably formed by a non-enzymic process. It is clear however that the role of a-ketoacids like (77),and the amino acid (78)in the biosynthesis of isoquinoline alkaloids should be subject to further scrutiny. Hn HO "q CO,H HO O q 'HH HO o r (76) Hz "H " Hoe' HO 8 Indole Alkaloids Much progress has been made in the synthesis of indole alkaloids in optically active form. A few examples have been selected. Kozikowski introduced the use of an intramolecular [3 + 21cycloaddition reaction with the nitrile oxide derived from a nitroethylindole [cJ (82)]in his synthesis of (*)-chano~lavine.~~ A similar strategy was employed for his first total synthesis of an ergot alkaloid in optically active form." The route to (+)-paliclavine (86)is outlined in Scheme 13.Wittig reaction of the N-protected indole aldehyde (80) with the optically active phosphorane (81) yielded an unsaturated alcohol which 66 V. Fajardo V. Elango B. K. Cassels and M. Shamma Tetrahedron Lett. 1982 23 39. 67 J. L. Moniot D. M. Hindenlang and M. Shamma J. Org. Chem. 1979 44 4343; C. Manikumar and M. Shamma Heterocycles 1980 14 827. 60 A. I. Scott S.-L. Lee and T. Hirata Heterocycles 1978 11 159. 69 M. Rueffer H. El-Shagi N. Nagakura and M. H. Zenk FEBSLett. 1981 129 5. 70 A. P. Kozikowski and H. Ishida J. Am. Chem. SOC.,1980 102 4865. 71 A. P. Kozikowski and Y. Y. Chen J.Org. Chem. 1981 46 5248; A. P. Kozikowski Acc. Chem. Res. 1984 17 410. 306 D. J. Robins CHO MsO 0-N i-iv v-viii (80) Ts + ___ ' NH 0-NMe xii t- \ Reagents i heat; ii dihydropyran pyridine p-TsOH; iii KOH MeOH; iv H,C=CHNO,; v PhNCO Et3N; vi Ac,O 4-dimethylaminopyridi$ejvii Dowex ion exchange resin H+ form; viii MsCl Et3N; ix PhSeNa then NaIO,; x Me30BF,; xi LiAlH,; xii Hg/AI; xiii MeCHO Scheme 13 was protected. Michael addition of this indole to nitroethene led to the nitro compound (82). The corresponding nitrile oxide was generated and underwent an intramolecular 1,3-dipolar cycloaddition reaction to afford after mesylation (83). The cycloaddition was not stereospecific but the mixture of diastereoisomeric mesylates could be separated.The double bond in (84) was introduced by displace- ment of the mesylate with a phenylseleno group followed by oxidative elimination. The final chiral centre was introduced by methylation of the isoxazoline (84) followed by hydride reduction. This led to a mixture of (85) and its C-5 epimer which had to be separated. Reductive cleavage of the N-0 bond in the minor product (85) gave (+)-paliclavine (86) while further condensation of (86) with ethanal afforded (+)-paspaclavine (87). Alkaloids 307 The first synthesis of (-)-antirhine has been reported by Takano and co-~orkers.~~ The chiral starting material was L-glutamic acid and this was converted into the optically active lactone (88).73The preparation of the key lactone aldehyde (89) then required 16 stages and proceeded in 14% overall yield.Condensation of (89) with tryptamine gave the amide (90),and reductive cyclization then led to (-)-antirhine (91)(Scheme 14).The intermediate (89)may be useful in the preparation of other alkaloids of the corynantheine-yohimbine type. II Reagents i tryptamine NaBH3CN aq.MeOH pH 6; ii DIBAH -78 "C; iii H@+ Scheme 14 The optically active lactone (88)used in the preceding synthesis has been converted into the (+)-and (-)-forms of quebrachamine by Takano et uL74*75The route to (+)-quebrachamine (93)is shown in Scheme 15.74The formation of epimers (92) was not a handicap in the synthesis as this chiral centre is not present in the final product (93). In continuation of their work on biomimetic alkaloid synthesis Brown and Pratt have reported the first biomimetic synthesis of the ring E carbocyclic yohimbine alkaloids (Scheme 16).76Treatment of the methyl ester (94)of secoxyloganin with P-glucosidase at pH 7 gave two epimeric aldehyde diesters (95).The synthesis was completed by acetylation and condensation with tryptamine leading to the yohim- bine acetate epimers (96),and their 19,20-didehydroanalogues.A rapidly growing feature in the study of the biosynthesis of terpenoid indole alkaloids is the use of enzyme preparations from plant tissue cultures. Further work on the biosynthetic pathway to the heteroyohimbine alkaloids has been published. Geissoschizine dehydrogenase has been isolated and partially purified from cell suspension cultures of Cutharunthus rose~s.~~ This enzyme catalyses the conversion 72 S.Takano N. Tamura and K. Ogasawara J. Chem. SOC.,Chem. Commun. 1981 1155. 73 S. Takano M. Yonaga and K. Ogasawara Synthesis 1981 265. 74 S. Takano K. Chiba M. Yonaga and K. Ogasawara J. Chem. SOC.,Chem. Commun. 1980 616. 75 S. Takano M. Yonaga and K. Ogasawara J. Chem SOC.,Chem. Commun. 1981 1153. 76 R. T. Brown and S. B. Pratt J. Chem. SOC.,Chem. Commun. 1980 165. 77 A. Pfitzner and J. Stockigt Phytochemisrry 1982 21 1585. 308 D. J. Robins -iii-v "Oyy (88) . .. CH,CH=CH Et CH,CH=CH H (93) Reagents i LiNPr', CH,=CHCH,Br -78°C; ii LiNPr', EtBr -78°C; iii HCl EtOH; iv NaOH v. NaIO,; vi tryptamine AcOH; vii B,H, DMS; viii NaOH H202;ix LiAIH,; x MsCl; xi Na NH3 Scheme 15 OGlc + OH (94) (95) Scheme 16 of geissoschizine (97) a shunt metabolite into 4,21-didehydrogeissoschizine (98) which is an important intermediate at a branch point in the biosynthetic pathway to ajmalicine (99).The enzyme was shown to remove the 21-pro-R hydrogen in geissoschizine in a reaction dependent on NDAP+ (Scheme 17). The ergot alkaloid elymoclavine (102) is believed to be formed biosynthetically from chanoclavine I (100) via the aldehyde (101). Hassan and Floss78 have used chirally tritiated (100) to demonstrate that the 17-pro-R hydrogen is lost and the 17-pro-S hydrogen is retained in the conversion of (100) into (102) (Scheme 18). The steric course of this reaction is the same as for reactions catalysed by yeast and '13 S.B. Hassan and H. G. Floss J. Nor. Prod. 1981. 44,756. Alkaloids 309 Me0,C 'YMe OH OH (97) (98) J (99) Scheme 17 ofic HOH,C __* __* liver alcohol dehydrogenases and indicates that (101) is an intermediate in the conversion of chanoclavine I into elymoclavine. This conclusion is supported by the isolation of the aldehyde (101) from a Claviceps mutant that is unable to make the tetracyclic ergot alkaloids.79 The first cell-free preparations that are able to make ergot alkaloids have been reported by Groger and co-workers." 79 W. Maier D. Erge and D. Groger Planta Med. 1980,45 104. W. Maier D. Erge B. Schumann and D. Groger Biochem. Biophys. Rex Commun. 1981 99 155 W.Maier D. Erge and D. Groger FEMS Microbiol. Lett. 1981 12 143.

ISSN:0069-3030    

DOI:10.1039/OC9848100291

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

13 Carbohydrates By J. THIEM 0rganisch-Chem isch es Ins titu t Un iversita t Muns ter Orleans -Ring 23 D-4400,Munster Federal Republic of Germany 1 Introduction A previous review in this series discussed the monosaccharide literature of 1976/7 and the present report is intended to focus on the processes currently enjoying interest among carbohydrate chemists with emphasis on the literature of 1983/4. For a comprehensive overview of the intermediate period the reader is referred to more detailed reviews e.g. Specialist Periodical Reports. Carbohydrate chemistry today may be viewed from a variety of standpoints depending on the focus of interest. One very old area fermentation is highlighted today by the biotechnology rush and is expected to become even more important in the near future.Another more technologically oriented branch concerns the transformation of mono- oligo- or polymeric carbohydrate materials into tailor- made polymers using renewable resources. A third main area might be called classical carbohydrate chemistry in which glycosylation modification and esoteric or useful construction of distinct carbohydrates from readily available sugars are dealt with. Finally a vastly expanding fourth branch of carbohydrate chemistry deals with on the one hand de novo syntheses of carbohydrates from non-carbohydrate precursors and on the other hand the transfer of carbohydrates or selectively prepared deriva- tives thereof into other chiral materials -the carbohydrate chiral template approach. These last mentioned areas are both inspired by partial and complete syntheses of complex structures relevant to biochemical processes.This review will concentrate on the last two areas with some emphasis on classical aspects. 2 Monosaccharides G1ycosides.-The stereoselective formation of glycosides continues to be one of the central goals of carbohydrate chemistry. Even though the original general approach by Koenigs and Knorr in 1901 has been improved considerably there remain a number of problems and challenges associated with the glycosylation procedure.' Most of the present glycoside syntheses aim at the construction of biologically important compounds and these frequently demand the preparation of di- tri- and higher oligomers. Consequently in this subchapter only a short survey of the development of glycosylation agents procedures and the formation of simple ' H.Paulsen Angew.Chem. 1982,94 184. 311 3 12 J. Thiern glycosides is discussed. Oligosaccharide synthesis will be treated in more detail below. By use of trimethylsilyl trifluoromethanesulphonate (TMSOTf) the pyranose (1) could be condensed (+)-4-demethoxy-anthracyclinone (2) to give the pure a-glycosylated anthracycline (3) in 99% yield.2 Schmidt and collaborators have pro- vided evidence for the detailed formation of trichloroacetimidates. The primary kinetic product seems to be the P-trichloroacetimidate which anomerizes slowly to its thermodynamically favoured ~y-anomer.~.~ Glycosylation of 2-azido-galactosyl trichloroacetimidates promoted by TMSOTf led exclusively to a-glycosides.A similar treatment of the glum-isomer with both TMSOTf or boron trifluoride etherate however gave alp mixtures.’ pNBzO NHCOCF Acyloxy leaving groups previously used for glycosylations in the presence of Lewis acids could be used successfully for stereoselective glycoside formation. Thus treatment of the p-bromoacetyl gluco-derivative (4) even with sterically demanding alcohols in the presence of trityl perchlorate gave clean inversions and almost exclusively a-glucoside formation (5 ; 75-90% yield). Similarly the P-ribose ,OBn furanose acetate (6) promoted by trityl perchlorate gave only the P-riboside (7) whereas in the presence of lithium perchlorate and molecular sieves a predominant a-riboside synthesis (8; a /3 = 70 30 75-90°h yield) was accomplished.6 In another interesting approach Mukaiyama and co-workers7 demonstrated a stereoselective P-xylofuranoside (10) preparation by reaction of the xylofuranose (9) with the aglycone and caesium fluoride in the presence of methyl fluorosulphonate (65-90% yield almost pure P).The attractive class of 2-0x0-glycosyl bromides [ e.g. (12)] was advantageously prepared by N-bromosuccinimide treatment of the hydroxyglycal esters [ e.g. (1 1)18 Y. Kimura M. Suzuki T. Matsumoto R. Abe and S. Terashima Chem. Lett. 1984 501. R. R. Schmidt and J. Michel Tetrahedron Lett. 1984 25 821. R. R. Schmidt J. Michel and M. Roos Liebigs Ann. Chem 1984 1343. G. Grundler and R. R. Schmidt Liebigs Ann.Chem. 1984 1826. T. Mukaiyama S. Kobayashi and S. Shoda Chem. Lett. 1984 907. M. Murakami and T. Mukaiyama Chem. Lett. 1983 1733. F. W. Lichtenthaler E. Cuny and S. Wepretz Angew. Chem. 1983 95 906. Carbohydrates AMe Bnovo 313 {/>OR ROH ROH {?OR TrCI0,-TrCIO OBn LICIO BnO OBn 0Bn (8) (6) (7) MeOSO,F CsF ROH BnomR OH I or by photochemically induced bromination of 1,s-anhydro-D-keto-hexose deriva-tives [e.g. (13)19in excellent yields. The latter process could also be applied to the oximino compounds [e.g. (14)]and gave an access to the oximino bromides [e.g. (191,derivatives which in turn represent very attractive saccharide units for the sequential construction of aminosugar-containing oligosaccharides. BzO BzO BzO 0Bz Br (1 1) (12) x=o (13) (15) X = NOH (14) Following early work on glycosyl fluorides by Micheel and collaborators," some time ago Mukaiyama et aZ.,ll then Noyori et all2 and a number of other groups have become interested in their preparation properties and glycosylation reactions.Although some of the material is still in the process of being patented a few papers have appeared already. Their increased stabilities render the fluorides so much different from the previously used glycosyl halides that a totally different approach that is by use of Lewis acid catalysis had to be developed for glycosylations. Nicolaou et aL13 prepared glycosyl fluorides from selectively blocked thiophenyl glycosides and claimed a 'practical' synthesis of oligosaccharides (see below).The same group could apply known glycosyl fluorides in the synthesis of 0-,N- S- and C-glycosides (see be lo^).'^.'^ In the very elegant total synthesis of the complex F. W. Lichtenthaler P. Jarglis and W. Hempe Liebigs Ann. Chem. 1983 1959. 10 F. Micheel and A. Werner Ado. Carbohydr. Chem. 1961 16 85. T. Mukaiyama Y. Murai and S. Shoda Chem. Left. 1981 431. 12 S. Hashimoto M. Hayashi and R. Noyori Tetrahedron Lett. 1984 1379. 13 K. C. Nicolaou R. E. Dolle and D. P. Papahatjis J. Am. Chem. SOC.,1984 106 4189. 14 K. C. Nicolaou R. E. Dolle A. Chucholowski and J. L. Randall J. Chem. SOC,Chem Commun. 1984 1153. Is K. C. Nicolaou A. Chucholowski R. E. Dolle and J. L. Randall J. Chem. SOC.,Chem. Commun. 1984 1155.314 J. Thiem aminoglycoside apramycin Tatsuta et all6 condensed the glycosyl fluoride of the terminal sugar unit to the neaminyl octodiose glycoside. A classical approach gave access to the a-and &fluorides of N-acetylneuraminic acid by reaction of the P-chloride with silver fluoride and pyridinium fluoride respectively." By use of the previously developed18 and often advantageously applied" N-iodosuccinimide procedure a successful anthracycline synthesis was nicely accom- plished.20 Treatment of diacetyl-L-rhamnal (16) with the racemic demethoxyadriamycinone (17) gave two easily separable 2-iodoglycosides because of a concommitant resolution of the diastereomers. Only the one with the natural (7S 9s) configuration (18) after deprotection led to a compound which showed activity in a leukaemia assay.0 -HO 0 OSiMe .Bu' OH 0 -HO OH = rac.Q-H AcO AcO NIS I (16) (18) Deoxy Branched and Higher Sugars.-Novel procedures for introduction of a deoxy function (or removal of a hydroxy function) continue to command interest. A reductive displacement of triflates using sodium borohydride was shown to be more effective than Barton-type reactions with primary alcoholic functions ; secondary groups however gave poor results because of concommitant eliminations.21 The stereoselective formation of 2-deoxy-a-~-glycopyranosidesmay be con-sidered a resolved problem2* because efficient methods are available like the N-iodosuccinimide glycosylation18 or the alkoxy ~elenation~~ followed by a reductive process.This approach was displayed in the use of the NIS method for assembling the sequence of the lanatoside oligodeoxy tetrasa~charide.'~ A series of attempts to apply modified glycosylations to 2-deoxy halides did not always meet with convincing results. Glycosylation of the labile 2,6-dideoxy glycosyl bromides most of which are easily accessible in situ by treatment of the corresponding acyl derivatives with trimethylsilyl bromide,24 was studied in the D-ribo case and with complex and simple aglycons led to only little ~tereoselection.~~ A first report on the use of a 2,6-dideoxy glycosyl fluoride for construction of the a,l + 4-linked disaccharide fragment of the antiparasitic agent avermectin B, and the natural compound itself a~peared,'~ 16 K.Tatsuta K. Akimoto H. Takahashi T. Hamatsu M. Annaka and M. Kinoshita Buff. Chem. SOC. Jpn. 1984 57 529. 17 M. N. Sharma and R. Eby Carbohydr. Res. 1984 127 201. J. Thiem H. Karl and J. Schwentner Synthesis 1978 693. l9 J. Thiem and P. Ossowski Liebigs Ann. Chem. 1983 2215. 2o D. Horton W. Priebe and 0.Varela Carbohydr. Res. 1984 130 C1. 21 E.-P. Barette and L. Goodman J. Org. Chem. 1984 49 176. 22 J. Thiem Nachr. Chem. Tech. Lab. 1984 32. 6. 23 G. Jaurand J.-M. Beau and P. Sinay J. Chem. Soc. Chem. Commun. 1981 571. 24 J. Thiem and B. Meyer Chem. Ber. 1980 113 3058 3075. 25 J. Thiem and S. Kopper J. Carbohydr. Chem. 1983 2 75. Carbohydrates 315 which may represent an interesting if more laborious alternative to the existing methodology.In an extension of the N-iodosuccinimide method uronic acid ester glycals could be glycosylated and showed enhanced yields of the 1,2-?runs diequatorial product which led to 2-deoxy-P-glycosides. In addition to a model study26 this concept could by applied in the preparation of a disaccharide part of flarnbamy~in.~~ A novel approach was reported to lead to 2-deoxy-P-glycosides exclusively.28 By addition of 0,O-dimethylphosphorodithioicacid to glycals [e.g. (19)] regio- and stereo-selectively the a-thiophosphate (20) was obtained which on reaction with sodium alcoholates gave 2-deoxy-P-glycosides (21) of simple alcohols (R = Me to Bu') in greater than 85% yield. Extension of this concept to more complex cases will be of relevance.OAc PAC Aco+O) 1. RONa P 2. Ac,O,Py OR AcO SP(S)(OMe)z AcO The ready a~ailability~~ of the C-2 epimeric 2,6-dibromo-2,6-dideoxy-a-~-manno-and gluco-pyranosyl bromides opens possibilities for the preparation of a-and P-2-deoxyarabino glycosides. As was demonstrated with simple alcohols30 the rnunno-isomer gave only a-glycosides in high yield whereas the glucosyl bromide led predominantly to the P-compounds. Reaction of the 2-bromoglucosyl bromide (22) with the selectively blocked 2,6-dideoxy-a- D-arabino compound (23) promoted by silver triflate gave 16% of the a-linked disaccharide and 57% isolated yield of the desired P,1-+4-linked compound (24). The latter could be transformed into the bamflalactone part (25) of flambamy~in.~' Use of the halide (22) with other more reactive sugar aglycons could be elaborated into a high yielding P-2-deoxydisac- charide synthesis (92% ;P :a = 7 :1) for oligosaccharides with a terminal arabino unit.32 A similar general stereoselective method for 2-deoxy-P-glycosides having the rib0 configuration did not exist but was highly desirable with respect to many natural compounds having this structural feature e.g.the cardiac glycosides. Wiesner and co-~orkers~~ have developed a method using the 4-p-methoxy-benzoyl-3-methyl-urethane of digitoxose (27) which on condensation with the digitoxigenin precursor (steroid 3-OH) in the presence of p-toluenesulphonic acid gave the glycoside (28) in 83% yield. After reductive cleavage of both ester groups the anomers (29) could be separated and were obtained in the ratio P :a = 7 1.The intermediate formation 26 J. Thiem and P. Ossowski J. Carbohydr. Chem. 1984 3 287. 27 A. Prahst Diss. Univ. Hamburg 1984. 28 M. Michalska and J. Borowiecka J. Carbohydr. Chem. 1983 2 99. 29 K. Bock I. Lundt and C. Pedersen Carbohydr. Res. 1981 90 7. 30 K. Bock I. Lundt and C. Pedersen Carbohydr. Res. 1984 130 125. 31 I. Lundt J. Thiem and A. Prahst 1.Org. Chem. 1984 49 3063. 32 J. Thiem and M. Gerken J. Carbohydr. Chem. 1982/3 1 229. 33 H. Jin T. Y. R. Tsai and K. Wiesner Can. J. Chem.. 1983 61 2442. 316 J Thiem Me HO HO of a charged species (30) by 1,3-participation is believed to account for appreciable stereoselection.In further studies towards the stereoselective synthesis of the com- plete digit~xin~~ the strategy had to be varied because a p-TsOH catalysis is ruled out owing to the acid lability of 2,6-dideoxy oligosaccharides. Along similar lines in a somewhat tedious protection-deprotection sequence the glycoside (3 1) was obtained which could be condensed with the a-thiodigitoxoside (32) in the presence of HgCI2-CdCO3 giving in 60% yield virtually only the &1+4 species. After partial deacylation a 3.5 :1 mixture of the regioisomeric esters (34) and (35) were obtained and separated the former could be used for another similar glycosylation with (33) to give the trisaccharide species in 58% yield. By further cleavage of the ester groups and oxidative refunctionalization of the butenolide portion in the aglycone the total synthesis of digitoxin (36) was finished.Contrary to the previously reported inversion of configuration in the course of HgC1,-promoted glycosylations of thioglyc~sides,~~ here the stereospecific outcome of the reaction was ascribed to the intermediacy of a 1,3-p-methoxybenzoxonium ion (37). Syntheses of methyl-branched amino- and nitro-sugars which represent the sugar moieties of antibiotics attract further efforts. A very efficient sequence consists of the cyanomesylation of a (mostly 3-) dose followed by reductive spiroaziridine formation and final reductive ring-opening. This approach of the groups of Brima~ombe~~ gave the compounds with equatorial methyl and and Y0shimu1-a~~ axial amino-group.By an additional oxidative step the corresponding methyl- branched nitro-sugars are obtained thus a kijanose derivative3* (for a previous preparation see re$ 39) and rubranitrose4’ were prepared. Under the catchword ‘pyranosidic homologation’ Fraser-Reid and his group4’ have studied the extension of the carbohydrate template via the secondary positions 34 T. Y. R. Tsai H. Jin and K. Wiesner Can. J. Chem. 1984,62 1403. 35 R. J. Ferrier R. W. Hay and N. Vethaviyasar Carbohydr. Res. 1973 27 55. 36 J. S. Brimacombe R. Hanna and L. C. N. Tucker J. Chem. Soc. Perkin Trans. I 1983 2277. 37 T. Yasumori K. Sato H. Hashimoto and J. Yoshimura Bull. Chem. SOC.Jpn. 1984 57 2538. 38 J. S. Brimacornbe and K. M. M. Rahman Carbohydr. Res.1983 123 C19. 39 K. Funaki K. Takeda and E. Yoshii Tetrahedron Lerr. 1982 23 3069. J. Yoshimura T. Yasumori T. Kondo and K. Sato Bull. Chem. SOC.Jpn. 1984 57 2535. 41 B. Fraser-Reid L. Magdzinski and B. Moho J. Am. Chem. Soc. 1984 106 731. Carbohydrates 3 17 OH .low NHMe OR' (27) (28) R' = pMeBz; R2= CONHMe (29) R' = R2= H (31) R' = R2= pMeBz OpMeBz SEt (32) R = pNBz +NHMe (33) R =p-MeBz I (30) Rlo++o-steroid OR' Op-MeOBz Rovl o-.+-0 (34) R' = H; R2= pMeBz 1. +(33) 2. LiAH41! (35) R' = pMeBz; R2= H OMe ~o (37) ODigitoxigenin OH OH OH C-2 to C-4 and the primary position at C-6. In this approach complete regio- and stereocontrolled reactions are made possible at 'off -template' positions because these are embedded into additional carbohydrate-like pyran or dihydropyran ring struc- tures.As an example the mannose derivative (38) on treatment with the diethyl- aluminium salt of propargylic alcohol gave as expected a regiospecific attack at the 2-position. Partial hydrogenation by Lindlar catalyst gave the ally1 alcohol (39) and after hydrolysis and reprotection of the primary C-6 position furnished the internal glycoside (40) which may be used for epoxidation and further functi~nalization.~~ A radical carbon-carbon linkage process by treatment of sugar methyl xanthates with tri-n-butyl stannic hydride and acrylonitrile introduced a P-cyanoethyl side- L. Magdzinski B. Cweiber and B. Fraser-Reid Tetrahedron Lett. 1983 24 5823. 318 J.Thiem OTBDMS 1. Et2Al-C=C- CH 2. Bu‘Me,SiCI 2. Lindlar BnO (38) (39) ~hain.4~ In the glucofuranose series a 7 :3 ratio in favour of the 3-branched gluco- compound was obtained and with the corresponding galactofuranose the reaction proceeded with complete diastereoselectivity to the C-branched galucto- derivative. By a biomimetic approach the a-alkylation of uloses could be achieved. Following proton abstraction with lithium di-isopropylamine methylation (or hydroxy methyl- ation) occurs stereo- and regio-specifically with methyl iodide (or formaldehyde) in HMPT at -70 “C in 40-80% yield.44 Routes to gem-dialkylated sugars by application of a highly stereoselective Claisen rearrangement were reported by Fraser-Reid and collaborator^^^ Following Wittig reaction of a 2-ulose and reduction the exocyclic ally1 alcohol was obtained and mildly transformed into the vinyl ether (41).Thermal treatment in refluxing ben- zonitrile gave exclusively the derivative of gluco-configuration (42;axial acetal- dehyde and equatorial vinyl group) in 85% yield. After cleavage of the TBDMS- blocking group lactol formation (43) occurs which is only possible in the depicted configuration. Obviously the presence or absence of the anomeric methoxy group (R = OMe or R = H) seems to be irrelevant which implies neither a steric hindrance nor a stereoelectronic influence for this oxy-Cope rearrangement. The stereoselec- tivity is attributed to an exclusive axial folding which results in an axial attack at C-2 and for similar reasons an equatorial attack at C-3.Another ‘pyranosidic homologation’ described by Fraser-Reid’s group& makes use of a Wittig-extension from a C-6-aldehydo-sugar (44). The facile formation of the olefin sugar (82% 4 1 E/Z-mixture) was followed by methanolysis to give a single isomer (45) in 90% yield termed a ‘satellite’ hexenopyranoside which proved to be a useful carbohydrate template. Part of the anthracycline antibiotic nogalamycin (46) is an unusual optically active 2,6-epoxy-2H-1-benzoxocin moiety. Starting with the xylofuranose (47)addition of a methyl Grignard then Collins oxidation and treatment with a second Grignard reagent obtained from 2-bromo-4-methyl-2-benzyloxybenzene gave the D-gluco 43 B. Giese J. A. Gonzalez-Gomez and T.Witzel Angew. Chem 1984 96,51. 44 A. Klemer and H. Thiemeyer Liebigs Ann Chem. 1984 1094. 45 D. B. Tulshian R. Tsang and B. Fraser-Reid J. Org. Chem. 1984,49 2347. 46 B. F. Moho L. Magdzinski and B. Fraser-Reid Tetrahedron Left. 1983 24 5819. Carbohydrates CHO Me0 7 HOWo\ 2. MeOH/PyH+OTs-BnO Bn OMe derivative (48) exclusively in 80% yield. A similar treatment with inversion of the Grignard additions 1 and 3 led to the L-ido isomer (49). This demonstrates stereo- specific additions of the Grignard reagents to the ketone intermediates according to Cram's rule. Further hydrogenolysis and hydrolysis of the glum compwnd (48) gave only a modest yield of the product (50) contaminated with the ~-ido isomer (51) owing to acid mediated R/S interconversion at the chiral tertiary alcohol function.The similar treatment of (49) gave the more stable pure L-ido-isomer (51) in approximately 60% yield.47 XD \ /\ OH--O--HO 9 (47) AcO Me Me 0 OAc OAc AcO OAc (48) R' = OH;R2 = H (50) (51) (49) R' = H;R2 = OH Halogeno- Phospho- and Thio-sugars.-Fluorinated saccharides seem to be of paramount interest owing to their biological properties. A review which updates the literature appeared recently.48 One prominent target molecule was 2-deoxy-2-(fluorine- lS)-fluoro-D-glucose useful in positron emission tomography. Rapid procedures were developed by SN2 inversion of a 2,3-cyclic sulphated mannose 47 F. M. Hauser and T.C. Adams Jr. J. Org. Chem 1984 49 2296.48 A. A. E. Penglis Adv. Carbohydr. Chem. Biochem 1981,38 195. 320 J. 7’hiem derivative with tetraethyl ammonium “fl~oride,”~ and of a 2-0-trifluoromethylsul-phony1 mannose with CSH’~F,.’’ Addition of hypofluorite and acetyl fluoride to the arabino-glycal,” and reaction of the selectively prepared benzy13,4,6-tri-O-benzyl-P-D-mannopyranoside with DAST and subsequent hydrogenoly~is’~ led to the same compound. Through reaction of the 1-triflate of 2,3;4,5-di- 0-isopropylidene-P- D- fructopyranose with tris(dimethy1amino)sulphonium difluorotrimethylsilicate (TASF) 1 -deoxy- 1 -fluoro-D-fructose was obtained and subsequently enzymatically condensed with UDP-glucose to give 1’-deoxy- l’-fl~oros~crose.~~ There have been only a few reports on the preparation of sugars with sulphur in the hemiacetal ring but an enormous number of papers for the syntheses of sugars with phosphorus in the hemiacetal ring and these have been recently re~iewed.’~.’’ The base-catalysed dialkylphosphite addition to aldose derivatives (free aldehydo- sugars6 or C-1 unblocked compound57) with subsequent internal transesterification led to formation of y-or 8-phostones respectively.Most isosteric phosphonate analogues of naturally occurring phosphates are prepared by the Michaelis-Arbuzov reaction on a halogenomethylene precursor. In this way the phosphono analogues of a-and P-D-mannopyranosyl pho~phate’~ were obtained. A more attractive approach59 to the a-and P-D-ribofuranosyl phosphate analogues [2,5-anhydro-1- deoxy-1 -(phosphono)-D-altritol or -allit011 may be considered the Horner-Emmons reaction of the C-1.unblocked ribofuranose derivative with methylene bis-dimethyl- phosphonate previously introduced by Moff att et aL6’ Although no synthetic reports have appeared yet the isolation and structure e1ucidation6l of the ribofuranoside (52) from the arsenic-accumulating brown kelp Ecklonia rudiata may inspire some. Me O \ I1 II HO OH R = SO,H,OH Amino-sugars.-An attractive cis-oxyamination procedure which starts from allyl- alcohols leads to aminodeoxy sugars of biological relevance was simultaneously developed and applied by several groups. Following comparable pathways improved 49 T. J. Tewson J. Nucl. Med. 1983 24 718 (Chem. Abstr. 1984 100 6969~).so S. Levy E. Livini D. R. Elmaleh D. A. Varnum and G. L. Brownell Znt. J. Appl. Rudiat. hot. 1983 34 1560 (Chem. Abstr. 1984 100 121 462u). ” M. J. Adam B. D. Pate J. R. Nesser and L. D. Hall Curbohydr. Res. 1983 124 215. s2 A. Dessinges A. Olesker G. Lukacs and T. T. Thang Curbohydr. Res. 1984 126 C6. ” P. J. Card and W. D. Hitz J. Am. Chem. Soc. 1984 106 5348. 54 Z. J. Witzak and R. L. Whistler J. Carbohydr. Chem. 1983 2 351. s5 H.Yamamoto and S. Inokawa Adu. Carbohydr. Chem. Biochem. 1984,42 135. 56 A. E. Wroblewski Curbohydr. Res. 1984 125 C1. s7 J. Thiem and M.Giinther Phosphorus Sulfur,1984 20 67. F. Nicotra R. Perego F. Ronchetti G. Russo and L. Toma Curbohydr. Res. 1984 131 180. 59 R. B. Meyer Jr. T. E. Stone and P. K. Jesthi J.Med. Chem. 1984 27 1095. G. H. Jones E. K. Hammura and J. G. Moffatt Tetrahedron Lett. 1968 5731. J. S. Edmunds and K. A. Francesconi J. Chem. SOC. Perkin Trans. 1 1983 2375. Carbohydrates 321 syntheses of L-daunosamine were reported.62d4 Thus L-rhamnose was converted into the glycal(53) which on Ferrier glycosylation C-4 mesylation and SN2inversion using caesium propionate provided the benzyl a-~-threo glycoside (54) in excellent yield. On treatment of its trichloroacetimidate (55) with N-iodosuccinimide an iodonium ion induced cyclization gave the 2-iodo-oxazoline (56).By acid hydrolysis the 3-amino-2,3,6-trideoxy-2-iodo-a-~-lyxo-derivative (57) was obtained which was converted into L-daunosamine using standard procedures.a Another elegant reaction sequence was developed along the idea of an iodonium induced cyclization of allylic amide systems by Fraser-Reid et al.The preparation of a garosaminide (62)65depicts the concept nicely; the well-known keto epoxide (59) is transformed into the methylene derivative (60)via Wittig reaction and then the opening of the epoxide ring by ammonia occurs regio- and stereo-selectively. For the decisive cyclization step to (61)iodo-bis-collidinium perchlorate was used effectively. Further reduction of the iodomethylene group with Bu;SnH then quater- nization with methyl iodide reduction with sodium borohydride and acid methanoly- sis gave the desired garosaminide (62)in an eight-step synthesis with 14% overall yield.65 3BzH WOMe OwoMe N 0Bz __* OMe 0 0Bz (59) MeHN-OH (62) 62 H.W. Pauls and B. Fraser-Reid J. Chem. SOC.,Chem. Commun. 1983 1031. 63 G. Cardillo M. Orena S. Sandri and C. Tomasini J. Org. Chem. 1984 49 3951. 64 D. Springer Diss. University Hamburg 1984. 65 H. W. Pauis and B. Fraser-Reid Can. J. Chem. 1984 62 1532. 322 J. Thiem Shifting of amino-functions opens up novel preparative processes for amino- sugars. Thus the xylopyranoside (63) in apolar medium formed an aziridinium intermediate (64) (proven by n.m.r.) which is opened regioselectively at C-3. This results in formation of the 4-amino-~-hexoside (65); in water a concerted process led to the 3-hydroxy-4-amino-derivative(66).66 Another complex synthesis of daunosamine also made use of such a shift of amino-groups from the 2-to the 3-position via an epimine intermediate.67 OMe (64) OMS-(65) R = Ms (66) R = H Primary and secondary triflate groups could be easily substituted with ammonia to give the inverted amino-sugars in 50-80% yield:' and amino-acid-substituted carbohydrates were similarly ~btained.~' There were two interesting reports on the Pictet-Spengler reaction between a sugar and biogenic amines.For instance dopamine and 2,5-anhydro-~-mannose (67) gave the isoquinoline adduct (68)." Similarly in following a route from methyl a-D-mannoside to heteroyohimbine alkaloids this reaction was used as a key step.71 C'HO Dopamine yo$ OH I LOH HO HO Finally a novel procedure for the synthesis of nitro-sugars may be mentioned here.Following known preparations of the corresponding primary and secondary azides (69a 70a) stirring with triphenyl- or tri-n-butylphosphine gave the phosphine imines (69b 70b) ozonolysis of which at -78 "C with 34 molar equivalents yielded the nitro-compounds (69c 70c) smoothly and in good yields.72 Anhydro-sugars.-An improved method for the preparation of 173-anhydro-sugars with gluco-configuration is reported.73 Using 170 n.m.r. and "0-induced isotopic shifts in 13C n.m.r. evidence is pre~ented'~ that in the formation of the anhydro- 66 D. Picq M. Cottin D. Anker and H. Pacheco Tetrahedron 1983 39 1797. 67 M. K. Gurjar V. J. Patil J. S. Yadav and A. V. R. Rao Carbohydr. Res. 1984 129 267. 68 A. Malik N. Mza M. Roosz and W.Voelter J. Chem. SOC.,Chem. Commun. 1984 1530. 69 A. Malik W. Kowallik P. Scheer N. Mia and W. Voelter J. Chem SOC.,Chem. Commun. 1984 1229. 70 D. B. MacLean W. A. Szarek and I. Kvarnstrom J. Chem SOC. Chem Commun. 1983 601. 71 J. Kervagoret J. Nemlin Q. Khuong-Huu and A. Pancrazi J. Chem SOC., Chem. Commun. 1983,1120. 72 E. J. Corey B. Samuelson and F. A. Luuio J. Am. Chem. Soc. 1984 106 3682. 73 F. Good and C. Schuerch Carbohydr. Res. 1984 125 165. 74 A. Dessinges S. Castillon A. Olesker T. T. Ton and G. Lukacs J. Am. Chem. Soc. 1984 106. 450. 323 Carbohydrates 3 Aco~ocH2cc,3 (b) X = N=PR AcO (a) N3 galactopyranose (72) by treatment of the glucopyranose (71) with sodium azide a P-oxyanion is the intermediate as previously proposed by Brimacombe et aZ.75 D-Mannose on tosylation subsequent treatment with water and then with sodium hydroxide at pH 9 gave an easy access to 1,6-anhydro-P-mannose (mannosan) which was isolated as the 2,3-acetonide in 60% overall yield.76 By epoxidation using the Payne procedure 1,2;5,6-dianhydro-3,4-dideoxy-~-threo-hex-3-enitol gave a mixture of two enantiomeric trianhydro-hexitols with D-rnanno (73) and Dido (74) configur-ation (ratio 1 3).A similar treatment of the corresponding erythro-isomer gave the racemate of the D,L-ghco-derivative (75).77This new class of sugar oligoepoxides awaits further interesting transformations. An important feature of the anhydro-compounds is an attractive transfer into linear glycanes using a Lewis acid ring-opening polymerization.The formation of a number of ( 1 +6)-glycanes from different 1,6-anhydro-precursors was studied and published.78i79Another approach by Schuerch's group described the polymeriz-ation of 1,3-anhydro-D-mannose derivatives into (1 -* 3)-a-D-rnannan.*' A stereoregular (3+6)-a-D-xylofuranan could be made from the oxetane derivative 75 J. S. Brimacombe J. Minshall and L. C. N. Tucker J. Chem. SOC,Perkin Trans. I 1973 2691. 76 M. Georges and B. Fraser-Reid Carbohydr. Res. 1984 127 162. 77 P. KOII M. Olting and J. Kopf Angew Chem. 1984 96 222. ?a T. Uryu Y. Sakamoto K. Hatanaka and K. Matsuzaki Macromolecules 1984 17 1307. 79 K. Kobayashi and H. Sumimoto Polym. 1.(Tokyo) 1984 16 297. 80 F. Kong and C.Schuerch Macromolecules 1984 17 983. 324 J. Thiem 3,5-anhydro-1,2-0-isopropylidene-~-~-xylofuranose.~~ The recent activities in this field were summarized by Uryu et aL8*and reference should be made to Schuerch’s previous review.83 Esters Ethers Acetals and some Protection-group Properties.-A thorough study of the direct mono-benzoylation of pento- and hexo-pyranosides using dibutyl stannic oxide or bis(tributy1 stannic)oxide has been published. Even in the presence of a primary OH-group an equatorial OH-group flanked by a cis-OH (or OMe) group is always selectively a~tivated.~ Another paper on the use of stannylidene com- pounds originally introduced by Moffatt et d.,85 also noted the regioselective activation of secondary OH-groups.It was shown here that different solvents or the presence of Lewis acids changed the co-ordination ability and hence the acylation ratios.86 By a classical approach methyl 4,6- 0-benzylidene-a-D-mannopyranoside was shown to be benzylated at the 3-position predominantly (66’/0).~~ Using the stannyl- idene approach for methyl 4,6- 0-benzylidene-P- D-glucopyranoside benzylation catalysed with tetrabutylammonium bromide gave the 3- and the 2-0-benzyl ethers in the ratio 2 1 (total yield 90’/0).~~ A very useful selective partial benzylation of galactosides was observed:89 methyl a-D-galactopyranoside and benzylchloride in the presence of lithium hydroxide as the base gave the 2,3,6-tri-O-benzyl derivative. With potassium or rubidium hydroxide however the 2,4,6-tri- 0-benzyl compound resulted as the main product.The P-anomer gave a 3,4,6-tri- 0-benzyl-ether irrespec- tive of the nature of the base. The kinetic acetonation in DMF with 2-methoxypropene and p-toluenesulphonic acid catalysisg0 could be used to prepare the 4,6-monoacetal (goo/,) or the 2,3;4,6- diacetal (73%) of a-or P-D-glucopyranosides depending on the molar ratio.” A detailed gas-liquid chromatography study of the preparation of 1,2 ;5,6-di- 0-isopropylidene-D-mannitol,an attractive starting material for the synthesis of other chiral compounds revealed that the classical procedure with acetone and zinc chloride led to the best results (65%) whereas dimethoxypropane in DME with SnC1,-catalysis led to a complex mixture.92 In contrast to previous results93 the use of 2-methoxypropene gave only 44% of that diacetal and in addition another 29% of the 1,2;4,6- and 17% of the 1,2 ;3,6-di- 0-isopropylidene-D-mannitolisomers.94 Three new protecting groups for the regiospecific blocking of a primary OH-group gave promising results.4-( Methylthiomethy1enoxy)butyricacid (76) and 0-(methyl-thiomethy1enoxy)methylbenzoic acid (77) provided the 5’-0-acyl derivatives of 81 T. Uryu Y. Koyama and K. Matsuzaki Macromol. Chem 1984 185 2099. 82 T. Uryu and K. Hatanaka Yuji Gosei Kagaku Kyokai Shi 1984,42 557 (Chem. Absrr. 1984 101 111 275s). 83 C. Schuerch Adu. Carbohydr. Chem. Biochem 1981 39 157. 84 Y. Tsuda M. E. Haque and K. Yoshimoto Chem Pharm. Bull. 1983 31 1612. 85 D. Wagner J. P. H. Verheyden and J.G. Moffatt J. Org. Chem. 1974 39 24. 86 C. W. Holzapfel J. M. Koekemoer and C. F. Marais S. Afr. J. Chem. 1984 37 19. 87 Y. Kondo K. Noumi S. Kitagawa and S. Hirano Carbonydr. Res. 1983 123 157. 88 K. Takeo and K.Shibata Carbohydr. Res. 1984 133 147. 89 N. Morishima S. Koto M. Oshima A. Sugimoto and S. Zen Bull. Chem. SOC.Jpn. 1983 56 2849. 90 J. Gelas Ado. Carbohydr. Chem. Biochem 1981 39 71. 91 J. L. Debost J. Gelas D. Horton and 0. Mols Carbohydr. Res. 1984 125 329. 92 J. Kuszman E. Tomori and I. Meerwald Carbohydr. Res. 1984 128 87. 93 J. L. Debost J. Gelas and D. Horton J. Org. Chem. 1983 48 1381. 94 J. Kuszman E. Tomori and P. Dvortsak Carbohydr. Res. 1984 132 178. Carbohydrates MeS-CH2-0-CH,-CH2-CH2-COOH (76) (77) MeS-CH2-0-CH 9 COOH CH,X CH,X I I H,C=C-O-CH,-Ph /O-C-O-CH,-Ph thymidine in 70% yield.95 Deacylation with conc.aqueous ammonia was slow but treatment with mercury perchlorate/2,4,6-~ollidineand then mild base gave a rapid cleavage. The 4,4',4''-tris-( 4,5-dichlorophthalimido)trityl group (CPTr) introduced via its bromide (78) in DMF with silver nitrate promotion also blocks primary OH-groups specifically in high yield. Cleavage is effected mildly using hydrazine in pyridine-acetic acid.96 A novel open acetal protecting function for primary OH-groups was developed by Mukaiyama et Treatment of the glucopyranoside (79) with 2-(benzy1oxy)- 1-propene and catalytic amounts of palladium dichloride- 1,5-octadiene complex gave the acetal (80; X = H) and no alkylidene derivative (in contrast cf ref 90).The fluoro-acetals (80; X = F) proved to be more resistant to acid hydrolysis?* Cleavage was smoothly effected by hydrogenation on palladium-charcoal. De No00 Synthesis of Carbohydrates.-For the majority of classical carbohydrate chemists the first approaches towards the preparation of n/ L-mixtures of sugars from non-carbohydrate sources were not interesting. Reasons for that were the rather troublesome resolutions necessary to obtain pure enantiomers and also the better understanding of transformation processes starting with abundant carbohydrate materials in enantiomerically pure form. During the last two decades however the new approach has developed into an attractive tool which nowadays in certain cases may compete advantageously with classical syntheses.The topic has been reviewed earliep9 and recently updated,'oo*'o' and another novel review article has 95 J. M. Brown C. Christodoulou C. B. Reese; and G. Sindona J. Chem. SOC.,Perkin Trans. 1 1984 1785. 96 M. Sekine and T. Hata .IAm. Chem. SOC.,1984 106 5763. 97 T. Mukaiyama M. Ohshirna and M. Murakarni Chem. Lett. 1984 165. 98 T. Mukaiyarna M. Ohshima H. Nagaoka and M. Murakami Chem. Lett.. 1984,615. 99 J. K. N. Jones and W. A. Szarek in 'The Total Synthesis of Natural Products' ed. J. W. ApSimon Vol. 1 Wiley-Interscience New York 1973 p. 1. I00 A. Zamojski A. Bannaszek and G. Grynkiewicz Adu. Carbohydr. Chem. Biochem. 1982,40 1. lo' A. Zamojski and G. Grynkiewicz in 'The Total Syntheses of Natural Products' ed.ApSimon Vol. 6 Wiley-Interscience New York 1984 p. 141. 326 J. Thiem covered the acyclic stereoselective synthesis of carbohydrates.lo2 Attractive target carbohydrates for total synthetic procedures are the antibiotic sugars like amino- deoxy- and branched-chain carbohydrates as well as unnatural enantiomers and complex higher carbon sugars. An unusual approach to amino-sugars by Weinreb et aL103makes use of an intramolecular N-sulphinyl dienophile Diels- Alder process. Treatment of the carba- mate of the (E,E)-diene alcohol (81) with thionyl chloride in pyridine gave a single Diels- Alder adduct (83) in 80% yield. Its stereoselective formation could be rational- ized by assuming the cycloaddition of the intermediate N-sulphinyl carbamate to occur through the depicted transition state (82) with the carbonyl group endo and the sulphinyl oxygen em.Further reaction of the dihydrothiazine oxide (83) via an allylic sulphoxide its [2,3]-sigmatropic rearrangement desulphurization and a series of further steps led to 5-epi-desosamine (84). Me Me (82) An asymmetric seven-step synthesis of methyl 3,4-anhydro-2,6-dideoxy-a-~-ribo-hexopyranoside the precursor for L-daunosamine was accomplished starting with cyclopentadiene. Key steps were the asymmetric hydroboration stereoselective epoxidation and Baeyer-Villiger oxidation giving the carbohydrate 1act0ne.l'~ Start- ing with L-glutamic acid the separable D-amiCetOnO and L-rhodinono y-lactones could be obtained which following reductions furnish the corresponding amino- sugars.'05 Ethyl (S)-lactate (85) was transformed into the nitrile (86) which on treatment with the magnesium enolate of t-butyl acetate gave the (Z)-B-amino acrylate derivative (87).This was further processed into N-benzoyl-L-acosamine (88). A corresponding approach using this nitrile-acetate coupling process led to formation of the C-4 epimeric N-benzoyl-L-daunosamine (89).'06 The nitrone cycloaddition represented another useful approach to amino-sugar components. Thus De Shong et aZ.lo7 transformed the ester (90) into a single (2) -benzyl nitrone (91) using standard procedures. This displayed high diastereofacial- and stereo-selectivities for the endo transition-state and its cycloaddi- tion reaction with ethyl vinyl ether gave the isoxazolidine isomer (92) exclusively.By catalytic hydrogenation and simple transformation the D/ L-daunosaminide (93) was obtained. Along corresponding lines an interesting use of the 1,3-dipolar 102 G. J. McGarvey M. Kimura T. Oh and J. M. Williams J. Carbohydr. Chem. 1984 3 125. 103 S. W. Remiszewski R. R. Whittle and S. M. Weinreb J. Org. Chem. 1984 49 3243. 104 G. Grethe J. Sereno T. H. Williams and M. R. Uskokovich J. Org. Chem 1983 48 5315. 105 G. Berti P. Caroti G. Catelani and L. Monti Carbohydr. Rex 1983 124 35. 106 T. Hiyama K. Nishide and K. Kobayashi Tetrahedron Lett. 1984 25 569; Chem. Lett. 1984 361. lo' P. DeShong C. M. Dicken J. M. Leginus and R. R. Whittle J.Am. Chem. Soc. 1984 106 5598. Carbohydrates OBu' I CH,=C-OMgX (88) R' = OH;R2 = H (89) R' = H;RZ= OH Me 0-PhCH2 -N I CH2Ph A~O MfKJoMe NHAc (93) cycloaddition of nitrile oxides was reportedlog to give isoxazolines which could be further transformed into amino-sugars e.g. methyl lividosaminide. A double asym- metric induction was observed in the diastereoselective hydroxyalkylation of the lithium salt of Schollkopf's L-alanine dimer (94) by 2,3-O-isopropylidene-~- gly~erinaldehyde.'~~ After hydrolyses with acetic acid the adduct (95) was obtained (80% yield) and could be further transformed into the pure lactone (96). 3. MeC0,H (94) (95) 108 V. Jager and R. Schohe Tetrahedron 1984,40 2199.109 J. C. Depezay A. Dureault and T. Prange Tetrahedron Lett. 1984. 25 1459 328 J. Thiem Roush et uL"o*lllhave developed very nice diastereoselective syntheses of most of the 2,6-dideoxyhexoses. The racemic (E)-allylic alcohol (97) by kinetic reso- lution-enantioselective epoxidation procedure of Sharpless et ~~2.l'~ gave the (+)-erythro epoxide (98) in addition to the kinetically resolved (-)-E-allylic alcohol (102). The urethane (99) obtained from (98) was transformed into the carbonate (100) with Et,AlCl and this on subsequent treatment with base and ozonolysis gave D-(+)-OliVOSe (101). The resolved (-)-E-allylic alcohol (102) could be epoxidized to give the (-)-erythro-epoxide (103) which on acid hydrolysis gave the D-n'bO-triOl (104) and further ozonolysis led to D-(+)-digitoxose (105).Based on crotonaldehyde the six-step synthesis of olivose gave approximately 17% overall yield; that of digitoxose amounted to 22%. (-)-DIPT Bu'OOH OH OR (97) (98) R = H (99) R = CONHPh Me Ti (0wj (+)-DET Bu'OOH Y -OH OH HO OH (104) 110 W. R. Roush R. J. Brown and M. DiMare J. Org. Chem. 1983,48 5083. 111 W.R. Roush and R. J. Brown J. Org. Chem 1983,48 5093. 112 V.S.Martin S. S. Woodard T. Katsuki Y. Yamada M. Ikeda and K. B. Sharpless J. Am. Chem SOC. 1981 103 6237. Carbohydrates 329 An excellent new approach for the synthesis of 3-deoxy-~- manno-2-octulosonic acid (KDO) used a biomimetic pathway in condensing a C3 unit acrylic acid derivative (mimicking pyruvate) to aldehydo-arabinose as the Cs unit."3 The crystal- line amide (106) was transformed into the dilithium salt (107) which attacked the arabinose (108) in a highly diastereoselective way giving the crystalline manno- compound (109) predominantly (85% yield munno :ghco > 15 1).Further trans- formation gave the enol lactone (110) which was previously reacted to give the KDO ammonium salt. OH R'bo (106) R = H (107) R = Li (R'/CHo) KDO In the cyclocondensation of the chiral butadiene (1 11) with furfural catalysed by Eu(hfc) after work-up with triethylamine-methanol the optically active 3-ketone (1 12) was obtained in 75% ~ie1d.I'~ Stereospecific reduction and ozonolytic cleavage of the furan ring with final reduction and acetylation steps gave the 4-deoxy-~- arabino-glycoside (1 13).This combination of a chiral auxiliary on the diene moiety with chiral catalyst seems to permit syntheses of optically pure saccharides without a resolution step. Zinc chloride catalysed cycloadditions of formaldehyde to sub- stituted dienes like (111) and led to a series of pentopyranose derivatives.115 0-( -)-Menth Eu(hfc) b? 0-(-)-Menth OAc 3 Oligosaccharides Part of the glycosylation procedures as well as synthesis and application of precursors for oligosaccharide synthesis have been discussed above under the chapter 'glyco- sides'. Nowadays an increasing number of researchers head towards larger substruc- tures of carbohydrate-containing biological material and there are some six groups in Canada France Germany Japan and Sweden whose leading activities in these areas should be mentioned.Most of the preparations of higher hetero-R. R. Schmidt and R. Betz Angew. Chern 1984 % 420. M. Bednarski and S. Danishefsky J. Am. Chern. Soc 1983 105,6968. 1IS S. Danishefsky and R. R.Webb 11. J. Org Chern. 1984. 49. 1955. 330 J. Thiem oligosaccharides require multi-step syntheses and a highly reliable sophisticated analysis mostly provided by extended 'H and 13Cn.m.r. spectroscopy is a necessity. The number of carbohydrate units and the complexity of the synthesis need not necessarily exhibit a linear correlation that is a disaccharide synthesis may be more difficult than a block synthesi3 of e.g. a nonameric oligosaccharide.An updating of the general concepts previously discussed' and some specific newer developments in oligosaccharide synthesis have been given recently by H. Paulsen.l16 G1ycoconjugates.-Within the living cells most hetero-oligosaccharide structures are more or less closely associated (or bound) to a variety of other mono- or oligomeric materials of biochemical relevance. The biochemical and structural aspects of these classes of compounds termed glycoconjugates have been reviewed recently e.g. see rej 117. During the recent decade synthetic efforts have increased considerably and there are quite a large number of most interesting glycoconjugates or substructural units thereof available by modern glycosylation approaches. Surveys by some of the leading groups have been given recently on the syntheses of complex oligosac- charide chains of glycoprotein~."~~"~ A particularly intensely- studied question was the approach to complex glycan chains which represent the core region of glycoproteins.One of the first successful reports'20*'21 started from a mannoside which by use of suitable blocking groups was built up to the mannotrisaccharide (115). After selectively deblocking the positions 2 and 4 in the one and 2 and 6 in the other terminal mannopyranoside x-2\a-D-Manp-(1 +3) x-4/ \ 4 x p-D-Galp-(1 -.* LZ)-cy-~-GlcNPhth-Br 1 + x-2 (114) \a-D-Manp-(1 -P 6)P-Man / X-6 (115) X = OH (1 16) X = p-D-Galp-(1 .+ 4)-p-~-GlcNAc unit this compound was glycosylated using a four molar equivalent of the disac- charide bromide of a P-D-Gal-( 1+4)-~-GlcNAcderivative (114) in a silver triflate promoted condensation.By this process the trisaccharide mannose unit was enlarged to an undecamer oligosaccharide (116) in a two-step process in 5% yield by a comparatively simple and efficient method. A similar approach was used in the synthesis of cell surface glycans which in the first series led to the preparation of a P-D-Man-( 1 -+4)-p-~-GlcNAc-( 1-* 4)-~-GlcNAc derivative (118) selectively 116 H. Paulsen in 'Selectivity -a Goal for Synthetic Efficiency' ed. W. Bartmann and B. M. Trost Proceedings 14th Workshop Conferences Hoechst Verlag Chemie Weinheim 1983 p. 169. 117 'The Glycoconjugates' ed. M. Horowitz Vol. 3 and 4 Academic Press New York 1982.H. Fsulsen Chem SOC.Reu. 1984 13 15. 119 T. Ogawa H. Yamamoto T. Nukada T. Kitajima and M. Sugimoto Pure AppL Chem. 1984 56 779. I2O J. harp H. Baumann H. Loenn J. Loenngren H. Nyman and H. Ottosson Acta Chem. Scand. Ser. R 1983 37 329. 121 H. Loenn and J. Loenngren Carbohydr. Res. 1983 120 17. Curboh ydru tes 331 2 x p-D-Galp-(1 +4)-p-~-GlcNAc-( 1 +a)-cu-~-Glcp-Br(1 17) I X-6 'P-D-Manp-( 1 -+ 4)-p-~-GlcNAc-( 1 +4)-p-~-GlcNAc 1 x-3' (118) X = OH (119) X = p-D-Galp-(1 -P 4)-p-~-GlcNAc-(l-+ 2)-a-~-Manp o-w I I Me Me Me unprotected at the positions 4 and 6 in the terminal non-reducing end. Its condensa- tion with two mols of the glycosyl bromide of p-D-Gal-(l+ 4)-&~-GlcNAc- (1 -+ 2)-~-Glc (1 17) led to formation of the nonahexosyl unit (119) in 60% yield.'22 Alternatively three disaccharide blocks could be linked successively and gave another cell surface glycan hexa~accharide.'~~ A stepwise strategy yielded a pentasac- charide part of the exocellular P-D-(1-+ 2)-glucan of Agrobucteriurn turnef~ciens.'~~ Block syntheses have been also employed to achieve the preparation of octa- and several penta-saccharides which represent the fundamental structures of the core regions of glycoproteins of the lactosamine type.12' Glycolipids represent another group of natural compounds which stimulated a number of synthetic efforts.Lipid A the carbohydrate part of which is a p-D-GlcNAcyl-( 1 -+ 6)-a-~-GlcNAcyl disaccharide phosphorylated in 1 and 4' carries long aliphatic chains on the amino-functions and the 3,3-hydroxy-groups are esterified similarly (120).A survey of compounds of the type found in the hydro- phobic region of many endotoxins has been given by Szabo et who also described one of the complex multi-step syntheses of a compound with additional hydroxylated aliphatic ~ide-chains.'~~ Lipid A analogues were prepared by Anderson et and Warren et synthesized similar tri- and tetra-saccharide compounds. Other approaches to lipid A precursors were disclosed by Japane~e'~' and Dutch 122 T. Ogawa T. Kitajima and T. Nukada Carbohydr. Rex 1983 123 C8. 123 T. Ogawa T. Nukada and T. Kitajima Carbohydr. Rex 1983 123 C12. 124 T. Ogawa and Y.Takanashi Curbohydr. Res. 1983 123 C16. 125 H.Paulsen and R. Lebuhn Carbohydr. Res. 1984 125,21; 130 85. 126 D. Charon C. Diolez M. Mondange S. R. Sarfati L. Szabo P. Szabo and F. Trigalo ACSSymp. Ser. 1983 231 301. 127 C. Diolez M. Mondange 8. R. Sarfati L. Szabo and P. Szabo J. Chem. SOC.,Perkin Trans. 1,1984,275. 128 L. Anderson and M. A. Nashed ACS Symp. Ser. 1983 231 255. 129 C. D. Warren M. L. Milat C. Auge and R. W. Jeanloz Carbohydr. Rds. 1984 126 61. 130 M. Imoto H. Yoshimura M. Yamamoto T. Shimamoto S. Kusumoto and T. Shiba Tetrahedron Lett. 1984,25 2667. 332 J. 7hiem group^,'^' and recently the corresponding structures and syntheses of the new lipids X and Y from E. coli mutants were de~cribed.'~~ The synthesis of fragments of bacterial polysaccharides and their application for the preparation of synthetic antigens has been reviewed.'33 Novel di- tri- and tetra-saccharides which represent the repeating units of the 0-specific side-chains of lipopolysaccharides from certain serotypes of Shigellu flexneri and Salmonella fyphimurium were published by a number of groups.134-137 Similarly the synthesis of blood-group antigens remains an area of high activity and tri- and tetra-saccharide haptens related to the asialo-form of gangliosides GM2 and GM1 have been In a block synthesis a hexasaccharide the p(1+ 3)-linked trimer of N-acetyl lactosamine useful as a potent inhibitor of anti-i-antibodies was pre- pared.'40 Other classical approaches were employed to synthesize a trisaccharide which represents the human blood-group PI-antigenic determir~ant'~' and a tetrasac- charide determinant of ABH type 1 and Leb blood-group antigens.'42 A preliminary report about the total synthesis of the pentasaccharide fragment of the polyanionic polysaccharide heparin appeared.'43 Starting with a glucofuranose derivative a number of steps led to the selectively blocked L-ido-orthoester (121) which by orthoester glycosylation with the 4-OH unprotected glucosamine derivative (122) led to the a-L-ido-uronic acid ester-( 1 -+ 4)-glucosaminide (123).In a second sequence the glucuronic acid ester bromide (124) could be linked to the 1,6-anhydro- 2-azido-P- ~-glucopyranose derivative (125) and gave the corresponding disac- charide which was further transformed into the glycosyl bromide (126).Glycosyla- tion of the protected a-L-IdoUA-( 1 -+ ~)-D-G~cNH, block (123) with this bromide of the protected P-D-G~cUA-( 1-+ ~)-D-G~cNH, precursor (126) gave the tetrasac- charide species (127). In the final step this was glycosylated in the 4""-position with the 2-azidoglucopyranosyl bromide (128) and gave a pentasaccharide. Following a series of deprotection and selective sulphation steps the derivative of ~-D-G~cNH,- (1 -+ 4)-P-D-GlcUA-( 1 -+ 4)-a-D-GlcNHZ-( 1 -+ 4)-a-~-IdoUA-( 1--* 4)-D-GlcNHZ (129) which represents the central structural element supposed to bind to antithrom- bin I11 was obtained. In fact this showed a high affinity to antithrombin I11 comparable to that of heparin itself whereas in contrast a trisaccharide precursor'4 exhibited none of these properties.13' C. A. A. van Boeckel J. P. G. Hermans P. Westerduin J. J. Oltvoort G. A. van der Marel and J. H. van Boom J.R. Neth. Chem. SOC.,1983 102 438. 13* S. Kusumoto M. Yamamoto and T. Shiba Tetrahedron Lett. 1984 25 3727. 133 N.K. Kochetkov Atre Appl. Chem. 1984 56 923. 134 K. Bock and M. Meldal Acta Chem. Scand. Ser. B. 1983 37 629; 775. 135 P. J. Garegg T. Norberg P. Konradsson and S. C. T. Svensson Carbohydr. Res. 1983 122 165. 136 H. Paulsen and W. Kutschker Carbohydr. Rex 1983 120 25. 137 D. R. Bundle M. A. J. Gidney S. Josephson and H. P. Wessel ACSSymp. Ser. 1983 231 49. 138 S. Sabesan and R. U. Lemieux Can. J. Chem. 1984,62 644. 139 H. P. Wessel T. Iversen and D. R. Bundle Carbohydr. Res. 1984 130 5.140 J. Alain and A. Veyrieres Tetrahedron Lett. 1983 24 5223. 141 P. H. A. Zollo J. C. Jaquinet and P. Sinay Carbohydr. Res. 1983 122 201. 142 N. V. Bovin and A. Ya. Khorlin Bioorg. Khim 1984 10 853. (Chem. Abstr. 1984 101 211 588q). 143 P. Sinay J. C. Jaquinet M. Petitou P. Duchaussoy I. Lederman Y. Choay and G. Tom Carbohydr. Rex 1984 132 C5. 144 J. C. Jaquinet M. Petitou P. Duchaussoy I. Lederman Y. Choay G. Tom and P. Sinay Carbohydr. Res. 1984 130 221. 333 Carbohydrates -==% 040~~1 Meooc&o Me + Ho&oBn I II CICH,C-0 BnO 0 (121) (1 22) ,OAc MeOOCw* 4' BnO HO OAc OBn COOMe ClCH2-!O* + BnO Bn Br HO N3 \O Ac MmcJyo* NH OBn OAc HO=:Fo COOBn BnO + OBn w*+ 0SO;Na' OH (129) N HSOiNa' 334 J.Thiem Much interest centred on the very ambitious syntheses of oligosaccharides involv- ing higher carbon sugars like the C,(KDO) or the C,(NANA) compounds. The basic chemistry and biological background of 3-deoxy-~-manno-2-octulosonic acid (KDO) has been discussed by U~~ger'~' These previously and enriched re~ent1y.l~~ groups and the one of Paulsen partly in collaboration have accomplished very impressive synthetic achievements involving the KDO molecule. The former have succeeded in stereoselectively condensing a ribofuranose via its bromide and pro- moting it by silver triflate to the KDO molecule.147 Similarly a ribo-ribo-KDO trisaccharide was prepared which constitutes the repeating unit of the E. coli capsular polysaccharide.The KDO glycosyl bromide could be used for the glycosylation of a 3-OH free glucosamine precursor and depending on the solvent by mercury ion promotion either the pure a-or the alpmixture of the KDO-(2 -+ 3)-~-GlcNAc derivative were obtained.14* Along corresponding lines the KDO bromide could be condensed to the 3'-OH unprotected P,1-+ 6-linked glucosamine dimer thus furnish- ing a-KDO-(2 +3)-p-~-GlcNAc-( 1.+6)-~-GlcNAc.'~* In addition to these conventional glycosylation procedures another stereo-controlled approach for a KDO disaccharide has been published'49 which makes use of the intramolecular mercury-cyclization previously applied in a number of other projects150 and by Mukaiyama et aLIS1in carbohydrate synthesis. Here 2,3-di-0- benzyl-D-mannose ( 130) was converted into the aldehydo-D-mannose derivative (131) which constitutes the precursor of the KDO unit.The diastereomeric mixture of the 6-0-phosphonogluco-compound (132) obtained by an insertion reaction of methyl diazo( dimethy1phosphono)acetate into the 6-OH unprotected saccharide was converted into the anion. By Horner-Emmons condensation with (131) the (E/Z) mixture of the enol ethers (133) and (134) was obtained (85% ; E/Z ratio 3 :2) and separated chromatographically. The mercury-cyclization with Hg( OCOCF3)* of the (E)-isomer afforded regio- and stereo-specifically the 3-chloromercury glycoside (85% ) which after demercuration hydrogenolysis and saponification afforded the pure P-linked disaccharide P-KDO-(2 -.+ 6)-D-Glc (135).Similarly the correspond- ing treatment of the (2)-isomer gave the a-KDO-(2 .+6)-D-Glc anomer (136) exclusively. Along a similar approach P-KDO(2 +3)-~-GalNAc which represents the repeating unit of the K antigen of Neisseria meningitis 29e was synthesized from the (E)-enol ether precursor which surprisingly was the only product obtained in that Horner-Emmons c~ndensation.'~~ Further use of this approach should demon- strate its compatibility with the classical procedure with respect to anomeric purity and the overall preparative value. The other highly complex monosaccharide N-acetylneuraminic acid (NANA) the best known member of the sialic acid family and a frequent component of glycoconjugates in the terminal positions of glycan chains has been subject to a 145 F.M. Unger Adu. Curbohydr. Chem. Biochem. 1981,38 323. 146 P. Waldstaetten R. Christian G. Schulz F. M. Unger P. Kosma C. Kratky and H. Paulsen ACS Symp. Ser. 1983 231 121. 147 P. Kosma G. Schulz and F. M. Unger Curbohydr. Res. 1984 132 261. 148 H. Paulsen Y. Hayauchi and F. M. Unger Liehigs Ann. Chem. 1984 1270; 1268. 149 F. Paquet and P. Sinay J. Am. Chem. SOC.,1984 106 8313. 150 P. A. Bartlett in 'Asymmetric Synthesis' ed. J. D. Morrison Vol. 3 Academic Press New York 1984 Chapter 6. 151 K. Suzuki and T. Mukaiyama Chem. Lett. 1982 683. Carbohydrates 335 COOMe OMe \ 11 / CH-P / \ B&$,:C OMe + Bnoh /OH -9 BnO BnO CHO OBn OMe * (133) (15):R' = Q BnO*R R2 (134) (2):R' = COOMe (E) + (2) R2 = Q 4 H"H;q'OH HTy+..HO HO CO;N a+ HO (135) (136) Ho OMe number of glycosylation reactions. The syntheses start with the NANA 2-chloride which e.g. by promotion with silver triflate can be glycosylated with the 6-OH free methyl 2,3,4-tri-O-benzyl-~-~-glucopyranoside to give a mixture of a-and p-NANA-(2 +6)-~-Glcin 50% yield (a:p = 1:4).152 The NANA trisaccharide a//?-NANA-(2 -+ 6)-/?-~-Gal-( 1 -* 4)-~-GlcNAc was correspondingly obtained from the same chloride and the lactosamine precursor in 22% a-and 23% p-yield.lS3 Ogawa et al.ls4 published again only short communications on the preparation of the glycoprotein component a/P-NANA-(2 4 6)-P-D-Gal-(1+4)-p-~-GlcNAc-(1 -+ 2)-D-Glc and that of a cell surface glycan a-NANA-(2 -* 8)-a-NANA-(2-* 1)-gly~erine."~An approach similar to the one outlined above for KDO-disac- ~harides'~~ was applied successfully to the stereocontrolled preparation of a-and &NANA-(2 +6)-D-Glc which determines the steric outcome of the reaction by a Horner- Emmons process rather than a terminal glycosylation step.'56 152 H.H. Brandstaetter and E. Zbiral Monatsh. Chem 1983 114 1247. 153 H. Paulsen and H. Tietz Carbohydr. Res. 1984 125 47. 154 T. Kitajima M. Sugimoto T. Nukada and T. Ogawa Carbohydr. Res. 1984 127 C1. 155 T. Ogawa and M. Sugimoto Carbohydr. Res. 1984 128 C1. 156 F. Paquet and P. Sinay Tetrahedron Left. 1984 25 3071. 336 J. Thiem General Oligosaccharide Synthesis and Further Topics.-Modification reactions of abundantly available oligosaccharides or their lower fragments have been previously used and worked out predominantly by Hough et al.e.g. with sucrose trehalose and also cellobiose and lactose. Some newer results also make use of the intact interglycosidic linkage and modify the cellobiose molecule starting with the glycal or the 1,6-anhydro-derivative into 2-azido-2-deoxy derivatives. 157 Chitin represents another natural product which may be used as cheap starting material for large scale syntheses. Its selective degradation by acetolysis led after chromatographic separation to chitotetraose peracetate the glycosyl chloride of which was conven- tionally glycosylated with 7-hydroxy-4-methyl-coumarin sodium salt to provide a tetrasaccharide glycoside useful as fluorometric assay for ly~ozyrne.'~~ Oligodeoxyoligosaccharide syntheses have progressed by application of the N-iodosuccinimide procedure employing glycals which e.g.in a block condensatim type approach yielded a lanatoside tetrasaccharide. l9 This approach a number of other methods the general problem of stereospecific 2-deoxy-glycoside syntheses and some further specific application in the aureolic acid synthesis were concisely reviewed.22 Oligomannosides di-to penta-saccharides e.g. a-D-Man-(1-* 3)-a-D-Man-(1-P 2)-a-D-Man-( 1 -+ 2)-a-D-Man were synthesized following the classical approach which as expected gave the a-glycosides excl~sively.'~~ Silver triflate promoted sequential condensation of glycosyl chloride blocked at C-2 with a non-participatihg residue led to formation of the heptasaccharide (137) which glucan fragment was said to be useful as a neoplasm inhibitor.16' In approaching a rather simple a,1-* 6-linked glucan target molecule Nicolaou et al.claimed the development of a 'practical oligosaccharide ~ynthesis'.'~ In their main concept the repetitive and block-based operation needed a variation of OH- a-~-Glcp-(l+ 3)-a-D-Glcp-(l+ 6)-a-~-Glcp-(l+ 6) \ D-Glc / 3)-c~-~-Glcp-(l+ c~-~-Gl~p-(l+ 6)-a-~-Glp-(l+3) (137) OTBDMS BnO BnO BnO R X n = 0,2,4 (138) (139) TBDMS TBDMS a-SPh F (141) (140) H a-SPh 157 T. K. M. Shing and A. S. Perlin Curbohydr. Res. 1984 130 65. 158 T. Inaba T. Ohgushi Y. Iga and E.Hasegawa Chem. Phurm. Bull. 1984,32 1597. 159 Institute of Physical and Chemical Research Sapporo Breweries Ltd. Jpn. Kokai Tokkyo Koho JP 59 36 691 and 59 36 690 (Chem Abstr. 1984 102 7028y and 70292). 160 Institute of Physical and Chemical Research Jpn. Kokai Tokkyo Koho JP 59 33 301 (Chem. Abstr. 1984 101 19 2397h). Carbohydra tes protecting groups in the reducing or aglyconic carbohydrate moiety. More important was the activation at the anomeric centre using phenylthioglycosides as stable precursors and glycosyl fluorides easily obtained therefrom by treatment with NBS and DAST as the reactive compound to be glycosylated. For instance the glucopyranoside (138) could be transformed (NBS DAST) into the a/P-glucosyl fluoride mixture (139).Simultaneously the TBDMS group could be removed and gave the aglyconic glucose derivative (140). Condensation of (139) and (140) using Mukaiyama's conditions (silver perchlorate stannic dichloride in dry ether) fur- nished the a,1+ 6-linked disaccharide (141;n = 0) in 75% yield. Similar treatment of this disaccharide as above gave the two fragments which could be condensed to a tetrasaccharide species (141; n = 2 70% yield) and the hexasaccharide (141; n = 4 66%) was obtained after further attachment of another disaccharide unit. Based on glucose the preparation of the starting phenylthio-glycoside (138) required eight (more or less) conventional steps (no yield mentioned) and the hexasaccharide synthesis gave an overall yield of approximately 26% for the outlined further eight steps.The practicality of this concept is not convincing and other well-established approaches may be favoured particularly if syntheses of more complex hetero- oligosaccharide targets than the ones mentioned above are desired. There was a previous report of an enzymically promoted condensation of a trisaccharide species to carminomycinone forming a class I1 anthracycline deriva- tive.16' A novel patent now describes the uncatalysed condensation of 2-hydroxy- aclavinone (142) and the trisaccharide (143;QH) in the presence of acetic anhydride in THF to give the class I1 anthracycline (144) which shows marked effects in the treatment of tumour growth.'62 Following classical procedures the first leaf-move- ment factor from Mimosa pudica L.consisting of a a,1+ 2-linked apiofuranosyl- glucopyranose P-glucosylated with gentisic acid (145) has been ~ynthesized.'~~ (142) Q = H (144) Q = (143) /OH COOH I I (145) H0 OH 161 A. Yoshimoto Y. Matsuzawa Y. Matsushita T. Oki T. Takeuchi and H. Umezawa J. Antibiotics 1981,34 1492. 162 Sanraku-Ocean Co. Ltd. Jpn. Kokai Tokkyo Koho JP 59 36 641 (Chem Abstr. 1984 101 38 780w). 163 P. Hettinger and H. Schildknecht Liebigs Ann. Chem. 1984 1230. 338 J. Thiem In the aminoglycoside field the groups of Szarek et uZ.164*165 and of Tatsuta et uL16*166 have accomplished syntheses of the very complex bicyclic amino-octodial- dose which together with 2-deoxy-streptamine represent the basic structures of the aminoglycoside antibiotics apramycin (155) and saccharocin (156).Tatsuta et uZ.16 started their total synthesis with the aminoglycoside antibiotic neamine (146) by preferential N-benzo yloxycarbonylation further N-tosylation and 0-cyclohexyl-idenation. The 6’-amino-group was N-methylated and the N-oxide (147) formed. On treatment with benzoyl chloride and Hunig’s base the 6’-aldehyde (148) was obtained which by reaction with allylmagnesium chloride gave a mixture (149) of the (6’s) and (6’R) alcohols in 37 and 41% yield respectively. Cleavage of the olefin-function with osmium tetraoxide and sodium metaperiodate resulted after acid removal of the alkylidene blocking groups in formation of the octodialdose derivative (150). 0-Tosylation and base treatment gave after acetylation the glycal (151).This diastereomer was also obtained from the (6’R) adduct (149) viu a mesylation-inversion sequence and further treatment as above. Azidonitration of the glycal gave both anomers at C-8’ but the 7’-azido groups was introduced stereospecifically (7’sonly). After a number of steps the 3’,6’-dimesylate was used to generate the 3’-deoxy function via a 3’-chloride and tributyltin hydride reduction and following epimerization at C-6’ the subsequent carbamate formation led to the derivative ( 152). By standard deblocking procedures this compound gave directly methyl P-aprosaminide. The unblocked N-carbobenzoxylated amino-octodialdose derivative could be glycosylated employing Mukaiyama’s conditions and the per- benzylated 4-azido-4-deoxy-glucopyranosyl( 153) or the normal glucopyranosyl fluorides (154).Further steps completed the syntheses of apramycin (155) and saccharocin (156). There are again some reports on the large-scale enzymic synthesis of oligosac- charides an area which may supplement and also compete favourably with the existing synthetic methodology. Employing sucrose synthetase 1-deoxy-1 -fluoro-D- fructose was accepted as a substrate and with UDP-glucose transformed into 1’- deoxy-1’-fluorosucrose in 60-80% yield.53 Only 20% yield was obtained in the preparation of P-D-Gal-( 1 + 6)-~-GalNAc using immobilized P-galact~sidase.’~~ Buckwheat a-glucosidase used maltose and sucrose to form one tetra- and two tri-saccharides named erlose esculose and theandrose (maltosylsucrose and two isomeric glucosylsucroses).An enzymic synthesis on an a-chymotrypsin-sensitive polymer was published by Zehavi et uZ.169Thus the ~-N-benzoyloxycarbonyl-2-phenylalanine glycoside of peracetylated cellobiose was elaborated into a polymer and the cellobiose residue represented the acceptor for a D-galactosyltransferase reaction using UDP-galactose. The resulting polymeric trisaccharide was digested with a-chymotrypsin and released the desired trisaccharide species p-D-Gal-( 1 -+ 4)-p-~-Glc-( 1 -+ 4)-~-Glc. Employing a system of five immobilized enzymes and 164 0.Martin and W. A. Szarek J. Chem. SOC.,Chem. Commun. 1983 926. 165 0. Martin and W. A. Szarek Carbohydr. Res. 1984 130 195. K. Tatsuta K. Akimoto H. Takahashi T.Hamatsu M. Annaka and M. Kinoshita Tetrahedron Lett. 1983 24 4861. 167 L. Hedbys P. 0.Larsson K. Mosbach and S. Svensson Biochem. Biophys. Res. Commun. 1984,123,s. 168 S. Chiba Y. Asada-Komatsu A. Kimura and K. Kawashima Agric. BioL Chem. 1984,48 1173. 169 U. Zehavi and M. Herchman Carbohydr. Rex 1984 133 339. Carbohydrates HO HO CX-0 OH 0 CY-0 MeO% BnO NHTs R *&F BnO (153) R’= N (154) R’= OBn (155) R = NH HO (156) R = OH OH 340 J. 7'hiern partially based on previous reports for the synthesis of N-acetyl-lactosamine by Whitesides et ~1.'~'the group of David et published quite simple preparations of the trisaccharides p-D-Gal-( 1 + 4)-p-~-GlcNAc-( 1+ 6)-~-Gal and P-D-Gal- (1 -P 4)-p-~-GlcNAc-( 1-.3)-D-Gal in very good yields. Some polymeric compounds with a carbohydrate base structure should be of interest. Acrylamide was radically copolymerized with a trisaccharide allyl glycoside which led to a linear polyacrylamide copolymer with carbohydrate branches (approximately 30% sugar content). This treatment of the allyl glycoside of p-D-Man-(1 -+ 4)-a-~-Rha-( 1+ 3)-~-Gal led to a polymer with a molecular weight larger than 100kD which functioned as a synthetic antigen and showed a group specificity E of salmonella species. 172 Another interesting project centred on the modification of natural polysaccharides ; e.g. chitosan was reductively alkylated with an aldose and sodium cyanoborohydride and gave aminoalkylated polysaccharides of comb- or tree-like structure.The derivative of chitosan with N-(sorbitol-1-yl) branches (stemming from glucose units) showed novel interesting properties for instance water ~olubility.'~~ 4 Carbohydrates as Chiral Templates The synthesis of challenging chiral structures starting from readily available or modifiable chiral precursors frequently referred to as 'chiral template approach' enjoys ever increasing interest in carbohydrate chemistry. Not surprisingly this area has attracted scientists both from the original carbohydrate field as well as from other areas of organic chemistry. The selection presented here has been deliberately divided into a subchapter on C-glycosides and another one on the use of carbohy- drate precursors or selectively modified derivatives thereof as chiral building units for the construction of various chiral entities.C-G1ycosides.-The detection of C-nucleosides has promoted quite intensive studies and their synthesis was reviewed re~ent1y.l~~ A number of procedures have been developed in this area and later adopted in the carbohydrate field. In recent years however many new approaches have also appeared some of which will be discussed. A general method was described for the conversion of aldono-lactones into the methyl aldulosonates a group of compounds which are represented by such impor- tant members as KDO or NANA (see above).'75 Treatment of e.g.the lactone (157) with tris(methy1thio)methyl-lithium as acyl equivalent at -78 "C and subsequent work-up with HgO-HgCI2 in methanol gave the corresponding methyl heptulosonate (158) in 40% yield.This method with a relatively good yield should be of interest for multi-step syntheses the more so because it was compatible with a number of base-stable protecting group^."^ In another short approach aldono-lactones could be transformed into methylene compounds by treatment with the titanium carbene 170 C. H. Wong S. L. Haynie and G. M. Whitesides J. Org. Chem. 1982 47 5416. 171 C. AugC S. David C. Mathieu and C. Gautheron Tetrahedron Lett. 1984 25 1467. 172 A. Ya. Chernyak A. B. Levinskii B. A. Dmitriev and N. K. Kochetkov Curbohydr. Res, 1984,128,269. 173 M. Yalpani and L. D. Hall Mucromolecules 1984 17 272. 174 J. G. Buchanan Prog. Chem. Org. Nut.Prod. 1983 44 243. 175 J. E. Hengeveld K. Grief J. Tadanier C. M. Lee D. Riley and P. A. Lartey Tetrahedron Lett. 1984 25 4075. Carbohydrates BnO /OBn (MeS),CH Hg2+ -__* BuLi BnO (157) BnO Bnoko OH (158) complex (159) in good yields. These exocyclic glycals could be further elaborated in a number of ways and also into C-glyc~sides.'~~ Baldwin et demonstrated that trapping of the C-1 radical formed by treatment of phenyl 2,3,4,6-tetra-0-acetyl-l-thio-~-~-glucopyranoside and triphenylstannane in refluxing toluene with methyl acrylate gave 40% of the a-(2-methoxycar-bony1)ethyl-glucoside derivative and 10% of a double substituted product a-(2,4-bis-methoxycarbony1)butyl-glucoside.Keck et showed that treatment of thio-phenyl glycosides with methallyl-tri-n-butylstannaneusing a photochemical initi- ation gave the C-allylated derivative in approximately 90% yield with an alp-ratio of 92 :8.However the same reaction performed in the presence of tri-n-butylstannanyl triflate with heating gave in 95% yield the p-anomer virtually exclusively. In contrast to other versions of the Claisen rearrangement the Eschenmoser variation (N,N-dimethylacetamide dimethyl acetal reflux) applied to the alcohol (160) gave the a-glycosylated N,N-dimethylacetamide (161) in 85% yield.'79 On reduction with Li[(OEt),AlH] only minor amounts of the a-aldehyde (162) resulted because of prevailing anomerization to the &derivative (163). In another approach \ R (161) R =NMe (162) R =H Wittig extension of the 4,6- 0-ethylidene-D-glucose (1 64) gave the trans-oct-2-enoate (165) which on cyclization with dilute base after one hour yielded a 1 :1 mixture of the a-and &derivatives (166).By further base treatment the p-anomer of (166) was obtained exclusively which by Cohen-Tipson reductive elimination gave the olefinic ester derivative (167).18' 176 C. S. Wilcox G. W. Long and H. Suh Tetrahedron Lett. 1984 25 395. 177 R. M. Adlington J. E. Baldwin A. Basak and R. P. Kozyrod J. Chem. SOC.,Chem Commun 1983,944. 178 G. E. Keck E. J. Enholm and D. F. Kachensky Tetrahedron Lett. 1984 25 1867. 179 D. B. Tulshian and B. Fraser-Reid J. Org. Chem 1984,49 518. 180 R. D. Dawe and B. Fraser-Reid J. Org. Chem. 1984 49 522. 342 J.Thiem I A most interesting paper of Sinay et reported the synthesis of the first C-disaccharide an interglycosidic oxygen isostere of a cellobioside. The straightfor- ward preparation started with a transformation of the 6-aldehydo-glucose derivative (168) into the dibromo-olefin (169). This on treatment with BuLi at -50 "C in situ provided the acetylenic anion which added to the perbenzylated lactone (170) and gave the hemiacetal (171). Its stereospecific reduction with Et,SiH BF3-Et20 led to the P-glycoside (1 72) exclusively and by a final reduction deblocking and saturation occurred to yield the product (173) which may be of interest in studies of sugar metabolism or as an enzyme inhibitor. In course of the preparation of the vineomycin B2 aglycone which features a P-C-glycosidic bond of a 2,6-dideoxy-arabino sugar to an unsymmetrical anthraquinone Danishefsky et aZ.'82reacted a 2-triethylsilyloxy- 173-pentadiene with + Bnoh BnO BnO OMe BnO 0 (168) R = CHO (170) (169) R = CH=CBr BnO&e!&J/o);n -H\&H2Cd&j OH BnO Ho OMe 0 (1 73) Bn X (171) X = OH (172) X = H 181 D.Rouzaud and P. Sinay 1. Chem Soe Chem. Commun. 1983 1353. 182 S. Danishefsky B. J. Uang and G. Quallich J. Am. Chem. Soc. 1984 106 2453. Carbohydrates 343 an aromatic aldehyde in the presence of Eu(fod)3. This hetero Diels-Alder reaction catalysed by the lanthanide complex gave the correct &bond of the (*) C-aryl glycoside in 92% yield. Reaction of 6-aldehydo-1,2;3,4-di-O-isopropylidene-c-D-galactopyranose with the diene mixture of 1- 0-benzoyl-2- O-trimethylsilyl-4-0- methylbutadiene in the presence of boron trifluoride at -78°C in ether provided 62% of a single cyclocondensation product (174) with high diastereofacial selectivity which may be considered a carbon-carbon linked disaccharide prec~rsor.'~~ 0 The cycloaddition adducts of the isoquinolinium salt (175) with the pyranose or furanose glycals (176) or (177) were opened to the amino-aldehyde derivatives which by abstraction of 2,4-dinitroaniline aromatized to the same sugar-substituted naph- thaldehyde (178) in approximately 60% yield.lS4A number of C-glycosides could be obtained by employing glycosyl fluorides as substrates Lewis acids as catalysts and e.g.ally1 silanes trialkyl aluminium or trimethylsilyl cyanide as nucleophiles ; in generally high yields the predominant formation of the a-compounds was repor- ted.14 Reetz et aZ.'*' published a mild and regiospecific method which could be used (175) CHO 183 S. Danishefsky C. J. Maring M. R. Barbachyn and B. E. Segmuller J. Org. Chem. 1984,49,4564. 184 R. W. Franck and R. B. Gupta J. Chem. SOC Chem Commun. 1984 761. 185 M. T. Reek and H. Muller-Starke Liebigs Ann. Chem 1983 1726. 344 J. Thiem for the synthesis of C-glycosides. Glycosyl halides or even acetates on treatment with silyl enolether 0-silyl ketene acetals or bis-silylacyloins in the presence of zinc halides gave a-alkyl-oxyalkylated carbonyl compounds. Similarly 1-0-acetyl- 2,3,5-tri-0-benzoyl-P-~-ribofuranosewith silyl enol ether and SnCl catalysis led to the formation of C-ribosides.'86 By use of 2,3,5-tri-O-benzyl-P-~-ribofuranosyl fluoride and the silyl enol ether of acetone under BF,.Et,O catalysis the alpmixture of the corresponding octulose was ~btained.'~~ Another grouplS8 demonstrated the direct C-allylation of a L-Z~XO acetate with allyltrimethylsilane in acetonitrile using BF3*Et20 catalysis in high yield and almost exclusive a-anomer formation.A large number of sugar substrates like glycosyl chlorides but also the more stable methyl glycosides could be C-allylated with various allylsilanes as nucleophiles. Catalysed by trimethylsilyl trifluoromethanesul- phonate or iodotrimethylsilane the reaction gave mainly a-anomer and in good ~ie1ds.l'~ Similarly Mukaiyama et uZ.'~' showed that the a-C-riboside was formed in excellent yields on treatment of ribopyranose acetate with silylenolethers or allylsilanes or trimethylsilyl cyanide ;the reaction was catalysed by trityl perchlorate.2-Acyloxy-3-keto glycals undergo stereospecific reaction with silyl enol-ethers with titanium chloride as catalyst to give P-C-glycosides of 4-deoxy-hex-3-en-2-ulose derivatives by way of a Michael-type addition.'" A very promising finding was disclosed by Sinay et ~2Z.l~~ who on treatment of the glucopyranoside (179) with lithium naphthalenide in THF at -78 to +5 "C generated by reductive lithiation and subsequent elimination (according to Ireland's procedure) the tri-0-benzyl glucal (180).After addition of gaseous HC1 the labile intermediate glycosyl .chloride was again treated with LiC10H7 in THF at -78 "C and in another reductive lithiation gave the first glycopyranosyl lithium derivative (181). By quenching with anisaldehyde the a-C-glycoside (182) was obtained as a 4:1 diastereomeric mixture. In a mechanistically somewhat peculiar reaction a-acetobromoglucose and diacetylphloroglucinol with sodium in methanol gave after chromatographic purifi- cation a 9% yield of the p-C-aryl-substituted glucose.'93 Even the classical appro ache^'^^ for the preparation of C-glycosides have been employed for the synthesis of P-C-ben~yl'~~ P-C-butyl xylopyrano~ides,'~~ or compounds which showed remarkable activities against certain tumours.Reaction of 4,6-0-benzyl-idene-3- 0-mesyl-D-allal with several alkyl Grignard reagents gave stereospecifically the P-C-allylated hex-2-enopyranosides in good ~ie1ds.l~~ By mild reaction of la6 Y.S. Yokayama T. Inoue and I. Kuwajima Bull. SOC.Chem Jpn. 1984,57 553. 187 Y. Araki K. Watanabe F. Kuan K. Itoh N. Kobayashi and Y. Ishido Carbohydr. Res. 1984,127 C5. 188 A. P.Kozikowski and K. L. Sorgi Tetrahedron Lett. 1984,25 2085. 189 A. Hosomi Y. Sakata and H. Sakurai Tetrahedron Lett. 1984,25 2383. 190 T.Mukaiyama S. Kobayashi and S. Shoda Chem. Lett. 1984 1529. 191 H.Kunz J. Weismuller and B. Muller Tetrahedron Lett. 1984,25 3571. 192 J. M. Lancelin L. Morin-Allory and P. Sinay J. Chem. SOC.,Chem. Commun. 1984 355. 193 H.Obara M.Hattori,and Y. Matsui Chem. Lett. 1984 1039. 194 W. A. Bonner Adv. Carbohydr. Chem 1951,6 251. 195 R. Noyori S. Suzuki M. Okayama K. Sakurai S. Komohara and Y. Ueno (Seikagaku Kogyo Co. Ltd.) USP 4 454 123 (Chem. Abstr. 1984,101 152261~). 196 R. Noyori S. Suzuki and M. Orayama (Seikagaku Kogyo Co.,Ltd.) USP4446312 (Chem. Abstr. 1984,101 91 397c). T.Ogihara and 0. Mitsunobu Tetrahedron Lett. 1983,24 3505. 19' 345 Carbohydrates pen / OBn /OBn hleO CHO BnO & BnO acylated glycals with diethylaluminium cyanide at room temperature the l-cyano- hex-2-enopyranosides were obtained in good yield and an alp-ratio of 2 3.’98 Under reflux the a-derivative predominated as demonstrated before.’79 Synthesis of Chiral Structures from Carbohydrate Precursors.-Comprehensive reviews covering this topic became available some time ago’99-201 and several more have appeared quite re~ently.~~~~~~~ This subchapter is meant to update and discuss recent developments.The highly specific cationic ionophore calcimycin (187) was synthesized from D-glucose. First the two selectively C-methylated and protected units (chirons) (183) and (184) were elaborated and their dithiane condensation gave the open-chain precursor (185). Mercury-mediated dithiane hydrolysis and acid treatment led to the spiroketal(l86) exclusively. In a number of further steps the two heteroaromatic residues could be introduced to give calcimycin (187).204 Another report has described the transformation of D-glucose uia 3,5-dideoxy-1,2-0-isopropylidene-a-D-erythro-hexofuranose as the key intermediate in only four steps into the enan- tiomerically pure 1,7-dioxaspiro[5,5 Jundecane (1 88) which represents the pheromone component of the olive fly (Dacus ole~e).”~ Treatment of the tetrabenzyl gluconolactone (170)with the lithium salt of 1-trimethylsilyloxy-3-butyneand mild acid work-up gave the C-1 alkylated alp-lactol(l89) in 92% yield and on hydrogen- ation over Lindlar catalyst this yielded the cis-olefin (190).This could be cyclized 198 D. S. Grierson M.Bonin H. P. Husson C. Monneret and J. C. Florent Tetrahedron Lett. 1984,25,4645. 199 S. Hanessian Acc. Chem. Res. 1979 8 192. 200 B. Fraser-Reid and R. C. Anderson Fortschr. Chem. Organ. Naturst.1980 39 1. 201 A. Vasella in ‘Modern Synthetic Methods’ ed. R. S. Scheffold Salle and Sauerlander Frankfurt 1980. 202 S. Hannessian ‘Total Synthesis of Natural Products’. The Chiron Approach’ Pergamon Oxford 1983. 203 T. D. Inch Tetrahedron 1984,40 3161. Y. Nakahara A. Fujita and T. Ogawa J. Carbohydr. Chem. 1984 3 487. *05 H. Redlich and W. Francke Angew. Chem. 1984 95 506. 346 J. Thiem TBDMSO f-t-D-Glucose OEE (183) (184) TBDMSO (186) R' = CH20H,R2 = CH20Bz YOOH (187) R' = NHMe R2 0 R' R2= fi with camphosulphonic acid to give the unsaturated model spiroacetal. The alp-ratio was 4:3and acid treatment anomerized the thermodynamically unstable @-derivative to the a-anomer (191).By debenzylation (Na in liquid ammonia) the unblocked 1,7-dioxaspiro[5,5]undecene subunit (192)of avermectin B1,was obtained.206 Irradi- ation of an a-(3-keto-3-pheny1propyl)glycoside led in a Norrish-type I1 cyclization to both diastereomers of the 4-hydroxy-4-phenyl-l,6-dioxaspiro[ 5,6]decane system.'07 There is considerable interest in syntheses of variously substituted anthracyc- hones and reports were given on an application of the Marschalk reaction employ- ing sugars.Leucoquinizarin (193)and the arabinose (194)could be condensed in alkaline solution and after oxidation by air gave the adduct (195).This following selective deblocking and oxidative cleavage could be elaborated into the highly functionalized A-ring anthracyclinone derivative (196).208 The same group published 206 S.Hanessian and A. Ugolini Carbohydr. Rex 1984 130 261. 207 P. Bron L. Cottier and G. Descotes J. Heterocycl. Chem. 1984 21 21. D. J. Mincher G. Shaw and E. DeClerq J. Chem. SOC.,Perkin Trans. 1 1983 613. Carbohydrates @&+ (191) R = Bn (192) R = H(189) R = -=*OH (190) R = moH CHO / \ 0 \ I I / o 0 HO OH (193) 0 i another improved anthracyclinone synthesis employing the xylofuranose as chiral template.209 o-Xylylenes ( 197) derived from 1,2-bis( bromomethy1)benzene by treat- ment with zinc powder and ultrasound irradiation gave rise to cycloaddition with the hex-2-enopyranoside-4-ulose ( 198) forming the carbohydrate adduct in 30-70% yield210 (for comparable cycloadditions see rej 21 1). Further transformation of the exocyclic enol ether function in (199) by solvolysis employing mercury salts gave the highly functionalized hexahydro-naphthacenes or -anthracenes (200).In the difficult stereoselective glycosylation steps of anthracyclines the P-glucoside of the functionalized butadiene (202) was employed for the cycloaddition to the tricyclic oxirane derivative (201).2'2 The cycloadduct was transformed into the 3-ketone (203) and following reduction of the oxirane introduction of the side-chain and Hg"- mediated work-up furnished the intact C-7 p-D-glucosylated anthracycline derivative (204). 209 D. J. Mincher and G. Shaw J. Chem. SOC.,Perkin Trans. 1 1984 1279. 210 S. Chew and R. J. Ferrier J. Chem. SOC.,Chem. Commun.,1984 911. 21 1 R.W. Franck and T. V. John J. Org. Chem 1983,48 3269. 212 R. C. Gupta P. A. Harland and R. J. Stoodley J. Chem. Soc. Chem. Commun.,1983 754. 348 J. Thiem I OBz D-Ribose as well as 1-deoxy-D-ribose were used for the preparations of dioxapros- tacyclin analogues.213 Horton et uL2149215 transformed aldehydo-sugars into a$-unsaturated esters using the Wittig method. Their Diels- Alder condensation with cyclopentadiene at low temperature and Lewis acid catalysis furnished sugar- substituted norbornene derivatives. Following hydroxylation glycol cleavage and reduction optically pure cyclopentane derivatives were obtained which owing to their five chiral centres similar to those in PG F1 may be of interest as prostaglandin synthons. Q= OAc AcO OAc 213 P.Heath J. Mann E. B. Walsh and A. H. Wadsworth J. Chem. SOC.,Perkin Trans. 1 1983 2675. 214 D. Horton T. Machinami Y. Takagi C. W. Bergmann and G. C. Christoph J. Chem. SOC Chem. Commun. 1983 1164. 215 D. Horton T. Machinami and Y. Takagi Curbohydr. Res. 1983 121 135. Carbohydrates 349 A key step in an efficient synthesis of methyl shikimate (207) was the intramolecular Horner- Emmons reaction. Starting with D-mannose the 5-O-triflyl-~-lyxofuranose (205) was obtained and alkylated with sodium trimethylphosphono acetate to give (206) as a 1 :1 diasteromeric mixture. Following hydrogenolysis the lactol anomers on base treatment gave the methyl shikimate (207) obtained after mild acid acetal cleavage.216 OH HOA / (205) R = OTf PO(OMe) (206) R = -CHEk -COOMe The C-3-C-8 and C-9-(2-13 fragments of the 14-membered macrelide antibiotic ~leandomycin~” and the C- 19-C-29 aliphatic sequence of rifamycin S218were both synthesized from D-glUCOSe following the chiron approach.Levoglucosenon (208) furnished an attractive starting material for preparations of (-)-S-multistriatin (209) and also of the (+)-Prelog-Djerassi lactonic acid (210).219 ,,COOH D-Glucose can be transformed into 6-epithienamycin (213) in a fourteen-step synthesis. The conversion centred around the base-mediated azetidinone formation (45%) of (212) from the D-lyxo-compound (211). Further elaboration of the carbon framework by Wittig reaction and along previously published lines gave the desired compound (213).220 A corresponding cyclization with Hunig’s base of the carbamate ester (214) derived from D-glucosamine gave the pyrrolidine (215) in 88% yield.216 G. W. J. Fleet and T. K. M. Shing J. Chem. SOC.,Chem. Commun. 1983 849. 217 S. S. Costa A. Olesker T. T. Ton and G. Lukacs J. Org. Chem. 1984 49 2338. 218 S. Hanessian J. R. Pougny and 1. K. Boessenkool Tetrahedron 1984 40,1289. 219 M. Mori T. Chuman and K. Kato Curbohydr. Res. 1984 129 73. A. Knierzinger and A. Vasella J. Chem. Soc. Chem. Commun. 1984,9. 220 350 J. Thiem -+ 0q COOR Its further transformation led to a synthesis of the carbapenem antibiotic (216; R = p-nitrophenyl) .221 Similarly treatment of the D-glucosamine-derived 2-amino- O-isopropylidene-5-O-tosyl-~-sorbitol 4,6-0-benzylidene-2-deoxy-l,3-with base gave the functionalized chiral pyrrolidine (217).222 Hanessian et uL223have published a stereocontrolled synthesis of the azetidinone (218) a monobactam precursor from D-glucosamine.This nine-step process gave the desired product in 16% overall yield and remains quite attractive even though the C4-C6 fragment of the starting sugar and thus two chiral centres had to be discarded. H3Nb-Me O 'so; (218) -+ HHoH N 2,3-0-Isopropylidene-D-erythroseserved as the precursor for a 10-step enantio- specific preparation of the lactone (219),224 the conversion of which into the pyr- rolizidine alkaloid (+)-retronecine (220)had been previously reported. Considerable interest has been centred on synthetic pathways for the hydroxylated indolizidine alkaloids castanospermine (221) deoxynojirimycin (222) and swainsonine (223) which are potent inhibitors of several carbohydrate processing enzymes.A straight-22 1 M. Miyashita N. Chida and A. Yoshikoshi L Chem. SOC,Chem Commun. 1984 195. 222 C. Morin Tetrahedron Lett. 1984 25 3205. 223 S. Hanessian and S. P. Sahoo Can. J. Chem 1984 62 1400. 224 J. G. Buchanan G. Singh and R. H. Wightman J. Chem. SOC.,Chem. Commun. 1984 1299. Carbohydrates 351 forward D-glucose-based preparation of (+)-deoxynojirimycin (222) and of (+)-castanospermine (221) was published.225 1,5-Dideoxy-l,5-imino-D-mannitol (1-deoxy-mannojirimycin) was synthesized either from D-mannose uia hydrogenation of its 5-azido-derivative or from D-glucose with the key step being nucleophilic 2-0-triflate inversion at C-2.226 Swainsonin (223) could be synthesized from D-mannose2279228 and from ~-glucose.~~~ The control of chirality at off-template sites in carbohydrate-derived syntheses is of concern in some recent contributions.Thus the platinum-catalysed hydrogenation of the a,P-unsaturated ester (224) derived from diacetone glucose in six straightfor- ward steps occurred from the si-si face exclusively most likely owing to the bulky substituent at C-3. The ester (225) or lactone (226) obtained could be further functionalized into the ketolactone (227) which is potentially useful as a sesquiter- pene precursor.230 Another 16-step stereocontrolled synthesis from diacetone glucose furnished the synthon (228) for the hemiacetal moiety (C13-C20) of the polyene macrolide antibiotic amphotericin B in an amazing 20% overall yield.231 Other approaches of the same group to achieve the stereocontrolled functionalization at off-template sites have been discussed (224) R = /=ioH Et0,C (226) R =OQ,H (225) R = Et02CxoH OH /OH Me 0 225 R.C. Bernotas and B. Ganem Tetrahedron Lett. 1984.25 165. 226 G. W. J. Fleet M. J. Gough and T. K. M. Shing Tetrahedron Lett. 1984 25 4029. 227 N. Yasuda H. Tsutsumi and T. Takaya Chem. Lett. 1984 1201. H. A. Mezher L. Hough and A. C. Richardson J. Chem. SOC.,Chem. Commun. 1984 447. G. W. J. Fleet M. J. Gough and P. W. Smith Tetrahedron Lett.1984 25 1853. M. Georges T. F. Tam and B. Fraser-Reid J. Chem. Soc. Chem Commun. 1984 1122. D. Liang H. W. Pauls and B. Fraser-Reid J. Chem. SOC.,Chem Commun.,1984 1123. 228 229 230 231 352 J. Thiem An unusual tetra( tripheny1)phosphine palladium-mediated rearrangement of the 5,6-anhydro- 1,2- O-isopropylidene-a-~-erythro-hex-3-enofuranose (229) led to a E/Z-mixture of the 4,5-unsaturated aldehyde (230). Reduction benzylation and hydrolysis gave the free-sugar intermediate which by aldol condensation yielded a precursor of (-)-pentenomycin I (231).232 A novel preparation of alkyl-branched cyclitols has been achieved by Klemer et aZ.233With strong bases for instance methyl lithium 1,6-anhydro-sugars like the P-D-galacto-derivative (232) undergo abstraction of H-5and in consequence a ring-opening reaction which gives the 5-enolate intermediate (233).This undergoes an intramolecular aldol addition and the ketone (234) adds another nucleophile to give both the diastereomers in the case ofmethyl lithium but a stereoselective addition with Bu"Li. This reaction resembles the procedure previously developed by Ferrier et aL234in which 6-deoxy-hex-5-enopyranosides are transformed into 2-deoxy- inososes induced by Hg" salts in aqueous media. A number of reports have appeared of the latter procedure being successfully used for the synthesis ofvarious cyclitols and aminocyclitols from carbohydrate precursor^.^^^,^^^ / u4 X OH OH (233) (234) X = 0 (235) X = OH,Me 232 S.Achab J. P. Cosson and B. C. Das J. Chem SOC.,Chem Commun. 1984 1040. 233 A. Klemer and M. Kohla Liebigs Ann. Chem 1984 1662. 234 R. J. Femer J. Chem SOC.,Perkin Trans. 1 1979 1455. 235 D. Semeria M. Philippe J. M. Delaumeny A. M. Sepulchre and S. D. Gero Synthesis 1983 710. 236 I. Pelyvas E. Sztariskai and R. Bognar J. Chem. SOC.,Chem Commun. 1984,104.

ISSN:0069-3030    

DOI:10.1039/OC9848100311

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

14 Peptides By C. E. DEMPSEY Department of Biochemistry University of Oxford South Parks Road Oxford OX1 3QU 1 Introduction This review covers literature on peptides published since the last peptide review in Annual Reports for 1980’ with emphasis on recent work from 1983/4. Research on peptides is increasing faster than ever (as evidenced by the appearance of three new journals for peptides Neuropeptides Peptides and Regulatory Peptides) due in part to significant advances in the methodology of solid-phase peptide synthesis in recent years which is providing peptide biologists with an ever-increasing supply of biologically active peptides and their analogues. The impact of peptide synthesis is widespread and synthetic peptides of some complexity are used for example to generate antisera for the isolation of proteins expressed by newly sequenced genes to probe the structure and specificity of antibody molecules and as synthetic vaccines.Although many of these applications are beyond the scope of this review they illustrate the importance of solid-phase peptide synthesis in many areas of biological research. It is timely that the 1984 Nobel prize for chemistry was awarded to R. B. Merrifield for his pioneering work in developing (and continuing to improve) these methods. It is impossible to make more than a passing survey of the huge volume of literature on peptides published in 1981-1984. The reviewer has chosen to illustrate those papers he feels to be particularly significant or illustrative of trends and to follow up lines of research that were developing when the field was last reviewed.It is emphasized that a selection of this type strongly reflects the personal bias of the reviewer. As in the last review of this series’ an attempt has been made to cover all areas of recent research in the peptide field and the biological aspects have been strongly emphasized. 2 Synthesis The series ‘Peptides’ edited by Gross and Meienhofer continues to be an excellent source of methods in peptide synthesis and includes a recent comprehensive treat- ment of protecting groups.2 Only a few recent examples of new protecting groups and their applications are illustrated here. ’ C. E. Dempsey and C. A. Vernon Annu. Rep. hog. Chem. Sect. B 1980 77,323. * ‘The Peptides Analysis Synthesis Biology’ Vol.3 ed. E. Gross and J. Meienhofer Academic Press New York 1981. 353 C. E. Dempsey Protecting Groups and Solution Syntheses.-Although many peptides have been synthesized using standard conditions [based on t-butyloxycarbonyl (Boc) or benzyl- oxycarbonyl (Z) protection] some sequences remain troublesome particularly those which contain amino-acids (such as Cys Tyr Trp and Met) sensitive to acid deprotection treatments in combination with these protecting groups. The use of phosphinamides as a new class of amino protecting group has been de~cribed.~ Phosphinamides have similar acid lability to the t-butyl- or benzyl-urethane groups but are free of the carbenium ion-mediated side reactions that can occur with side chain functions of sensitive amino-acids during deprotection.The acid lability of the P-N bond of phosphinamides can be modulated by varying the substituents on phosphorus and the diphenylphosphinamide (Dpp) group was chosen to evaluate these compounds as amino protecting groups. N" -Diphenylphosphinyl amino-acids were prepared (with 75-8570 yield in crystalline form) via the benzyl or methyl esters (Scheme 1) and the use of the Dpp group was illustrated with the synthesis Cl-H,fh-CH(R)CO,Me A Dpp-NH-CH(R)-CO,Me 1ii Dpp-NH-CH( R)-C02H (Dpp-= diphenylphosphinyl) Reagents i Ph,PO(CI)-N-methylmorpholine 0 "C;ii OH-H+ Scheme 1 of the partially protected tetrapeptide amide (1) using 0.25 M hydrochloric acid (in trifluoroethanol :water (9 :1) and HC1-methanol for successive cleavages of the N-protecting group (which was monitored by 31P n.m.r.).This sequence is the C-terminal tetrapeptide amide of gastrin. The same tetrapeptide having a free carboxyl terminus (protected as the phenyl ester) was synthesized taking precautions to evaluate cleavage conditions which leave the C-terminal phenyl ester intact and could be converted into the protected tetrapeptide amide in 90% yield by treatment Trp-Met-Asp( 0Bu')-Phe-NH2 (1) with ammonia in dichloromethane. This method is suggested to be a convenient general route in the synthesis of peptide amides. N"-diphenylphosphinyl amino- acids preserve their chirality during condensation reactions and the Dpp group is selectively cleaved in combination with side-chain protection based on t-butyl and benzyl alcohols.Phosphinic chlorides (2) have been used for carboxyl activation via the mixed amino-acid carboxylic-phosphinic anhydride and both diphenylphos- phinic chloride (2a) and 1-oxo-1 -chlorophospholane (3) are useful the latter having the advantage that the cyclic phosphinic acid ammonolysis by-product is water soluble and readily removed from the product ~eptide.~ R. Ramage D. Hopton M. J. Parrott G. W. Kenner and G. A. Moore J. Chem. SOC.,Perkin Trans. 1 1984 1357. R. Ramage C. P. Ashton D. Hopton and M. J. Parrott. Tetrahedron Lett. 1984 25 4825. Peptides 355 A new protecting group for the histidine imidazole is the v-benzyloxymethyl group and the (commercially available) protected histidine (4) has been used in a solid-phase synthesis of the octapeptide angiotensin and the solution synthesis of His-His-His.’ Compound (4) is activated and coupled without significant racemiz- ation [whereas the 7-benzyloxymethyl analogue of (4) is optically labile] and the protecting group is cleaved by hydrogenolysis as other benzyl-based groups.BOC-NH-CH-COzH Many biologically important polypeptides are coupled to carbohydrate via side-chain 0-or N-glycosidic linkages at Ser or Thr residues. The function of peptide- linked carbohydrate is of considerable interest and this has stimulated attempts to synthesize 0-glycopeptides for biological studies. Because of the lability (to both acid and base) of the 0-glycosidic bond side-chain protecting groups removable under mild neutral conditions have been sought and the allyl group has been shown to be useful both as a carboxyl-6 and as an a-amino- (as allyloxycarbonyl; Aloc) protecting group.7 The glycopentapeptide (6) was prepared from (5) by ethyl-2- ethoxy-l,2-dihydroquinoline-1-carboxylate (EEDQ)-promoted coupling of dipep- tide allyl esters according to Scheme 2.The use of the allyl group is based on its Z-Ser-Ala- Ala-Gly- Ala-OAll ZNHCHCO,All ZNHCHC0,H ii iii iv OBzl OBzl (6) (Bzl = benzyl; All = Allyl) Reagents i (Ph3PI4Pd morpholine THF (tetrahydrofuran) ; ii HCI- H-Ala-Ala-OAl1 NEt3 EEDQ CH,Cl,; iii deprotection (as i) ; iv HC1.H-Gly-Ala-OAlI NEt, EEDQ DMF (dimethyl- formamide) Scheme 2 ’ T. Brown J. H. Jones and J.D. Richards J. Chem. Soc. Perkin Trans. I 1982 1553. H. Kunz and H. Waldemann Angew. Chem. Inz. Ed. Engl. 1984 23 71. ’H. Kunz and C. Unverzagt Angew. Chem. Inf. Ed. EnrI.. 1984. 23,436. -!-+ Ser( But)-OBu' +Aloc-Ala-OH 356 C. E. Dempsey mild quantitative and selective cleavage by 10 mol% of tetrakis(tripheny1phos- phane)palladium(o) with morpholine as the allyl acceptor. The same catalytic transfer method (using 5,5-dimethylcyclohexane-1,3-dione as the allyl acceptor) cleanly removes the Aloc group from the a-amino-group and the protected tetrapep- tide ester (9) was prepared in high yield (95%) according to Scheme 3. The high yield in the dipeptide condensation was attributed to the small size of the Aloc group. Aloc-Ala-Ser( But)-OBu' A H-Ala-Ser( Bu')-OBu' (7) Aloc-Met-OH + Phe-OBut -!+ Aloc-Met-Phe-OBu' -Aloc-Met-Phe-OH (8) (7) + (8) -% Aloc-Met-Phe-Ala-Ser( But)-OBu' (9) (Aloc = allyloxycarbonyl) Reagents i EEDQ CH,CI,; ii (Ph3P),Pd 5,5-dimethylcyclohexane-1,3-dione, THF; iii trifluoroacetic acid (TFA); iv EEDQ THF Scheme 3 The formyl group is seldom used for amino protection in peptide synthesis but has proved useful in the selective modification of amino groups in native peptides.& N*-amino groups of the bee venom peptides apamin (19) and peptide-401 (sequence not shown) were formylated with high selectivity using the mixed formic-acetic anhydride in formic acid.p-Nitrophenyl formate at pH 9.5 was usefully selective for the &-amino group. The N-formyl group was cleaved from apamin in MeOH-HCl (0.1 M) at room temperature with acceptably low levels of methanolysis of side chain or a-amides.Selective reductive methylation (using formaldehyde and sodium cyanoborohydride at pH 6.8) of the a-or &-amino group of apamin was therefore possible by using the formyl group as a selective reversible amino protecting group. Using this strategy it could be shown that a decrease in biological activity on reductive methylation of apamin was due to dimethylation of the a-,and not the &-amino group. PHI (Peptide having N-terminal Histidine and C-terminal Isoleucine amide) was isolated from porcine intestine using a chemical assay for C-terminally amidated peptides.' The sequence" of PHI (10) shows a marked homology to a number of gut peptides of the glucagon family including secretin and VIP and also to a recently isolated growth hormone releasing factor (13).A surprising difference is at residue-24 10 His-Ala-Asp-Gly-Val-Phe-Thr-Ser-Asp-Phe-Ser-Arg-Leu-Leu-Gly-Gln-Leu- 20 27 -Ser-Ala-Lys-Lys-Tyr-Leu-Glu-Ser- Leu-Ile-NH (10) C. E. Dempsey J. Chem. SOC.,Perkin Trans. 1 1982 2625. K. Tatemoto and V. Mutt Nature (London) 1980 285 417. 10 K. Tatemoto and V. Mutt Proc. Natl. Acad. Sci. USA 1981 78 6603. Peptides 357 where PHI has glutamic acid; all other members of this family of peptides have a neutral amino-acid at this position. It was considered that an error in sequence determination or desamidation during isolation of PHI might be responsible for this difference and to test these possibilities porcine PHI and its Gln-24 analogue were synthesized." Six fragments corresponding to residues 1-6 7-1 1 12-14 15-18,19-23 and 24-27 of (10) were prepared by a stepwise active ester procedure using N-hydroxysuccinamide esters and catalytic hydrogenolysis to remove the N"-Boc group.Side-chain protection groups were derived from t-butyl alcohol and 1-adamantanol and the fragments were coupled with dicyclohexylcarbodi-imidein the presence of 1,2-dinucleophiles to suppress racemization. In assembling the Gln-24 analogue the pentapeptide fragment 23-27 (and the fragment 19-22) was used because of the tendency for the C-terminal tetrapeptide to cyclize to the pyroglutamyl peptide. The synthetic peptides were deprotected with trifluoroacetic acid (TFA) and purified to apparent homogeneity as judged by amino-acid analysis and high performance liquid chromatography (h.p.1.c.).The synthetic Glu-24 PHI was indistinguishable from native PHI by h.p.1.c. whereas the Gln-24 analogue could be resolved from PHI. This confirms the original assignment of glutamic acid to position-24 of PHI. Native PHI and the Gln-24 analogue were equally effective in a number of biological assays leaving unresolved the possibility that Gln-24 of PHI arose as an artifact of the purification procedure. Later sequence analysis of cloned DNA coding for the biosynthetic precursor to the human equivalent of PHI (PHM; having a C-terminal methionine amide) showed glutamic acid at residue-24,12 and it seems likely that the original sequence of PHI shown to be correct from the synthetic study is also the native structure of PHI in uiuo.A limiting factor in solution synthesis of peptides is often the solubility of protected fragments and this has been a particular problem with C-terminal fragments of VIP-related peptides. In the PHI synthesis solubility problems were overcome by interchanging side-chain protecting groups derived from t-butyl alcohol and 1-adamantol the latter group improving the solubility of hydrophilic peptides in organic solvent^.'^ In a synthesis of C-terminal fragments of VIP the temporary replacement of C-terminal asparagine with aspartic acid (protected as the t-butyl ester) greatly improved the solubility of the fragment^.'^ After removing side-chain protecting groups the C-terminal pentadecapeptide fragment of VIP was amidated via the mixed anhydride (with succinate) to generate the asparagine residue.An attempt has been made to predict the solubility of protected peptide fragments in solvents used for fragment coupling based on the sequence-dependent tendency of peptides to aggregate by forming intramolecular hydrogen-bonded @-sheet structure^.'^ It was suggested that the solubility of poorly soluble peptides can be im- proved by protecting the amide bond at suitable intervals in the sequence thus precluding intermolecular association by hydrogen-bond formation. Some success in these predictions and in the improvement of fragment solubility (using the I' L.Moroder W. Gohring P. Lucietto J. Musiol R. Scharf P. Thamm G. Bovermann E. Wunsch J. Lundberg K. Tatemoto and V. Mutt Hoppe-Seyler's 2. PhysioL Chem. 1983 364,1563. 12 N. Itoh K. Obata N. Yanaihara and H. Okamoto Nature (London) 1983 304,547. l3 R. Geiger and W. Konig in ref 2 p. 34. 14 W. M. M. Schaaper and D. Voskamp Red. Trau. Chim Pays-Bas 1984 103 17. l5 M. Narita K. Ishikawa J.-Y. Chen and Y. Kim fnt. J. Pepride Protein Res. 1984 24,580. 358 C. E. Dempsey 2,4-dimethyloxybenzyl or 2,4,6-trimethyloxybenzylprotecting group16) was achieved with a number of poorly soluble peptides. Many large peptides have been synthesized by fragment coupling indicating that with suitable strategies solubility problems can generally be overcome Recent examples include syntheses of human17 and mouse18 epidermal growth factor (homologous 53-residue peptides with three disulphide bonds) the first using the maximal protection strategy with a final deprotection in liquid hydrogen fluoride (HF) and the second using a milder protection strategy based on protecting groups labile to TFA or trifluoromethylsulphonic acid.Solid-phase Synthesis.-From a survey of the recent literature on the preparation of medium to large peptides for biological studies solid-phase synthesis -in many cases using commercial synthesizers -appears to be the preferred method. For many large peptides a successful strategy is the solid-phase synthesis of fragments which can be purified before coupling in solution or after re-immobilization on solid supports.Recent improvements have greatly extended the versatility of the solid- phase method and it has been stated” that ‘almost any desired sequence can be synthesized routinely’. Limitations in solid-phase synthesis remain however and these include the possibility of incomplete coupling during chain extension and side-reactions during the acid treatments required to remove protecting groups and cleave the peptide from the support. High resolution purification methods are therefore essential in the isolation of the synthetic target. In the development of solid-phase synthesis as a routine method the premium is on those with expertise in peptide chemistry to provide improvements in these areas and much progress has been made.Sheppard and his colleagues have published extensive details of the methods used in their laboratories.20 Polar polymethylacrylamide resins are used as supports and the authors believe these permit optimal solvation of the growing peptide and reagents and minimize aggregation within the matrix. The vigorous acid treatments required in the conventional Merrifield method are replaced by a single mild acid-cleavage step (in TFA) by using the base-labile p-fluorenylmethoxycarbonyl (Fmoc) protecting group for the a-amino function and acid-labile t-butyl or p-alkoxybenzyl groups for side chain and carboxy-terminal groups. These methods were illustrated by comparative syntheses of human P-endorphin (11) using a 10 Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu- 20 30 -Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (11) ‘’ R.Geiger and W. Konig in ref. 2 p. 55. 17 D. Hagiwara M. Neya Y. Miyazaki K. Hemmi and M. Hashimoto J. Chem. SOC.,Chem. Commun. 1984 1676. H. Yajima K. Akaji N. Fujii K. Hayashi K. Mizuta M. Aono and M. Moriga J. Chem. SOC.,Chem. Commun. 1984 1103. 19 P. A. Kiberstis A. Pessi E. Atherton R. Jackson T. Hunter and D. Zimmern FEBS Lett. 1983 164 355. ** (a) E. Atherton M. Caviezel H. Fox D. Harkiss H. Over and R. C. Sheppard J. Chem. SOC.,Perkin Trans. 1 1983 65; (b) E. Brown R. C. Sheppard and B. J. Williams ibid. 1984,75; (c) E. Brown R. C. Sheppard and B. J. Williams ibid. 1983 1161. Peptides 359 polydimethylacrylamide resin first with conventional protection (N"-Boc and ben- zyl side-chain protection with HF deprotection) and then with the mild protection strategy based on the Fmoc group.The yield of purified homogeneous /3-endorphin was 41% using the mild protection strategy and 9% using Boc-based protection. The advantages of mild deprotection are clearly seen in the chromatography (on carboxymethylcellulose) of the crude products obtained on deprotection and cleavage from the resin. A large number of by-products were resolved in the run of the HF-cleaved product whereas the crude product obtained by mild acid cleavage ran as a major peak with only minor by-products. Despite the demonstrated benefits of a mild deprotection strategy the majority of recent syntheses have employed conventional protection and cleavage procedures.This is due in part to the development of routine procedures using commercial synthesizers with the attendant ease and rapidity with which peptides of considerable length can be prepared and the use of h.p.1.c. to isolate the target peptide from complex product mixtures. It is commonplace for the isolation and characterization of novel peptides to be closely followed by published syntheses and an example is the family of natriuretic peptides isolated from rat atria. It has been known for some time that endogenous factors exist which promote the excretion of sodium from the kidney (natriuresis). Because of the potential link between the regulation of extracel- lular fluid volume (by variation in the concentration of plasma sodium) and essential hypertension the characterization of these factors is of considerable interest.A number of natriuretic peptides were isolated in 1983 and 1984; all are contained within the sequence of the largest of the isolated peptide (12). Three of large biologically active fragments of (12) were reported in 1984. Atlas et al. 10 Leu- Ala-GI y-Pro-Arg-Ser-Leu- Phe-Gly-Gly-Arg-Ile-Asp- Arg- Arg-Ser-Ser-Cys- 20 33 -Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly-Cys-Asn-Ser-Phe-Arg-Tyr synthesized a 24-residue peptide corresponding to residues 9-32 of (12) using a commercial synthesizer.2* Nu-Boc amino-acids were coupled using a water soluble carbodi-imide (the coupling solvent was not reported) and repetitive removal of the Boc group was done with TFA.Conventional side-group protection was used. After cleavage from the resin with HF the peptide was purified by gel filtration oxidized to the disulphide and directly compared with the native peptide of the same sequence in its ability to relax histamine-contracted aortic rings. The peptide was equally effective as the native peptide and 10-fold more active than the unoxidized synthetic peptide. Although the authors claim the first synthesis of a mammalian natriuretic and vasoactive factor no evidence was given to establish the homogeneity amino- acid composition or sequence of the synthetic peptide. In a later synthesis of two peptides corresponding to residues 10-30 and 9-33 of (12) by similar methods on a commercial synthesizer the crude HF-cleaved peptides required purification by gel-filtration ion-exchange and repeated h.p.1.c.before homogeneity was 21 S. A. Atlas H. D. Kleinert M. J. Camargo A. Januszewicz J. E. Sealey J. H. Laragh J. W. Schilling J. A. Lewicki L. K. Johnson and T. Maack Nature (London) 1984 309,717. 360 C.E. Dempsey achieved., The pure synthetic peptides (obtained in 15% yield) were sequenced by Edman degradation. The longer peptide was indistinguishable from the native peptide by h.p.1.c. and in several biological assays and was 70-fold more effective than the 21-residue peptide in natriuretic activity. A third synthesis23 of an atrial natriuretic factor [residues 8-33 of (12)] was done by solution condensation of fragments corresponding to sequences 8-15 16-21 22-25 and 26-33 of (12) which were synthesized on solid supports.The advantages of this approach are i small peptides of suitable sequence can be prepared with minimal side-group protection ;here fragment one required only thiol protection (as carboxamidomethyl ; Acm); ii alternative cleavage methods are often possible with small peptides and fragments one two and three were cleaved by transesterification or catalytic hydro- genation; and iii fragments may be purified before coupling in solution (to 97-99% homogeneity in the present case). Side-chain protecting groups [Asp( Bzl) and Arg(NO,)] were removed by hydrogenolysis and the fragments were condensed in sequence using a modified azide procedure. The Acm protecting groups were removed with simultaneous formation of the disulphide bond by treatment with iodine.The purified peptide was characterized by amino-acid and sequence analysis h.p.l.c. and fast atom bombardment mass spectrometry of fragments and was equipotent with a native peptide [residues 8-33 of (12)] in contracting smooth muscle and more potent in natriuretic activity. The rapid syntheses of atrial natriuretic peptides were no doubt facilitated by the small number of ‘difficult’ amino-acids in these peptides [sequence (12) contains no Lys Trp or Met]. Merrifield has continued to explore alternatives to the final cleavage with HF which is recognized to be the main source of side reactions in the standard solid-phase method. Side reactions arise from acylation or alkylation of the peptide by carbenium ions generated (by an SNl mechanism) after protonation of the protecting group carbonyl in HF.It was argued that these could be avoided if the acid deprotection was diverted through an SN2-type mechanism by-passing formation of reactive carbenium ions.24 This could be achieved by diluting the HF (and so reducing its acidity function) with a weak base (dimethyl sulphide; DMS) which remains unprotonated under the acid conditions required to protonate the protecting group and so is available for nucleophilic participation in the cleavage reaction. A low concentration of HF in DMS (HF DMS :p-cresol; 25 :65 :10 v/v) was suitable and could deprotect synthetic peptides containing most standard protecting groups in high yield with a low degree of side reactions.For those protecting groups stable to low HF concentrations (such as tosyl for Arg or 4-methylbenzyl for Cys) the low HF treatment must be followed by the standard high concentration of HF. The latter treatment is now relatively free of side reactions however because most of the protecting groups generating carbenium ions are removed in the low HF treatment. Rat transforming growth factor a fifty-residue peptide containing three disulphide bonds has been synthesized using standard 22 M. Sugiyama H. Fukumi R. T. Grammer K. S. Misono Y. Yabe Y. Monsawa and T. Inagami Biochem. Biophys. Res. Commun. 1984 123 338. 23 N. G. Seidah C. Lazure M. Chretien G. Thibault R. Garcia M. Cantin J. Genest R. F. Nutt S. F. Brady T.A. Lyle W. J. Paleveda C. D. Colton T. M. Ciccarone and D. F. Veber Proc. Natl. Acad. Sci. USA 1984,81 2640. 24 J. P. Tam W. F. Heath and R. B. Memfield J. Am. Chem. Soc. 1983 105 6442. Peptides 361 Merrifield methods in combination with the 'low-high' HF deprotection and ~leavage.~' The crude peptide was oxidized (using glutathione) to avoid polymeriz- ation during purification by gel-filtration and reverse-phase h.p.1.c. The peptide was characterized by amino-acid analysis (of both enzymatic and acid hydrolysates) and co-eluted with native rat transforming growth peptide on h.p.1.c. The yield of homogeneous peptide was a remarkable 31% based on the ini?ial loading of alanine to the resin. The same strategy has also been used in an improved synthesis of crystalline glucagon in 41 YO yield.26 Improvements have been made in the use of hydrogenolysis as an alternative to acidolytic deprotection and cleavage although the method is still limited by the presence of sulphur-containing amino-acids.Thymosin (28 amino-acids with no Cys or Met) has been synthesized on a benzhydrylamine resin without acidolytic treatments2' N"-Fmoc protecting groups were repetitively cleaved with 55YO pyridine in DMF and hydrogenolysis-labile side-chain protection (benzyl and Boc) was used. The peptide was cleaved and deprotected by repeated (3-times) catalytic transfer hydrogenation with cyclohexa- 1,4-diene in the presence of palladium black in 84% yield and the overall yield of purified peptide was 22%.In another example,28 an ACTH pentadecapeptide fragment analogue (having no Cys or Met) was synthe- sized using N"-Boc amino-acids and benzyl side-chain protection on a poly(styrene- 1'10 divinylbenzene) resin. The peptide was cleaved and deprotected by catalytic transfer hydrogenation using a palladium catalyst and ammonium formate as the in situ hydrogen source with a yield after work up of 94%. 3 Sequence Determination Instrumental improvements in the automated peptide sequencer based on the Edman degradation continue to be reported and it is now possible to carry out routine sequence analysis with less than 100 picomoles of pol~peptide.~~ A recent advance is the so-called 'gas-phase' microsequencerZ9 in which the peptide is non-covalently immobilized on a Polybrene" support and the Edman reagents are delivered as vapours in a stream of argon.This modification has several advantages over the conventional spinning-cup sequencer including the minimization of loss of peptide from the reaction chamber and the reduction in volume of reagents required to effect both the Edman coupling and cleavage reactions and extraction of the resulting anilinothiazolinones. The latter are converted into phenylthiohydantoin (PTH) amino-acids and analysed by h.p.1.c. with picomole sensitivity. The increased efficiency and sensitivity afforded by technical improvements of this type can be important as the amount of peptide available for sequencing is often very small. An example is the isolation and sequencing of human hypothalamic growth hormone releasing factor (GRF).The hypothalamus has long been known to contain factors 25 J. P.Tam H. Marquardt D. F. Rosberger T. W. Wong and G. J. Todaro Nature (London) 1984,309 376. 26 S. Mojsov and R. B. Merrifield Eur. J. Biochem. 1984 145 601. 27 R. Colombo J. Chem. Soc. Chem. Commun. 1981 1012. 28 M. K. Anwer A. F. Spatola C. D. Bossinger E. Flanigan R.C. Liu D. B. Olsen and D. Stevenson J. Org. Chem. 1983 48 3503. 29 M. W. Hunkapillar J. E. Strickler and K. J. Wilson Science 1984 226 304. * Polybrene is a quaternary ammonium salt which adheres strongly to both polypeptides and glass surfaces. C. E. Dempsey with stimulatory and inhibitory effects on growth hormone secretion but previously only the inhibitory factor (somatostatin) could be characterized.It was found however that certain pancreatic tumours secrete a factor with GRF activity and using an immobilized antibody raised against a synthetic fragment of the pancreatic factor 1.3 nmol of hypothalamic GRF could be ~btained.~' Two samples of 0.5 nmol were sequenced using the gas-phase sequencer and the first 43 residues were directly established. The C-terminal leucine was deduced from the quantitative amino-acid composition. It was not possible to determine by sequencing whether the C-terminal carboxyl was amidated or free and this was done by synthesizing the a-amidated 44 residue peptide and its free a-carboxyl analogue. Comparison with the native peptide in two h.p.1.c. systems established the C-terminal amide and indirectly confirmed the sequence (13).10 Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Va~-Leu-Gly-Gln-Leu-Ser- 20 30 -Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln- 40 44 -Glu-Arg-Gl y-Ala-Arg-Ala-Arg-Leu-NHZ (13) The sensitivity in sequencing by direct Edman degradation is ultimately limited by that achievable in identifying the cleaved N-terminal amino-acid derivative. Dimethylaminoazobenzene isothiocyanate [DABITC ;(14)] has been introduced as a modified Edman reagent for manual ~equencing.~' DABTH*-amino-acids absorb strongly at visible wavelengths and can be analysed by t.1.c. or h.p.l.c. in the latter case with subpicomole ~ensitivity.~~ Fluorescein isothiocyanate is also used in manual sequencing and an improved h.p.1.c.separation of fluorescein thiohydantoin amino acids with an analytical sensitivity of 50 femtomoles has been reported.33 These modified Edman reagents are limited by low solubility and coupling efficiency and must be used with an additional PITCT coupling to ensure maximal cleavage at each cycle. A modified reagent with similar sequencing efficiency as PITC is 4-(Nu-Boc-aminomethyl) phenylisothiocyanate (15).34 Compound (15) contains a cryptic amino-group which is revealed by hydrolysis of the Boc protecting group during acid cleavage of the coupled N-terminal amino acid. This amino group can be 30 N. Ling F. Esch P. Bohlen P. Brazeau W. B. Wehrenberg and R. Guillemin Proc. Natl. Acad. Sci.USA 1984,81 4302. 31 J.-Y. Chang Methods Enzymol. 1983 91 455. 32 C.-Y. Yang and S. J. Wakil Anal. Biochem. 1984 137 54. 33 K. Muramoto H. Kamiya and H. Kawauchi Anal Biochem 1984 141 446. 34 J. J. L'Italien and S. B. H. Kent J. Chromafop-.,1984. 283 149. * DABTH = dimethylaminoazobenzene thiohydantoin. t PITC = phenyl isothiocyanate. Peptides 363 derivatized to yield a fluorescent (or otherwise modified) thiohydantoin to enhance detection sensitivity. It is still possible in practice to approach the sensitivity of automated sequencers by manual sequencing using the dansyl-Edman method. Porcine neuropeptide Y a 36 residue C-terminally amidated peptide from mammalian brain was sequenced using 17 nanomoles of ~eptide.~’ The required sensitivity was achieved by using h.p.1.c.to isolate tryptic peptides and a subtractive dansyl-Edman technique in which an aliquot of the acid hydrolysate obtained from the dansylated peptide after each cycle of Edman degradation was redansylated and analysed by t.1.c. This allows the amino-acid lost in each cycle to be identified and provides an independent check on the course of the degradation. The sequence of secapin (from bee venom) has been revised by dansyl-Edman ~equencing.~~ The new sequence (16) corrects two previously proposed sequences one of which was obtained by mass spectrometry. 10 Tyr-Ile-Ile-Asp-Val-Pro-Pro-Arg-Cys-Pro-Pro-Gly-Ser-Lys-Phe-Ile-Lys- 20 25 -Asn- Arg-C& Arg-Val-Ile-Val- Pro (16) Fast atom bombardment (FAB) mass spectrometry has been used to study pep- tides.37 Underivatized polar molecules can be ionized by bombarding with a stream of fast neutral atoms (typically argon or xenon) and pseudomolecular ions have been observed from polypeptides of molecular weights above 9000.Fragment ions are considerably less abundant than the molecular ion but can be used to obtain sequence information if sufficient peptide is used (2-50 nmol). The technique is most useful for peptide sequencing in combination with more traditional methods of peptide chemistry and this approach was used in sequencing human Calcitonin Gene-Related Peptide [CGRP; (17)].38The molecular weight of intact CGRP and 10 Ala-C$s- As p-Thr-Ala-Thr-C$s-Val-Thr-His-Arg- Leu- Ala-Gly-Leu-Leu-Ser- Arg- 20 30 -Ser-GI y-Gly-Val-Val-Lys- Asn- Asn- Phe-Val-Pro-Thr-Asn-Val-Gly-Ser-Lys-37 -Ala- Phe- NH of tryptic peptides (in an unfractionated digest) were obtained by FAB mass spectrometry.Several of the tryptic peptides were sequenced by a combination of mass spectrometry further proteolytic digestion and amino-acid analysis (which was necessary to distinguish leucine from isoleucine). The low-mass region of the FAB spectrum of intact CGRP gave C-terminal sequence ions which established 35 K. Tatemoto Proc. Natl. Acad. Sci. USA 1982 79 5485. 36 L. K. Liu and C. A. Vernon J. Chem. Res. (S) 1984 10. 37 (a) M. Barber R. S. Bordoli R. D. Sedgwick and A. N. Tyler J. Chem. Soc. Chem. Commun. 1981 325; (6) D. H. Williams C. Bradley G. Bojesen S.Santikarn and L. C. E. Taylor J. Am. Chem. SOC. 1981 103 5700. 38 H. R. Moms M. Panico T. Etienne J. Tippins S. I. Girgis and I. MacIntyre Nature (London),1984 308 746. 364 C. E. Dempsey the sequence 20-3 1. Other sequence information was obtained by N-terminal analysis (by the dansyl method) of purified tryptic fragments and mass spectrometry of the reduced and carboxymethylated peptide. It is noteworthy that the disulphide bond and the presence of a C-terminal amide could be unambiguously established from the fragmentation information. An alternative method for peptide sequencing39 makes use of the greatly increased detection limit for charged compounds relative to uncharged ones in FAB or secondary ion mass spectrometry (SIMS).If the N-terminal amino group of a peptide is selectively derivatized with a charged group non-specifically cleaved with acid and the resulting mixture esterified and acylated (to eliminate residual charged sites) then the mass spectrum of the resulting mixture will preferentially reveal ions containing the charged group. These ions originate from the N-terminal end of the peptide and the sequence can thus be determined from the mass differences between the ions. The method has so far only been applied to simple tripeptides. Mass spectrometry is uniquely suited to structural analysis of small amounts of peptide containing structural units other than the standard amino-acids. The struc- tures of urinary sleep-promoting factors have been solved by FAB mass spectrometry in combination with structural studies on muramyl peptides of known structure.40 These factors appear to be a family of related muramyl peptides and a representative structure is (18) (where Dap is diaminopimelic acid).The necessary information CH,OH I NHCOMe ,J NHCOM~ Me CH(CO)-Ala-y-D-Glu-Dap-D-Ala for structure determination was achieved by FAB molecular weight and fragmenta- tion analysis of components purified by h.p.l.c. then acetylation and methylation to determine (by mass spectrometry) amino and carboxyl groups respectively and enzymatic cleavage of the disaccharide followed by FAB analysis of the purified free sugar and peptide. Endogenous muramyl peptides probably arise from bacterial cell wall fragments that are absorbed in the gut and incorporated into neuromodu- lators in the brain.The isolation and characterization of these factors is a result of some fifteen years effort an interesting historical account of which is available.41 Some of the most difficult structures are those peptides from micro-organisms many of which are cyclic and may contain D-amino-acids novel blocking groups and new or highly conjugated amino-acids. The structural studies of D. H. Williams and his collaborators are notable in this area and have been reviewed?2 39 D. A. Kidwell M. M. Ross and R.J. Colton J. Am. Chem. Soc. 1984 106 2219. 40 S. A. Martin M. L. Karnovsky J. M. Krueger J. R. Pappenheimer and K. Biemann J. Biol Chem. 1984 259 12652. 41 J. R. Pappenheimer J. Physiol.(London) 1983 336 1. 42 D. H.Williams Chem. SOC.Rev. 1984 13. 131. Peptides 365 Peptide Sequences from DNA Sequencing.-The sequences of some endogenous peptides have been determined by DNA sequencing even before their existence in vivo has been realized. This peculiar situation arises from the fact that most if not all endogenous peptides are biosynthesized as part of large precursors which may contain the sequences of several peptides. It is sometimes possible to isolate messenger RNA coding for peptide precursors and this can be used as a template for in vitro biosynthesis of the complementary DNA (cDNA). The cDNA is isolated hybridized (to form the base-paired double helical dimer) and inserted into the genetic material of a bacterium (via a bacterial plasmid).With suitable manipulations (see for example ref 43) a bacterial clone containing the desired precursor cDNA is obtained from which the latter can be isolated and sequenced by chemical methods. Potential endogenous peptides are sequences bounded by pairs of basic amino-acids from which the peptide is liberated by proteolytic excision (although C-terminal proteolytic cleavage at single arginine residues is known). A C-terminally amidated peptide is predicted if the amino-acid preceding the C-terminal proteolytic excision point is glycine. The amino-acid sequence of an enkephalin precursor (bovine proenkephalin A) was obtained in this way4 and a novel C-terminally amidated peptide of 26 amino-acids was predicted (residues 104-129 of the precursor sequence).Extracts of bovine adrenal medulla were fractionated using antibodies raised against synthetic fragments of the predicted peptide and a peptide having the requisite immunoreactivity was isolated.45 The peptide (named amidorphin) was sequenced and had the structure predicted from the precursor sequence. This confirms that amidorphin a peptide predicted from analysis of a DNA sequence is a true endogenous peptide (the physiological function of which remains to be determined). It is of course not possible to determine from the DNA sequence whether post-translational modification of the polypeptide will occur; this can only be done by isolation and structural characterization of the expressed polypeptide. The sequence of human T-cell growth factor (also called interleukin 2) was predicted by cDNA sequencing but when the purified peptide was subjected to Edman degradation an unassignable PTH amino-acid was found at position-3.It was subsequently found by analysis of the N-terminal tryptic peptide using FAB mass spectrometry that the third amino-acid residue of the growth factor was serine with an 0-linked N-acetylgalactosamine residue.46 The function of polypeptide-linked carbohydrate in this case and in general remains obscure. 4 Physical Studies Many studies of the conformational properties of peptides in solution continue to be reported. The information available from high resolution n.m.r. has been enhan- ced by the application of two-dimensional (2-D) n.m.r. methods to peptide 43 J.E. Davies and H. G. Gassen Angew. Chem. Inf. Ed. EngL 1983 22 13. 44 (a) M. Noda Y. Furutani H. Takahashi M. Toyosato T. Hirose S. Inayarna S. Nakanishi and S. Nurna Nume (London) 1982 295 202; (b) U. Gubler P. Seeburg B. J. Hoffrnann L. P. Gage and S. Udenfriend ibid. 1982 295 206. 45 B. R. Seizinger D. C. Liebisch C. Grarnsch A. Herr E. Weber C. J. Evans F. S. Esch and P. Bohlen Nature (London) 1985 313 57. 46 R. J. Robb R. M. Kutny M. Panico H. Morris W. F. DeGrado and V. Chowdhry Biochem. Biophys. Res. Comrnun. 1983 116 1049. 366 C. E. Dempsey conformations and the use of versatile techniques for following the exchange of magnetization between nuclei or among chemical species (reviewed in re$ 47).The most useful of the latter techniques for peptide conformations are the nuclear Overhauser effect (n.O.e.) which allows the separation of nuclei to be estimated over short (24 A) distances (assuming a reasonable degree of conformational stability) and saturation transfer which can (in favourable cases) yield exchange rates between interconverting conformational states and more generally be used to measure the rates of exchange of peptide amide protons with water. The potential of high resolution 2-D n.m.r. for studying the conformation (and conformational fluctuations) even of small proteins is best illustrated in the work of Wuthrich and his collaborators on the bovine pancreatic trypsin inhibitor.48 A conformational study49 of apamin (19) using one dimensional n.m.r.was illustrated in Annual Reports for 19801 and the conformation in water has been re-investigated using 2-D n.m.r. methods5' An essentially complete assignment of the proton n.m.r. spectrum of apamin was achieved by 2-D correlated spectroscopy (which establishes a complete set of J-coupling relationships in the molecule) and 2-D n.0.e. spectroscopy. Based on revised resonance assignments and the distance constraints between protons from n.0.e. experiments a new model for the conforma- tion of apamin in water has been proposed. The most interesting feature of the model is the presence of a helix comprising residues 9-18 of sequence (19). This helix contains the residues (Arg-13 Arg-14) whose side-chain guanidino groups are important for the biological activities of apamin.The p-turn enclosing residues 2-5 proposed by Bystrov et is retained and hydrogen bonds between the amide proton of Thr-8 and the Ala-5 carbonyl and between the amide of Lys-4 and the side-chain carbonyl of Asn-2 are added. The new conformation is consistent with previously determined49 coupling constants and amide exchange rates. lo 18 I I Cys-Asn-Cys-Lys-Ala-Pro-Glu-Thr-Ala-Leu-Cys-~a-~g-Arg-Cys-Gln-Gln-His-NH~ I I It continues to be true that the most useful and unambiguous information on the conformations of peptides in water is obtained from large polypeptides or those containing multiple disulphide bonds i.e. peptides having a high degree of conforma- tional stability. Small linear peptides of which many of the known hormones and neuropeptides are examples are highly flexible in physiological solutions ; n.m.r.studies on ~omatostatin~~ for example have been concerned with and brad~kinin,~~ their conformational diversity. An extreme example of the difficulty in defining unambiguous conformational information for small peptides is provided by work 47 R. Benn and H. Giinther Angew. Chem. Int. Ed. EngL 1983 22 350. 48 (a) K. Wuthrich G. Wider G. Wagner and W. Braun J. Mol. Biol. 1982 155 311; (6)G. Wagner C. I. Stassinopoulou and K. Wuthrich Eur. J. Biochem. 1984 145 431. V. F. Bystrov V. V. Okhanov A. I. Miroshnikov and Yu. A. Ovchinnikov FEBS Lett. 1980 119 113. D. Wemmer and N. R. Kallenbach Biochemistry 1983,22 1901. M.Knappenberg A. Michel A. Scarso J. Brison J. Zanen K. Hallenga P. Deschrijver and G. Van 49 50 51 Binst Biochem Biophys. Acta 1982 700 229. 52 L. Denys A. A. Bothner-By G. H. Fisher and J. W. Ryan Biochemistry 1982 21,6531. Peptides 367 on leucine-enkephalin (20). N.m.r. and model building studies have indicated that a conformation with a P-turn involving a hydrogen bond between the amide of Phe-4 and the Tyr-1 carbonyl is a dominant low energy conformer although it has also been shown that the conformations of enkephalins are sensitive to changes in the properties of the solvent.53 The enkephalins have been studied by proton and 13C n.m.r. in the presence of phospholipid vesicles and the lipid environment is proposed to promote a folded conformation with a &turn between Leu (or Met) and Gly-2 and the side chains of residues 1,3 and 5 buried within the lipid matrix.54 Both leucine-enkephalin5’ and methionine-enkephalins6 have been crystallized (from water-dimethylformamide mixtures and from water respectively) and in each case an extended anti-parallel P-sheet conformation has been found.Moreover even in the crystal the conformations are heterogeneous; the unit cell of the leucine- enkephalin crystal contains four independent pentapeptide conformers and that of methionine-enkephalin contains two. These studies indicate the variety of conforma- tions accessible to the enkephalins but say little about the important receptor-bound conformations. More direct information has come from the use of conformationally constrained analogues.A semi-rigid analogue (21)(where A,bu is a,y-diaminobutyric acid) has been synthesized and compared with leucine-enkephalin for binding ability in a guinea pig ileum (GPI) assay (which is relatively specific for the psubclass of opiate receptors) and the mouse vas deferens (where opiate effects are mediated Tyr-Gl y-Gl y-Phe- Leu Tyr-cyclo[-NY-~-A,bu-Gly-Phe-Leu-] (20) (21) mainly by S-receptors).” The cyclic analogue (21) was 17-times more potent than leucine-enkephalin in the preceptor assay and seven times less potent as a &receptor agonist. A linear analogue of (21) was equipotent in both assays. Compound (21) was therefore assumed to have a conformation highly favourable for interaction with the opiate preceptor but less able to adopt the conformation required to bind optimally to the &receptor.These results are of interest because they indicate that p-and S-opiate receptor subtypes have different conformational requirements for ligand binding. Because the analogue (21) is semi-rigid it was possible to explore the preferred conformation for the preceptor and notably it could be shown that (21) was unable to adopt the P-turn conformation suggested by the n.m.r. and model building studies.58 The use of classical structure-activity studies to identify functional groups together with conformational analysis to direct the synthesis of conformationally constrained analogues having predicted agonist or antagonistic properties has been a fruitful approach to peptide drug design.With this strategy the minimal functional structure of somatostatin (14 amino-acids) has been reduced to a cyclic hexapeptide having 50-100-times the potency of the native peptide in the inhibition of release 53 L. Zetta and F. Cabassi Eur. J. Biochem. 1982 122 215. 54 B. A. Behnam and C. M. Deber J. Biol. Chem. 1984,259 14935. 55 A. Camerman D. Mastropaolo I. Karle J. Karle and N. Camerman Nature (London) 1983,306,447. 56 T. Ishida M. Kenmotsu Y. Mino M. Inoue T. Fujiwara K. Tornita T. Kirnura and S. Sakakibara Biochem. J. 1984 218 677. 57 P. W. Schiller and J. DiMaio Nature (London) 1982 297 74. 58 J. DiMaio and P. W. Schiller Roc. Nafl. Acad. Sci. USA 1980 77 7162. 368 C.E.Dempsey of insulin glucagon and growth hormone in rats.59 A bicyclic analogue [(22) where Mpa is P-mercaptopropionic acid and the side chains of Asp-5 and Lys-8 are linked by an amide bond] of vasopressin (30) (see p. 000) was predicted and found to be an antagonist of the antidiuretic activity of the native peptide and in addition was selective in that the antipressor activity of the latter peptide was only partially antagonized.60 Mpa-Tyr-Phe-Gln-cyclo[ -P-Asp-Cys-Pro-Lys-N'-] -Gly-NH (22) Much evidence has arisen for the notion that some linear peptide hormones can adopt ordered conformations at membrane surfaces and that these conformations are important for biological activity. A number of peptides have been shown by circular dichroism studies to adopt helical conformations in the presence of deter- gents or phospholipids,61 and in one case that of adrenocorticotropin (ACTH) a 39-residue peptide which induces the synthesis of steroid hormones in the adrenal cortex the biological activities of fragments correlate with their ability to penetrate phospholipid bilayers6* ACTH( 1-21) is a fully potent agonist of native ACTH and it is known from structure-activity studies that the N-terminal decapeptide is responsible for triggering the biological responses of ACTH while the C-terminal sequence modulates the activity with respect to different receptors.The conformation of ACTH(1-21) in lipid bilayers was studied by a combination of photoaffinity labelling using a hydrophobic photoactivable compound 3-trifluoromethyl-3-( m-['''1 ]iodophenyl)diazirine which upon photolysis labels regions of the peptide that enter the hydrophobic core of the membrane and infrared attenuated total reflection spectroscopy which can be used to estimate the orientation of ordered peptide segments in the membrane.63 It was suggested from these experiments that the N-terminal decapeptide enters the membrane as a perpendicular helix while the C-terminal region lies along the membrane surface stabilizing the association of peptide and membrane.Interestingly neither the N-terminal decapeptide nor the C-terminal fragment of ACTH( 1-21) was able in isolation to associate with membranes. Kaiser and his colleagues have proposed that the potential for some peptides to adopt so-called amphiphilic helices in which hydrophobic and hydrophilic amino- acids segregate on different faces of the helix (Figure 1) may be an important property but one which is relatively non-specific with respect to the amino-acid sequence.64 Their approach to this idea is illustrated for @-endorphin (11).p-Endorphin has the potential to form an amphiphilic n-helix (see Figure 1) or a-helix and is known to adopt a helical conformation on interaction with phospholipids. An analogue of @-endorphin was synthesized in which the C-terminal residues 59 D. F. Veber R. Saperstein R. F. Nutt R. M. Freidinger S. F. Brady P. Curley D. S. Perlow W. J. Paleveda C. D. Colton A. G. Zacchei D. J. Tocco D. R. Hoff R. L. Vandlen J. E. Gerich L. Hall L. Mandarino E.H. Cordes P. S. Anderson and R. Hirschmann LifeSci. 1984 34 1371. 60 G. Skala C. W. Smith C. J. Taylor and J. H. Ludens Science 1984 226 443. 61 C.-S. C. Wu A. Hachimori and J. T. Yang Biochemistry 1982 21 4556. B. Gysin and R. Schwyzer FEBS Lett. 1983 158 12. 63 H.-U. Gremlich U.-P. Fringeli and R. W. Schwyzer Biochemistry 1984 23 1808. 64 E. T. Kaiser and F. Z. Kezdy Science 1984 223 249. Pept ides 369 Tyrl -Gly-Gly-Phc-Met ---1tyl2 Figure 1 Amphiphilic distribution of amino-acids in the C-terminal sequence of P-endorphin [see (1l)] on formation of a .rr-helix (viewed down the helix axis). Hydrophobic amino-acids are shaded (residues 14-31) were replaced by a non-homologous sequence but which was predicted to generate a similar amphiphilic structure on helix formation.Only leucine glutamine and lysine were used for this region and the N-terminal sequence (residues 1-13) was left unchanged. The analogue was more potent than P-endor- phin in the GPI assay (which is of little significance because the preceptor has little sensitivity to C-terminal structure of enkephalin-containing sequences) and was about one-fifth as active in the rat vas deferens assay in which the opiate effects are mediated by a third class of opiate-receptors the &-receptor. The latter activity is remarkable because the &-opiate receptor is highly specific for P-endorphin and is very sensitive to changes in the C-terminal part of the peptide. An analogue having a similar potential for C-terminal amphiphilic helix formation but consisting only of D-amino-acids in residues 13-31 again had high activity in the &-receptor assay.65 A third analogue was designed to minimize the potential for the amphiphilic helix but retained a similar amino-acid composition to the active analogues.This (negative) model showed little activity in the &-receptor assay. These experiments support the idea that the potential for amphiphilic helix formation is an important function for the C-terminal sequence of P-endorphin and similar conclusions have been reached for several other biologically active pep tide^.^^ 5 Endogenous Peptides An increasing number of peptides are isolated using antibodies raised against (synthetic) peptides originally purified from non-mammalian species or predicted from the sequences of cloned DNA coding for peptide precursors.Systematic screening of tissue extracts using chemical or immunochemical assays as well as bioassay has produced many novel peptides. Much research continues to be aimed at defining the distribution of these peptides in vivo and their physiological functions. J. P. Blanc and E. T. Kaiser J. Bid. Chem. 1984. 259 9549. 370 C.E. Dempsey CGRP (171 for example was originally predicted from a cDNA sequence coding for a precursor generated by alternative processing of the calcitonin gene.66 In the thyroid the calcitonin gene is processed to form the calcitonin precursor whereas in non-thyroid tissue (particularly the central and peripheral nervous system) the precursor for CGRP is formed.CGRP has been localized in the nervous system (using a fluorescently labelled antibody),66 was released from stimulated cultured neurons and when injected into the brains of rats produced a marked increase in blood pressure and heart These experiments indicate that CGRP is an endogenous neuropeptide. CGRP also produced peripheral eff ecd7 and it has been shown that injection of as little as 15 femtomoles (15 x mol) into rabbit or human skin induces a marked vasodilatory response.68 This extraordinary potency suggests that the vasodilatory action of CGRP has a physiological function. If a peptide can be shown to have a biological activity at concentrations similar to those occurring in vivo then this supports the idea that the activity is physiologically relevant.An interesting example is Nerve Growth Factor (NGF). NGF is character- ized by its activity on the development of sympathetic and sensory neurons. The main sources of NGF are diverse (mouse salivary gland snake venoms and placenta) but the concentrations in mammalian sera are very low -a few pg per litre. Indeed the low concentrations of NGF complicate its quantification and there is some dispute over serum levels.69970 Nevertheless it has been shown that NGF is a power- ful anti-inflammatory agent in the rat (it suppresses the inflammatory response to an irritant injected into the rat hind paw) and is effective at concentrations of 5 pg kg-'.69 These levels are similar to the concentration of NGF in serum that can be measured by bioassay.NGF has also been shown to induce directed migration in vitro of human cells that are involved in the inflammatory response (although at higher concentrations than are required for anti-inflammatory a~tivity).~' Whether these new activities of NGF are related is not known. Many sequences of biosynthetic precursors for peptide hormones and neuropep- tides have now been obtained by analysis of cloned DNA sequences and this has been of great value in understanding the biosynthetic origins and interrelationships of endogenous peptides. Immunohistochemical co-localization of structurally related peptides has in some cases indicated a common biosynthetic origin and PHI (10) and VIP for example have been identified within the same cell and subsequently found to share a common precursor.12 The evidence that the neurohypophysial hormones oxytocin and vasopressin are processed from precursors which also encode their respective neurophysins has been confirmed by cDNA sequence analysi~.'~ The precursor relationships between families of endogenous peptides are best characterized for the opiate peptides.All the known endogenous opiate peptides 66 M. G. Rosenfeld J.-J. Mermod S. G. Amara L. W. Swanson P. E. Sawchenko J. Rivier W. W. Vale and R. M. Evans Nature (London) 1983 304,129. 67 L. A. Fisher D. 0. Kikkawa J. E. Rivier S. G. Amara R. M. Evans M. G. Rosenfeld W. W. Vale and M. R. Brown Nature (London) 1984 305 535. 68 S. D. Brain T. J. Williams J. R. Tippens H. R. Morris and I.MacIntyre Nature (London) 1985,313 54. 69 B. E. C. Banks C. A. Vernon and J. A. Warner Neurosci. Lett. 1984,47 41. 'O S. Korsching and H. Thoenen Roc. Natl. Acad. Sci USA 1983 80 3513. 71 A. P. Gee M. D. P. Boyle K. L. Munger M. J. P. Lawman and M. Young Proc. Natl. Acad. Sci. USA 1983 80 7215. 72 H. Land G. Schutz H. Schmale. and D. Richter Nature (London) 1982 295 299. Peptides 37 1 are encoded within the sequences of three precursors which have been sequenced from their cDNA. The precursor named pro-opiomelanocortin contains &endorphin (plus several non-opiate peptides like ACTH) proenkephalin A contains the enkephalins (plus a number of C-terminally extended enkephalins such as amidor- phin) and proenkephalin B contains the dynorphin pep tide^.^^ Each of these biosynthetic precursors is processed within anatomically distinct neuronal systems and may undergo differential processing to generate distinct sets of bioactive peptides in different areas of the nervous Two (bovine) precursors containing the sequence of substance P (23) have been sequenced from their cDNA~~ and one of these additionally has the sequence of a peptide homologous to the frog skin peptide kassinin (24).The new peptide [(25) named alternatively substance K,75neurokinin or neuromedin L77] has been independently purified from porcine spinal cord by two Japanese groups76v77 in addition to a second homologous peptide (26) neurokinin p76or neuromedin K.77 Arg-Pro-Lys- Pro-Gln-Gln- Phe- Phe- Gly-Leu-Met- NH (23) Asp-Val- Pro-Lys-Ser- Asp-Gln- Phe-Val- Gly-Leu-Met- NH (24) His-Lys-Thr-Asp-Ser-Phe-Val- Gly-Leu-Met- NH (25) Asp-Met-His-Asp-Phe- Phe-Val- Gly-Leu-Met- NH (26) Peptide (26) is presumably generated from a novel precursor.These peptides are members of a larger class of peptides named tachykinins having the common (italicized) C-terminal sequence and originally discovered in frog skin and octopus salivary gland. As with the opioids tachykinin receptor sub-types exist and it is proposed that peptides (25) and (26) are the endogenous agonists of one subtype (SP-E receptors) while substance P acts at ‘so-called’ SP-P receptors.78 Other peptides homologous to frog skin peptides have been isolated from mammalian tissues. These include neuromedin B and C from porcine spinal which with one amino-acid substitution have the same sequence as the C-terminal decapeptide of bombesin and ovine corticotropin-releasing factor (CRF),80a 41 residue peptide homologous to sauvagine.The enzymatic mechanism for generating C-terminally amidated peptides from their precursors has been studied using model peptides having a CJterminal glycine 73 R. J. Miller J. Med. Chem. 1984 27 1239. 74 N. Zamir E. Weber M. Palkovits and M. Brownstein Roc Nutl. Acud. Sci. USA 1984 81 6886. 75 H. Nawa H. Kotani and S. Nakanishi Nuture (London) 1984 312 729. 76 S. Kimura M. Okada Y. Sugita I. Kanazawa and E. Munekata Roc. Jpn. Acud. Ser. B 1983,59 101. 77 K. Kangawa N. Minamino A. Fukuda and H.Matsuo Biochem. Biophys. Res. Commun. 1983,114,533. 78 J. C. Hunter and J. E. Maggio Eur. J. PharmucoL 1984 97 159. 79 N. Minamino K. Kangawa and H. Matsuo Biochem. Biophys. Res. Commun. 1984 124 925. 80 W. Vale J. Spiess C. Rivier and J. Rivier Science 1981 213 1394. C.E. Dempsey which is known from precursor sequences to precede the basic C-terminal cleavage point of amidated peptides.81 When peptide (27) was synthesized using "N-labelled glycine and incubated with extracts of porcine pituitary (a source of the amidating enzyme) the label was shown by mass spectrometry to be retained in the dipeptide amide (28). When a I4C a-carboxyl analogue of (27) was used the label was found in glyoxylate. These experiments support an oxidative mechanism involving removal of hydrogen from the C-terminal glycine and spontaneous hydrolysis of the resulting imino group (Scheme 4).Results from later experiments have been consistent with this mechanism.82 D-Tyr-Val- NH -CH2C0,H + D-Tyr-Val- N=CHC02H -* D-Tyr-Val- NH2 + CHOC0,H (27) (28) Scheme 4 A large number of peptides have been identified in neurons and nerve terminals of the mammalian central nervous system and these include almost all the known brain and gut peptides many of the classical hormones and a number of peptides first identified in non-mammalian species. Much effort has been spent on determining the distribution of these neuropeptides and their receptors with the expectation that some indication of function might be inferred.Immunohistochemical methods can be used to provide precise localization of immunoreactive species within individual neurons although cross-reaction between antisera and antigens structurally related to the 'target' peptide remains a source of error. This problem is particularly acute with the existence of multiple forms and homologous families of peptidesg3 Studies on neuropeptide Y are illustrative. Immunoreactive peptides recognized using anti- bodies raised against avian pancreatic polypeptide (APP) were localized in peripheral non-adrenergic neurons and in neurons of the human cerebral cortex although attempts to isolate and characterize the immunoreactive peptide have been unsu~cessful.~~ Neuropeptide Y has considerable homology with APP and when antibodies were raised against the former peptide immunoreactive material was found to co-exist in neurons with APP-like irnmunoreacti~ity.~~ When these neurons were re-examined using an antiserum more specific for APP the latter peptide was now undetectable.It was concluded that neuropeptide Y is the endogenous pan- creatic-polypeptide-like species in the mammalian nervous system. In peripheral tissues neuropeptide Y is localized in nerve fibres around blood vessels suggesting an effect on the vasculature and accordingly the peptide has been found to induce vasoconstriction although the concentrations required were rather high. At much lower concentrations neuropeptide Y enhanced the response of blood vessels to other vasoconstrictor agents.86 It is interesting that neuropeptide Y is co-localized 81 A.F. Bradbury M. D. A. Finnie and D. G. Smyth Nature (London) 1982 298 686. 82 C. C. Glembotski B. A. Eipper and R. E. Mains J. Biol. Chem. 1984 259 6385. 83 T. Hokfelt 0.Johansson and M. Goldstein Science 1984 225 1326. 84 J. M. Lundberg T. Hokfelt A. Angglrd L. Terenius R. Elde K. Markey M. Goldstein and J. Kimmel Proc. Natl. Acad. Sci. USA 1982 79 1303. 85 T. E. Adrian J. M. Allen S. R. Bloom M. A. Ghatei M. N. Rossor G. W. Roberts T. J. Crow K. Tatemoto and J. M. Polak Nature (London) 1983. 306 584. 86 L. Edvinsson E. Ekblad R. HHkanson and C. Wahlestedt Br. J. Pharmacol. 1984 83 519. Peptides 373 in sympathetic noradrenergic neurons with the transmitter norepinephrine which itself produces vasoc~nstriction.~~ It is suggested that in this system86 (and perhaps generally83) the peptide co-localized with a classical transmitter supports (or other- wise modulates) the action of the transmitter.Examples of the co-existence of multiple peptides within the same neurons have also been reported. In single rat hypothalamic neurons for example three immunoreactive peptides corresponding to PHI enkephalin and CRF have been identified.87 From the known actions of these peptides their co-release would be predicted to result in the parallel secretion of prolactin ACTH and growth hormone from the anterior pituitary. Such an effect is known to occur in the physiological response to stress and it is suggested that the neuronal co-existence of the former set of peptides may be involved in this response.The study of the function of neuropeptides and particularly their status as neurotransmitters is limited by the lack of truly selective antagonists for their effects in the brain. Recent work on cholecystokinin (CCK) provides an example. CCK is one of the most abundant of neuropeptides. It has been confirmed that a CCK-%like component is the major form in rat brain and that gastrins (which share the C-terminal pentapeptide amide) do not contribute significantly to CCK-like immunoreactivity in the brain.88 In addition CCK-like immunoreactivity has been purified from post-mortem human brain characterized by Edman degradation and negative ion FAB-MS and shown to be largely the sulphated CCK octapeptide (29).89CCK-like immunoreactivity is co-localized with the transmitter dopamine Asp-Tyr(OS03H)-Met-Gly-Trp-Met- Asp-Phe-NH (29) and because there is evidence that a hyperactive dopamine system underlies some of the symptoms of schizophrenia a role for CCK in the disease has been sought.Accordingly it has been shown that CCK increases the neuronal activity of dopamine-containing neurons suppresses the release of dopamine from neurons and is deficient in the brain and cerebrospinal fluid of untreated schizophrenics (see re$ 90). Confirmation of the central effects of CCK requires that they be blocked by a specific antagonist. An antagonist of the peripheral effects of CCK is proglumide (a glutaramic acid derivative). When proglumide was tested on the effects of CCK on dopamine-containing neurons the drug was effective in blocking the increase in neuronal activity of dopaminergic neurons by CCK but not the attenuation of dopamine release.It was suggested that the two actions of CCK are mediated by different receptor subtypes one of which is unresponsive to the effects of progl~mide.~' Receptors for vasopressin (30)are also heterogeneous in their response to antagon- ists and this has led to controversy over the role of the peptide in stress-induced secretion of ACTH from the pituitary. The hypothalamic factor responsible for the 87 T. Hokfelt J. Fahrenkrug K. Tatemoto V. Mutt S. Werner A.-L. Hulting L. Terenius and K. J. Chang Roc. Natl. Acad. Sci. USA 1983 80 895. 88 P.D. Marley J. F. Rehfeld and P. C. Emson J. Neurochem. 1984 42 1523. 89 L. J. Miller I. Jardine E. Weissman V. L. W. Go and D. Speicher J. Neurochem. 1984 43 835. 90 R.Y. Wang F. J. White and M. M. Voigt Trends Pharmacol. Sci. 1984 5 436. 374 C.E. Dempsey stress-induced release of ACTH is known to be a multifactorial complex one component of which appears to be CRF." Arginine vasopressin (30) has been proposed as another component and the peptide is known to potentiate the ACTH- releasing activity of CRF in vitro. A potent antagonist of the physiological effects of vasopressin is the synthetic analogue (31) and this was found to inhibit the increase in ACTH levels induced by vasopre~sin.~~ Levels of ACTH induced by stress were not inhibited by the drug (31) however and it was concluded from this that vasopressin is not involved in stress-induced release of ACTH.This conclusion was later disputed when it was shown that the pituitary vasopressin receptor is unresponsive to the vasopressin antagonist (3 1).92 Recent experiments have suppor- ted the idea that there are two distinct effects of vasopressin on the release of ACTH and that the indirect effect characterized by the potentiation of CRF-induced ACTH release (and apparently unresponsive to the standard vasopressin antagonists) is of physiological relevan~e.~~?~~ There is some evidence to suggest that metabolites of several brain peptides (rather than or in addition to the native peptide) may mediate particular effects in the brain.The idea (of De Wied) that vasopressin is involved in the consolidation of long term memory was described in Annual Reports for 1980.' Synthetic fragments of vasopressin are fully effective in mediating the behavioural effects of the peptide and for this reason an active metabolite has been proposed to occur in the brain. To test this idea vasopressin was incubated with isolated rat brain synaptic mem- branes and the metabolites were recovered and ~haracterized.~~ Arginine vasopressin was found to be degraded by an aminopeptidase which cleaved the peptide from the N-terminus but left the disulphide bond intact. Proteolysis was inhibited on formation of an N-terminal pyroglutamyl residue from Gln-4 and the stable meta- bolite (32) therefore accumulated.This peptide was 1000-times more active than Cys-Tyr-Phe-Gln- Asn-Cis-Pro- Arg-GI y-NH (30) CMe,-CH,-CO-Tyr( 0Me)-Phe-Gln- Asn-Cys-Pro-Arg-Gly-NH S-1 (31) pGlu-Am-&( Cis)-Pro- Arg-Gly-NH (32) arginine vasopressin in potentiating passive avoidance behaviour in rats a behavioural test used to assess the consolidation of long term memory. The authors report that preliminary studies using radioimmunoassay and h.p.1.c. indicate that a peptide with the properties of the metabolite (32) is present in rat brain. 91 P. Mormbde Nature (London) 1983,302 345. 92 A. J. Baertschi B. Gahwiler F. A. Antoni M. C. Holmes and G. B. Makara Nature (London) 1984 308 85. 93 J. C. Buckingham Br. J. PharmacoL 1985,84 213. 94 J. P. H. Burbach G.L. Kovics D. De Wied J. W. van Nispen and H. M. Greven Science 1984,221 1310. Peptides 375 Enzymatic processing of endogenous peptides may also result in peptides having antagonist properties. @Endorphin (1-27) is present in considerable amounts in the brain and has been assumed to be an inactivated form of &endorphin (11). Synthetic /3-endorphin (1-27) was found to be a potent antagonist of P-endorphin- induced analgesia and it is suggested that the fragment may have a physiological function perhaps of modulating the activity of opiates in ~ivo.~' 6 Exogenous Peptides A number of toxic peptides have been purified from the venom of the marine mollusc Conus geogruphus. Conotoxin GI (33)96 has an amidated C-terminus and two disulphide bonds paired97 in a manner similar to the bee venom peptides apamin and peptide-401.Two homologues of conotoxin GI have in one case a C-terminal Gly-Lys-NH extension and in the other amino-acid substitutions at positions 4 Glu-C~s-Cys-Asn-Pro-Ala-Cls-Gly-Arg-His-Tyr-Ser-~y~-~~* (33) 9 and 11 of the sequence.96 The conotoxins are postsynaptic toxins and appear to bind competitively to the acetylcholine receptor. Three longer toxins have been isolated from the same source and are characterized by an unusual number of hydroxylated amino-acids including hydroxyproline (Hyp).98*99 Each has two disul- phide bonds (one has consecutive cysteines as in the conotoxins) but the disulphide pairings have not been determined. One of these peptides o-conotoxin (34),99 acts presynaptically at the frog skeletal neuromuscular junction to block transmitter release apparently by blocking the stimulated influx of calcium.loO 10 Cys-Lys-Ser-Hyp-Gly-Ser-Ser-Cys-Ser-Hyp-Thr-Ser-Tyr-Asn-Cys-Cys-~g-Ser- 20 27 -Cys-Asn-Hyp-Tyr-Thr-Lys-Arg-Cys-Tyr-NH2 (34) Precursors encoding neuropeptides of the marine mollusc ApZysia have been sequenced from their cDNA and this has led to interesting speculation about the role of neuropeptides in the mediation of behaviour in this species."' The egg-laying behaviour of ApZysiu is accompanied by a stereotyped behavioural pattern which is known to be controlled by 'so-called' bag cells in the abdominal ganglion.Peptides seem to be neurotransmitters in the regulation of egg-laying behaviour and an egg-laying hormone (ELH) has previously been isolated and characterized.The 95 R. G. Hammonds P. Nicolas and C. H. Li Roc. Natl. Acad. Sci. USA 1984 81 1389. 96 W. R. Gray A. Luque B. M. Olivera J. Barrett and L. J. Cruz J. Biol. Chem. 1981 256 4734. 97 W. R. Gray F. A. Luque R. Galyean E. Atherton R. C. Sheppard B. L. Stone A. Reyes J. Alford M. McIntosh B. M. Olivera L. J. Cruz and J. Rivier Biochemistry 1984 23 2796. 98 S. Sato H. Nakamura Y. Ohizumi J. Kobayashi and Y. Hirata FEBS Let?. 1983 155 277. 99 B. M. Olivera J. M. McIntosh L .J. Cruz F. A. Luque and W. R. Gray Biochemistry 1984 23 5087. 100 L. M. Kerr and D. Yoshikami Nature (London) 1984,308 282. 101 R. H. Scheller J. F. Jackson L. B. McAllister B. S.Rothman E. Mayeri and R. Axel Cell 1983 32 7. C. E. Dempsey precursor for ELH also contains the sequence of a second egg-laying hormone which has been isolated from bag cells and named a-bag cell peptide (35). The precursor additionally contains the sequence of eight further potential peptides and it is proposed that the co-ordinated release of these peptides from bag cells mediates the stereotyped behaviour associated with egg laying. It remains to be seen whether the predicted peptides are released and contribute to the behavioural pattern as suggested. Ala-Pro- Arg-Leu- Arg-Phe-Tyr-Ser-Leu (35) The characterization of peptides from non-mammalian sources has been stimu- lated by the finding that many of the peptides are highly conserved phylogenetically and are found as neuropeptides in mammals.An extraordinary example is the head activator peptide from the freshwater coelenterate hydra. The peptide is characterized by its ability to activate the regeneration of a head in hydra which have been surgically decapitated and has the structure (36). A peptide having an identical structure has been isolated from bovine and human hypothalami.lo2 The function of the peptide in mammalian brain is not known. pGlu-Pro-Pro-Gly-Gly-Ser-Lys-Val-Ile-Leu-Phe (36) Equally surprising is a report that pig brain contains a peptide equivalent to apamin (19).'03Apamin is a potent neurotoxin and its activity arises from its ability to block the Ca2+-activated increase in permeability to K+ in neurons (and hepatocytes) possibly by binding to a K+-selective channel.The apamin-like pig brain peptide has not been fully characterized but has the following properties i it strongly cross-reacts with an antiserum raised against apamin; ii it binds with high affinity to Ca2+-activated K+ channels in synaptosomal membranes and dis- places bound apamin; iii it contracts intestinal smooth muscle preparations in a manner similar to apamin; and iv like apamin [see sequence (19)] it is inactivated by trypsin but is resistant to chymotrypsin. This is the first indication that endogenous equivalents of natural toxins exist and the structure of the apamin-like factor is of great interest. It is likely that this finding will stimulate the search for other endogenous peptides related to channel-specific venom toxins.102 H. Bodenmuller and H. C. Schaller Nature (London) 1981 293 579. 103 M. Fosset H. Schmid-Antomarchi M. Hugues G. Romey and M. Lazdunski Roc. Natl. Acad. Sci. USA 1984,81 7228.

ISSN:0069-3030    

DOI:10.1039/OC9848100353

出版商:RSC    

年代:1984

数据来源: RSC

摘要:

Abbaspour A. 203 Abbott D. 286 Abbott D. E. 134 254 Abboud J.-L. M. 22 64 Abdelmagid A 172 Abe K. 139 Abe R. 312 Abeln R. 214 Abenhaim D. 141 Abeywickrema A. N. 23 Abiko A. 135 Abraham J. 97 Abraham M. H. 22 Abraham R. J. 9 Abram D. M. H. 222 Abramovitch R. A. 94 Abrams S. R. 117 Abril C. 205 Achab S. 352 Ackroyd J. 177 Adam M. J. 320 Adams R. D. 179 Adams T. C. jun. 319 Adcock W. 23 Adiwidjaja G. 187 190 Adlington R. M. 114 119 144,341 Adrian T. E. 372 knggfrd A. 372 Aerssens M. H. P. J. 107 Afanas’ev I. B. 22 64 Afza N. 322 Agami C. 174 Agawa T. 155 185 Ager D. J. 150 259 Agmon N. 18 21 Agosta W. C. 4 89 179 Ahmad F. 117 Ahn J. 59 Aicher T.157 Aime S. 13 Aitken R. A. 95 Aizpurua J. M. 188 +kzji k.,358 Akermark B. 146 219 220 Akiba K. 261 Akimoto K. 314 338 Akiyama T. 149 Akutagawa S. 225 Author Index Alagona G. 26 Alain J. 332 Alberola A. 197 Albini A. 105 210 Albrecht H. 193 Albrecht P. 101 Alexakis A. 126 215 261 Al-Fekri D. M. 156 Alford J. 375 Al-Hassan M. 260 Ali E. 304 Ali M. B. 29 166 Ali M. H. 300 Al-Kaabi S. S. 58 Allaime H. 72 Allayarov S. R. 74 Allen F. H. 61 Allen J. M. 372 Allen L. C. 176 Allinger N. L. 26 Almlof J. 26 Alnaimi I. S. 96 Alnajjar M. S. 157 244 Alpegiani M. 105 Alper H. 110 111 116 140 226 261 Alt H. G. 211 Alt R. 86 Alunni S. 22 Alvarez F.115 162 Alvarez R. 13 Alvarez-Builla J. 205 Alward S. J. 175 179 181 Aly F. M. 37 Amara S. G. 370 Amatore C. 59 61 Amemiya Y. 297 Ammon H. L. 43 Anczak K. 175 Andersen K. K. 149 Anderson G. H. 90 Anderson L. 331 Anderson P. S. 368 Anderson R. C. 345 Anderson W. G. 102 130 Andisik D. 113 Ando K. 141 Ando T. 50 66 127 Ando W. 185 242 377 Andreeti G. D. 228 Andreev N. A. 201 Andrus A. 188 Angeletakis C. N. 94 Angelici R. J. 192 Angus R. O. jun. 168 Anh N. T. 44 Anhede B. 55 Anisman M. S. 59 Anker D. 322 Annaka M. 314. 338 Annis G. D. 160 Annunziata R. 13 136 Ansari A. A. 304 Anselme J.-P. 147 Antczak K. 179 Antoni F. A. 374 Antropiusova H.176 224 Anwer M. K. 361 Aono M. 358 Aoyama H. 104 105 Apotecher B. 226 Arad D. 60 Araki K. 115 Araki S. 199 Araki Y. 344 Arase A. 148 Argile A. 22 66 Argyropoulos J. N. 55 127 Ariga A. 205 Aripova S. F. 293 Armani E. 137 278 Armistead D. M. 200 Amarp J. 330 Arnaud R. 25 159 Amett E. M. 64 Arnold D. R. 76 100 Amold E. 302 Arnott D. M. 105 Arques J. S. 138 Arrieta A. 188 Arvanaghi M. 49 Arvanitis A. 141 ArsenijeviC L. 129 Asada-Komatsu Y. 338 Asai N. 253 Asai Y. 19 Asensio G. 116 Ashby E. C. 55 127 Ashe A. J. 245 Ashton C. P. 354 Aslanian R. 220 Astrab D. P. 164 Astruc D. 263 Atherton E. 358 375 Atkins P.J. 61 Atkinson R. S. 40 94 95 Atlas S. A. 359 Attah-Poku S. K. 179 Atta-ut-Rahman 304 Atwood J. L. 229 237 246 Aue D. H. 65 AugC C. 331 340 Aurbach D. 169 Auvinen E. M. 139 Avasthi K. 97 170 224 Aviv M. 49 Awasthi A. K. 188 Axel R. 375 Axiotis G. 135 Azerad R. 156 Aznar F. 42 Azuma K.-I. 44,124 272 Azuma S. 180 Azuma Y. 243 Babler J. H. 192 Babston R. E. 140 Bach R. D. 18 Bachrach S. M. 20 Baciocchi E. 100 Back M. H. 76 Bae D.-H. 55 127 Bae S. 278 Bae S. K. 123 Baeckvall J. E. 220 Baertschi A. J. 374 Bailey A. R. 27 Bailey W. F. 127 Baird G. J. 212 Baird M. S. 88 Baker J. P. 172 Baker R. 117 164 Balaban A. T. 63 211 Balasabramanian K.K. 201 Balasubramanian N. 206 Balasubramanian P. 86 Balavoine G. 125 Baldwin J. E. 69 114 119 144 157 341 Bamfield P. 265 Ban M. 179 Bandara R. B. M. 218 Bandy J. A. 212 Banfi L. 149 Banks B. E. C. 370 Bannaszek A. 325 Bar R. 47 Barbachyn M. R. 276 343 Barbarella G. 13 Barber M. 363 Barbot F. 128 Barchi J. J. 180 Barden,.T. C. 157 Barette E.-P. 314 Barkalov I. M. 74 Barkhash V. A. 47 Barluenga J. 42 110 115 116 162 Barnett G. B. 60 Barnier J. P. 158 Barraclough P. 175 Barrett J. 375 Barry J. 57 Barth A. 63 Bartlett P. A. 165 Bartmess J. E. 44 Barton D. H. R. 70 102 119 123 142 146 148 192 273 283 284 Barton T. J. 96 Basak A. 114 144 341 Bassigani L.103 Bates R. B. 114 Bats J. W. 101 Batsuyan Y. 199 Batt D. G. 180 Battersby A. R. 105 Battioni P. 219 Battye P. J. 45 Baudler M. 246 Bauer B. 30 Bauer T. 31 Bauld N. L. 32 Baum M. W. 11 67 Baumann H. 75 330 Baumgartner R. 0. W. 239 Baumgart K.-D. 90 161 Baus U. 137 Bax A. 4 Bayaban A. T. 147 Bayod M. 42 Baysdon S. L. 160 Baze M. E. 90 161 Beach D. L. 109 Beachly 0. T. 237 Beak P. 258 Beau J.-M. 314 Beaudoin S. 259 Beck A. 29 Beck K. 36 Becker G. 38 199 Becker R. 281 Bedford G. R. 9 Bedi G. 219 Bednarski M. 31 329 Beecroft R. A. 100 Begland R. W. 40 Begley M. J. 173 Behnam B. A. 367 Behrens C. H. 126 Beletskaya I.P. 117 Bell E. A. 302 Bell N. A. 235 Bellama J. M. 244 Bellville D. J. 32 Author Index Belmonte F. G. 108 Benati L. 112 Benkeser R. A. 108 166 Benn M. 297 Benn R. 232 233 366 Benson S. W. 76 Bentley T. W. 51 Bergbreiter D. E. 140 Berger S. 5 Bergman J. 183 Bergman N.-A. 55 Bergmann C. W. 348 Bernad P. 115 162 Bernal I. 245 Bernardi F. 18 25 Bernardinelli G. 30 167 265 Bernath G. 208 Berndt A. 242 Berner H. 93 Bernhard W. 138 250 Bernotas R. C. 351 Berry M. 79 Berthelot M. 64 Berti G. 326 Bertonnesque E. 135 Bertran J. 24 26 99 Bertrand G. 241 Bertrand M. 123 Bertz S. H. 157 263 Bestmann H. J. 145 169 200 258 Bettinetti G. F. 210 Betz R.329 Bhattacharya A. 304 Bickelhaupt F. 91 Biemann K. 364 Bigelow S. 254 Billhardt U.-M. 101 Billmers J. 278 Billups W. E. 156 Binkley J. S. 25 Binsch G. 178 Birbaum J.-L. 178 Birch A. J. 218 Birch D. 101 Bisaha J. 143 167 172 265 Biding M. 126 Bitler S. P. 117 Blackburn B. K. 90 194 Blackstock S. C. 33 Blackstock W. P. 163 Blanc J. P. 369 Blanchette M. A. 150 Blanda M. T. 243 Blankenship C. 155 Blasko G. 304 Blechert S. 180 194 Bleich H. 5 Bloodworth A. J. 75 Bloom A. J. 113 Bloom S. H. 153 Bloom S. R. 372 Bocelli G. 228 Bock C. W. 25 Author Index 379 Bock H. 176 Brazeau P. 362 Bunnelle W. H. 181 Bock K. 315 332 Brehm E. C. 59 Buono G.115 Boden E. 254 Breslow R. 95 210 285 Burbach J. P. H. 374 Boden E. P. 134 Breulet J. 25 29 Burchill M. T. 55 Bodenmuller H. 376 Bodurow C. 201 225 Breunig H. J. 245 Bridon D. 273 Burgess E. M. 18 58 Burk R. M. 145 192 Bohlen P. 362 365 Boehm M. C. 29 Briggs A. J. 62 Brimacombe J’. S. 316 323 Burke S. D. 143 172 181 200 Boersma J. 216 234 235 Brinckman F. E. 244 Burnier J. S. 27 Boessenkool I. K. 349 Brinker U. H. 89 90 Bums D. H. 172 Bogavac M. 129 BodganoviC B. 233 Boger D. 269 Boger D. L. 159 195 Bognar R. 352 Boireau G. 141 Bogesen G. 363 Brison J. 366 Brizzi V. 8 Broadley K. 212 Bron P. 346 Bronberger F. 36 Broquist H. P. 300 Brotherton C. E. 159 269 Burt R. A. 62 Burton D. J. 27 Burton L. P. J. 90 Buschek J. M. 57 Buss A. D. 150 Buter J. 286 Buxton S. R.88 Bonacic-Koutecky V. 91 Bonin M. 345 Brower K. R. 52 Brown D. A. 232 Buynak J. D. 190 Bystroem E. S. 220 Bonner W. A. 344 Brown E. 358 Bystrov V. F. 366 Borchardt R. T. 67 Brown F. K. 24 30 Borden W. T. 19 24 44 Brown H. C. 110 111 121 Bordoli R. S. 363 128 131 132 133 139 140 Cabassi F. 367 Bordwell F. G. 22 64 66 141 282 Cacchi S. 260 284 Borg R. M. 100 Borghese A. 72 Borowiecka J. 315 Brown J. M. 13 222 223 325 Brown K. 295 Brown L. 123 Cadogan J. I. G. 95 Cahiez G. 124 130 Caines G. H. 10 Bose A. K. 234 Brown M. R. 370 Calabrese J. 33 265 Bossinger C. D. 361 Brown P. A. 180 Caldebari G. 141 Bother-By A. A. 366 Brown R. D. 25 157 Calderazzo F. 245 246 Botkin J. H. 49 Brown R. F. C. 79 Calestani G. 228 Bottaro J. C. 119 Brown R. J. 328 Callen G.R. 132 257 Bottoni A. 25 Brown R. S. 57 116 Calvert D. J. 64 Bou Y. 225 Brown R. T. 163 307 Camargo M. J. 359 Boudjouk P. 234 242 Boudreaux G. J. 149 Brown T. 355 Brownawell M.L. 59 66 Cambou B. 122 Camerman A. 367 Boule P. 100 Brownell G. L. 320 Camerman N. 367 Bouma W. J. 26 Brownstein M. 371 Cameron A. G. 163 173 Bourne N. 52 56 Broxterman Q. B. 74 Cameron T. S. 100 Bovermann G. 357 Bruce M. R. 52 Camp R. N. 25 Bovin N. V. 332 Bruekelman S. P. 194 Campbell K. A. 26 Bowie J. H. 54 Bruhn P. 213 Campbell M. M. 165 188 Box V. G. S. 41 Bruice P. Y. 66 Canadell E. 237 Boxberger M. 90 Bruneel K. 170 Cane D. E. 181 Boyd G. V. 206 Brunet J.-J. 107 281 Cantin M. 360 Boyle M. D. P. 370 Braat K. 192 Bradbury A. F. 372 Braden M. L. 18 Brunner H. 217 281 Bryan S.J. 232 Bryson T. A. 173 Buchanan J. G. 297 340 350 Capdeville P. 140 Capson T. L. 145 Carceller E. 181 Card P. J. 320 Bradley C. 363 Buchi G. 271 Cardani S. 248 Brady J. E. 22 Brady S. F. 360 368 Braekhof N. L. J. M. 150 Brain S. D. 370 Bram G. 57 Brand J. C. 74 Brandsma L. 107 Brandstaetter H. H. 335 Brandt A. 103 Brauer B.-E. 84 Brauman J. I. 65 Braun H. 32 167 Braun M. 132 141 251 Braun W. 366 Buchwald S. L. 52 137 Buchwalter S. L. 157 Buckingham J. C. 374 Buckley D. G. 291 Budzelaar P. H. M. 234 235 Buisson D. 156 Bujnicki B. 149 Bulsing J. M. 3 Bumagin N. A. 117 Bunce R. A. 150 Buncel E. 53 61 Bundle D. R. 332 Bunina-Krivorakova L. I. 201 242 Cardillo G. 276 321 Cardin D. B. 144 Carey F. A. 47 Carless H. A. J. 104 Carlson R. 147 Carmichael C. S. 179 214 Carmona E.13 Caroti P.,326 Carpenter B. K. 46 47 Carr P. W. 22 Carre M.-C. 79 CamC R. 29 38 199 Carrion F. 19 54 Carrupt. P.-A. 178 Author Index Canuthers M.C. 188 Carsky P. 25 160 Carson H.J. 192 Cartaya-Marin C. P. 173 Carter G. E. 51 Casadei M. A. 153 Casal H. L. 84 Cashen M.J. 61 Casnati G. 137 278 Cassels B. K. 305 Casserly E. W. 156 Cassidei L. 13 Castaldi G. 204 Castedo L. 91 126 183 224 Castelhano A. L. 76 Castillon S. 12 322 Castro J. L. 91 126 183 Catalan J. 21 Catelani G. 326 Caubere P. 79 107 281 Caviezel M.,358 Cervell6 J. 99 Cevasco G. 56 Cha J. 271 282 Cha J. K. 41 223 Cha J. S. 140 Chaabouni R. 147 Chamberlin A. R. 124 153 276 297 Chambers C.A. 62 Champion R. 157 Chan D. M. T. 90 Chan L. 222 Chan T. H. 128 Chancharunee S. 149 163 Chandra H. 73 Chandrasegaran S. 9 Chandrasekhar J. 25 26 54 96 Chang C. 50 Chang C.-A. 117 Chang J. 59 Chang J.-Y. 362 Chang K. J. 373 Chang T. C. T. 218 Chang Y. 278 Chang Y. K. 123 Chao K. H. 218 Chao S.,43 Chapleur Y. 165 Chapman K. T. 143 167 172 265 Chapman 0. L. 87 Chapuis C. 30 167 265 Charon D. 331 Charton M.,22 64 Chaudhuri R. K. 293 Cheikh R. 147 Chen C.-C. 26 Chen C.-S. 48 131 281 Chen H.-T. E. 77 Chen J.-Y. 357 Chen M.-J.. 34 Chen; M. Y..21 65 Chen P. 34 Chen S. L. A. A. 199 Chen Y.-S. 277 Chen. Y. Y. 305 Chenard B. 287 Chenard B.L. 140 Chen-Chih Cheng 97 Chernyak A. Ya. 340 Chew S. 347 Chiacchio U. 87 Chiang A.-P. 233 Chiang W.-L. 99 Chiang Y. 62 136 Chiba K. 307 Chiba S. 338 Chicz R. M. 59 Chida N. 350 Childs R. F. 48 97 Chiles R. A, 26 Chin J. 63 Chinn J. W. 231 Chishov 0. S. 148 Chishti N. H. 83 Cho W. 128 Choay Y. 332 Choi C. 52 Cholcha W. 165 Chono M. 146 Chou C. 278 Chow H.-F. 165 Chowdhry V. 365 Choy W. 150 Chretien F. 165 Chretien M. 360 Christ W. J. 223 Christensen B. G. 188 Christian R. 334 Christie P. A. 94 Christodoulou C. 325 Christofides J. C. 10 Christoph G. C. 348 Chu I.-S. 89 Chu K.-H. 111 Chuchani G. 57 Chucholowski A. 313 Chuman T.349 Chung J. Y. L. 297 Ciccarone T. M.,360 Ciganek E. 266 Cinquini M. 136 Cizek J. 24 Claesson A. 118 Clancy M. G. 93 Clardy J. C. 179 Clardy P. J. 302 Clark G. 180 Clark G. R. 4 Clark T. 60 74 230 Clary D. C. 19 Clawson L. 137 Clegg W. 178 232 Cleland W. W. 67 Clemens. A. H.. 12 Cievenstine E.C. 300 Clift S. M.,220 Clouser K. A. 192 Coa J.-R. 76 Coda A. C. 138 Cohen L. A. 87 Cohen T. 200 Colegate S. M.,300 Coleman R.S. 195 Collum D. 284 Colombo L. 132 248 Colombo R. 361 Colquhoun H. M. 211 Colton C. D. 360 368 Colton R.J. 364 Commercon A. 215 Compagnini A. 87 Concellon J. M.,115 162 Considine J. L. 243 Cook J. M.,157 Cooper K.181 Cordell G. A. 291 Cordes E. H. 368 Corey E. J. 119 136 145 148 155 169 173 248 278 290 322 Corsaro A. 87 Cortes D. 278 Cory R. M.,90 176 Cossio F. P. 188 Cosson J. P. 352 Costa S. S. 349 Cottier L. 346 Cottin M. 322 Coulentianos C. 215 Cournoyer M. E. 26 Courtneidge J. L.,74 75 Couture A, 104 Couture Y. 102 Covey W. D. 59 Cowan R. L. 59 Cowburn D. 4 Cowley A. H. 195 238 240 246 Cox D. P. 82 Coyle J. D. 101 Cozak D. 111 Cozzi F. 136 Crabtree R. H.,211 Craig N. C. 156 Cramm D. 62 Crammer B. 158 Creary X. 49 Cremer D. 20 Crich D. 70 119 123 142 273 Crisp G. 260 261 Cronin K. G. 117 Crotts D. D. 117 Crow T. J. 372 Crow W.D. 90 Crowte R. J. 5 Cruse W. B. 150 Cruz L.J. 375 Csizrnadia 1. G. 25 Author Index Cuny E. 312 Curci R. 109 125 Curley P. 368 Curran D. P. 205 Curtis P. J. 144 212 Cushman M. 203 Cweiber B. 317 Dabbagh G. 157,263 Dailey W. P. 97 DalgHrd N. K. A. 148 Dall’Occo T. 197 Dalton D. R. 291 Dan S. 302 d’Angelo J. 156 252 Danheiser R. 28 Danishefsky S. 31 266 329 342 343 Dannenberg J. J. 102 130 Danyluk S. S. 9 Dappen M. 267 Das B. C. 352 Dastidar P. P. G. 304 Dauben W. G. 150 174 Dauzonne D. 203 David S. 340 Davidson A. H. 162 Davidson E. R. 19 24 Davidson G. R.,44 Davidson I. M. T. 96 Davidson P. J. 238 Davidson R. S. 97 100 Davidson W.R. 65 Davies A. 3 Davies A. B. 3 Davies A. G. 71 74 75 243 Davies D. B. 9 10 Davies D. H.,3 Davies J. E. 365 Davies M. J. 72 Davies N. 127 Davies S. 240 Davies S. G. 108 136 144 212 251 Davis A. M. 63 Davis D. G. 4 Davis F. A. 278 Davis J. T. 150 Davis P. 252 261 Davis R. J. 16 Davis S. A. 75 Dawe R. D. 126 287 341 Dawes H. M. 243 Dawson B. A. 181 Deacon G.B. 235 Deber C. M. 367 Deberley A. 141 De Blois C. 111 De Boer H. J. R.,91 Debost J. L. 324 de Bruijn S. 24 De Carvalho M.-E. 109 DeClerq E. 346 Decodts G. 57 Defoin A. 101 Defoin-Straatmann R.,101 Dega-Szafran Z. 50 DeGrado W. F. 365 Deguchi R. 165 De Haan F. P. 59 Dehasse-De Lombaert C.270 Dehghan M. 240 Dehmlow E. V. 91 de Kaifer C. F. 142 De Kanter F. J. J. 91 De Keukeleire D. 170 Dekker J. 234 de la Mare P. B. D. 51 Delaumeny J. M. 352 Delbecq F. 44 Delker G. L. 59 Delord T. J. 243 Delorme D. 119 259 de Lucchi O. 29 253 266 Dembech P. 126 de Meijere A. 88 156 170 Demerseman P. 192 Demidov S. V. 74 Dempsey C. E. 353 356 Demurs J. R. 72 Demuth M. 180 Denis J.-M. 203 Denis P. 115 Denmark S. E. 42 134 172 267 Denys L. 366 de Paz J. L. G. 21 Depezay J. C. 327 de Poorter B. 125 De Priest R. N. 55 127 des Abbayes H. 130 Desai M. C. 133 Deschrijver P. 366 Descotes G. 346 Deshayes H.,107 Deshmukh M. 280 De Shong P.326 Deshpande S. 203 Desimoni G. 138 Desjardins S. G. 76 Deslongchamps P. 168 Desmeeules P. 26 Despeyroux B. 110 116 Dessinges A. 12 320 322 Devant R. 141 251 Devlin J. A. 295 Dewar M. J. S. 18 19 26 29 44,41 54 81 166 244 De Wied D. 374 DeWolf W. H. 91 Dhanak D. 169 Dicken C. M. 326 Diercksen G. H. F. 24 Dietrich H. 230 Differding E. 270 Digenis G. A. 147 Dike M. S. 181 Dillen J. L. M. 178 DiMaio J. 367 DiMare M.,328 DiMari S. J. 300 Dimonie M. 211 Ding W. 155 Diolez C. 331 Diou R. P. 211 Disch R. L. 181 Ditrich K. 133 248 Dittmann R. G. 25 Dix L. R. 58 Dixon D. A. 50 Dmitriev B. A. 340 Doan P. E. 23 Doba T. 75 Dodd J. A. 65 Doecke C.W. 178 Doering W. von E. 176 Doggweiler H.,51 81 Doherty R. M. 22 Dolbier W. R. jun. 27 156 Dolgoplask B. A. 211 Dolle R. E. 313 Dolling V.-H., 252 Domaille P. J. 14 211 Dombrovski V. A. 162 Dominguez R. M. 57 Dondoni A. 197 Donnella J. 21 65 Dordor I. M. 136 212 251 Dona G. 281 Dorling P. R. 300 Dorsch M. 181 Dossena A. 137 278 Dotz K. H. 211 263 Douady J. 25 Doubleday C. jun. 25 72 Douglas K. T. 56 Doyle M. P. 82 Drabowicz J. 149 Drago R. S. 23 Dragutan V. 211 Dreiding A. S. 177 Drone F. J. 245 D’Rozario P. 53 Druliner J. D. 21 1 Dubiez R. 104 Dubois J.-E. 22 66 135 138 Duchaussoy P. 332 Diirner G. 101 Duffey B. 97 Dufresne Y. 119 Duggan M.E. 123 Dulcere J.-P. 123 Dumas F. 252 Dumont C. 159 Dumont W. 91 183 duMont W.-W. 239 Dunach E. 117 280 Dunbar B. L. W. 86 Duncan D. P. 243 Dupuy C. 127 137 Dureault A. 219 327 Durkhart G. 226 Durr H. 85 Dussauge A. 159 Dvortsak P. 324 Dykema K. J. 25,96 Eaborn C. 60 232 Eades R. A. 50 Eastwood F. W. 79 Eaton P. E. 177 181 Ebenhoch J. 236 Eberhardt W. H. 18 58 Eby R. 314 Eckrich T. M. 155 Edelson E. H. 52 Edgar J. A. 294 Edmunds J. S. 320 Edvinsson L. 372 Egawa H. 105 Egbertson M. 197 Egert E. 178 Eggers N. J. 294 Egged H. 14 Ehrenkaufer R. E. 145 Ehrenreich W. 246 Eichenauer H. 137 Eicher T. 165 Einhorn J. 192 Eipper B.A. 372 Eis M. 262 Eisenstein O. 237 Eisenthal K. B. 84 Ekblad E. 372 Elango V. 305 Elde R. 372 Elgemei G. E. N. 147 Elguero J. 21 147 Eliel E. L. 129 166 Elling J. W. 192 Ellinger Y. 25 Elliott J. D. 122 Elliott R. C. 122 Ellis J. E. 13 Ellis M. K. 123 Ellison S. L. R. 166 Elmaleh D. R. 320 Elmes P. S. 157 Elmoghayar M.R. H. 147 Elnagdi M. H. 147 Elsevier C. J. 214 El-Shagi H. 305 Emson P. C. 373 Enders D. 137 Engberts J. B. F. N. 62 Engel N. 144 Engel P. 181 Engelhardt L. M. 229 Engler T. A. 173 Engman L. 108 142 288 Enholm E. J. 134 341 Ennis M. D. 139 Epiotis N. D. 18 Erastov 0. A. 150 Erdik E. 128 263 Erge D. 309 Ernst L. 4 Ernst R.R. 3 6 Esch F. S. 362 365 Eskenazi C. 125 Essenfeld A. P. 150 172 Etienne T. 363 Etter J. B. 170 Euerly M. R. 205 Evans C. J. 365 Evans C. M. 57 Evans D. A. 119 139 143 167 172 222 248 265 281 Evans J. 5 Evans J. N. S. 12 Evans R. M. 370 Exner O. 23 Eyley S. C. 116 Fabisch B. 234 Fagerness P. E. 12 Fahrenkrug J. 373 Fajardo V. 305 Falck J. R. 137 150 174 Falkenberg-Andersen C. 159 Faller J. W. 218 Faller P. 127 Fallis A. G. 29 175 179 181 266 Fananas J. F. 219 Fang H. W. 114 258 Fankhauser J. 289 Fanni T. 53 Fan Tai A. 109 223 Fantin G. 197 Fiircasiu D. 147 Farkhani D. 127 Farnell L. 25 Farries H. 95 Faucher H. 159 Favorskaya I.A. 139 Fawcett J. 95 180 Fekarurhobo G. K. 104 Felber H. 32 167 Felberg J. D. 51 81 Feller D. 19 24 44 Fellows C. A. 201 Fellows M. S. 166 Ferguson G. S. 117 Fernandez A. 18 Ferrara D. M. 59 Ferrier R. J. 316 347 352 Ferrino S. 180 Fessenden R. W. 73 Fiakpui C. Y. 49 Fiandenese V. 130 Fiandorese V. 13 Fibiger R. 113 Fiechter A. 141 Fiegenbaum P. 220 259 Figueredo M. 99 Fink M. J. 238 Author Index Finn J. 278 Finn M. G. 125 223 Finnie M. D. A. 372 Fiorentino M. 109 125 Firouzabadi H. 151 Fisch M. H. 102 130 Fischer G. 63 101 106 Fischer H. 208 Fischer J. 187 Fischetti W. 116 Fisher G. H.,366 Fisher L. A. 370 Fishwick C. W. G. 79 Fitjer L.J. 178 Fitzner J. 289 Fitzpatrkk J. 58 Fitzsimmons B. F. 156 Fjeldberg T. 229 238 Flanigan E. 361 Fleet G. W. J. 165 300 349 351 Fleischmann M. 113 Fleming I. 114 119 129 138 165,250 Flippin L. A. 249 Florent J. C. 345 Floss H. G. 308 Flynn K. E. 176 Fobare W. 143 Forster W.-R. 190 Fogagnolo M. 197 Fong C. H. 59 Fonskii D. Y. 162 Fontecave M. 109 Forner W. 24 Forsyth D. A. 49 Fortin R. 119 Fosset M. 376 Foucaud A. 144 Fox H. 358 Fox M. A. 26 28 Francesconi K. A. 320 Francis C. J. 145 Franck R. W. 34 343 347 Francke W. 345 Franck-Neumann M. 88 Francl M. M. 21 Frankhanser J. E. 147 Franklin C. C. 109 223 Fraser A. M. 304 Fraser-Reid B. 41 156 316 317 318 321 323 341 345 351 Frater G.141 161 Freed K. F. 24 Freeman A. E. 51 Frei B. 89 Freidinger R. M. 368 Frenking G. 26 79 Frey R. 50 Freyer A. J. 147 304 Frick V. 194 Fried J. 209 Friedheirn J. E. 26 Author Index Friedl Z. 23 Friedman J. M. 52 Frigo T. B. 33 Fringeli U.-P. 368 Friour G. 130 Fristad W. E. 140 Fritz H. 209 Fritz S. 127 Frohlich S. 51 Fronczek F. R. 37 Fueno T. 62 91 Fuji K. 119 Fujihara H. 63 Fujii M. 138 Fujii N. 358 Fujikura S. 153 293 Fujimoto K. 44 Fujisawa T. 127 141 143 Fujita A. 345 Fujita E. 119 273 Fujita M. 150 282 Fujiwara J. 129 Fujiwara S. 164 Fujiwara T. 367 Fujiwara W. 62 Fujiwara Y.140 Fukao M. 158 Fukisawa T. 143 Fukuda A. 371 Fukugawa Y. 189 Fukui M.,137 Fukumi H. 360 Fukumoto K. 179 297 Fukunaga T. 40 Fukuoka S. 146 Fukushima H.,281 Fukutani Y. 129 Fukuyama T. 190 Fukuzaki K. 172 Fulop F. 208 Funaki K. 316 Funakoshi K. 162 264 Funk R. L. 204 Furukata T. 185 Furukawa S. 153 Furukawa Y. 274 Furuta K. 164 Furutani Y. 365 Gabioud R. 176 Gabrielsen B. 54 Gadek T. R. 117 Gadwood R. C. 160 Gaffney A. H. 55 Gage L. P. 365 Gagnier R. P.,127 Gahwiler B. 374 Gainsford G. J. 294 Gais H.-J. 287 Gajewski J. J. 158 Gal J.-F. 64 Galera S. 26 Gallacher G. 179 Galli C. 59 153 Galow P.,240 Galyean R. 375 Ganboa I.188 Gandesequi M. T. 205 Gandino J. 136 Gandler J. R. 55 Ganem B. 126 180 185 262 351 Gano D. R. 25 79 Garcia M. L. 181 Garcia R. 360 Gareau Y. 33 Garegg P. J. 332 Garigipati R. S. 147 Garland R. 140 Garrett P.J. 58 Garst M. E. 30 167 176 287 Gaspar P. P. 86 Gaspamni F. 290 Gassen H. G. 365 Gassman P. G. 32 50 172 Gathling W. 156 Gautheron C. 340 Gawley R. E. 148 Gedye R. 57 Gee A. P. 370 Gee S. K. 28 Geiger R. 357 358 Geissman T. A. 297 Gelas J. 324 Gellert E. 300 Genest J. 360 Gennari C. 132 248 Georg G. I. 159 George C. 25 George P. 25 Georges M. 323 351 Gerdes J. M. 150 Gerich J. E. 368 Gerken M. 315 Germanas J. P. 172 Germon G.215 Gero S. D. 352 Gesselin P. 53 Gey E. 25 Ghadiri M. 263 Ghatei M. A. 372 Ghibri A. 126 Ghio C. 26 Ghosez L. 270 Ghosh A. K. 38 181 Ghosh S. 224 Ghribi A. 261 Giacomelli G. 131 Gibbons W. A. 8 Gidney M. A. J. 332 Giese B. 23 69 318 Giguere R. J. 176 Gilbert B. C. 72 75 Gilbert J. C. 90 161 194 Gill M. 192 Gillard J. W. 119 Gillis H. R. 172 Gingrich H. L. 87 Giovannini F. 141 Giovannoli M. 290 Girgis S. I. 363 Givens R. S. 106 Gladysz J. A. 211 Glass R. S. 34 Gleiter R. 29 179 Glembotski C. C. 372 Glenn R. 62 Glenneberg J. 100 Glidewell C. 25 26 Gluchowski C. 140 Go C. H. L. 92 Go V. L. W. 373 Gobetto R. 13 Godfrey P. D.157 Goedken V. 212 Goedken V. L. 237 Gohring W. 357 Goel A. B. 127 Gorisch H. 144 Gol C. 107 Gold V.,61 Golding B. T. 123 Goldman E. W. 243 Goldschmidt Z. 158 Goldstein M.,372 Goldstein M. J. 229 Golebiewski W. M. 303 304 Gollnick K. 98 Gonzalez A. 188 Gonzalez A. M. 197 Gonzalez N. 57 Gonzhlez-Gbmez J. A. 69 318 Good F. 322 Goodman L. 314 Goodwin D. 100 Gopalan A. S. 144 Gopalan R. 63 Gopinathan M. S. 20 Gordon B. 114 Gordon M. S. 25 79 96 Gordon P. F. 265 Gorenstein D. G. 12 53 63 Gosney I. 95 Gothling W. 88 Gough M. J. 300 351 Gould I. R. 75 Gould S. J. 5 Goure W. 261 Goya P. 147 Grabowski E. 252 Grabowski J. J. 159 Graden D.W. 6 Grady G. L. 244 Graffland T. 62 Graham R. 267 Graham R. S. 31 144 Gramens L. A. 192 Grammer €2. T. 360 Gramsch C. 365 384 Graness A. 75 Granik V. G. 147 Gray W. R. 375 GrdeniC D. 235 Grdina M. J. 51 Gready J. E. 20 Grie R. 29 Green I. G. 77 Greeves N. 150 Gregoire B. 79 Gregory B. 138 Gremlich H.-V. 368 Grenz M. 239 Grethe G. 326 Greven H. M. 374 Gribble G. W. 81 Grieco P. A. 180 Grief K. 340 Crierson D. S. 345 Griesbeck A. 98 Griffin R. 16 Grigg R.,37 164 215 Griller D. 75 76 85 86 96 Grob C. A. 50 Groger D. 309 Gross A. W. 136 145 248 Grossman W. E. L. 102 130 Grubbs R. H. 137 Grue-Sorensen G. 298 299 Grundler G. 312 Grunwald E.21 22 Grynkiewicz G. 325 Gu J.-M. 43 Gu Z. 155 Guanti G. 56 149 Gubler V. 365 Guengerich F. P. 300 Giinther H. 366 Giinther M. 320 Giinther W. 141 161 Guerry P. 203 Guessous A. 30 149 167 Guilhem J. 174 Guillemin J.-C. 203 Guillemin R.,362 Guilmet E. 109 Guindon Y. 119 Guldner K. 246 Gunawardana D. A. 79 Gupta K. 234 Gupta R. B. 34 343 Gupta R. C. 79 347 Gurak J. A. 231 Gurjar M. K. 322 Gurudutt K. N. 126 Gysin B. 368 Ha T.-K. 26 Haaland A. 238 Hachiken H. 205 Hachimori A. $68 Hackenberger A. 85 Haddadin M. J. 199 Hadel L. M. 85 86 Haga T. 134 Hagihara M.,155 Hagiwara D. 358 Hahm E. 239 Hahn C. 278 Hahn C. S. 123 Hahn G.116 257 Hakamada I. 31 149 167 Hikanson R. 372 Haley G. J. 179 Hall D. 26 Hall J. B. 50 Hall L. 368 Hall L. D. 320 340 Hall M. L. 243 Hall S. A. 222 Hallenga K. 366 Hailer K. J. 238 Hallett G. 58 Hallinan E. A. 209 Hallock R. B. 237 Halpern M. 57 Halton B. 156 Halweg K. M. 180 Hamamoto I. 148 Hamatsu T. 314 338 Hammer B. 217 Hammer C. F. 9 Hammond B. L. 15 Hammond S. J. 8 Hammonds R. G. 375 Hammura E. K. 320 Han B. H. 234 Han T. H. 189 Hanafusa T. 50 127 Hanamura M. 50 Hanessian S. 119 259 345 346 349 350 Hanna R. 316 Hanne M. 140 Hansen H. J. 225 Hansen S. W. 27 Hanson B. E. 16 Hanson J. R. 10 Hanson P. 64 Hanus V. 176 224 Hanyu Y.185 Haque M. E. 324 Harada T. 13 1 Harazono T. 243 Harcourt R. D. 24 Harkema S. 162 Harkiss D. 358 Harland P. A. 347 Harmata M. A. 42 Harper J. D. 59 Harpp D. N. 33 148 Harrelson J. A. 64 Hamngton C. K. 50 Hams D. H. 238 Hams H. C. 51 Ham's T. M. 300 Author Index Harrison L. 268 Harrison P. J. 105 Harrison W. L. 201 Hart D. J. 297 Hart H. 80 Hartmann H. 196 Hartmann T. 303 Hartstock F. W. 116 Harvey D. 266 Harvey D. F. 31 Hasegawa E. 336 Hasegawa M. 129 Hashem K. E. 140 261 Hashimoto H. 127 316 Hashimoto K. 112 Hashimoto M. 358 Hashimoto S. 313 Hassan S. B. 308 Hassner A. 113 Hata T. 325 Hatanaka K. 323 324 Hattori M.,344 Haufe G.169 Hauser F. M.,319 Hawari J. A. 96 241 Hawkes G. E. 13 Hay R. W. 316 Hayakawa S. 130 Hayakawo K. 148 Hayama T. 113 Hayashi H. 134 Hayashi K. 148 358 Hayashi M. 313 Hayashi N. 83 Hayashi S. 26 Hayashi T. 168 219 Hayashi Y. 198 217 Hayauchi Y. 334 Hayes R. N. 54 Haynie S. L. 340 Healy E. F. 18 44 Heath P. 348 Heath W. F. 360 Heathcock C. H. 249 Heck J. V. 188 Heck R. F. 116 Hedbys L. 338 Heeg M. J. 240 Hegarty A. F. 54 56 58 Hegedus L. S. 114 116 211 219 221 263 Hehre W. J. 21 Heidrich D. 18 Heimann M. R. 180 Heimbach H. 137 Heinemann G. 144 Helbert M. 64 Helmchen G. 30 213 255 Helquist P. 211 220 Hemmi K. 358 Hempe W.313 Henderson G. B. 105 Hendewerk M. L. 50 Hendrickson J. B. 149 Author Index 385 Hengeveld J. E. 340 Henggeler B. 89 Henne A. 74 Hoefnagel A. J. 22 64 Hohn A. 36 Hokfelt T. 372 373 Hua D. H. 119 Huang Y. 155 Hubert-Habart M.,206 Hennig J. 16 Henning R. 119 250 Herber R. H. 240 243 Honicke R.,144 Hossig R. 148 Howeler U. 20 Hubner F. 137 Hunig S.,36 Huttenhain S. H. 137 Herberhold M. 246 Herchman M. 338 Herman F. 95 Hoff D. R. 368 Hoffman E. G. 234 Hoffman R. V. 147 Huffman J. C. 245 Hug K. T. 249 Hughes D. L. 22 66 Hermans J. P. G. 332 Hoffmann B. J. 365 Hugues M. 376 Hermeling D. 266 Hermes J. D. 67 Hoffmann H. M. R. 167 176 27 1 Hui R. C. 147 Huisgen R. 36 Hernandez D. 108 Hoffmann R. 18 Hulting A.-L. 373 Hertz V. 101 Hoffmann R.W. 87 119 132 Hung M.-H. 143 179 214 HervC Y. 70 102 133 248 254 Hungate R. W. 196 Herz A. 365 Hesabi M. M. 93 Hogeveen H. 74 Hohenschutz L. D. 302 Hunkapillar M. 361 Hunkler D. 29 106 209 Hess B. A. 24 25 160 Hollinshead D. M. 217 Hunter J. C. 371 Hesse M. 291 Hettinger P. 337 Heuckeroth R. O. 105 Holloway M. K. 26 Holm K. H. 89 Holmes J. 76 Hunter T. 358 Hunter W. E. 246 Hunziker H. E. 73 Hewson A. T. 163 Holmes M. C. 374 Hupe D. J. 66 Hibbert F. 48 60 Hiberty P. C. 20 65 Hickmott P. W. 147 Hida T. 172 Holzapfel C. W. 324 Honda T. 179 208 Honjou N. 87 Honkan V. 157 Hurst J. R. 28 Hursthouse M. B. 243 Husain A. 52 Huskey W. P.,67 Hiemstra H. 174 Hook J. M. 180 Husson H. P. 345 Highsmith T. K. 114 Hoover J. F. 34 Hutchinson J. H. 171 Higuchi T. 242 Hild W.132 Hill R. K. 40 Hill R. R. 101 Hope H. 231 Hopf H. 116 Hopfinger A. J. 26 Hopkins H. P. 65 Huxtable C. R. 300 Hvistendahl G. 26 Hwang C. K. 127 Hwu J. R. 180 Hillner K. 38 Hopkins M. 287 Hillock C. S. 62 Hillson R. A. 46 Hopkins P. 289 Hopkins P. B. 147 Ichihara J. 127 Hiltunen L. 166 Himbert G. 191 Hopkinson A. C. 26 Hoppe D. 144 254 Iga Y. 336 Ihara M. 179 297 Hindenlang D. M. 305 Hoppe M. 156 Iida H. 137 Him W. 138 Hioki T. 249 Hopton D. 354 Hori I. 126 Iida S. 127 Iihama T. 137 Hirai Y. 105 Hori K. 19 91 Iimura Y. 300 Hirama M. 275 Horinchi C. A. 127 Iio H. 174 Hirano S. 324 Hirano T. 164 Home D. 136 Horton D. 314 324 348 Ijadi-Maghsoodi S. 96 Ikan R. 158 Hirao I. 142 154 187 249 Horton M. 177 Ikeda M. 103 205 328 Hirao T. 155 Hoshi M. 148 Ikeda N.164 256 Hirata N. 180 Hoshimine Y. 87 Ikeda T. 225 Hirata T. 305 Hoshino M. 79 185 Ikeda Y. 114 142 256 Hirata Y. 375 Hoshino Y. 293 Ila H. 195 Hiroi K. 149 Hosie L. 62 Imai Y. 140 Hirose T. 365 Hirota K. 193 Hirotsu K. 242 Hirschmann R. 368 Hitachi A. 73 Hitchock P. B. 232 238 Hitz W. D. 320 Hiyama T. 150 282 326 Ho P.-T. 127 Ho Y.-P.,199 Hoberg H. 219 226 Hodge C. N. 176 Hodge P. 127 Hodgson S. T. 217 Hosmane N. S. 240 Hosomi A, 344 Hough L. 300 351 Houk K. N. 18 24 25 27 30 37 50 55 60 82 276 Houminer Y. 49 Hout R. F. 21 Hoyle C. E. 94 Hoz S. 53 169 Hrubiec R. T. 155 157 Hsu M. 268 Hu D. D. 22 66 HOU,K.-C. 137 HSU,S.-Y. 277 Imamoto T. 132 136 149 Imoto M. 331 Inaba S. 130 Inaba T. 336 Inagami T. 360 Inanaga J. 180 Inayama S. 365 Inch T. D. 345 Ingold C. F. 151 Ingold K.U. 73 75 157 244 Inokawa S. 320 Inoue M. 153 367 Inoue T. 344 Inoue Y. 127 Ip W. M. 51 Irani C. D. 59 Ireland R. E. 41 122 Iriguchi J. 248 Isaacs N. S. 56 Iseki T. 103 Ishibashi H. 103 Ishida H. 305 Ishida M. 198 Ishida N. 188 258 Ishida T. 367 Ishido Y. 344 Ishiguro Y. 162 264 Ishihara Y. 134 Ishikawa M. 242 Ishikura M. 225 Ishikura T. 189 Iskikawa K. 357 Islam T. S. A. 76 Isoe S. 139 181 273 Isornura K. 91 Isoni K. 5 Issari B. 56 Ito H. 237 Ito K. 181 It6 S. 275 Ito T. 180 237 Ito W. 146 257 Ito Y. 251 Itoh K. 70 215 344 Itoh N. 357 Itoh T. 141 282 Iuaba S. 51 Iversen T. 332 Iwahara T. 258 Iwaki M. 125 Iwarnura H.93 Iwasawa N. 134 Iwashita M. 275 Izawa M. 180 Izawa Y. 83 84 Izurni Y. 138 Jackman L. M. 228 Jackson J. E. 176 Jackson J. F. 375 Jackson R. 358 Jacobi P. 197 Jacobson R. A. 192 Jachav P. K. 132 133 141 Jager V. 37 181 327 Jager J. 62 Jahagirdar D. V. 65 Jakovac I. J. 144 Jalander L. 144 James L. F. 300 Janiak C. 240 Janousek Z. 71 Januszewicz A. 359 Jansen M. 180 Janssen N. J. M. L. 34 Januszkiewicz K. R. 11 1 Jaquinet J. C. 332 Jardine I. 373 Jarglis P. 313 Jarosz S. 31 Jason M. E. 179 Jastrzebski J. 231 Jaurand G. 314 Jawad H. 245 Jay M. 147 Jeanloz R. W. 331 Jeffery T. 142 Jeffrey D. A. 179 Jeffs G. E. 101 Jeger O. 89 Jemrnis E.D. 230 Jencks W. P. 49 53 54 Jendralla H. 35 178 Jenkins P. R. 175 180 Jenneskens L. W. 91 Jensen A. 24 Jesthi P. K. 320 Jewess P. J. 302 Jiminez C. 110 Jin H. 315 316 Jinbo Y. 219 Jobe P. G. 177 Johannsen I. 14 Johansson O. 372 John T. V. 347 Johnson C. R. 122 136 170 276 Johnson L. K. 359 Johnson R. A. 125 223 Johnson R. D. 8 Johnson R. P. 25 168 Johnson W. S. 122 Johnston L. J. 75 157 Johnston M. D. 10 Jones A. J. 294 Jones D. W. 45 Jones G. H. 320 Jones H. W. 22 Jones J. B. 144 145 Jones J. H. 355 Jones J. K. N. 325 Jones M. 91 Jones P. G. 62 Jones R. A. 138 Jones R. A. Y. 47 Jones R. H. 212 Jorgensen W. L. 26 27 54 Josephson S.332 Jug K. 20 Julia M. 137 Jung A. 132 249 Jung C. D. 220 Jung H. 134 Jung M. E. 172 180 Jung S.-H. 146 Junjappa H. 195 Jurczak J. 31 Jurlina J. L. 181 Jutzi P. 240 Kachensky D. F. 341 Kadeiibek V. 56 Author Index Kadow J. F. 170 Kagan H. 280 Kagan H. B. 139 148 223 Kai Y. 148 Kaiser E. T. 368 369 Kaji K. 112 Kajimoto O. 91 Kajirnoto T. 119 Kakimoto M. 140 Kakirnoto N. 243 Kakisawa H. 302 Kakiuchi K. 103 181 Kalfus K. 23 Kallenbach N. R. 366 Kamada T. 58 Kametani T. 179 208 297 Karnikawaji Y. 148 Kaminoyama M. 91 Karnitori S. 242 Karniya H. 362 Kamlet M. J. 22 64 Kanatani R. 122 258 Kanazawa I. 371 Kaneko C. 99 Kanemasa S. 204 205 209 Kanernatsu K.148 Kanemoto S. 123 Kang J. 128 Kang Y.-H., 113 Kangawa K. 371 Kankara H. 191 Kankarajan K. 198 Kant J. 199 Karl H. 314 Karle I. 367 Karle J. 367 Karnovsky M. L. 364 Karpeles R. 51 Karpf M. 163 177 Karunaratne V. 181 Kass S. R. 170 Kasselrnayer M. A. 83 Kasuga T. 44 Katayama E. 138 272 Kato K. 349 Kato S. 24 26 44 198 261 293 Kato T. 164 Katritzky A. R.,47 50 54 285 Katsuki T. 251 328 Kauffmann,T. 126 214 220 259 Kawa H.,230 Kawabata Y.,18 54 Kawada M. 115 138 Kawamura S. 249 274 Kawanarni Y. 251 Kawanisi M. 179 Kawao S. 62 Kawashima K. 338 Kawashima M. 143 Kawashirna T. 205 Kawate T. 127 Author Index 387 Kawauchi H.362 Kinoshita M. 297 314 338 Koga K. 141 Kaye A. D. 165 Kayser R. H. 61 Kazoura S. A. 241 Kiplinger J. P. 44 Kirby A. J. 47 57 61 62 Kirmse W. 27 Kohl F. X. 240 Kohl N. 195 Kohla M. 352 Kazubski A. 144 Keay B. A. 165 Keck G. E. 134 254 297 341 Kirschleger B. 127 Kiryukhin D. P. 74 Kishi N. 41 162 Kohn H. 146 Kohno M. 146 Kohnstam G. 59 Keen R. B. 164 Kishi Y. 223 Koizumi T. 31 149 167 Keese R. 179 Kita Y. 33 Koji A. 148 Kelley D. R. 69 Kello V. 24 Kellogg R. M. 286 Kelly L. F. 218 Kelly M. J. 30 167 Kelly S. E. 209 Kelly T. R.,29 141 Kemp R. A. 195 Kitagawa S. 324 Kitagawa T. 251 Kitahara E. 124 Kitahara T. 168 Kitajima N. 211 Kitajima T. 70 330 331 335 Kitamura K. 219 Kitamura T. 49 Kok G. B. 23 Kokel B. 206 Kole S. L. 213 Kolhe J. N. 119 Kollman P.A. 26 Komatsu M. 185 Komatsu T. 146 256 Komohara S. 344 Kemper B. 132 Kendrick R. D. 16 230 Kenmotsu M. 367 Kitayama R. 149 Kjonaas R. A. 130 Klaerner F. G. 40 Kon K. 181 Kondo T. 127 316 Kondo Y. 324 Kennard O. 150 Kennedy G. D. 87 Kennedy J. D. 227 230 243 Kenner G. W. 354 244 Wages U. 178 Klaver W. J. 174 Kleibomer B. 157 Kleijn H. 214 Kleinert H. D. 359 Koneeda M. 123 Kong F. 323 Konishi M. 219 Konopelski J. P. 181 Konradsson P. 332 Kent S. B. H. 362 Kleinschmidt J. 75 Konwar D. 208 Kerr L. M. 375 Klemer A. 313 318 352 Kopecky K. R. 57 Kervagoret J. 322 Kesseler K. 132 134 249 Klessinger M. 20 Klibanov A. M. 122 Kopf J. 323 Kopinski R. P. 144 Kestner N. R. 21 65 Klicnar J. 56 Koppel G. A. 190 Kettering J. K. 167 Keumi T. 51 Klingebiel U. 242 Klusik H.242 Kopple K. D. 14 Koreeda M. 33 Kevill D. N. 22 64 Keyaniyan S. 88 156 Kezdy F. Z. 368 Khan H. A. 298 Khan M. 213 Knapp S. 180 Knappenberg M. 366 Knierzinger A. 349 Knight D. W. 173 Knochel P. 128 191 Koroniak H. 27 156 Korp J.P. 245 Korpar-Colig B. 235 Korsching S. 370 Korshak Y. V. 211 Khorlin A. Ya. 332 Knorr R. 229 Korth H. 72 Khoshdel E. 127 Knothe L. 29 Kos A. J. 60 230 Khuong-Huu Q. 322 Knowles J. R. 52 Kosach S. 191 Kiberstis P. A. 358 KO Y. Y. C. Y. L. 199 Koslowski J. A. 216 Kice J. L. 133 Kido M. 103 Kidwell D. A. 364 Kigoshi H. 172 Kobayashi H. 205 Kobayashi J. 375 Kobayashi K. 150 157 323 326 Kosma P. 334 Kostikov R. 88 Kotani H. 371 Kothawala F. G. 130 Kikkawa D. O. 370 Kilduff J. E. 246 Kim H. 180 Kim J. Y. 59 Kim K. 278 Kim K. S. 123 Kim S.-C.26 111 Kim Y. 357 Kobayashi M. 163 Kobayashi N. 344 Kobayashi S. 49 312 344 Kobayashi Y. 187 213 Koch A. S. 61 Koch H. F. 48 61 Kochergin P. M. 162 Kochetkov N. K. 332 340 Kotian K. D. 169 Koto S. 324 Koumaglo K. 128 Kovacs G. L. 374 Kowallik W. 322 Koyama K. 103 Koyama Y. 324 Kozavich J. W. 11 Kimmel J. 372 Kimura A. 338 Kimura M. 326 Kimura S. 371 Kimura T. 367 Kimura Y. 312 King G. S. D. 187 King H. F. 25 King R. W. 50 Kingma R. F. 74 Kingston J. F. 175 179 Kochhar K. S. 192 Kochi J. K. 59 61 KoEovskg P. 140 Kodpinid M. 154 Kocher J. 38 Koekemoer J. M. 324 Koll P. 323 IiGnig W. 357 358 Kopper S. 314 Koermer G. S. 243 Koft E. R. 104 174 Kozikowski A. P. 38 204 Kozlowski J. A. 126 211 261 Koz'min A. S. 114 Kozyrod R. P. 341 Krageloh K. 90 Kraka E. 20 Kramer A. 221 Kramer R.91 Kratky C. 334 Kraus G. A. 128 144 305 344 388 Krebs A. 165 Kreevoy M. M. 65 Kreher R. P. 195 Kremer K. A. M. 137 211 Kremer K. G. 157 Kresge A. J. 62 136 Krespan C. G. 60 Kress A. O. 94 Kresze G. 32 167 288 Kretzschmar G. 273 Krewson K. R. 158 Krief A. 91 183 Krieger C. 208 Krishnamurthy V. V. 49 Krogh-Jespersen K. 242 Kropp P. J. 48 106 128 Krueger C. 226 233 Krueger J. M. 364 Kruger J. D. 15 Kuan F. 344 Kuehnling W. R. 210 Kuhn D. R. 81 244 Kuhn H. J. 101 Kuhn W. 178 Kuhnel W. 25 Kuivila H. G. 157 243 244 Kulinkovich 0. G. 191 274 Kullertz G. 63 Kumada M. 122 129 219 258 Kumar A. 3 147 Kumobayashi H. 225 Kunamoto S. 209 Kunkel E.155 Kunng F. A. 43 Kunz H. 24,344 355 KUO,S.-C. 205 KupEe E. 12 Kuraoka S. 205 Kurek J. T. 110 Kuroda A. 297 Kuromaru H. 140 Kurth M. J. 172 271 Kusumoto S. 331 332 Kuszman J. 324 Kutny R. M. 365 Kutschker W. 332 Kuwajima I. 162 172 264 344 Kuwajima S. 20 Kuwakino J. 209 Kvarnstrom I. 322 Kwart H. 55 Laabassi M. 29 Labadie S. S. 134 261 L'gbbe G. 187 Lablanche-Combier A. 104 Laboureur J. L. 91 183 Ladduwahetty T. 123 Ladik J. 24 Laganis E. D. 140 287 Lagow R. J. 230 Laguna M.A. 197 Lahousse F. 72 Lai K. 12 63 Laird A. A. 190 La John L. A. 60 Laloi-Diard M.,53 La Mar G. N. 8 La Mattina J. L. 195 Lambert C. 145 Lambert J. B. 157 Lammertsa K.51 Lamothe S. 168 Lancelin J. M. 344 Land H. 370 Landgrebe K. 128 144 Landini D. 108 Landmann B. 132 Landor S. R. 146 Lane E. D. 3 Langan J. 84 Langan J. R. 99 Lanz K. 156 Lapin S. C. 84 Laplante J.-P. 19 Lappert M. F. 229 238 239 Laragh J. H. 359 Lardicci L. 131 Larock R. C. 111 183 201 214 219 268 Larsen J. W. 62 Larsen K. E. 148 Larsen S. D. 295 Larson G. L. 108 142 Larsson P. O. 338 Lartey P. A. 340 Lasch J. G. 195 240 246 Lasne M.-C. 203 Laszlo P. 32 137 167 266 Lau H. H. 183 201 214 Lau W. 59 Laugal J. A. 166 Laurence C. 64 Laurent A. 147 Lautens M. 179 214 Lawman M. J. P. 370 Lawrynowicz W. 82 Lazdunski M. 376 Lazrak T.127 Lazure C. 360 Le T. 139 Leach S. E. 194 Leardini R. 205 Lebioda L. 176 Leblanc Y. 259 Lebuhn R. 331 Lechtken P. 74 Lecomte J. T. J. 6 Lederman I. 332 Lee C. C. 49 Lee C. M. 340 Lee G. E. 297 Lee 1.S. H. 65 Lee M. 40 94 Lee S.-L. 305 Lee T. J. 25 Author Index Lee W. K. 128 Leeper R. J. 3 Leete E. 291 292 293 Lefebvre C. 137 Lefebvre E. 57 Leffler J. E. 21 Leftin H. M.,114 219 Leginus J. M. 326 Lehmann R. 200 Lehmkuhl H. 232 233 234 Lelucca G. 35 Lemaire J. 100 Lemal D. M. 97 Lemieuz R. U. 332 le Noble W. J. 50 54 Lenox R. S. 94 Lenz B. G. 208 Leopold E. J. 180 Lepage L. 191 Lepage Y. 191 Lerche H. 280 Lesch D. A. 192 Leskela M.166 Lessard J. 102 Levashova V. I. 201 Levin D. 150 Levine R. D. 21 Levinskii A. B. 340 Levy G. C. 8 Levy S. 320 Lewars E. G. 187 Lewicki J. A. 359 Lewis E. S. 22 66 Lewis S. 271 Lewis S. C. 41 Leworthy D. P. 302 Ley S. V. 217 Li C. H. 375 Li M.-Y. 66 Li W. S. 127 Liang D. 351 Liao S.-T. 233 Libman J. 243 Lichtenberg F. 144 254 Lichtenthaler F. W. 312 313 Liebeskind L. S. 136 160 212 Liebisch D. C. 365 Lien M. H. 26 LiepinS E. 12 243 Liesbcher J. 196 Liescheski P. B. 26 Light L. A. 172 Limbach H. H. 15 16 Lin C.-T. 86 Lin H.-S. 168 Lin L. J. 156 Lindell S. D. 122 Lindley J. 48 211 263 Lindley P. F. 206 Line D. H. 4 Ling N.362 Lion C. 138 Liotta C. L. 18 58 Lippard S. J. 223 Author Index 389 Lipshutz B. H. 126 196 211 216,261 Luzzio F. A. 290 322 Luzzio F. P. 148 Mai K. 147 Maier G. 86 87 156 176 Lissavetzky J. 147 L’Italien J. J. 362 Lyle T. A. 360 Lynch J. E. 129 Maier W. 309 239 Little R. D. 24 Lynch L. E. 90 Maier W. F. 179 Littrnan D. 239 Lynn D. G. 6 Maignan C. 30 149 167 Liu C.-L. 183 214 Maillard B. 244 Liu L. K. 363 Maack T. 359 Mains R. E. 372 Liu M.-T. 200 Maas G. 167 191 Maj S. P. 73 Liu M. T. H. 83 Mabelis R. P. 3 Makara G. B. 374 Liu R. C. 361 McAllister L. B. 375 Maki Y. 193 Lively D. L. 190 Livini E. 320 McBride B. 287 McCaffrey J. G. 25 Malek J. 25 Malfroot T. 147 286 Liz R. 42 McCallion D. 253 Malik A. 322 Llinas M.6 McCallum R. J. 64 Malleron A. 138 Lloyd D. 25 Lluch J. M. 24 26 99 McCarnmon J. A. 18 McCarthy K. E. 196 Mallory C. W. 100 183 Mallory F. B. 100 183 Loach D. R. 219 McClelland R. A. 62 Malpass J. R. 40 94 95 Loenn H. 330 MacCoss M. 9 Mandai T. 115 138 Loenngren J. 330 Lok S. M. 15 Macdonald D. I. 148 McDonald J. G. 148 Mandal A. K. 131 Mandarino L. 368 Lomax T. D. 64 Lommes P. 72 McDonell J. A. 292 McDougal P. G. 28 Mandel G. 139 Mandel N. 139 Long G. W. 341 Lopez-Rodriguez M. L. 50 Loreto M. A. 95 McDowell C. A. 14 McFarlane W. 244 McGarvey G. J. 326 Mandelbaum A. 115 Mander L. N. 180 Manders W. F. 244 Lossing F. P. 76 Lothar K. 89 Mach K. 176 224 Machinami T. 348 Mandolini L. 153 Manhas M. S. 234 Loudon G. M. 145 Macho V. 15 Manikurnar C. 305 Lough W.J. 222 Loupy A. 57 Lovich S. F. 116 McIntosh J. M. 375 MacIntyre I. 363 370 McIver J. W. 25 Mann J. 348 Manna S. 137 174 Mannschreck A. 9 Lowe D. 41 McIver R. T. 64 Manoharan M. 166 Lowe G. 149 Lu L. D.-L. 125 223 Mack D. P. 86 Mackay K. M. 243 Mansuy D. 109 219 Manuel G. 241 Lu X.-D. 49 Mackenzie N. E. 12 Marais C. F. 324 Lubineau A. 138 McKervey A. M. 221 Marchelli R. 137 278 Lucan A. J. Y. 105 Lucchetti J. 32 167 266 McKinney M. A. 157 McKinney R. J. 21 1 Marchese G. 13 130 Marcus R. A. 21 Lucchini V. 29 McLaren F. R. 90 Mareda J. 82 Luche J.-L. 127 137 MacLean D. B. 322 Mariano P. S. 43 105 Lucietto P. 357 McLennan D. J. 53,64 Maricich T. J. 94 Lucon M. 64 Lucy A. R. 13 223 Ludens J. H. 368 McLoughlin J. I. 131 McMahon R. J. 87 McManis J. 110 277 Marinetti A.187 Maring C. J. 343 Marino G. 147 Ludwig E. G. 245 McManus J. 125 Marino J. P. 270 Luengo J. I. 33 McManus S. P. 94 Markey K. 372 Lukacs G. 12 320 322 349 Lukevics E. 12 243 Lundberg J. M. 357 372 McMurry J. E. 140 176 179 Macpherson A. J. 150 McQuaid L. A. 165 Marley P. D. 373 Marlier J. F. 63 Maroldo S. G. 64 Lundt I. 315 Luong-Thi N. T. 229 LUO F.-T. 116 Macura S. 3 Maddaluno J. 252 Maeda K. 129 Marquardt H. 361 Marquet J. 50 99 Mamott S. 20 23 24 64 Lupton E. C.,Jun. 22 170 Maeda N. 134 Marsh R. 61 Luque F. A. 375 Maeda T. 41 162 Marshall J. A. 176 Lusser M. 235 Maercker A. 230 Marshall L. 110 125 277 Lusztyk E. 74 244 Lusztyk J. 74 75 Lusztyk L. 244 Luthe C. 165 Lutke H. 169 Lutz R. P. 154 271 Magdzinski L. 316 317 318 Maggio J. E. 371 Magnin D.R. 172 Magnoli D. E. 21 Magnusson E. 20 Mahdi W. 230 Marshall P. J. 62 Marsi M. 218 258 Marson C. M. 47 285 Martin M. G. 126 185 Martin O. 338 Martin P. 194 Luyten M. 179 Mahidol C. 183 Martin S. A. 364 Luz z. 10 Mahy J.-P. 219 Martin V. S. 328 390 Author Index Martha V. 130 Martinez G. R. 295 Martz J. T. 147 286 Maruoka K. 129 262 Maruyama F. 180 Maruyama H. 188 Maruyama K. 123 128 134 142 146 256 257 Maruyanoff B. E. 150 Marx R. 38 Masaki Y. 112 Masalov N. V. 274 Meier M. 272 Meier R. 203 Meinhold R. W. 59 Meldal M. 332 Mellor J. M. 113 Mencel J. J. 171 Mendenhall E. D. 77 Menear K. A. 175 Menidi G. 206 Menon B. C. 61 Merckel C. 75 MerCnyi R. 71 72 Minami T. 217 Minamino N. 371 Minato T. 18 54 91 Mincher D. J. 346 347 Mindle J. 56 Mingos D. M. P. 11 Minisci F.204 Mino Y. 367 Minobe M. 274 Minoli G. 210 Minshall J. 323 Min-zhi D. 142 Masamune S. 238 Masamune T. 175 Mermod J.-J. 370 Merrifield R. B. 360 361 Mioskowski C. 137 150 Miranti T. S. 224 Mashima M. 64 Merz K. M. 244 Mironov V. A, 162 Maskill H. 51 Mestichelli L. J. J. 292 Miroshnikov A. I. 366 Maslak P. 210 Meth-Cohn O. 39 93 Misiti D. 290 Mason J. 11 Mason S. C. 63 Mastalerz H. 290 Metral J.-L. 167 Metternich R. 119 254 Metz J. 276 Mislow K. 9 Mison P. 147 Misono K. S. 360 Mastropaolo D. 367 Metz J. T. 25 Misumi A. 164 Masuda Y. 148 Meunier B. 109 215 Mitani M. 103 Masuko H. 188 Meunier F. 125 Mitchell R. H. 58 Masumune S. 150 Meyer B. 314 Mitchell T. N. 234 Masumume T. 135 Meyer R. B. jun. 320 Mitschler A. 187 Masuyama Y. 123 Meyer T. A.58 Mitsudo T.-A. 116 Mather A. N. 162 Meyers A. I. 80 133 140 Mitsui H. 279 Mathey F. 187 Mezher H. A. 351 Mitsunobu O. 344 Mathieu C. 340 Mathur H. H. 203 Math S. A. 181 222 Matsubara S. 137 Matsuda I. 138 Matsui Y. 344 Matsumota K. 128 Michalczyk J. 238 Michalska M. 315 Micha-Screttas M. 228 263 Micheel F. 313 Michel A. 366 Michel J. 312 Michel S. J. 188 Miura M. 193 Miwa T. 134 Miyashita A. 150 225 Miyashita M. 142 350 Miyazaki Y. 358 Miyazawa Y. 163 Mizuno K. 98 Matsumoto M. 70 278 Michelin R. A. 109 Mizuta K. 358 Matsurnoto T. 180 272 312 Michelotti E. L. 114 219 Mizutani M. 274 Matsumura E. 205 Matsumura N. 253 Matsuo H. 371 Michl J. 238 Middleton R. W. 183 Midland M. M. 31 131 144 Mizuya J. 199 Mjanger R. 94 Mochizuki A. 140 Matsushita Y. 337 267 272 Mochizuki M.164 Matsuura T. 99 Miesch M. 88 Mock W. L. 53 Matsuyama H. 163 Matsuzaki K. 323 324 Miginiac L. 124 Mignani S. 71 Modena G. 29,253,266 Moffatt J. G. 320 324 Matsuzaki Y. 126 Mihm G. 239 Mohamadi F. 284 Matsuzawa S. 242 Matsuzawa Y. 337 Mika-Gibala A. 97 Mikami K. 41 44 124 162 Mojsov S. 361 Molander G. A. 170 Mattocks A. R. 295 171 272 Molino B. F. 316 318 Matturro M. G. 179 Matuszewski B. 106 Matz J. R. 179 Mikhailov A. I. 74 Miki Y. 205 Mikolajnyk M. 149 150 Molinski T. F. 126 287 Molloy K.C. 243 Mols O. 324 Maumy M. 140 Milat M. L. 331 Molyneux R. J. 300 May C. 81 Mayer B. J. 55 Mayeri E. 375 Maynier F. 174 Miles S. J. 238 Milesi L. 108 Miller J. A. 213 Miller J. D. 245 Mondange M. 331 Mondon M. 102 Money T. 171 Moniot J. L. 305 Meakins G. D. 194 Miller K.D. 59 Monkiewicz J. 150 Medici A. 197 Miller L. J. 373 Monneret C. 345 Meerwald I. 324 Miller M. 165 Monney H. 183 Mehdi R. T. 245 Miller R. 260 Montevecchi P. C. 112 Mehler K. 232 233 Miller R. D. 148 Monti L. 326 Mehrotra S. K. 246 Miller R. J. 371 Montreux A. 115 Mehta G. 160 173 181 Meier. H. 198 Mills S. 145 Minami I. 139 142 Moody C. J. 81 92 Mooiweer H. H. 214 Author Index Moolenaar M. J. 174 Moon M. W. 193 Moore G. A. 354 Morella A. M. 113 127 277 Moreno-Mafias M. 99 Morera E. 260 284 Morey M. C. 196 Mori A. 164 262 Mori K. 168 175 Mori M. 225 349 Moriarty R. M. 137 Moriga M. 358 Morimoto K. 296 Morimoto T. 145 258 Morin C. 350 Morin-Allory L. 344 Morisaki Y. 115 Morisawa Y.360 Morishima N. 324 Moriyama T. 138 Morizawa Y. 137 153 Mormtde P. 374 Moroder K. 357 Morokuma K. 24 26 44 50 Morris D. G. 64 Morris H. R. 363 365 370 Morris M. D. 164 Morris-Natschke S. 129 Morrison C. L. 97 Momssey M. M. 119 222 28 1 Mosbach K. 338 Moses S. R. 37 Moskal J. 257 Moss R. A. 82 84 Mosset P. 29 Motherwell W. B. 70 119 146 148 192 273 283 284 Mettoh A. 191 Moulik P. S. 65 Moyano A. 181 Muchowski J. M. 193 Muller B. 344 Muller G. 236 239 Mueller P. H. 157 Muller U. 141 Muller-Starke H. 343 Muench A. 38 199 Muhlstadt M. 169 Mukaiyama T. 123 134 143 149 296 312 313 325 334 344 Mukhopadhyay R. 304 Mularski C. J. 195 Mulholland R.L. jun. 124 276 Mullally D. 25 Mullane M. F. 54 56 Muller U. 161 Mundy B. P. 181 Munekata E. 371 Munger J. D. 204 Munger K. L. 370 Munjal R. C. 84 Murahashi S. 279 Murai A. 175 Murai K. 135 Murai S. 248 261 Murai T. 261 Murakami M. 143 312 325 Murakami S. 238 Murakoshi I. 103 Muramatsu S. 99 Muramoto K. 362 Murata S. 93 140 Murdoch J. R. 21 65 Murray H. H. 218 Murtiashaw C. W. 181 Murty A. N. 173 Murugesan N. 304 Musai Y. 313 Musiol J. 357 Musumarra G. 47 Mutt V. 356 357 373 Myers A. G. 169 Myhre P. C. 15 Mynott R. 233 Naden M. 151 Naef R.,141 Nafti A. 147 Nagakura N. 305 Nagao Y. 273 Nagaoka H. 180 325 Nagarajan M.86 Nagarajan V. 73 Nagase H. 172 Nagase S. 50 Nagashima H. 108 215 Nagatsuma M. 143 Nagy T. 148 Naito T. 99 Najem T. 56 Nijera C. 110 Nakahara Y.,345 Nakai H. 172 Nakai T. 41 44 124 143 162 272 Nakajima M. 147 Nakamura E. 172 Nakamura H. 375 Nakamura K. 131 138 139 180 Nakanishi H. 198 Nakanishi S. 365 371 Nakashima N. 93 Nakata T. 126 131 137 282 Nakatani K. 139 273 Nakayama J. 79 185 Nakayama Y. 138 Nakazaki M. 281 Nakita A. 148 Namy J.-L. 139 Narang S. C. 49 Narasaka K. 134 296 Narasimhan S. 11 1 Narayana V. L. 188 Narayanan K. 111 391 Narisamo E. 149 Narita M. 357 Naritomi T. 204 Nashed M. A. 331 Nassal M. 84 Natsugari H.146 Nawa H. 371 Nawad N. A. 95 Nazer B. 140 282 Nazran A. S. 75 85 86 96 253 Nazrul I. 213 Negishi E.-I. 116 213 Negoro T. 114 Neh H. 180 Nehl H. 234 Nelson G. O. 34 Nelson S. F. 33 Nemlin J. 322 Nencivengo D. J. 66 Nesser J. R. 320 Neugebauer F. A. 208 Neumann W. P. 38 239 Neuroho K. J. 3 Newcomb H. 140 Newcomb M. 55 243 Newman P. A. 51 Newton T. W. 114 129 Neya M. 358 Ng A. S. 179 Ng G. S. Y. 144 Nguyen M.-T. 26 58 Nguyen S. 261 Niccolai N. 8 Nicholas A. M. de P. 76 Nickell D. G. 297 Nicolaou G. A. 206 Nicolaou K. C. 123 127 313 Nicolas P. 375 Nicotra F. 320 Niitsuma S. 168 Niiyama K. 172 Nikaido M. 220 Nikishin G. I. 148 Nikonov G.N. 150 Nilsson A. 147 Nishida S. 158 Nishide K. 119 326 Nishikawa T. 205 Nishimura K. 130 Nishio T. 89 Nishiyama H. 70 Nishizawa M. 131 Nivard R. J. F. 34 Niwa H. 172 297 Njoroge F. G. 169 Nobbs M. S. 175 Nobes R. H. 26 Noda M. 119 365 Noga J. 24 Noltemeyer M. 178 Nome F. 57 Nomura Y. 113 Nonako T. 123 392 Author Index Nonhebel D. C. 73 77 Norberg T. 332 Nordberg R. E. 220 Norden T. D. 156 Norlander J. E. 169 Norman N. C. 195 240 246 Norman R. 0.C. 72 Normant J. F. 126 128 130 191 215 261 Nomnder U. 20 Norskov-Lauritsen L. 26 Northrup S. H. 18 Noumi K. 324 Noyori R. 131 150,225 313 344 Nozaki H. 123 137 145 153 293 Nugent W.A. 33 265 Nukada T. 330 331 335 Numa S. 365 Nutt R. F. 360 368 Nyman H. 330 Obara H. 344 Obata K. 357 Obaza-Nutaitis J. A. 81 O’Brien J. B. 149 O’Brien M. J. 172 Obrzut M. L. 145 Ochiai H. 138 Ochiai M. 273 O’Connor C. J. 64 O’Connor M. J. 235 Oda D. 148 Odaira Y. 103 181 Olting M. 323 Offerman W. 9 Offor M. N. 94 Ogasawara K. 307 Ogata S. 140 Ogawa T. 330 331 335 345 Ogawa Y. 119 Ogihara T. 344 Ogimura Y. 165 Ogumi N. 132 Ogura K. 153 Oguro K.,137 Oh T. 326 Ohanessian G. 20 65 Ohashi Y. 162 269 Ohga K. 105 Ohgushi T. 336 Ohira S. 172 Ohizumi Y. 375 Ohmiya S. 103 Ohno A. 131 138 Ohno K. 84 Ohno M. 172 Ohsawa K.180 Ohsawa T. 297 Ohshima M. 143 325 Ohshiro Y. 155 185 Ohta H. 148 Ohta M. 134 Ohta S. 130 Ohtsuka H. 137 Ohtsuka Y. 168 Ohyama T. 59 Oikawa S. 99 Oinuma H. 302 Oishi T. 126 131 137 168 282 Ok D. 80 Oka S. 109 131 138 Okada H. 138 Okada M. 371 Okamoto H. 357 Okamoto M. 130 Okamoto T. 109 Okamoto Y. 148 Okamura Y. 99 Okano K. 258 Okarma P. J. 179 Okawara M. 146 Okayama M. 344 Okazaki M. 14 Okhanov V. V. 366 Oki M. 48 Oki T. 337 Okuda Y. 153 Okukado N. 116 Okumoto H. 142 225 Okumura H. 139 Okuyama T. 62 Olah G. A. 49 51 52 59 81 Olah J. A. 59 O’Leary M. H. 63 Oleksyszyn J. 245 Olesker A. 12 320 322 349 Oliva A. 24 Olivera B.M. 375 Olivia A. 26 Ollivier J. 158 Olmsted W. N. 64 Olofson R. A.,,J47 286 Olsen D. B. 361 Olson G. J. 244 Olsson L. F. 219 Oltvoort J. J. 332 O’Mahony M. J. 117 Omelanczuk J. 150 Omi T. 132 Omote Y. 104 105 Onan K. D. 55 172 O’Neill M. E. 58 Ono N. 148 Onopchenko A. 109 Oosterbeek W. 22 64 Oplinger J. A. 172 181 Oppolzer W. 29 30 167 265 Oram D. 231 Orban J. 247 Orena M. 276 321 Ortar G. 260 284 Ortega M. 24 Osammor M. I. 163 Osamura Y. 24 44 Osawa T. 131 Osei-Twun E. Y. 253 Osella D. 13 Oshima K. 123 137 153 Oshima M. 324 Osman S. M.,117 Ossowski P. 314 315 Osterman V. M. 49 O’Sullivan A. 89 Otera J. 115 138 Otomasu H. 103 Otsuji Y.98 Otsuka S. 225 Ottosson H. 330 Ousset J. B. 150 Ovchinnikov Yu. A. 366 Over H. 358 Overman L. E. 40 48 145 192 211 271 Oyamada H. 131 Ozin G. A. 25 Pabon R. A. 32 Pacansky J. 87 Pacey P. D. 76 Pachaly B. 242 Pacheco H. 322 Pacofsky G. J. 143 Paddon-Row M. N. 25 50 276 Padwa A. 87 Page M. 25 Page M. I. 48 63 Pages O. 252 Pai G. G. 141 Pajak J. 52 Pajouhesh H. 190 Pakiari A. M. 26 Pakrashi S. C. 304 Pakulski M. 246 Palaniswamy V. A. 5 Paldus J. 25 Paleveda W. J. 360 368 Palkovits M. 371 Palla F. 131 Palling D. J. 54 Palmer M. H. 95 Palmien G. 290 Palomo C. 188 Palumbo P. S. 149 Pancrazi A. 322 Pang Y. T. 90 Panico M.363 365 Panicucci R. 253 Pansegrau P. D. 80 Panyachotipun C. 183 Papahatjis D. P. 313 Papini A. 126 Pappenheimer J. R. 364 Paquet F. 334 335 Paquette L. A. 29 35 155 160 178 181 Pardo S. N. 142 Parente J. E. 53 Park K. H. 59 Author Index Park P. 204 Park W.-S. 55 127 Parker D. 126 261 Parr R. G. 18 19 Parrick J. 183 Parrott M. J. 354 Parry J. L. 192 Parshall G. W. 220 Parsons P. J. 116 Pascal R. A. jun. 11 67 Pascard C. 174 Pascual A. 89 Pasha M. A. 126 Pasquato L. 29 253 Passarotti C. 281 Pasto D. J. 114 Patapoff T. U. 157 Pate B. D. 320 Patel D. D. 130 Patel H. A. 181 Patil G. 147 Patil V. J. 322 Patricia J. J. 127 Pattenden G.177 181 Pauls H. W. 321 351 Paulsen H. 311 330 331 332 334 335 Paulus E. F. 101 Pavitt N. 26 Pavlov S. 129 Pazhanisamy S. 63 Pearlstein R. A. 26 Pearson A. J. 213 277 Pearson R. G. 19 Pearson W. H. 31 266 Pedersen C. 315 Pedersen S. F. 223 Pedley M. D. 65 Pedrini P. 197 Pedulli G. F. 205 Peevey R. M. 147 289 Peiffer G. 115 Pelizzi G. 245 246 Pellacani L. 95 Pelter A. 145 Pelyvas I. 352 Penglis A. A. E. 319 Penkava T. R. 56 Penning T. D. 122 Perego R. 320 Pereyre M. 102 130 Perez A. 270 Pirez-Prieto J. 116 Peringer P. 235 Perlin A. S. 336 Perlow D. S. 368 Pero F. 149 Perrin C. L. 48 Perry D. 279 Perry R. J. 116 Perumal P. T. 132 Pessi A.358 Petch W. A. 59 Pete J.-P. 107 Peters E.-M. 213 255 Peters K. 213 255 Peters K. S. 159 Peterson J. C. 176 Peterson J. R. 140 Petit F. 11 5 Petitou M. 332 Petrier C. 127 137 Petrusova L. 176 224 Ptitzner A. 307 Pham T. N. 127 Philippe M. 352 Philson S. B. 13 Phinyocheep P. 163 Pickardt J. 239 Picq D. 322 Pierini A. B. 29 166 Piers E. 170 175 181 Pietrusiewicz K. M. 150 Pigeon P. 57 Pillai C. 263 Pinhey J. T. 144 Pinkerton A. A. 178 Pinkus A. G. 63 Pinnick H. W. 192 Piper S. E. 171 Pitchen P. 148 223 280 Piteau M. 147 286 Pitner P. 5 Pitt I. G. 185 Plant H. 119 Plant J. 9 Platz M. S. 84 85 86 Plaut H. 250 Pliura D. H. 52 Pohl E.R. 66 Pohmakotr M. 149 163 Poilblanc R. 109 Poirier R. A. 25 Pojer P. M. 131 Polak J. M. 372 Poli G. 132 248 Poli R. 245 246 Poll T. 30 Polla E. 137 Pollack R. M. 61 Pollack S. 20 Ponec R. 17 25 Ponomaryov A. B. 117 Popp F. D. 199 Pomet J. 124 Porter A. J. 64 Porzi G. 276 Potier P. 70 102 Potman R. P. 34 Potts K. T. 210 Poulter C. D. 145 Poupko R. 10 Poveda M. L. 13 Powell A. L. 22 Power P. P. 231 Prahst A. 315 Prajapati D. 208 Prange T. 327 Prapansiri V. 183 Pratt J. E. 100 Pratt S. B. 307 Price A. J. 243 Price M. F. 44 Priebe W. 314 Prinzbach H. 29 106 209 Procter G. 162 Proctor P. 63 Prokschy F. 36 Pross A. 18 19 21 53 65 Proust S.M. 167 Prout K. 212 Pryce R. J. 302 Puchot C. 174 Pudova O. 12 Pulido F. J. 197 Pulwer M. J. 87 Purrello G. 87 Quadri M. L. 108 Quallich G. 342 Quapp W. 18 Quillen S. L. 105 Quinkert G. 101 Quinn D. M. 63 Quinoa E. 224 Quintinilla M. G. 205 Rabinovitz M. 57 Racherla U. S. 139 Radom L. 25 26 Raff D. E. 169 Ragauskas A. J. 181 Raghavachari K. 25 96 Rahman A. 195 Rahman K. M. M. 316 Rajagopalan K. 201 Rajapaksa D. 165 Ram B. 188 Ram S. 145 Ramage R. 354 Ramaiah M. 269 Ramalakshmi Y. 190 Raman K. 158 Ramaprasad S. 8 Ramaswany R. 62 Rambaud M. 127 150 Ramirez J. R. 142 Rana J. 298 299 303 Rance M. 6 Randall C. J. 156 Randall D.101 Randall E. W. 13 Randall J. L. 313 Randles K. R. 208 Randrianoelina B. 124 Ranganayakulu K. 159 Rao A. V. R. 322 Rao K. S. 160 181 Rao T. S. 203 Rao V. B. 179 Rappa A. 166 Rappoport Z. 49 394 Rastall M. H. 90 Raston C. L. 233 Rautenstrauch V. 163 265 Ravindranath B. 126 140 Ray T. 213 277 Raychaudhuri S. R. 97 170 224 Re L. 103 Rebek J. jun. 48 110 125 277 Reddy A. V. 181 Reddy D. S. 181 Reddy G. J. 188 Reddy G. S. 220 Reddy P. S. 147 Redlich H. 345 Rees C. W. 92 Reese C. B. 169 191 325 Reese P. B. 10 Reetz M. T. 48 132 134 135 137,249,257 343 Regitz M. 38 Rehfeld J. F. 373 Rei M.-H. 110 Reich H. J. 33 Reich I.L. 33 Reichelt I. 155 Reichert J. 208 Reingold I. D. 177 Reinhoudt D. N. 162 Reisenauer H. P. 86 87 156 239 Reissig H.-V. 155 208 Reitz A. B. 150 Reitz D. 258 Remiszewski S. W. 326 Renaud P. 141 Renneboog R. M. 90 176 Rens J. 102 130 Replogle K. S. 46 Restelli A. 136 Reuben J. 11 Reutrakul V. 183 Revial G. 156 252 Reyes A. 375 Reynolds W. F. 22 23 64 Rezende M. C. 57 Rheingold A. L. 158 Ricci A. 126 Richard J. P. 49 56 Richards I. C. 213 Richards J. D. 355 Richardson A. C. 300 351 Richardson J. W. 192 Richter D. 370 Ridd J. H. 12 Ridley D. D. 167 Riede J. 236 239 Rieke R. D. 130 Riemann A. 87 Riepl G. 281 Riga J. 71 Rigby J. H. 206 Righetti P.138 Riguera R. 91 183 224 Rihs G. 209 Riley D. 340 Rimmelin P. 51 Ripoli J.-L. 203 Risbood P. A. 253 Risley J. M. 53 63 Ritchie C. D. 19 62 Ritchie G. A. F. 3 Ritterskamp P. 180 Rivier C. 371 Rivier J. 370 371 375 Rivikre H. 125 Roacher N. M. 123 Robb M. A. 18 25 Robb R. J. 365 Roberto D. 226 Roberts B. P. 71 74 Roberts G. W. 372 Roberts J. E. 16 Roberts K. A, 90 Roberts M. P. 59 Roberts V. A. 30 167 176 Robins D. J. 294 295 298 299 303 304 Robinson M. J. T. 166 Roder H. 213 255 Rodgers L. R. 11 67 Rodrigo R. 165 Rodriguez J. 123 Roe D. C. 211 Rosch L. 233 Roessac F. 167 Rogers D. A. 64 Rogers R. D. 237 Roguera R. 126 Rohde C.60 Rol C. 100 Rolla F. 108 Romas M. J. 226 Romey G. 376 Ronald R. C. 169 Ronchetti F. 320 Rondan N. G. 18 24 25 27 30 37 55 60 82 276 Ronzini L. 130 Roos M. 312 Roosz M. 322 Rosberger D. F. 361 Rosch W. 38 Rose K. D. 147 Rosenblum M. 164 218 258 Rosenfeld M. G. 370 Rosenquist N. R. 22 Rosenthal R. J. 87 Roslik N. A. 191 Ross M. M. 364 Rossana D. M. 172 Rosser R. M.,145 Rossi C. 8 Rossiter B. E. 125 Rossky P. J. 26 Rossor M. N. 372 Roth B. 176 Author Index Rothenberg M. E. 49 Rothman B. S. 375 Rotinov A. 57 Roudier J.-F. 144 Rouessac F. 30 149 Rougny J. R. 349 Roush W. R. 150 172 328 Rouzaud D. 342 Rowe B. A. 144 Rowe J. E. 54 Royer R.192 Royes R. 203 Rozeboom M. D. 44 Rozen S. 107 Ruasse M.-F. 22 57 66 Rubio J. 237 Ruchardt C. 272 Ruder S. M. 169 Rucher C. 136 Rueger H. 297 Rueffer M. 305 Rufinska A. 232 233 Ruoff P. 23 Russell D. R. 95 180 Russell G. B. 294 Russell R. A. 185 Russo G. 320 Ryan J. W. 366 Ryu I. 248 Sabesan S. 332 Sabourin E. T. 109 Sabuni M. 32 167 Sadler I. H. 10 Sahlberg C. 118 Sahoo S. P. 350 Sahraoui-Taleb S. 270 Sainsbury M. 165 Saito A. 99 Saito I. 99 Saito Y. 123 Sakai K. 162 264 Sakai T. 150 Sakakibara S. 367 Sakakura T. 296 Sakamoto M. 104 105 Sakamoto Y. 323 Sakan K. 180 Sakata Y. 344 Sakdarat S. 295 Sakizadeh K. 54 Sakuma K.112 Sakurai H. 344 Sakurai K. 344 Sakuri Y. 261 Sala R. 281 Salamone S. J. 149 Salaun J. 158 Salem G. 51 233 Salomon M. F. 142 Salomon R. G. 97 142 170 224 Samuelsson B. 148 278 290 322 Author Index Sanchez-Delgado R. 13 Sand P. 183 Sandall J. P. B. 12 Sandhu J. S. 208 Sandri S. 276 321 San Filippo J. 59 66 Sansoulet J. 57 Santikarn S. 363 Saperstein R. 368 Sardarian A. R. 151 Sarfati S. R. 331 Sarkar S. K. 14 Sas W. 110 Sasson Y. 57 Sato F. 191 213 Sato K. 142 225 316 Sato S. 138 149 175 375 Sato T. 101 127 141 143 2' 2 Satoh H. 188 Satoh J. Y. 127 Satomi H. 249 Sauer I. 245 Sauerwald M. 135 Saulnier M. 81 Saumtally I.138 Saunders J. O. 181 Saunders W. H. 55 56 Savino T. G. 86 Sawchenko P. E. 370 Sawlewicz P. 50 Sawyer J. A. 106 128 Sayo N. 44 124 143 272 Scaiano J. C. 75 84 85 86 103 157 Scarmoutzos L. M. 228 Scarso A. 366 Scavo F. 220 Schaad L. J. 24 25 160 Schaaper W. M. M. 357 Schaefer D. 226 Schaefer H. F. 23 25 29 Schafer H. 266 Schafer W. 179 Schaffner K. 180 Schaller H. C. 376 Scharf R. 357 Schaumann E. 187 190 Scheer P. 322 Scheeren J. W. 34 Scheller R. H. 375 Schenk H. 62 Schiebel H.-M. 303 Schildknecht H. 337 Schiller P. W. 367 Schilling B. E. R. 238 Schilling J. W. 359 Schilling S. L. 64 Schinzer D. 162 Schlegel H. B. 25 79 Schlesener C.J. 59 61 Schleyer P. von R. 60 230 Schlichte K. 233 Schlosser M. 200 Schliiter E. 240 Schmale H. 370 Schmid C. 278 Schmid G. 200 Schmid G. H. 57 148 Schmid R. 225 Schmid-Antomarchi H. 376 Schmidbauer H. 236 Schmidhauser J. C. 176 Schmidpeter A. 38 Schmidt C. A. 190 Schmidt J. 26 79 Schmidt R. R. 312 329 Schmit C. 270 Schmitt M. 36 Schmitz L. R. 159 Schnabel W. 74 Schnatter W. 201 Schnatterer A. 98 Schneider M. 127 144 Schneider M. J. 300 Schnick W. 180 Schoenen F. J. 200 Schohe R. 37 327 Scholz D. 144 Schormann N. 178 Schowen R. L. 63 67 Schreiber S. L. 209 Schrock A. K. 92 Schrock R. R. 220 Schroth G. 233 Schubert B. 233 Schubert H. 137 Schuda P.F. 180 Schuerch C. 322 323 324 Schulman J. M. 181 Schultz F. W. 117 Schultz K.-D. 239 Schulz G. 93 334 Schulz W. J. jun. 157 Schumann B. 309 Schurig V. 125 Schuster G. B. 49 84 92 Schutz G. 370 Schwabacher A. W. 95 Schwager L. 178 Schwartz J. 211 220 Schwarzenbach D. 178 Schweizer W. B. 141 Schwellnus K. 137 Schwentner J. 314 Schwobel A. 288 Schwyze; R. W. 368 Sciacovelli O. 13 Scolastico C. 149 248 Scott A. I. 12 305 Scott c.P. 34 Scott W. 260 261 Screttas C. G. 228 263 Scribner M. E. 87 Sealey J. E. 359 Seaman N. E. 62 Sebastiani G. V. 100 Seconi G. 126 Seda R. 142 Sedgwick R. D. 363 Seebach D. 141 288 Seeburg P. 365 Seeman J. I. 48 Seevogel K.234 Segmuller B. 179 Segmuller S. E. 343 Seidah N. G. 360 Seidel W. C. 211 Seitz S. P. 119 Seizinger B. R. 365 Sekatsis I. P. 243 Sekiguchi A. 242 Sekine M. 325 Sekiya M. 145 258 Sellers S. F. 156 Semeria D. 352 Semmelhack M. F. 201 225 278 Senet J.-P. 147 286 Sepulchre A. M. 352 Serena B. 100 Sereno J. 326 Serio M. R. 109 125 Serratosa F. 181 Seshadri S. 71 Seto K. 147 Severin T. 280 Seyferth D. 147 243 Sgarabotto P. 228 Shaffer D. K. 123 Shah D. O. 12 63 Shaik S. S. 19 47 Shakir R. 229 Sham H. L. 180 Shamma M. 304 305 Shankaran K. 80 Shannon M. L. 243 Shanzer A. 243 Shapiro G. 174 Sharma K. K. 142 Sharma M. N. 314 Sharova E.G. 293 Sharpless K. B. 125 126 223 328 Shaw G. 346,347 Shaw G. S. 27 Shea R. 289 Shearer H. M. M. 235 Shechter H. 86 Sheldon J. C. 54 Sheldrick G. M. 178 Shen Y. 155 Sheppard R. C. 358 375 Sheridan R. S. 83 Sherman D. 11 Sherman H. L. 192 Sherry L. J. S. 95 Shiba T. 331 332 Shibasaki M. 119 Shibata K. 187 324 Shida J. 145 Shimada N. 135 Shimagaki M. 126 Shimamoto T. 331 Shimauchi Y. 189 Shimizu I. 139 142 162 269 Shimizu M. 149 Shimizu N. 100 123 Shimizu T. 198 Shimo T. 209 Shine H. J. 59 Shing T. K. M. 165 336 349 35 1 Shiota T. 279 Shiozaki M. 188 Shirahama H. 180 Shirai F. 143 Shoda S. 312 313 344 Shoemaker R. A.94 Shridhar S. R. 188 Shubin V. G. 47 Shutske G. M. 198 Sibi M. P. 81 Siddiqui M. M. 117 Siddiqui S. 86 Siebrand W. 19 75 Siegel J. 9 Siehl H.-V. 49 Siewinski A. 89 Sih C. J. 48 131 144 281 Sikirica M. 235 Sillapnaa S. 166 Simchen G. 194 Simon E. S. 146 284 Simon J. D. 159 Simonetta M. 17 47 Simpson I. 95 Sinanoglu O. 17 18 Sinay P. 314 332 334 335 342 344 Sindona G. 325 Singaram B. 111 121 Singh A. 229 Singh A. K. 203 Singh G. 297 350 Singh S. M. 139 Singleton D. A. 32 172 Sinnott M.L. 62 Sirmokadam N. N. 240 Sitzmann E. V.,84 Skala G. 368 Skare S. 157 Skattebal L. 89 Skell P. S. 71 Skinner K. L. 95 Skoog M. T. 53 Slebocka-Tilk H. 57 Sloan K.L. 156 Slocum G. H. 49 Slowey P. D. 58 Smadja W. 124 Smalley R. K. 92 Smart B. E. 60 Smith A. B. 104 174 181 Smith C. W. 368 Smith D. A. 180 Smith D. J. H. 110 150 Smith G. F. 157 Smith J. D. 232 Smith J. G. 126 Smith J. K. 140 Smith J. M. 71 Smith K. 228 Smith K. M. 193 Smith M. B. 155 157 Smith M. R. 94 Smith P. W. 300 351 Smith S. F. 26 54 Smyth D. G. 372 Smyth R. L. 53 Snider B. B. 173 Snieckus V. 80 Snow J. T. 238 Snyder J. J. 106 128 Soai K. 131 Solas D. R. 193 Soldi T. F. 210 Solladie-Cavallo A. 127 136 Somayaji V. 111 128 Somekawa K. 209 Sommer J. 51 Sonnleitner B. 141 Sonoda N. 248,261 Sonola O. 146 Sooriyakumaran R.242 Sarensen 0. W. 6 Sorensen T. S. 159 Sorgi K. L. 344 Sorokin V. D. 114 Sosa C. 25 79 Souchi T. 150 Souppe J. 139 Spagnolo P. 112 Spatola A. F. 361 Speckamp W. N. 174 Speicher D. 373 Spek A. L. 216 234 235 Spencer C. B. 235 Spencer T. A. 55 Spenser I. D. 292 298 299 303 304 Spiess J. 371 Spina K. P. 192 Spitznagel G. W. 60 Sponlein W. 181 Sprague J. R. 156 Springer D. 321 Springer J. 201 Sridharan V. 37 Srikrishna A. 181 Srinivas P. 126 140 Staab H. A. 86 Stadler E. 57 Stajer G. 208 Staley S. W. 156 Stanczyk W. A. 60 Stang P. J. 90 156 Stassinopoulou C. I. 366 Staunton J. 3 Author Index Stein R. L. 63 Steinfink H. 230 Steliou K.33 Stempfle W. 234 Stephenson D. S. 178 StErba V. 56 Sternbach D. D. 172 Sternberg E. D. 224 Sternberg J. 267 Stevens K. E. 181 Stevens P. S. 156 Stevens R. W. 134 Stevenson D. 361 Stevenson J. W. S. 173 Stevenson P. 164 215 Stewart C. A. 195 Stewart J. J. P. 18 Sticker O. 293 Stille J. K. 134 260 261 Stirling C. J. M.,56 Stock L. M. 52 Stocker A. W. 92 Stockigt J. 307 Stoler E. M. 59 Stolow A. 60 Stone B. L. 375 Stone T. E. 320 Stoodley R. J. 347 Stork G. 180 Storr R. C. 79 208 Stothers J. B. 181 Stowell J. C. 151 263 Stratt R. M. 76 Streitwieser A. 20 48 Stretton G. N. 235 Strickler J. E. 361 Strukul G. 109 Stuchlik P. 93 SU,W.-Y. 55 127 Suami T.300 Subra R. 25 159 Subramanian R. 55 83 Suemune H. 162 264 Suffert J. 127 136 Sugawara T. 93 Sugimoto A. 324 Sugimoto M. 330 335 Sugino K. 138 Sugita Y. 371 Sugiura Y. 132 Sugiyama H. 99 Sugiyama M. 360 Suh H. 341 Suh Y. J. 59 Sullivan A. C. 232 Sullivan M. J. 16 Sumi S. 127 Sumimoto H.,323 Sumiyoshi T. 74 Sundberg R.J. 47 Sunitha K. 201 Surya Prakash G. K. 49 Sustmann R. 72 Suzukamo G. 158 Author Index Suzuki K. 130 138 272 334 Suzuki M. 153 172 312 Suzuki S. 261 344 Svensson S. C. T. 332 338 Svitanko I. V. 148 Swain C. G. 22 64 Swain C. J. 117 Swain M. S. 22 Swanson L. W. 3.70 Sydnes L. K. 157 Symons M. C. R. 73 Szabo A.E. 208 Szabo L. 331 Szabo P. 331 Szarek W. A. 322 325 338 Szeimies G. 90 161 Sztariskai E. 352 Szwedo M. J. 209 Tabba H. D. 193 Taber D. F. 158 Tabor D. C. 51 Tacconi G. 138 Tadanier J. 340 Tadano K. 300 Taddei M. 126 Tadokoro H. 168 Taft R. W. 20 22 23 64 Taghavi H. 51 Tagmazyan N. K. 147 Taira K. 53 Tajima K. 143 Takagi Y. 348 Takahashi H. 297 314 338 Takahashi K. 137 142 Takahashi M. 25 Takahashi S. 147 Takahashi T. 145 219 258 Takamura N. 180 Takanaka S. 205 Takanashi Y. 331 Takano S. 307 Takata T. 180 185 Takaya H. 225 Takaya T. 351 Takeda K. 316 Takei Y. 163 Takemasa Y. 141 Takemura S. 205 Takeo K. 324 Taketomi T. 225 Takeuchi R.145 Takeuchi T. 337 Takeuchi Y. 113 243 Takeue S. 79 185 Takeyama T. 136 Takiyama N. 132 Tam J. P. 360 361 Tam T. F. 351 Tamada M. 103 Tamao K. 122 129 258 Tamariz J. 179 Tamaru Y. 138 249 274 Tamura K. 101 Tamura M. 158 Tamura N. 307 Tamura O. 33 Tamura R. 148 Tamura S. 50 Tamura Y. 33 103 Tan T. S. 162 Tanabe H. 66 Tanaka C. 146 Tanaka J. 204 Tanaka M. 293 Tanaka S. 142,249 Tanaka Y. 191 Tang M. 59 Tang P.-C. 220 268 Tang Y. S. 136 Tanguy G. 130 Taniguchi H. 49 91 140 Taniguchi Y. 251 Tames H. T. 199 Tao Y.-T. 56 Tardella P. A. 95 Tarkhouni R. 127 Tatchell A. R. 146 Tatemoto K. 356 357 363 372 373 Tatsuta K. 297 314 338 Tayako H.150 Taylor C. J. 368 Taylor L. C. E. 363 Teague S. J. 181 Tebbe F. N. 220 Temura R. 201 Tencer M. 83 Teramura K. 198 Terashima S. 312 Terenius L. 372 373 Terpstra J. W. 82 Terrier F. 53 Tetef M. L. 91 Tewson T. J. 320 Tezuka T. 125 Thaisrivongs S. 288 Thamm P. 357 Thang T. T. 12 320 Thea S. 56 Thebtaranonth Y. 154 Theis M. 231 Theodore M. S. 180 Thewalt U. 236 Thianpatanagul S. 37 Thibault G. 360 Thiem J. 314 315 320 Thiemeyer H. 318 Thierry J. 70 102 Thoenen H. 370 Thomaides J. S. 210 Thomas P. J. 181 Thomas S. E. 108 Thompson D. W. 117 Thompson K. L.,110 Thompson P. 257 Thompson P. A. 132 145 Thompson W. J. 136 Thorne A.J. 229 238 Tidwell T. T. 48 Tien T.-P. 26 Tietz H. 335 Tillman N. 96 Timpe H.-J. 75 Tiner-Harding T. 140 Tinley E. J. 95 Tinyakova E. I. 211 Tippins J. 363 370 Tirel M. D. 194 Tishchenko I. G. 191 274 Tissot A. 100 Tius M. A. 164 Tobe Y. 103 181 Tobita H. 238 Tocco D. J. 368 Todaro G. J. 361 Toki T. 261 Tokida Y.,205 Tokoroyama T. 174 Tolbert L. M. 29 86 166 Tolman C. A. 211 Toma L. 320 Tomasini C. 276 321 Tomino I. 131 Tomioka H. 82 83 84 Tomioka I. 123 Tomioka K. 141 Tomita K. 367 Tomiyoshi N. 180 Tomoda S. 113 Tomooka K. 130 Tomori E. 324 Ton T. T. 322 349 Tonachini G. 25 Toni K. 225 Toniato E. 95 Toppet S. 187 Topsom R.D. 20,22,23,24,64 Torchia D. A. 14 Torosyan G. O. 147 Torres N. E. 167 Tom G. 332 Torsell K. B. G. 142 148 Tortelli V. 204 Touchard D. 102 Toullec J. 136 Toussaint O. 140 Toyonaga B. 57 Toyosato M. 365 Toyota M. 179 Trachtman M. 25 Trahanovsky W. S. 87 Tramontano A. 144 Traylor T. G. 243 Trendel J. M. 101 Trigalo F. 331 Trivedi G. K. 203 Trompenaars W. P. 162 Trope A. F. 180 Trost B. M. 28 123 143 151 179 214 263 Author Index Trousson P. M. R. 73 Troyansky E. I. 148 Tsai D. 272 Tsai D. J. S. 144 Tsai T. Y. R.,315 316 Tsang R. 3 18 Tse H. L. A. 170 Tseng R. 41 Tsoi S. C. 92 TSOU U.-P. E. 87 Tsuboniwa N. 137 Tsuchihashi G. 130 138 148 153 272 Tsuda M.99 Tsuda Y. 324 Tsuge O. 204 205 209 Tsugoshi T. 139 Tsuji J. 108 110 130 139 142 162 165 219 225 269 Tsuji T. 158 188 Tsuji Y. 145 Tsukamoto M. 142 174 249 Tsuno Y. 100 Tsutsumi H. 351 Tucker L. C. N. 316 323 Tufariello J. J. 297 Tuladhar S. M. 221 Tulshian D. B. 41 318 341 Tundo A. 205 Turecek F. 176 224 Turkenburg L. A. M. 91 Turner J. V. 126 287 Turner R. W. 164 Turner T. 247 Turro N. J. 72 75 97 Tuthill P. A. 180 Twitchin B. 247 Twohig F. M. 221 Tyler A. N. 363 Uang B. J. 342 Ubukata M. 5 Uchimaru T. 296 Uchino T. 103 Udenfriend S. 365 Uehara S. 103 Uemura H. 209 Uemura M. 217 Ueno K. 162 264 Ueno Y. 146 344 Uesaka M. 185 Uff B. C. 199 Uggeri F. 181 Uggerud E.26 Ugolini A. 346 Uguen D. 148 Ukai J. 256 Ukita T. 273 Umemura J. 26 Umeyama K. 213 Umezawa H. 337 Umezu K. 143 Uncuta C. 63 Ungar S. H. 22 Ungemach F. S. 300 Unger F. M. 334 Uno M. 147 Unverzagt C. 355 Urabe H. 162 264 Urabe T. 99 Urban M. 24 Urech R. 180 Uryu T. 323 324 Ushio K. 131 Uskokovich M. R.,326 Utimoto K. 145 153 293 Uyehara T. 164 Uzawa J. 5 Vaagberg J. 220 Valdeomillos A. M. 147 Vale W. W. 370 371 Valentine J. S. 109 223 Valpey R. S. 160 Van Atta R. B. 109 223 Van Binst G. 366 van Boeckel C. A. A, 332 van Boom J. H. 332 Van-Catledge F. A. 60 van den Goorbergh J. A. M. 141 van der Gen A. 141 150 van der Hart D. L. 14 Van der Kerk G. J. M. 216 234 235 van der Kerk S.M.,66 van der Marel G. A. 332 Vandewalle M. 170 Vandlen R. L. 368 Van Duyne G. 179 Van Etten R. L. 53 63 van Gerresheim W. 66 Vangheluwe P. 187 van Hummel G. J. 162 van Koten G. 231 van Leusen A. 257 van Meervelt L. 187 van Nispen J. W. 374 van Vuuren G. 39 Vara Prasad J. 263 Varaprath S. 183 201 214 Varela O. 314 Varney M. D. 41 122 Varnum D. A. 320 Varvoglis A. 280 Vasella A. 32 167 349 Vasil’eva E. V. 139 Veber D. F. 360 368 Vedejs E. 114 258 273 279 295 Vega S. 16 Venkatachalam T. K. 61 Verbist J. 71 Verboom W. 162 Verheyden J. P. H. 324 Verhoeven J. W. 24 66 Vermeer P. 214 Vernon C. A. 353 363 370 Vessal B. 151 Vethaviyasar N. 316 Veyrieres A. 332 Vick S.C. 243 Vidal M. 159 Vidari G. 180 Viehe H. G. 71 72 Vieler R. 239 Vieth H. M. 15 Viile G. 124 Villikras J. 127 150 Vincens M. 159 Vishwakarma L. 278 Vismara E. 204 Visser G. W. 162 Vitali D. 245 Voelter W. 322 Vogel C. 79 Vogel D. 271 Vogel P. 29 167 176 178 179 Voigt M. M. 373 Volden H. V. 238 Vollhardt K. P. C. 117 211 224 269 von Daacke A. 193 von Nagy-Felsobuki E. 20 von Roman T. 229 von Schnering H. G. 213,255 Voskamp D. 357 Vriesma B. 286 Vyplel H. 93 Wada M. 261 Waddell W. H. 92 Wade K. 232 Wade R. A. 193 Wadsworth A. H. 348 Wagner C. K. 11 67 Wagner D. 324 Wagner G. 239 366 Wagner P. J. 103 Wahlestedt C. 372 Waigh R. D. 205 Waiss A. C. 297 Wakamatsu H.215 Wakamatsu K. 172 Wakil S. J. 362 Waku M. 175 Waldemann H. 355 Waldstaetten P. 334 Walker J. A. 117 Walker J. C. 212 Walker M. E. 136 Waller T. 180 Walsh E. B. 348 Walter H. 49 Walton J. C. 77 Walz P. 137 Wang K. K. 111 Wang R. Y. 373 Wanigasekera D. 49 Wanninger G. 280 Author Index 399 Ward A. D. 113 127 277 Wardle F. W. M. 11 Warkentin J. 253 Warner J. A. 370 Warner J. C. 147 Warner J. M. 158 Warner P. 136 212 251 Warner P. M. 83 89 Warnock G. F. 13 Whistler R. L. 320 White A. H. 229 White D. H.,179 White F. J. 373 White J. J. 114 Whitesides G. M. 340 Whitley J. S. 88 Whittle R. R. 146 147 326 Whittlesey B. R.,246 Wolber G. J. 18 Wolf H. R. 89 Wolfe S. 21 60 65 151 Wolfel C. 258 Wolff S. 89 179 Wong C.H. 340 Wong P. C. 86 Wong T. C. 4 Wong T. W. 361 Warr S. M. 165 Warren C. D. 331 Warren S. 150 Wiberg K. B. 170 179 Wiberg N. 239 Wickham G. 155 Wood T. G. 11 Woodard S. S. 328 Woodthorpe K. L. 95 Warrener R. N. 185 Wider G. 3 366 Woodward R. B. 18 Washburne W. N. 46 Wassef W. N. 61 Widgery M. J. 166 Wieber M. 245 Worakun T. 164 215 Wriede K. 187 Wasserman D. J. 170 Wasserman H. H. 189 Wieschollek R. 220 259 Wiesner K. 315 316 Wright B. 9 Wright B. B. 84 Watanabe K. 100 344 Wietfeldt-Haltenhoff S. 246 Wright M. 261 Watanabe N. 278 Watanabe Y. 145 Waterson D. 138 250 Wigle I. D. 292 Wightman R. H. 297 350 Wilcox C. S. 140 341 Wright M. E. 34 Wrobel J. 262 Wroblewski A. E. 320 Watkins J. C. 164 Wilde J. 5 Wu C.-S. C. 368 Watkinson P. J. 243 Watson W. P. 123 Wildman T.A. 19 73 75 Wilhelm D. 74 230 WU S.-E. 67 WU S.-L. 56 Watt I. 63 Wilhelm R. S. 126 211 Wu Y.-D, 25 37 276 Wattanasin S. 130 Wilk K. A, 55 Wude F. 117 Webb H. M. 65 Webb R. R. 31 329 Wilkening D. 181 Wilkenloh J. 91 Wiinsch E. 357 Wuest J. D. 131 Weber A. 176 Wilkins A. L. 243 Wiithrich K. 3 366 Weber E. 365 371 Willhalm A, 38 Wulff W. D. 220 268 Weber E. J. 134 Williams A. 52 53 56 Wuts P. G. M. 132 145 254 Weber J.-V. 127 Williams B. J. 358 257 Weber W. P. 96 241 Williams D. E. 169 Wehle D. 178 Williams D. H. 363 364 Yabe Y. 360 Wehrenberg W. B. 362 Wiliiams D. J. 238 Yadav J. S. 147 322 Wehrmann R. 242 Williams D. L. H. 58 59 Yajima H. 358 Wei-hua K. 142 Williams E. L. 59 Yalpani M. 340 Weinberger B. 130 Williams I. D. 223 Yamaba S.18 Weinreb S. M. 146 147 326 Williams I. H. 26 53 Yamabe S. 54 Weiss E. 233 Williams J. M. 326 Yamabe T. 19 91 Weiss K. 197 Williams T. H. 326 Yamada K. 172 297 Weissman E. 373 Williams T. J. 370 Yamada M. 131 172 Weissmiiller J. 344 Williams R. V. 58 Yamada Y. 180 328 Weisz A. 115 Wilson A. A. 51 Yamagata T. 225 Weisz 0.A. 11 Wilson K. J. 361 Yamaguchi M. 142 154 187 Welker M. E. 212 Wilson S. 24 249 251 Wells G. J. 155 Wilson S. R. 44 Yamaguchi R. 142 179 Welzel P. 29 Wimalasena J. H. 76 Yamamoto A. 99 Wemmer D. 366 Winemiller J. J. 169 Yamamoto H. 129 142 164 Wenderoth B. 127 Wingbermiihle D. 214 256 262 320 330 Wendt H. R. 73 Wingfield M. 163 Yamamoto K. 165 189 281 Wenkert E. 114 219 Wink M. 303 Yamamoto M. 331 332 Wennerstrom H.20 Winkler T. 293 Yamamoto Y. 123 128 133 Wentrup C. 47 Winstein S. 22 134 142 146 256 257 Wenzel T. T. 229 Winter C. H. 82 Yamanoi T. 131 Wepretz S. 312 Winter P. M. 188 Yamashita J. 127 Wepster B. M. 22 64 Win J. 136 Yamashita M. 153 Werner S. 373 Wiseman F. W. 21 165 Yamashita S. 181 Werstiuk N. H. 84 Wistuba D. 125 Yamashita T. 181 Wessel H. P. 332 Witzak Z. J. 320 Yamataka H. 50 West P. R. 87 Witzel T. 69 318 Yamataka Y. 66 West R. 238 242 Wolfel G. 145 Yamazaki T. 105 Westeppe U. 233 Woell J. B. 110 140 261 Yamazaki Y. 275 Westerduin P. 332 Wolak R. 110 125 277 Yan T.-H. 155 Yanagi K. 274 Yanagi T. 11 5 Yanagiya M. 180 Yanaihara N. 357 Yanez M.,21 Yang C.-Y. 362 Yang J. T. 368 Yang N. C. 34 99 Yang T.-K.297 Yang W. 18 Yang Y. L. 150 174 Yannoni C. S. 15 16 230 Yasuda H. 33 Yasuda N. 351 Yasumori T. 316 Yatagai H. 134 Yavarzadeh R. 165 Yazdi S. N. 74 Yelm K. E. 33 Yeung B. W. A. 175 Yeung Lam KO,Y. Y. C. 38 Yoakim C. 119 Yogo M. 193 Yokoyama M.,136 149 Yokoyama T. 55 Yokoyama Y. S. 344 Yonaga M. 307 Yoneda S. 253 Yong-ti T. 142 Yoon N. M.,140 282 Yoon U. C. 105 Yoshida Y. 185 Yoshida Z.-I. 138 249 274 Yoshihara K. 93 Yoshii E. 31 149 167 316 Yoshikami D. 375 Yoshikoshi A. 142 350 Yoshimoto A. 337 Yoshimoto K. 324 Yoshimura H. 331 Yoshimura J. 316 Yoshioka K. 98 Yoshioka M. 172 Yoshioka T. 189 Young J. K. 63 Young M. 370 Yu C. 8 Yu C.-M. 271 Yu M.-L. 291 Yuan L.-C.144 Yunusov S. Yu. 293 Yus M. 110 115 162 Zablocka M.,150 Zacchei A. G. 368 Zacharie B. 131 Zafiropoulos T. 236 Zajdel W. 258 Zamir L. O. 165 Zamir N. 371 Zamojski A. 325 Zanardi G. 205 Zanen J. 366 Zanette D. 57 Zard S. 273 283 284 Zard S. Z.. 146 148 192 Author Index Zaugg H. 258 Zbiral E. 335 Zefirov N. S. 114 Zehavi U. 338 Zekter A. S. 10 Zeller J. R. 136 Zen S. 324 Zenk M. H. 305 Zenki S. 279 Zetta L. 367 Zetterberg K. 146 219 Zgierski M. Z. 19 75 Zhang B.-L. 57 Zhi-Chu Sheng 105 Zhou Z. 222 Zicmane I. A. 243 Ziegler C.-B. 69 Ziegler F. E. 171 Zimmerman H. 10 Zimmerman S. 285 Zimmern D. 358 Zimmt M.B. 72 Zipperer B. 209 Zoebisch E. G. 26 ZoIIo P. H. A.332 Zou X. 63 Zuckerman J. J. 240 243 Zuger M.F. 141 Zwanenburg B. 208 Zweifel G. 116 257 Zygmunt J. 59

ISSN:0069-3030    

DOI:10.1039/OC9848100377

出版商:RSC    

年代:1984

数据来源: RSC