摘要:

8 Heterocyclic Compounds By H. McNAB Department of Chemistry University of Edinburgh West Mains Road Edinburgh EH9 3JJ 1 Introduction The continued but changing importance of heterocyclic compounds in the main- stream of research in organic chemistry is highlighted by the October issue of Chemical Reviews devoted to ‘Emerging Organic Reactions’. About half of the fourteen articles contain a substantial proportion of heterocyclic chemistry but only three are concerned with cyclization reactions predominantly giving reduced ring systems.’ The other relevant reviews deal with heterocycles as synthetic intermedi- ates,* whether as azadienes in Diels-Alder reactions as a means of carboxylate protection and activation or as a source of 1,3-diradicals in the formation of fused 5-membered carbo~ycles.~ Four continuing series review more traditional areas.Two volumes of Advances in Heterocyclic Chemistry6 and a Specialist Periodical Report7 are joined by mono- graphs which cover areas of 5-membered ring chemistry including thiophenes,’ oxaz~les,~ and ‘51 ring systems in which an imidazole ring is fused to an additional 5-membered ring.’” A new volume of ‘Rodd’ is devoted to systems with two or more heteroatoms in the ring.” Katritzky and others have used in situ n.m.r. spectroscopy to investigate the progress of reactions leading to heterocycles.’* The techniques of I3Cand 15Nn.m.r. (a) G. H. Posner Chem. Reu. 1986 86,831; (b) T.A. Blumenkopf and L. E. Overman Chem. Reu. 1986 86,857; (c) E. Vedejs and F.G. West Chem. Reu. 1986 86 941. ’B. H. Lipshutz Chem. Rev. 1986 86 795. D. L. Boger Chem. Rev. 1986,86 781. H. H. Wasserman K. E. McCarthy and K. S. Prowse Chem. Rev. 1986 86 845. R. D. Little Chem. Reu. 1986 86,875. ‘Advances in Heterocyclic Chemistry’ Vol. 39 and 40 ed. A. R. Katritzky Academic Press Orlando 1986. ’‘Heterocyclic Chemistry’ Vol. 5 a Specialist Periodical Report ed. H. Suschitzky The Royal Society of chemistry London 1986. ‘The Chemistry of Heterocyclic Compounds. Thiophene and its Derivatives Parts 2 and 3’ Vol. 44 ed. S. Gronowitz 2nd Edn. Wiley-Interscience New York 1986. ’‘The Chemistry of Heterocyclic Compounds. Oxazoles’ Vol. 45 ed. I. J. Turchi Wiley-Interscience New York 1986. ‘The Chemistry of Heterocyclic Compounds. Condensed Imidazoles-5-5 Ring Systems’ Vol.46 ed. P. N. Preston Wiley-Interscience New York 1986. ’’ ‘Rodd’s Chemistry of Carbon Compounds. Heterocyclic Compounds’ Vol. 4 Parts C and D ed. M. F. Ansell 2nd Edn. Elsevier Amsterdam 1986. I2 (a) A. R. Katritzky T. I. Yousaf B. C. Chen. and Z Guanp7hi. Tetrahedron. 1986. 42. 623 (h) N. S. Zefirov S. I. Kozhushkov T. S. Kuznetsova B. A. Ershov and S. A. Selivanov Tetrahedron 1986,42 709; (c) A. R. Katritzky and T. I. Yousaf Can. J. Chem. 1986 64 2087; (d) A. R. Katritzky D. L. Ostercamp and T. I. Yousaf Tetrahedron 1986 42 5729; (e) A. R. Katritzky P. Barczynski D. L. Ostercamp and T. I. Yousaf J. Org. Chem. 1986 51 4037; (f)P. W. Kenny and M.J. T. Robinson Tetrahedron Lett. 1986 27 6277. 171 172 H.McNab using labelled precursors if necessary,'2f have proved particularly useful for the identification of intermediates. As a simple illustration of the technique the con- densation of acetylacetone with amidines has been shown to proceed via the diol (l) whereas in the analogous reaction with urea dehydration precedes the cycliz- ation step to give an enamide intermediate (2) (Scheme 1).12" Other applications to the formation of pyrroles,"' pyrazoles,12' isoxazolones,12e pyra~olines,'~~ and to the Hantzsch pyridine synthesis'2d have been reported. MefiMe slow -MenMe NKNH 0 NH 0 H2N4 0 (2) Scheme 1 Saturated chiral heterocyclic alcohols can now be prepared in high enantiomeric purity by a hydroboration technique (e.g. Scheme 2).13 With the ready availability of both (+)-and (-)-a-pinene both enantiomers are easily obtained.H. C. Brown and J. V. N. Vara Prasad J. Am. Chem SOC.,1986 108,2049. 173 Heterocyclic Compounds /' ,OH 80% (100%e.e.) Reagents i -25 "C 15 h; ii MeCHO; iii NaOH H202 Scheme 2 2 Three-membered Rings Matrix photolysis of furan and thiophene has produced further e~idence'~ for the existence of the 'Dewar' isomers (3) and (4) reported last year (Annu. Rep. Progr. Chem. Sect. B 1985 82 182). (3) x = 0 (4) x = s The ring-opening reactions of 3-amino-2H-azirines (5) have provided access to a number of novel systems. New examples include an unusual ring expansion reaction with isoxazolidinones (6) to give oxadiazocinones (7) (characterized by X-ray ~rystallography,'~" and an easy synthesis of thiazol-5-thiones (8) from thiocar- boxylic acids'5b (Scheme 3).Clear evidence has been obtained for the existence of 0 Me 0-N hNMe2 Me2N (7;97%) Me (5) 0 Me Me 2 Me$je MeAN)\fNMe2 HS (88%) (8,85%) Reagents i (6); ii MeCOSH; iii Lawesson's reagent Scheme 3 l4 W. A. Rendall A. Clement M. Torres and 0.P. Strausz J. Am. Chem. SOL,1986 108 1691. (a)B. Hostettler J. P. Obrecht R. Prewo J. H. Bieri and H. Heimgartner Helu. Chim. Act& 1986,69 298; (b) C. Jenny and H. Heimgartner Helu. Chim. Actq 1986 69,374. 174 H. McNab 1H-azirines (9) in the solution photolysis of 1,2,3-triazoles containing electron- withdrawing substituents,16 by which indoles are produced via carbene insertion (Scheme 4).The isolation of a substantial amount of the ‘rearranged’ indole 3-carboxylic ester from (11) is consistent with the symmetrical intermediate (9) while the absence of the corresponding rearrangement product from (10) is thought to be due to a substantial energy difference between the two isomeric carbenes16 (Scheme 4). Me. mze 1 H From (10) 55% From (10) 0% From (11) 42% From (11) 21% Scheme 4 The case for dithiiranes (12) as reactive intermediates has been reviewed and some new results presented.” 3-Bromo-3-methyldiazirine (13) undergoes substitu- tion reactions with strong nucleophiles (e.g.MeO- F- CN-) its reactivity relative to 3-aryl analogues follows the pattern established in the cyclopropenium series rather than that found for simple carbocations.18 The products are useful precursors of unusual carbenes.The dioxirane (14) prepared in solution in acetone can be s-s N=N 0-0 K K K R’ R2 Me Br Me Me used in synthesis as an efficient oxygen atom donor.” For example dimethylcyc- lohexanes are oxidized to the corresponding tertiary alcohol in variable yield but with complete retention of stereochemi~try,’~~ while oxidation of amines to nitro- compounds (84-97% yield) takes only a few minutes at room temperature.lgb The first C-unsubstituted diphosphirane (15) has been made simply by reacting the l6 G. Mitchell and C. W. Rees J. Chem. SOC.,Chem Commun. 1986 399. A. Senning H. C. Hansen M. F. Abdel-Megeed W. Mazurkiewicz and B.Jensen Tetrahedron 1986 42 739. R. A. Moss M. Fedorynski,G.Kmiecik-tawrynowicz and J. Terpinski Tetrahedron Lett. 1986,27,2707. l9 (a)R. W. Murray R. Jeyaraman and L. Mohan J. Am. Chem. SOC.,1986 108,2470; (6) R. W. Murray R. Jeyaraman and L. Mohan Tetrahedron Lett. 1986 27 2335. Heterocyclic Compounds Ar \P=P\ CHzN2 ArP-PAr Ar = V Ar (15) (16) Scbeme 5 diphosphene (16) with excess diazomethane (Scheme 5).20 This process illustrates the synthetic potential of the new low-coordinate phosphorus moieties which have been discovered in recent years. Previous examples of the fragile triaziridine system e.g. (17) have contained electron-withdrawing substituents. Careful demethylation and decarboxylation of (17; R = C0,Me) has now given the dialkyl derivative e.g.(17; R = H) which can itself be N-alkylated via the anion to give trialkyl compounds e.g. (17; R = Me); Pr N /\ Pr N-NR (17) lithium aluminium hydride reduction of the ester gives the methanol derivative (17; R = CH20H).2' As might be expected these materials show unusual properties for example they are non-basic and the methanol (17; R = CH20H) does not cleave like a normal aminal. Such behaviour has been explained by postulating a strong localization of the lone pairs a conclusion supported by "N n.m.r. data.21b 3 Four-member4 Rings The first monocyclic azete (18) with only alkyl substituents has been isolated by gentle thermolysis of an azidocyclopropene (Scheme 6).22 The product is stable for Scheme 6 several days in solution at 100°C but cleaves to an acetylene and a nitrile under flash pyrolysis conditions.Since only two discrete t-butyl signals are observed in the 'H n.m.r. spectrum,22 it is assumed that rapid valence isomerization is taking place as shown in Scheme 6. The chemistry and applications of diketene (19) have been examined in a compre- hensive review of over 600 ~eferences,~~ while the susceptibility of its exocyclic 20 J. Bellan G. Etemad-Moghadam M. Payard and M. Koenig Tetrahedron Lett. 1986 27 1145. 21 (a) H. Hilpert L. Hoesch and A. S. Dreiding Helu. Chim Acta 1986,69 2087; (b) H. Hilpert and R. Hollenstein Helu. Chim. Acta 1986 69 136. 22 U.-J.Vogelbacher M. Regitz and R. Mynott Angew. Chem. Znt. Ed. Engl 1986 25 842.23 R. J. Clemens Chem. Rev. 1986 86 241. 176 H.McNab double bond to addition by sulphur phosphorus halogenocarbon and chlorine radicals has been explored.24 Reaction invariably takes place at the terminus and good large-scale yields of addition products are often possible.24 Ring-expansion of azetidin-3-ones by Beckmann rearrangement gives the first synthesis of the parent imidazolidin-4-0ne~~ (Scheme 7) in a useful preparative application of these unusual p-lactam isomers. H Reagents i H2NOH; ii ClS02Ar NaH; iii alumina (Beckmann rearrangement); iv H,/Pd/C (R = CH2Ph) Scheme 7 In an extraordinarily productive year in this area the Regitz group has accom- plished cycloaddition reactions of the cyclobutadiene (20) with activated nitriles and with phosphaalkynes to give new ‘Dewar’ pyridine derivatives and the first examples of ‘Dewar’ phosphinines (21) respectively26 (Scheme 8).Crystallization of the crude mixture of (21) and (22) (typically 85 :15 ratio) gives isomerically pure (21) which is remarkably stable both towards oxygen and towards heat no ring- opening to the phosphabenzene is observed for example even at 220°C.26bAn R Reagents i RC=N; ii RCGP (22) Scheme 8 24 J. G. Dingwall and B. Tuck L Chem Soc Perkin Trans. 1 1986,2081. 25 Y. Nitta T. Yamaguchi and T. Tanaka Heterocycles 1986 24 25. 26 (a) J. Fink and M. Regitz Bull Soc Chin Fr. 1986 239; (b) J. Fink W. Rosch U.-J.Vogelbacher, and M. Regitz Angew. Chem Znr. Ed Engl. 1986,25 280. Heterocyclic Compounds unusual dimerization of pentacovalent phosphaalkyne derivatives leads to new examples of A '-1,3-dipho~phetes,~' (Scheme 9) while an unusual reaction of such diphosphetes with phosphaalkynes gives the first triphosphabenzene derivative (Scheme Dimerization of simple phosphaalkynes in the presence of the cobalt complex (23) leads to the new h 3-1,3 -diphosphete structural unit29 (24).L ph/ 'ph Scheme 9 MezN- NMe2 I Pa-NMe2 I NMez + Bu'CEP-Scheme 10 c.0 \' b CO 0 'NPri I P(NP Ph II 0 Me2N NMe2 \/ fp) NMe2 pyp< NMe2 But A comprehensive paper on the preparation and properties of the 1,2-oxathietane system3' (25) augments related work on dioxetanes reported last year (Annu. Rep. Progr. Chem. Sect. B.1985 82 135). The 3,3,4,4-tetramethyl derivative is stable enough to be isolated but more usual decomposition reactions include formal [a2 + a2.J cycloreversions to generate thiocarbonyl compounds.30 P-Lactams.-Work on p-lactams continues apace. There have been considerable advances in the understanding of penicillin biosynthesis as considered elsewhere in this Volume (Annu. Rep. Progr. Chem. Sect. B 1986 83 chapter 13) and these lessons are being applied to total synthesis.31 There is considerable activity in asymmetric synthesis of antibiotics and notable achievements this year include two 27 H. Keller G. Maas and M. Regitz Tetrahedron Lett. 1986 27 1903. 28 E. Fluck G. Becker B. Neumuller R. Knebl G. Heckmann and H. Riffel Angew. Chem. Znt. Ed. EngL 1986 25 1002.29 (a) P. B. Hitchcock M. J. Maah and J. F. Nixon J. Chem. SOC.,Chem. Commun. 1986 737; (b) P. Binger R. Milczarek R. Mynott M.Regitz and W. Rbch Angew. Chem. Znt. Ed. Engl. 1986,25 644. 30 J. W. Lown and R.R. Koganty J. Am. Chem SOC.,1986 108 3811. 31 For example C. A. Townsend G. M. Salituro L. T. Nguyen and M. J. DiNovi Tetrahedron Lett. 1986,27 3819. 178 H. McNab enantioselective routes to (+)-PS-5 (26);’ and a formal synthesis of thienamycin (27).33 Meanwhile p-lactams of exotic structure continue to be prepared. An interesting new example is the stable ‘anti-Bredt amide’ (28) which may have ‘novel chemical and possibly biological properties.’ 34 TBSO I SCH2CH2NH2 N/ c02h 4 Five-membered Rings A variety of new cyclization methods generate the pyrrole ring system at different oxidation level^.^'-^^ A three-step route from ketones to pyrroles (e.g.Scheme 11) gives rise to 2-substituted and 2,3-disubstituted derivatives in ca. 60% overall yield a simple recipe for the key 0-(2-hydroxyethy1)hydroxylamineunit (Scheme 11) is given in the paper.35 Alternatively a palladium-catalysed carbonylation of allenes has been extended to give pyrrolidines in 5686% yield (e.g. Scheme 12):36 Reagents i H+ pyridine; ii (PhO),$MeI-; iii KOBU‘ Bu‘OH 5 h reflux Scheme 11 32 (a) D. A. Evans and E. B. Sjogren Tetrahedron Lett. 1986 27 3119; (b) D. J. Hart C.-S. Lee W. H. Pirkle M. H. Hyon and A. Tsipouras J. Am. Chem. Soc. 1986 108 6054. 33 D. A. Evans and E.B. Sjogren Tetrahedron Lett. 1986 27 4961. 34 R. M. Williams and B. H. Lee J. Am. Chem. Soc 1986 108 6431. 35 D. Dhanak C. B. Reese S. Romana and G. Zappia J. Chem Soc. Chem. Commun. 1986 903. 36 D. Lathbury P. Vernon and T. Gallagher Tetrahedron Lett. 1986 27 6009. Heterocyclic Compounds n n \' I COzMe CHzPh CH2Ph Reagents i CO Pd2+ MeOH Scheme 12 piperidines can be made similarly. Fused pyrrolidines result in similar yields from intramolecular aza-ally1 anion cycloaddition~~~ (e.g. Scheme 13) cis-fused products are obtained with high stereoselectivity and the procedure is useful for the assembly of sterically congested systems.37 ?l Reagents i LDA; ii H20 Scheme 13 A useful paper in traditional pyrrole chemistry compares H/ D exchange processes for systems substituted with electron-withdrawing groups as follows 1 -substituted relative reactivity 2 > 3-position; 2-subsitituted relative reactivity 4 > 5 > 3-position; 3-substituted relative reactivity 5 > 2 > 4-po~ition.~~ A recent study by Ree~e~~ is now the leading reference for N-protection of pyrroles or indoles.The first example of an addition-elimination electrophilic substitution mechanism in the pyrrole series explains the formation of minor products in the chlorination of N-methylpyrrole with N-chloroacetanilide (Scheme 14):' and should be compared with a detailed study of corresponding processes in the chemistry of furan nitration!l MeCO Me Scheme 14 37 W. H. Pearson M. A.Walters and K. D. Oswell J. Am. Chem. SOC.,1986 108 2769. 38 H. M. Gilow Y. H. Hong P. L. Millirons R. C. Snyder and W. J. Casteel jun. J. Heterocycl. Chem. 1986 23 1475. 39 D. Dhanak and C. B. Reese J. Chem. SOC.,Perkin Trans. 1 1986 2181. 40 M. De Rosa and I. Brillembourg J. Chem. SOC.,Chem. Commun. 1986 1585. 41 G. Balina P. Kesler J. Petre D. Pham and A. Vollmar J. Org. Chem. 1986 51 3811. 180 H. McNab A number of useful syntheses of bi-heterocyclic systems have appeared this year (see also Section 5 below). These include two routes to 2,2'-bipyrroles (29),"2 in which the second ring is independently constructed round a substituent of the first and routes to a wide range of bi- and terthienyls [e.g. (30)] in 61-93'/0 yield by nickel-catalysed coupling of a thienyl Grignard reagent with the appropriate bromo- or dibr~mo-thiophene.~~" The series of 14 possible terthienyls was completed with similar couplings using brom~bithiophenes.~~ Conditions for the N-alkylation of the electron-rich thiophenes (31) and (32) to give secondary and tertiary amino-derivatives have been worked out;44a the enamine character of these products has been explored by protonation bromination reduc- tive alkylation and reaction with carbonyl compounds to give a series of 2-substituted derivatives.44b Other electron-rich thiophenes include the trimethylsilyl derivative 2, Q-0 N I I x@H2 = H (33) Xx = s :I" R R (31) X (30) (32) X = NH (34) x = 0 (33) made from the 3-lithio-derivative by treatment with bis(trimethylsily1)peroxide the furan derivative (34) is similarly available and is an active diene in Diels-Alder reactions.45 A new two-step synthesis of 2-substituted 3-thiophenylfurans from an aldehyde derivative gives products which are similarly reactive (Scheme 15),46 yet 3,4-dialkoxyfurans act as apparent dienophiles on treatment with methyl co~malate.~~ [0p S P h i-iii QMe SPh _.* phQ0 iv 0 59% 0 Reagents i Bu'Li DME; ii MeCHO; iii H+;iv maleic anhydride Scheme 15 Formation of adducts [e.g.(35)] in this case is probably non-concerted but is nevertheless remarkable in that the aromaticity of two heterocyclic systems is destroyed under mild conditions (2h in refluxing methanol).47 The intramolecular cycloaddition of benzyne to simple furans proceeds efficiently in more normal fashion4*" (e.g.Scheme 16) and the reaction has been applied to the synthesis of natural products with a naphthopyran ~keleton.~" 42 W. Hinz R. A. Jones S. U. Patel and M.-H. Karatza Tetrahedron 1986 42 3753. 43 (a)N. Jayasuriya and J. Kagan Heterocycles 1986,24,2261;(b)N. Jayasuriya and J. Kagan Heterocycles 1986,24 2901. 44 (a) F. Outurquin P. Lerouge and C. Paulmier Bull. SOC.Chim. Fr, 1986 259; (b) F. Outurquin P. Lerouge and C. Paulmier Bull. SOC.Chim. Fr. 1986 267. 45 L. Camici A. Ricci and M. Taddei Tetrahedron Lett. 1986 27 5155. 46 P. G. McDougal and Y.-I. Oh Tetrahedron Lett. 1986 27 139. 41 M. E. Jung L. J-Street and Y. Usui J. Am. Chem. Soc. 1986 108 6810.48 (a) W. M. Best and D. Wege Aust. J. Chem. 1986 39 635; (b) W. M. Best and D. Wege Aust. J. Chem. 1986 39 647. Heterocyclic Compounds MeO,C M&o 0 The most unusual furans and thiophenes to be detected this year are the 3,4-methylene derivatives (36; X = 0,S) obtained by photolysis or ‘thermolysis’ (>0 “C!)of the diazenes (37; X = 0,S).49 The products were identified spectroscopi- cally in a matrix and indirectly by their dimerization reaction with oxygen and I + qi! 74% 0 flMe Reagents i heat. 0 ; ii H,/Pd/C; iii H+ Scheme 16 their stereospecific reactions with alkene~?~ Full details have appeared of the chemistry of pentaarylboroles (38) including the formation of complexes with pyridine oxidation in air to tetraphenylfuran and reduction to a dianion with potassium metal.50 Two ring systems dominate the year’s output of benzo-fused five-membered rings.The continued importance of indoles occasions no surprise but the level of activity (a) J. K. Stone M. M. Greenberg J. L. Goodman K. S. Peters and J. A. Berson J. Am. Chem. SOC. 1986 108 8008; (b) P.Du D. A. Hrovat and W. T. Borden J. Am. Chem. SOC.,1986 108 8086. J. J. Eisch J. E. Galle and S. Kozima J. Am.Chem. Soc. 1986 108 379. 182 H. McNab in the isobenzofuran field may signal a renewal of interest in this heterocycle. Both rings of indole have been generated in a single step by intramolecular allene cy~loaddition~' (e.g. Scheme 17) while the heterocyclic ring of indol-3-ones has Reagents i heat (160 "C);ii DDQ Scheme 17 Scheme 18 been constructed by a base-induced azide decompositionSZ (Scheme 18).Yields of up to 96% were ~btained.~' An alternative approach involves synthesis of the benzene ring by electrocyclization of 4,5-dialkenylpyrroles followed by aromatization and leads in good yield to 3-benzoyl derivatives heavily substituted in the carbocyclic rings3 (Scheme 19). A related cycloaddition method has beerr adapted to generate php COPh i COPh ii Phmph -__* \ N R2\ N R2 Me R2 Me R' Me R' R' Reagents; i heat or hv; ii DDQ Scheme 19 the benzenoid ring of benzo[ b]-and benzo[ ~l-thiophenes.~~ The fused pyrrole (39) has been elaborated by Matsumoto's group to give a host of important 4-substituted in dole^,^^ including amino,55" ~yano,~~~ cyan~methyl,~~~~ f0rmy1,~~' and butanoic derivatives.51 K. Hayakawa T. Yasukouchi and K. Kanematsu Tetrahedron Lett. 1986 27 1837. 52 M. Azadi-Ardakani M. A. Alkhader J. H.Lippiatt D. I. Patel R. K. Smalley and S. Higson 1. Chem. SOC. Perkin Trans. I 1986 1107. 53 (a) J. Moskal R. van Stralen D. Postma and A. M. van Leusen Tetrahedron Lett. 1986,27,2173; (b) J. Moskal and A. M. van Leusen J. Org. Chem. 1986 51 4131. 54 J. W. Terpstra and A. M. van Leusen J. Org. Chem. 1986 51 230. 55 (a) M. Matsumoto Y. Ishida and N. Hatanaka Heterocycles 1986,24 1667; (b)N. Hatanaka and M. Matusumoto Heterocycles 1986 24 1963; (c) N. Hatanaka N. Watanabe and M. Matusmoto Heterocycles 1986,24 1987; (d) M. Matsumoto and N.Watanabe Heterocycles 1986 24,2611; (e) M. Matsumoto and N. Watanabe Heterocycles 1986 24 3149; (A M. Matsumoto N. Watanabe and Y. Ishida Heterocycles 1986 24 3157. Heterocyclic Compounds 0 New reactions of indoles have led to improved syntheses of 2-alkylthio derivatives by irreversible acid-catalysed rearrangement of the readily available 3-alkylthio (Scheme 20) and to a range of 2- and 3-halogenoindole~:~~ the use & a-H H H H H H I WSR a S R Reagents i RSCI; ii H+ H H Scheme 20 of N-bromosuccinimide in dichloromethane in the presence of silica gel is a par- ticularly convenient The complex acid-catalysed reactions of 3-alkylindoles with aromatic aldehydes are now better understood following the isolation of some key intermediate^.^^ New isobenzofurans (40) which have been generated and reacted with dienophiles include 1-~henyl,~~ 1 -dialkylamino,60 and substituted 1 -cyano61 derivatives.The latter derivatives are extremely stable and have led to the first X-ray crystal structure of an isobenzofuran being reported the geometry of the five-membered ring is found to be close to that of furan.61 Full details of the generation of both naphtho[ clfuran isomers have appeared.62 Rickborn has applied the cycloaddition of arynes with 1,3-bistrimethylsilylisobenzofurans,reported last year (Annu. Rep. Progr. Chern. 56 R. Plate and H. C. J. Ottenheijrn Tetmhedron 1986 42 4511. 57 (a) M. R. Brennan K. L. Erickson F. S. Szmalc M. J. Tansey and J. M. Thornton Heterocycles 1986 24 2879; (b) A.G. Mistry K. Smith and M. R. Bye Tetrahedron Lett. 1986 27 1051. 58 K. Dittmann and U. Pindur Heterocycles 1986 24 1079. 59 D. Tobia and B. Rickborn J. Org. Chem. 1986 51 3849. 60 C. W. Chen and P. Beak J. Org. Chem. 1986 51 3325. R. Rodrigo S. M. Knabe N. J. Taylor D. Rajapaksa and M. J. Chemishenko J. Org. Chem. 1986 51 3973. 62 J. G. Smith P. W. Dibble and R. E. Sandborn J. Org. Chem. 1986 51 3762. 184 H. McNab Sec. B 1985 82 189) to the synthesis of a range of polycyclic aromatics.63 The preparation of pentaphene (41) is an impressive example of this strategy,63c the use of a repeat procedure resulting in sixteen of the carbon atoms of the product being derived from isobenzofuran units (Scheme 21).SiMe3 c1 Me3Si C1 \' \ \ Me& A + %Me3 W iv SiMe3 (41) Reagents i TFA; ii LiAIH4 iii H+; iv Lithium tetramethyipiperidide; v Zn HOAc Scheme 21 The pyrrolo[ 1,2-a]indole nucleus (42) is assuming increased importance as the basis for the mitomycin series of anti-tumour antibiotics and synthetic approaches have been reviewed.64 A new approach to functionalized 2,3-dihydro derivatives employs 1,3-dipolar cycloaddition reactions of azomethine ylides generated from the silylated indoles (43) by treatment with silver fluoride.65 (Scheme 22). The P-trimethylsilylethoxymethyl group has been advocated for N-protection of imidazoles:66 it proved compatible with metallation at the 2-position from which CH2SiMe3 (43) CH 50-80% Reagents i AgF; ii A=B Scheme 22 63 (a) J.Netka S. L. Crump and B. Rickborn J. Org. Chern. 1986 51 1189; (b) D. J. Pollart and B. Rickborn J. Org. Chern. 1986,51,3155; (c) R. Camenzind andB. Rickborn J. Org. Chern. 1986,51,1914. 64 W. Verboom and D. N. Reinhoudt Recl. Trau. Chim. Pays-Bas 1986 105 199. 65 A. Padwa and J. R. Gasdaska J. Am. Chern. Soc. 1986 108 1104. 66 B. H.Lipshutz W. Vaccaro and B. Huff Tetrahedron Lett. 1986 27 4095. Heterocyclic Compounds 185 a range of 2-substituted derivatives could be obtained typically in >70% yield though trapping with alkyl and acyl halides was surprisingly inefficient.66 Regioselec- tive 5-metallation of N-protected imidazoles and subsequent trapping with elec- trophiles is possible if the 2-position is first blocked with a trimethylsilyl group (Scheme 23):67 both protecting groups can be cleaved by mild hydrolysis.The surprising use of oxalyl chloride as a carboxylating agent has been applied to pyrazole chemistry.68 The 4-carboxylic acid chloride is obtained in high yield from the neutral heterocycle after 24h at room temperature in an excess of oxalyl chloride as solvent.68 Further applications of this apparently mild and convenient procedure are awaited with interest. SOZNMe2 SOzN Mez Reagents i ClSOzNMe2 Et,N; ii Bu”Li; iii R,SiCI; iv R’Li; v E+; vi H,O;vii KOH (aq.) Scheme 23 The coupling of diazoimidazoles with aliphatic or aromatic amines leads to triazines which are readily cyclized on heating to imidazotriazines in 50-80% yield6’ (e.g.Scheme 24). 2,2‘-Biimidazole (44) is conveniently obtained on a >40 g scale by a two-step pro~edure,’~ while the preparation of specifically halogenated thiazoles has been simplified by use of organotin and organosilicon meth~dology.~~ Reagents i RNH, ii EtOAc (reflux) Scheme 24 Two unusual cycloadditions have been discovered in which oxazoles and isoxazoles can act as dien~philes.’~,~~ Thus the electron-rich oxazole (45) reacts with electron-deficient dienes (e.g. Scheme 25),72 while the electron-deficient isoxazole (46) reacts with electron-rich dienes (Scheme 26)73 to give in both cases 67 A. J. Carpenter and D. J. Chadwick Tetrahedron 1986,42 2351. 68 C. 1. Chiriac. Synthesis 1986 753. 69 K. E. Andersen and E.B. Pedersen Liebigs Ann. Chem. 1986 1012. 70 D. P. Matthews J. P. Whitten and J. R. McCarthy Synthesis 1986 336. 71 A. Dondoni A. R. Mastellari A. Medici E. Negrini and P.Pedrini Synthesis 1986 757. 72 A. Dondoni M. Fogagnolo A. Mastellan P. Pedrini and F. Ugozzoli Tetrahedron Lett. 1986,27,3915. 73 R. Nesi D. Giomi S. Papaleo and L. Quartara J. Chem. SOC.,Chem. Cornmun. 1986 1536. 186 H. McNab Scheme 25 do‘CO,Et + 1 qo2 + N,& COzEt (46) 87% Scheme 26 + NfN high yields of Diels- Alder adducts. The exotic tetrazolotetrazole anion (47) is proposed to account for the scrambling of isotopic label in the azidotetrazole (48) under basic condition^.'^ Examples of the 1,2,4-diaza-phosphole (49)75a and -arsole (50)75cring systems have been prepared by Markl’s group using complementary methodologies.For example reaction of tris(trimethylsilylphosphine) with an oxadiazolium salt gives (49),75“ a strategy which has been adapted also to give 1,3-azaphospholes (51).75b Alternatively treatment of an arsacyanine with hydrazine gives (50); these com- pounds react with 1,3-dipoles to give products of addition across the As=C double bond.75A stable 1,2,4-thiadiphosphole (52) has been isolated,76 and the P ring (53) has been characterized in a ‘triple decker’ chromium complex,77 complementing the analogous formation of a P6 species reported last year (Annu. Rep. Progr. Chem. Sect. B 1985 82 201). (49) x = P (51) (53) (50) X = As 74 J. A. Gorini J.Farras M. Feiiz S. Olivella A. Solt and J. Vilarrasa J. Cbem. Soc. Chem. Commun. 1986,959. 75 (a) G. Markl and G. Dorfmeister Tetrahedron Lett. 1986 27 4419; (b) G. Markl and S. Maum Tetrahedron Lett. 1986 27 4415; (c) G. Markl and H. Seitz Tetrahedron Lett. 1986 27 2957. 76 R. Appel and R. Moors Angew. Chem. Int. Ed. EngZ. 1986 25 567. 77 0. J. Scherer J. Schwalb G. Wolmershauser W. Kaim and R. Gross Angew. Chem. Znt. Ed. EngZ. 1986 25 363. Heterocyclic Compounds There has been considerable progress in the characterization of new fused five- membered ring systems exemplified by the first syntheses of the parent thieno[3,4- blfurans (54)78 and thieno[2,3-c]pyrroles (55),79 and the first example (the 1,3- diphenyl derivative) of a thieno[2,3-c]furan (56).80 Both (55) and (56) readily undergo cycloaddition reactions as expected of isobenzofuran and isoindole analogues (e.g.Scheme 27)79*80 New nitrogen bridgehead systems include the parent imidazo[ 1,2-a]imidazole (57),prepared in two steps by standard methods,81 and the parent mesomeric betaine (58) obtained by the action of carbon suboxide on pyrazole.82 This ring system is isomeric with the ‘bimanes’ (59) whose halogenoalkyl derivatives have been the subject of recent mechanistic investigation^.^^ C02Me I - C02Me &C02Me C02Me Ph Scheme 27 (55) X = S,Y = NH (56) X = S,Y = 0 (57) A simple one-pot synthesis of N-substituted carbazoles involves heating an amine hydrochloride overnight with 2,5-dimethoxytetrahydrofuranin a mixture of water and benzene (Scheme 28).84The p-carboline system (60)has been synthesized from indoles and azabutadienes (Scheme 29).85Though an aza-Diels- Alder mechanism3 N R Scheme 28 78 J.Moursounidis and D. Wege Tetrahedron Lett. 1986 27 3045. 79 C.-K. Sha and C.-P. Tsou J. Chem. SOC.,Chem. Commun. 1986 310. 80 W. Friedrichsen and A. Schoning Heterocycles 1986 24 307. ” F. Compernolle and S. Toppet J. Heterocycl. Chem. 1986 23 541. 82 K. T. Potts and P. Murphy J. Chem. SOC.,Chem. Commun. 1986 144. 83 (a) A. E. Radkowsky and E. M. Kosower J. Am. Chem. SOC.,1986 108 4527; (b) A. E. Radkowsky E. M. Kosower D. Eisenberg and I. Goldberg J. Am. Chem. Soc. 1986 108,4532. 84 C. Kashima S. Hibi T. Maruyama and Y.Omote Tetrahedron Lett. 1986 27 2131. 85 H. Biere R. Russe and W. Seelen Liebigs Ann. Chem. 1986 1749. 188 H. McNab + TR' R rN -H+ w H N NMe H (40) Scheme 29 has been considered the reaction probably involves a stepwise substitution in which the protonated azadiene acts as electrophileg5 (cf Scheme 28). The importance of pyridocarbazoles as anti-tumour agents is highlighted by a review on the synthesis biosynthesis and mode of action of ellipticine (61).86 Q&J H Me (41) The use of carbodiimide methodology has resulted in an improved approach to guanosine nucle'oside analogues and to guanosine itself (e.g. Scheme 30).87The reaction of guanosine with p-( p-nitrophenoxyacrolein) has been investigated because of the mutagenicity of malondialdehyde derivatives.88 The formation of a R= Reagents i PdO cyclohexene 48 h reflux; ii NH,OH pyridine HO OH Scheme 30 86 V.K. Kansal and P. Potier Tetrahedron 1986 42 2389. a7 (a) M. P. Groziak J.-W.Chern and L. B. Townsend J. Org. Chem. 1986,51 1065; (b)M. P. Groziak and L. B. Townsend J. Org. Chem. 1986 51 1277. 88 L. J. Marnett A. K. Basu S. M. O'Hara P. E. Weller A. F. M. M. Rahman and J. P. Oliver J. Am. Chem. Soc. 1986 108 1348. Heterocyclic Compounds 1:2 product was confirmed by an X-ray crystal structure determination of the derived guanine adduct (62; R = H).88 Chemical and biochemical implications of the use of purine analogues as dimensional probes have been reviewed by Leonard and Hiremath.89 CHO 5 Six-membered Rings The catalysed cycloaddition reaction of alkoxybutadienes with electron-deficient nitriles gives a new one-step route to pyridines (Scheme 31).90 The regiochemistry is controlled by the size of the substitutent R that shown in Scheme 31 is found EtO (catalyst) 50 "C,toluene 7 days Scheme 31 for large substituents while the 4-alkyl product is obtained when R = Me.90 Another new pyridine synthesis builds the ring from a three-carbon unit (enone) and a two-carbon unit (ketone) by stepwise condensation reactions (e.g.Scheme 32).91 $MIi_ F~~ fpb ii-ijj / SPh 98Yo Bu' 82% SPh Bu' Iv iPh 0 Me 80% Reagents i PhSH Et,N; ii MeCOBu' LDA -78 "C; iii SOCI, DMAP; iv NaIO,; v TFAA pyridine; vi NH3 Scheme 32 89 N.J. Leonard and S. P.Hiremath Tetrahedron 1986 42 1917. 90 B. Potthoff and E. Breitmaier Synthesis 1986 584. 91 (a) K. Konno K. Hashimoto H. Shirahama and T. Matsumoto Tetrahedron Lett. 1986,27,3865; (b) H. Konno K. Hashimoto Y.Ohfune H. Shirahama and T. Matsumoto Tetrahedron Lea 1986,27,607. 190 H. McNab Overall yields are in the range 50-60% giving a variety of 2,3- and 2,4-disubstituted and 2,3,5- 2,3,4- and 2,4,5-trisubstituted product^,"^ while the scheme has also been utilized in a natural product synthesis." Dihydropyridines are currently commanding much attention. 1,2-Dihydro isomers (63) substituted in the 2-position can be made by addition of an organometallic reagent and a trapping electrophile (diethyl carbonate or a chloroformate) to a 4-substituted pyridine (Scheme 33).92,93 The products are useful synthetic intermedi- ates.Thus mild hydrolysis gives the pyridones (64)92393a which can be further X . .. 1-11 -X = NMe C02Me \ C02R' I C02R1 (66) Reagents i RMgX or RLi or Zn enolate; ii R'OCOCI or (R'O),CO; iii Si02/H20 or H+; iv MeO,CC=CCO,Me; v oxalic acid Scheme 33 elaborated e.g. to quin~lizidinones,~~" while cycloaddition followed by imine elimination gives a new approach to aminophthalates (65).92 4-Unsubstituted deriva- tives (66) can be made by the same general approach via the 4-trimethylstannyl derivative (63; X = SnMe,) (Scheme 33) giving starting materials for quinolizidine alkaloid synthesis.93 Organotin chemistry has also been applied to the preparation of 4-benzyl- 1,4-dihydropyridines (Scheme 34).94 The conditions are compatible with a variety of substituents in the 3-position and even give yields of 90-99% when electron-withdrawing groups are present at the 4-po~ition.~~ The importance of 1 ,cdihydropyridines as NADH analogues is highlighted by a Tetrahedron 'Sym-posium-imprint' (No.25 pp. 941- 11 16) devoted to hydride-transfer processes. The more recent interest in therapeutic applications of 4-aryl-l,4-dihydropyridines has 92 H.Bader and H.-U.Reissig Tetrahedron 1986 42 835. 93 (a)D. L. Comins and J. D. Brown Tetrahedron Lett. 1986,27,4549; (b)D. L. Comins and J. D. Brown Tetrahedron Lett. 1986 27 2219. 94 R. Yamaguchi M. Moriyasu and M.Kawanisi Tetrahedron Lett. 1986 27 211. Heterocyclic Compounds C02Me C02Me Scheme 34 led to a number of publications in this area of which Meyers' asymmetric synthesesg5 are amongst the most elegant. Nucleophilic addition to a pyridinium salt (c$ Scheme 33) is again the key step with asymmetry induced by a chiral dihydrooxazole substituent at the 3-po~ition.'~ 'A generally useful synthesis of piperidines from primary amines formaldehyde and allylsilanes' has been discovered by Grie~o~~ (e.g. Scheme 35) as an extension of the tetrahydropyridine synthesis reported last year (Annu. Rep. Progr. Chern. CH2PhNH CH2Ph + PhCH2NH2 + CF3C02H + CH2O SiMe3 I CHzPh Scheme 35 OH 81% Sect. B 1986 82 197). The frightening ability of the tetrahydropyridine (67) to induce irreversibly Parkinson's Disease syndrome in man was brought to the attention of the present author by a television programme though studies of possible metabolites are now being reported in the chemical literat~re.~' A very useful paper gives precise instructions for the reduction of pyridines to piperidines in yields of up to 90% using nickel-aluminium alloy.98 The first examples of stable N-fluoropyridinium salts [e.g.(68)] have been isolated this year by reaction of the pyridine with fluorine in acetonitrile at -40 "C in the presence of sodium triflate.99 Symmetrical bipyridines are best prepared from the bromo- or iodo-derivative by a metal-catalysed coupling process. The use of nickel-phosphine methodology has been applied to the total synthesis of orellanine (69) a toxic mushroom metabolite,'" while the development of a new NaH-Bu'ONa-Ni(OAc)2-PPh catalyst system is 95 (a) A.1. Meyers and T. Oppenlaender J. Am. Chem. SOC.,1986 108 1989; (b) A. I. Meyers and T. Oppenlaender J. Chem. Soc. Chem. Commun. 1986 920. 96 (a) S. D. Larsen P. A. Grieco and W. F. Fobare J. Am. Chem. SOC.,1986 108,3512; (b) P. A. Grieco and W. F. Fobare Tetrahedron Lett. 1986 27 5067. 97 L. M. Sayre P. K. Arora S. C. Feke and F. L. Urbach J. Am. Chem. SOC.,1986 108 2464. 98 G. Lunn and E. B. Sansone J. Org. Chem. 1986 51 513. 99 T. Umemoto and K. Tomita Tetrahedron Lett. 1986 27 3271. I00 M. Tiecco M. Tingoli L. Testaferri D. Chianelli and E. Wenkert Tetrahedron 1986 42 1475.192 H.McNab R 0 1 Me F OTf-(69) OH applicable to the coupling of either chloropyridine or bromopyridine derivatives."' Specific cross-coupling reactions are now possible using a palladium-catalysed reaction of bromo compounds with organotin reagents (Scheme 36).'02 Intramolecular cycloadditions of pyrones have been extended to the syntheses of fused lactam derivatives in a two-step sequence (Scheme 37).'03 The initial adducts 59-7 70% Reagents i (Ph,P),Pd xylene 12 h reflux Scheme 36 HN I CHzPh n = 2,3 0Qcoc -%I"- .. w"N CH Ph 0 / CH2Ph n = 1\ n = 1-3 I CH2Ph Reagents i heat (70) Scheme 37 (70) can be isolated only in the 5-membered ring series.103 The increasing use of exotic heter~dien~phile~'~~~'~~ is exemplified by the report of more than 30 thiapyran derivatives [e.g.(71)] obtained by cycloaddition of dienes and thioaldehydes (gener- ated in situ by photolysis of phenacyl sulphides)'" and by the use of phosphaalkenes in the syntheses of functionalized phosphabenzene derivatives (e.g. Scheme 38).'05 LO1 R.Vanderesse M. Lourak Y. Fort and P. Caubere Tetrahedron Lett. 1986 27 5483. '02 Y. Yamamoto Y. Azuma and H. Mitoh Synthesis 1986 564. 103 M. Noguchi S. Kakimoto H. Kawakami and S. Kajigaeshi Bull. Chem. SOC.Jpn. 1986 59 1355. 104 E. Vedejs T. H. Eberlein D. J. Mazur C. K. McClure D. A. Perry R. Ruggeri E. Schwartz J. S. Stults D. L. Varie R. G. Wilde and S. Wittenberger J. Org. Chem. 1986 51 1556. 105 P.Pellon Y.Y.C. Yeung Lam KO,P. Cosquer J. Hamelin and R.CarriC Tetrahedron Lett. 1986,27 4299. 193 Heterocyclic Compounds TMSOeOMe I I CI R = H,TMS CI Scheme 38 Another intramolecular cycloaddition strategy gives good yields of hexahy- droisoquinolines'06 (e.g. Scheme 39). The acylation of the imidate (72) is the key step cyclization is rapid and efficient and gives predominantly the cis isomer (8 :1 ratio).lo6 A conceptually similar approach gives dihydrooxazines from N-acyliminium cyclizations (e.g. Scheme 40) though in this case the ring fusion is stereospecifically trans.lo' Conjugate addition of organocopper reagents to the sulphinyl chromone (73) proceeds with high diastereoselectivity while the use of a single enantiomer provides a route to chiral 2-alkylchromanones e.g.(74).'08 The successful preparation of (75) completes the series of possible monoazapyrene~.'~~ /yNH 4yNw + c1w2+ OEt 0 OEt 0 qr Reagents i Et3N; ii heat OEt Scheme 39 (PhC0NH)zCH-/ Me -Reagents; i BF3.Et20 20 "C 24 h Scheme 40 '06 K.J. Shea and J. J. Svoboda Tetrahedron Lett. 1986 27 4837. lo' P. M. Scola and S. M. Weinreb J. Org. Chem. 1986 51 3248. log S. T. Saengchantara and T. W. Wallace J. Chem. Soc. Chem. Commun. 1986 1592. M. J. Tanga and E. J. Reist J. Heterocycl. Chem. 1986 23 747. 194 H. McNab Cycloaddition of electron-deficient alkenes with the novel heterodiene (76) gives 6H-1,3-thiazines after elimination of dimethylamine [2 + 2Jcvcloaddition of these products with ketenes produces new p-lactam derivatives"' (Scheme 41).Full details details have appeared"' of the preparation and properties of fused thieno- benzo- NMe (76) X = CHO COCH,; Y = Ph C1 Scheme 41 and furo-lh4,2-thiazines (77) and (78) in which the N-S bond is generated by an azide decomposition."'" A range of thermal "' and photochemical"" rearrange-ments is also reported. A variety of physical measurements on the conjugated sulphone (79) have proved that the d-orbitals of the sulphur atom are capable of overlap with the r-system of the ring."' COMe In the diazine field Diels- Alder reactions of pyrazinones with acetylenic dienophiles have been found to give mixtures of pyridines and pyridones by competi- tive cleavage ofthe initial adduct (e.g.Scheme42).'l3 With unsymmetrical dienophiles relatively low regioselectivity is ~bserved."~ The complex reactions of ynamines 110 J.P. Pradere J. C. Roze H. Quiniou R. Danion-Bougot D. Danion and L. Toupet Can. J. Chem. 1986 64 597. 111 (a) R. S. Cairns R. D. Grant C. J. Moody C. W. Rees and S. C. Tsoi J. Chern. Soc. Perkin Trans. 1 1986 483; (b) R. S. Gairns R. D. Grant C. J. Moody C. W. Rees and S. C. Tsoi J. Chem. SOC. Perkin Trans. 1 1986 491; (c) R. S. Gairns C. J. Moody C. W. Rees and S. C. Tsoi J. Chem. SOC. Perkin Trans. 1 1986 497. 112 G. Fraenkel A. Chow J. Gallucci S. Q. A. Rizvi S. C. Wong and H. Finkelstein J. Am. Chem. Soc. 1986 108 5339. 113 M. Tutonda D. Vanderzande J. Vekemans S. Toppet and G. Hoornaert Tetrahedron Lett.1986 27 2509. Heterocyclic Compounds ?O2Me Scheme 42 with 5-substituted pyrimidines have been the subject of a full paper by van der Plas.l14 5-Ethoxycarbonyl and 5-methylsulphonyl derivatives (80) and (8 1) yield pyridines by cycloaddition across the 2- and 5-positions followed by nitrile extrusion (cf. Scheme 42) though the corresponding 5-nitro compounds yield the amazing azetodiazocines [e.g.(82)] via a complex sequence of additions and ring expansions and contractions.' l4 The chemistry of the possible dihydropyrimidine isomers is being systematically studied by Weis and co-workers. They havz now shown that lithium aluminium hydride reduction of pyrimidines gives the 1,2-dihydro com- pounds [e.g. (83)] which can exist in solvent-dependent equilibrium with their hitherto unknown 2,Sdihydro isomers [e.g.(84)]."5 Me l\yyx Me (SO) X = CO,Et (81) X = SO,Me The paucity of routes to simple quinazolines has been rectified by a report of two general syntheses utilizing addition of a Grignard reagent to 2-aminobenzonitrile derivatives (Scheme 43).It6 The authors recommend- route B (Scheme 43) in prefer- ence to route A because of greater flexibility and generally better yields which are often in the range 60-90%. The first monosubstituted 1,2,4-triazine di-N-oxide has been reported in a paper which also gives a detailed review of the 13C n.m.r. spectra of 1,2,4-triazines and their N-0~ides.l~~ The first 1,5,2,4-dioxadiazines [e.g. (SS)] have been isolated but decompose at 90°C to give a nitroso compound and t-butylisocyanate the ring is also cleaved by nucleophiles and on hydrogenation.' l8 114 A.T. M. Marcelis and H. C. van der Plas J. Org. Chem. 1986,51,67. 115 A. L.Weis F. Frolow and R. Vishkautsan J. Org. Chem. 1986,51,4623. 116 J. Bergman A. Brynolf B. Elman and E. Vuorinen Tetrahedron 1986,42 3697 117 M. V. Jovanovic Heterocycles 1986,24 951. 118 J. C.Stowell and C. M. Lau J. Org. Chem. 1986,51,3355. 196 H. McNab N R' H R Reagents i R'COX; ii RMgX Scheme 43 0 I1 N But' KN\Bd 0 The question of homoaromaticity in 1,6-dihydro-1,2,4,5-tetrazines (86) first raised in 1981 has been the subject of an extensive study utilizing n.m.r. and X-ray crystal structure determination.' l9 The problem is to explain dramatic shielding and deshielding effects of the protons around the 6-position and the authors (reluc- tantly?) conclude that 'if (the results) are not indicative of homoaromaticity they must await some other e~planation.'"~ 6 Seven-membered Rings In two comprehensive papers Prinzbach and co-workers have investigated the 3a + 357 route to azepines'20 (benzene imines) and oxepines'*' (benzene oxides) (Scheme 44).The influence of substituents on individual steps of the rearrangement has been more clearly defined and inter- and intra-molecular trapping of intermedi-ate azomethine or carbonyl ylides with dipolarophiles has been carried out.A useful heat -6 X = 0,NR X Scheme 44 119 C.P. R. Jennison D. Mackay K. N. Watson and N. J. Taylor J. Org. Chem. 1986 51 3043. 120 H. Prinzbach H. Bingrnann H. Fritz J. Markert L. Knothe W. Eberbach J. Brokatzky-Geiger J. C. Sekutowski and C. Kriiger Chem. Ber. 1986 119 616. 121 H. Prinzbach H. Bingmann J. Markert G.Fischer L. Knothe W. Eberbach and J. Brokatzky-Geiger Chem. Ber. 1986 119 589. Heterocyclic Compounds three-step synthesis of the stable oxepine (87) has been reported together with details of its acid-catalysed rearrangement to 2,6-diphenylphenol and its X-ray crystal structure.'22 The boat-shaped geometry of the oxepine system was confirmed by related variable temperature n.m.r. studies and by the X-ray structure of a simple mono-substituted derivative (88).'23 (87) R1= R2= Ph (89) (88) R1= H,R2 = CO2But The first fully unsaturated 1,4-0xazepines'~~ have been synthe- and thia~epines'~~ sized independently by Japanese workers.Tsuchiya's ring-expansion route applied successfully last year to a dioxocine (Annu. Rep. Progr. Chem. Sect. B 1985 82 206) gave the 1,4-oxazepines e.g. (89) by irradiation of tricyclic valence isomers. Thermolysis in toluene results either in ring-contraction to a hydroxypyridine or isomerization to a 1,3-0xazepine depending on the substitution pattern.'24 The thiazepine (90) was obtained by a multi-step route in which the key ring-expansion was accomplished by a Beckmann rearrangement (Scheme 45). The thiazepine (90) shows high thermal stability though sulphur extrusion to a pyridine derivative takes place at 110 "Cin the presence of triphenylph~sphine.'~' Reagents i Et,N dioxane water; ii m-chloroperbenzoic acid; iii T.F.A.; iv Me,OfBF Scheme 45 7 Eight-membered and Larger Rings Despite the considerable potential for variety which is possible in the design of large-ring structures relatively few novel systems have captured the attention of the present author during 1986.However it has been shown that the properties of strained alkynes can be significantly modified by the presence of a heteroatom. For example nucleophilic addition of water to the thiacyclooctyne (91) can take place even at room temperature.'26 The isolation of a number of medium-ring cyclic ethers 122 M. J. McManus G. A. Berchtold D. R. Boyd D. A. Kennedy and J.F. Malone J. Org. Chem. 1986 51 2784. 123 W. B. Jennings M. Rutherford S. K. Agarwal D. R. Boyd J. F. Malone and D. A. Kennedy J. Chem. SOC.,Chem. Commun. 1986 970. 124 J. Kurita K. Iwata and T. Tsuchiya J. Chem. SOC.,Chem. Commun. 1986 1188. 125 K. Yamamoto S. Yamazaki H. Osedo and I. Murata Angew. Chem. Znt. Ed. Engl. 1986 25 635. 126 H. Meier E. Stavridou and C. Storek Angew. Chem. Int. Ed. Engl. 1986 25 809. 198 H. McNab from marine sources has stimulated interest in their synthesis and Overman's cyclization of unsaturated acetals (Scheme 46) is a simple and convenient example of a model system applicable to eight- and nine-membered rings.*27 Further function- alization with trimethylsilyl substituents is also p~ssible.'~' Reagents i SnCl, -20°C Scheme 46 The chemistry of polycyclic compounds with macrocyclic periphery has been advanced with the optimization of a procedure for the preparation of tetraarylpor-phyrins from pyrrole and an aromatic aldehyde,'28 and the isolation of a porphyrin isomer (92) by reductive coupling of 5,5'-dif0rmylbipyrrole.'~~This macrocycle shows porphyrin-like spectroscopic properties and can form metal complexes despite the small size of its central cavity.'29 The remarkable extended porphyrin (93) has also been prepared by self-condensation of the vinylpyrrole (94) (Scheme Et bt Reagents i TsOH AcOH 20°C; ii Br (93) Scheme 47 I27 L.E. Overman T. A. Blumenkopf A. Castaiieda. and A. S. Thompson J. Am. Chem. SOC.,1986,108 3516.I28 J. S. Lindsey H. C. Hsu and I. C. Schreiman Tetrahedron Lett. 1986 27 4969. E. Vogel M. Kocher H. Schmickler and J. Lex Angew. Chem. Znt. Ed. Engl 1986 25 257. Heterocyclic Compounds 47).130 The 26~-electron periphery of (93) is strongly diatropic with >25 p.p.m. chemical shift difference between its 'inner' and 'outer' ring protons; the occurrence of the N-methyl signals at 6 -9.09 despite their partial positive charge is also n~teworthy!'~' I30 M. Gosrnann and B. Franck Angew. Chem. Int. Ed. Engl. 1986 25 1100.

ISSN:0069-3030    

DOI:10.1039/OC9868300171

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

9 0rgan om et aI I ic Chemistry Part (i)The Transition Elements By D. PARKER Department of Chemistry University of Durham South Road Durham DH 1 3LE 1 Introduction There continues to be a growth in the number of publications devoted to the synthetic utility and mechanisms of organotransition metal reactions. As in previous years the summary contained herein reflects the taste and whim of the author and should not be regarded as a full survey of the 1986 literature. Stereoselective syntheses now abound and there also is a growing awareness of the synthetic utility of metal carbenes in diverse areas-from the obvious olefination reactions to the more striking metathetical processes. Another general textbook appeared,’ which was again rather over-priced and the importance of organotransition metal courses in the undergraduate curriculum was recognized with the publication of a useful problems and solutions text.2 A weighty tome appeared in which the mechanistic themes underpinning the use of organotransition metal catalysts in organic chemistry were clearly defined.3 Further stylized and reputable series were launched with the publication of the introductory volumes of ‘Reactions of Co-ordinated Ligand~’,~ which also emphasizes mechanistic aspects and ‘Stereochemistry of Organometallic and Inorganic Compounds’.’ Emphasis on the surface chemistry aspects of catalytic hydrogenation was given in a well-written volume,6 and the needs of organozirconium and hafnium chemists were satiated in a comprehensive m~nograph.~ Useful reviews appeared to keep us up to date with the rapid progress in organopal- ladium chemistry particularly of .rr-allyl~,**~ while a more specialized summary drew attention to the palladium-catalysed cross-coupling reactions of organotin reagents with organic electrophiles.” The importance of metal carbene complexes in catalytic A.Yamamoto ‘Organotransition Metal Chemistry’ Wiley Chichester 1986. S. E. Kegley and A. R. Pinhas ‘Problems and Solutions in Organotransition Metal Chemistry’ OUP Oxford 1986. P. A. Chaloner ‘Handbook of Coordination Catalysis in Organic Chemistry’ Butterworth London 1986. ‘Reactions of Coordinated Ligands’ ed. P. S. Braterman Vol. 1 Plenum New York 1986. ‘Stereochemistry of Organometallic and Inorganic Compounds’ ed.I. Bernal Vol. 1 Elsevier Amsterdam 1986. ‘Catalytic Hydrogenation’ L. Cerveny Elsevier New York 1986. ’ D. J. Cardin M. F. Lappert and C. L. Raston ‘Chemistry of Organo-zirconium and Hafnium Compounds’ Ellis Horwood Chichester 1986. J. Tsuji Tetrahedron 1986 12 4361. J. Tsuji Pure Appl. Chem. 1986 58 869. lo J. Stilie Angew. Chem. Int. Ed. EngI. 1986 25 508. 201 202 D. Parker transformations was underlined in two similar articles,"7l2 while selective syntheses using nucleophilic organocuprates have been reviewed. l3 The rich organometallic chemistry of transition metal porphyrin complexes was discussed emphasizing the importance of free-radical proce~ses.'~ Such an article may herald an upsurge of interest in single electron transfer processes in organotransition metal chemistry.2 Uses of Metal Carbenes and Metathesis The rapid development of metal carbene complexes in stoicheiometric and catalytic transformations has been a feature of the last three or four years. The reaction of cobalt carbene complexes with alkynes has been further studied and observed to proceed via the intermediacy of v4-vinylketene complexe~.'~ The methoxyalky- lidene(triphenylstannyl)tricarbonylcobalt(o) complex (l) reacts with alkynes to form exclusively 2-alkoxyfurans such as (2) which was an intermediate in the synthesis of bovolide (3). The related reaction of alkynes with aminocarbene iron R-C =C -R' Ph Sn(C0)3Co PhH/SO"C ' OMe OMe OMe (1) (2) or chromium(o) carbonyl complexes permits the synthesis of 5-amin0furans.'~ A ferrocyclobutene was postulated as a key intermediate which permits insertion of carbon monoxide to generate a ferrocyclopentenone.In order to aid the metal- carbene-mediated synthesis of anthracyclinones a quinone ring has been introduced directly via the metal carbene complex." The alkoxycarbene intermediate (4) may be alkylated or treated with acid to give the two useful carbenes (5) and (6)(Scheme 1). A short series of papers has reported the further diverse reactions of chromium and molybdenum carbonyl carbenes with isocyanides.'s-20 Whereas reaction of electron-rich aryl isocyanides with (7) proceeds to give 2-aryl-3-aminoindoles with electron-withdrawing substituents on the aryl ring non-cyclic products are formed M.P. Doyle Acc. Chem. Res. 1986 19 348. 12 M. P. Doyle Chem. Rev. 1986 86 917. l3 Y. Yamamoto Angew. Chem. Int. Ed. Engf. 1986 25 947. 14 P. J. Brothers and J. P. Collmann Acc. Chem. Rex 1986 19 209. I5 W. D. Wulff S. R. Gilbertson and J. P. Springer J. Am. Chem. Soc. 1986 108 520. 16 M.F. Semmelhack and J. Park Organometallics 1986 2550. 17 K. H. Dotz H. Popall G. Muller and K. Ackermann Angew. Chem. Int. Ed. EngL 1986 25 911. I8 R. Aumann and H. Heinen Chem. Ber. 1986 119 2289. 19 R. Aumann H. Heinen C. Kineger and Y. H. Tsay Chem. Ber. 1986 119 3141. *' R. Aumann and H. Heinen Chem. Ber. 1986 119 3801. Organometallic Chemistry -Part (i) The Transition Elements M(CO)5 Me0 OMe Me0 OMe ”;-. Me0 OMe (5) Br Me0 OMe Me0 OMe qOEt Meo OMeM(CO)5 such as (8).Reaction was proposed to proceed via the intermediate formation of a ketenimine complex to which isocyanides are attached at the central carbon of the NCC unit. Under similar reaction conditions (7b) reacts with phenylisocyanide to give the carboline (9). Furthermore similar alkenylcarbene complexes react with isocyanides to give l-aza-1,2,4-pentatriene complexes such as (lo) which are suitable building blocks for pyrrole synthesis via intramolecular cycloadditions or of five- and six-ring carbocyclics via intermolecular cycloaddition reactions.20 Rhodium(11) complexes are well-established catalysts for the decomposition of a-diazocarbonyls. A thoughtful use of this reaction has been discussed leading to (C0l5M< OEt 02NaOq0N02 R’ Ph N\ (7) (a) M = Cr,Mo R’ = Ph Me OEt (b) R’ = CH=CHRR” = Ph CH=CHPh (8) M = Cr Ph R’ = Ph or I CH=CHPh OEt R’ = cyclohexyl Me Me,C (9) (10) R2= Ph 204 D.Parker 0 0 -Rhz(OAc) CH,CI Scheme 2 Me the generation of oxonium ylides Scheme 2.2'322The reaction has aided the synthesis of the eight-membered ring heterocycle (12) from the diazocarbonyl (1 I) using Rh2(OAc) in dichloromethane via a [2,3] sigmatropic rearrangement of the inter- mediate ylide. Alkene metathesis has been the subject of close scrutiny for over ten years and alkyne metathesis is being keenly studied now. The principles of alkene metathesis parallel those of alkyne metathesis five-coordinate trigonal-bipyramidal metallacyc- lic intermediates seem to be favoured and more electron-withdrawing alkoxide ligands produce the most active catalyst systems.23 The reactivity of high-oxidation state molybdenum and tungsten alkylidene complexes as catalysts for alkyne meta- thesis has been studied in further The tungsten complex (13) is a highly active and Lewis acid free catalyst.It catalyses cis-2-pentene metathesis at more than one thousand turnovers per minute at ambient temperature and also catalyses fairly efficiently the reaction of terminal alkenes. (13) The use of metathesis catalysts in ring-opening polymerization reactions has been widely reported since its inventive application to the synthesis of poly(acety1ene). Such catalysts are being investigated for the synthesis of some stereoregular fluoropolymers.In the polymerization of some fluorinated norbornadienes the highest proportion of trans-vinylene units in the product poly(cyclopenteny1enes) was found with catalysts based on MoC~,.~~ Fluorinated derivatives of benzonorbor- nadiene also undergo ring-opening polymerization at the unsubstituted double bond in the presence of WCl,/Me,Sn or MoCl,/ Me,Sn catalysts.26 M. C. Pirring and J. A. Werner J. Am. Chem. SOC.,1986 108 6061. 22 E. J. Rosekamp and C. R. Johnson J. Am. Chem. Soc. 1986 108 6062. 23 R. R. Schrock Acc. Chem. Rex 1986 19 342. 24 C. J. Schavarien J. C. Dewan and R. R. Schrock J. Am. Chem. Soc. 1986 108 2771. 25 A. Arisol P. M. Blakemore J. H. Edwards W.J. Feast and B.Wilson Polymer 1986 27 1281. 26 W. J. Feast and L. A. H. Shahada Polymer 1986 27 1289. Organometallic Chemistry -Part (i) The Transition Elements 3 Asymmetric Carbon-Carbon Bond Formation The development of highly efficient asymmetric Diels- Alder reactions for the con- struction of chiral compounds is an important target in organic chemistry. The enantiomerically pure chiral iron complex (15) has been used as a chiral acrylate equivalent and is conveniently prepared from the resolved menthol ether derivative (14).27 endo-Addition with cyclopentadiene occurs to (S)-( + ) -(15) in the cisoid configuration from the face away from the bulky triphenylphosphine ligand.28 I Me (14) Oxidation of the iron acyl (1 5) followed by iodolactonization yielded the tricyclic lactone with greater than 95% enantiomeric purity Scheme 3.The related iron-acyl (16) has also been reported to undergo Lewis acid catalysed stereoselective cyclo- addition reactions. On the basis of some carbon-13 n.m.r. studies it was suggested that the reacting species was an alkoxycarbene complex rather than an iron acyl species.29 Further details of the previously reported synthesis of the p-lactam ring-system using the chiral iron acyl complex (17) were disclosed.30 Ce4+/THF/H,0 ! Scheme 3 27 S. G. Davies I. M. Dordor-Hedgcock K. H. Sutton J. C. Walker C. Bourne R. H. Jones and K. Prout J. Chem. SOC., Chem. Commun. 1986 607. 28 S. G. Davies and J. C. Walker J. Chem. SOC.,Chem. Commun.1986 609. 29 J. W. Herndon J. Org. Chem. 1986 51 2853. 30 L. S. Liebeskind M. E. Walker and R.W. Fengal J. Am. Chem. SOC.,1986 108. 6328. 206 D. Parker PPh (18) (a) X = NMe,or NMe(CH,),NEt2 (18) (b) X = MeNCH(CH,OH) or N(CH,CH,OH) An imaginative catalytic asymmetric aldol reaction has been defined using a gold( I) complex of the chiral ferrocenylphosphine (18a).31 The gold( I) complex catalyses the reaction of an isocyanate with various aldehydes to give chiral5-alkyl-2- oxazoline-4-carboxylates with good diastereoselectivity and striking enantioselec- tivity Scheme 4. The oxazolines are useful precursors for the synthesis of P-hydroxyamino acids. The corresponding silver( I) and copper( I) complexes of (18a) R R E z R EIZ % e.e.of E isomer Ph 89 1 96 Me,CH 98:2 92 cyclohex 97:3 92 Me,C 1oo:o 97 Scheme 4 were quite inferior presumably their lack of activity is related to their propensity to bind the nitrogen in the ligand (18a). Chiral ferrocenylphosphine ligands have proved popular this year. The palladium(r1) chloride complex of (19) catalyses the cross-coupling of a-trimethylsilylalkyl Grignard reagents with alkenyl bromides to give chiral allylsilanes with high enantiomeric purity (up to 95% e.e).'* The com- plexes of palladium with (18b) catalyse the alkylation of the allylic acetate (20) with various nucleophiles derived from P-keto esters and P-diketones and reaction proceeds with high enantioselectivity (up to 92% e.e). It was suggested that the 3' Y.Ito M. Sawamura and T. Hayashi J. Am. Chem. Soc. 1986 108 6405. T. Hayashi. M. Konishi Y. Okamoto. K. Kabeta. and M. Kumada. J. Org. Chem. 1986 51. 3772. Organometallic Chemistry -Part (i) The Transition Elements high enantioselectivity of the product was related to hydrogen-bonding between the n-allylpalladium complex of the ferrocenyl ligand (18b) and the incoming n~cleophile.~~ It is well established however that in the palladium phosphine catalysed asymmetric alkylation of n-allyls the high enantioselectivity observed is related to the selective binding of the major product-related .rr-ally1 diastereomeric species i.e. prior to nucleophilic attack. Intramolecular allylation of the chiral enamine (21a) derived from S-proline gives the 2-ally1 cyclohexanone (22) in high enantiomeric purity.The corresponding intermolecular allylation of (21b) with ally1 acetate proceeded in lower yield to give a product of lower-enantiomeric purity. Intramolecular allylation presumably pro- ceeds via a cyclic transition state involving a chelated palladium all~l.~~ The dihy- drodioxin-Fp complex [Fp = q2-CSHsFe(CO),] (23) adds to various nucleophiles to give chiral adducts in which the nucleophile and iron-carbon bond are trans-diaxial (24).35 The iron complex (23) may serve as a useful reagent for the synthesis of chiral enol ether or alkene iron cations of defined absolute configuration and high enantiomeric purity. They constitute an interesting class of chiral metal-alkene complexes which are chiral by virtue of selective binding to the si or re face of the alkene.A OAc (20) (21) (22) (a) R = (b) R = OEt NEt Nu = H Me Ph or CN 0 Fp = Fe(Cp)(CO)? (23) Further refinements have been disclosed about some chirally modified alkylation reagents. The N-sulphonylated derivatives of norephedrine are useful ligands for modified methyltitanium reagents and the chelated titanium alkyl reacts enan- tioselectively with aldehydes to give R carbinols with high optical (Scheme 5). Enhanced enantioselectivities have also been reported in the well-documented asymmetric cyclopropanation of alkenes with diazoacetates. In the presence of catalytic quantities of the chiral copper complex (29 cyclopropanes were isolated A. Yamamoto T.Hagihara and Y. Ito Terruhedron Lett. 1986 27 191. '' K. Hiroi K. Suya and S. Sato J. Chem. Soc. Chem. Commun. 1986 469. '' M. Rosenblum M. M. Turnbull and E. M. Foxman Organometallics 1986 5 1062. '' M. T. Reetz T. Kukenhohner and P. Wernig Tetrahedron Lerr. 1986 27 5711. 208 D. Parker in up to 97% enantiomeric purity. The chiral ligand used is a semicorrin ligand easily derived from pyroglutamic acid." The synthesis of an unusual chiral helical cobaltocene oligomer (26) has been reported involving a photocyclization reaction in which a bromine atom is used to direct photocyclization and the helicity of the complex is governed by the stereogenicity of one carbon centre.38 Scheme 5 M R h;lr I 4 Palladium-mediated Cyclizations and Allylations The synthesis of some condensed thiazoles is aided by Pd" catalysis of the cyclization of propargylthi~pyrimidinones.~~ Cyclization of (27) gives (28) with specific deuteri- ation of the exocyclic alkene consistent with a mechanism in which coordination of Pd" to the propargyl triple bond is followed by trans nucleophilic attack of the N-3 nitrogen to form a vinyl-palladium intermediate (Scheme 6).A related general method involving Pd" catalysis for the synthesis of heterocycles has been defined. Simple routes to the dendrobine skeleton and a carbapenem have illustrated the mildness of the reaction and clearly exemplify its scope. Intramolecular cyclization of propargyl-allylamines or -amides such as (29) is catalysed by palladium acetate in the presence of triarylphosphines to give the substituted carbapenem (30).40The 37 H.Fritschi U. Lentenegger and A. Pfaltz Angew. Chem. Inf.Ed. EngL 1986 25 1005. 38 A. Sudhakar T. J. Katz. and B. W. Young. J. Am. Chem. Sor. 1986. 108 2790. 3Y M. Mizutani Y. Samenutsu Y. Tamaru and Z. I. Yoshida Tetrahedron 1986,42 305. 40 B. M. Trost and S. F. Chen J. Am. Chem. Soc. 1986 108 6053. Organometallic Chemistry -Part (i) The Transition Elements LClzPd R3 I R3 H- H' D D (27) I R' c1 L R' Scheme 6 pyrrolizidine nucleus has also been formed under similar reaction conditions in good yield (Scheme 7). Cyclopentanoid syntheses remain popular and palladium-catalysed reactions leading to this ring system have been reviewed.41 With this target in mind an impressive array of carboxylative trimethylenemethane cycloaddition reactions cata- lysed by palladium(0) complexes have been described:* The silyl-substituted trimethylenemethane-palladiumcomplex derived from the acetate (3 1) adds directly with electron-poor alkenes to give silyl-substituted methylenecyclopentanes (Scheme 8).Using the carbonate (32) the trimethylenemethanepalladium(TMM-Pd) com- plex may be intercepted by an electrophile that is more reactive than the conventional TMM-Pd acceptors. The product still bearing a silicon substituent may regenerate 41 B. M. Trost Angew. Chem. Int. Ed. Engl. 1986,25 1. 42 B. M.Trost S. M. Mignani and T. N. Nanninga J. Am. Chem. SOC.,1986,108 6051. 210 D.Parker SiMe SiMe3 L,Pd(O) Me3SiA-O-C02Me L2Pd''Y --bE+ L2Pd+ (32) (33) I Scheme 8 TiMe3 I Z L,Pd' Scheme 9 a TMM-Pd complex for subsequent cycloaddition (Scheme 9). The methyltrimethyl- silylcarbonate which is released following formation of the TMM-Pd complex acts as a source of carbon dioxide which can then function as the electrophile capturing the intermediate (33) rapidly. This sequence has been harnessed in the synthesis of the spiro-compound (3m5) from the vinyl ether (34). 0 / OMe + Pd( PPh,) &co2H OMe 51% 80 "C/PhMe w Me3Si OC0,Me (34) (35) A key step in the synthesis of alloyohimbone involved the cyclization of a stereospecific Michael reaction equivalent based on a palladium allyl intermediate derived from Reaction of (36) with base followed by the palladium(0) complex gave (37) in good yield and formed the cis ring junction exclusively.The well-worked catalyst PdCl,( MeCN) catalyses the cyclization-coupling reaction of lithium alkyn- oates with allyl or vinyl halides to give unsaturated lactones4 (Scheme 10). Lithium 5-alkynoates (n = 3) gave 8-alkylidenevalerolactonesvia an exo-digonal cycliz- ation while lithium 3-decynoate (38) reacted with allyl chloride to afford 3-allyl-3- decen-4-olide (39) by an endo-digonal cyclization. 43 S. A. Godleski and E. B. Villhauer. J. Org. Chem. 1986 51 486. 44 N. Yanagihara C. Lambert K. Iritani K. Utimoto and H. Nozaki J. Am. Chem. SOC.,1986 108 2753. Organometallic Chemistry -Part (i) The Transition Elemerlts 1.NaH 2. Pd(diphos) H (361 SPh (37) R'C=C(CH2),CO2Li + R' 1Pd" + RZCH=CR3CHR4CI Scheme 10 (39) The conversion of saturated carbonyls and esters into the corresponding ap-unsaturated compounds is a useful synthetic transformation. Silyl enol ethers and ketone allyl acetals may be converted into ap-unsaturated carbonyls esters or lactones by treatment with allyl carbonates in the presence of Pd(diphos), (Scheme 11).45 Tin enolates generated in situ by reaction of an enol acetate with methoxytributyltin react similarly. In this way the unsaturated enone (41) was prepared from the enol acetate (40). The transmetallation of the tin enolate with the r-allylpalladium methoxide complex gives the constitutionally isomeric enolate complexes (42) and (43) which undergo p-elimination to give the product enone with regeneration of the Pdo catalyst (Scheme 12).+OC02Me + 05'Me3 Pd(OAc), diphos ,o&SiMe3 MeCN 90% Scheme I1 I. Minami K. Takahashi 1. Shimizu T. Kimura and J. Tsuji Tetrahedron 1986 42 2971. 212 D. Parker OSnBu3 I Jocoe Pd'L R' '0 Scheme 12 A potentially useful transformation of 0-allyl-S-alkyldithiocarbamateshas been reported forming alkylallylsulphides with retention of configuration by treatment with palladium(0) phosphine complexes.46 The limits of palladium-catalysed alkyla- tions and acylations continue to be re-defined various alkenyl-copper reagents as their magnesium salts may be acylated in the presence of palladium(o) catalysts to form stereodefined enones.The reaction sequence has been adapted for the synthesis of isoegomaketone which is a natural fragrance47 (Scheme 13). A reductive coupling 0 Me I 0 Scheme 13 46 P. R. Auburn J. Whelan and B. Bosnich J. Chem. Sor. Chem. Cornwn. 1986 146. 47 N. Jabri A. Alexakis and J. F. Normant Terrohedron 1986 42 1369. Organometallic Chemistry -Part (i) The Transition Elements reaction of allylic acetates with carbonyl compounds proceeds in the presence of samarium iodide under palladium( 0) catalysis to give homoallylic alcohols such as (44),derived from cyclohexanone and 3-phenylallyl acetate.48 The scope of the Heck aryl coupling reaction has been further The coupling of polyoxyge- nated and polyalkylated aryl iodides with different aryl Grignard reagents using palladium(0) catalysts was investigated.The method was found to tolerate up to two ortho substituents in the product biaryl preferably on the precursor arylmag- nesium moiety. The telomerization of butadiene with acetic acid yields acetoxyoctadienes and some dinuclear palladium ally1 complexes have been structurally characterized as intermediates in this rea~tion.~' In related work the reaction of octadienylpalladium complexes with C-H acidic methylene compounds has been monitored by 31Pand C n.m.r. and several intermediates identified in the palladium-catalysed telomeriz- ation of butadiene with acids.51 5 Coupling Carbonylation and Carboxylation Reactions Further evidence of the versatility of cobalt carbonyl complexes in cyclization and coupling reactions has been provided.The hypothetical 1,3,5-~yclohexatriene is an oft-quoted model for bond-localized benzene. The cobalt-catalysed synthesis of tris( benzocyclobutadienato) benzene (45) has been accomplished Scheme 14 and in this [4]phenylene the central ring possesses a 'bond localized' cyclohexatriene structure. The X-ray structure reveals bond lengths alternating between 1.33 A and 1.50 A and the compound undergoes a thermal retrocyclization to give a triben- zohexadecahydro [12]ann~lene.~* The related phenylene (46) also shows consider- JX T. Tabuchi J. Inanaga and M. Yamaguchi Tetrahedron Lett. 1986 27 1196. 49 D. A. Widdowson and Y.Z. Zhanp. Tetrahedron. 1986 42 2111. 50 A. Behr G. V. Ilsemann W. Keim C. Krueger and H. Y. Tsay Organometallics 1986 5 514. '' P. W. Jolly R. Mynott B. Raspel and K. P. Schick Organornetallics 1986 5 473. 52 R. Diercks and K. P. C. Vollhardt J. Am. Chem. Soc. 1986. 108 3150. 214 D. Parker Br 1. PdCI,(PPh,),/CuI Et,N Me,Si-r-H 1. CpCo(CO), ' ';xl:c. // * 2. H+ ' (45) 2. KF/18-C-6/glyme / Br Br Br@ Br Ill Scheme 4 able bond lo~alization.~~ A remarkably efficient cobalt-catalysed synthesis of all four rings of B-ring aromatic steroids from acyclic precursors has been dis~losed.~~ The enetriyne (47) may be cyclized to the target steroid (48)possessing a trans CD ring junction in a high yield one-step reaction. H I Ill -CH 2- I CH(CH2) CH(0R)CCH 2R'IICH2 CPCO(CO) - H R20 -=-H RZO (47) (48 1 The reaction of the tetracarbonylcobalt anion with cyclopropenyl cations yields an 7 3-oxocyclobutenyltricarbonylcomplex which undergoes nucleophilic attack to give some 2H-pyran-2-ones regio~pecifically~~ (Scheme 15).An important step in this sequence must involve transfer of an acyl or formyl ligand from cobalt to the oxocyclobutenyl ring. Ph R' = H,Me,Ph R2= Me Ph H Scheme 15 The use of organoiron complexes in synthesis continues to proliferate. An attractive iron(o)-catalysed cross-coupling of allylic ethers to 2,3-disubstituted 1,3-butadienes gives either a formal [4+ 41 ene reaction across the diene or a net 1,4-insertion of the diene into the C-H bond at the 2-position of the allylic ether.The observed reaction pathway is determined by the nature of the ligands attached to the iron (Scheme 16).56 Use of chelating diphosphine ligands such as bis( diphenylphos- phino)ethane (diphos) yields mainly the 1,4-hydrovinylation product (50) while 53 R. Diercks and K. P. C. Vollhardt Angew. Chem. Znt. Ed. Engl. 1986 25 266. 54 S. A. Lecker N. H. Nguyen and K. P. C. Vollhardt J. Am. Chem. SOC.,1986 108 856. 55 W. P. Henry and K. P. Hughes J. Am. Chern. SOC.,1986 108 7862. 56 J. M. Takacs L. G. Anderson B. G. V. Madhavan W. M. Cresswell F. L. Seely and W. F. Devroy Organometallics 1986 5 2395. Organometallic Chemistry -Part (i) The Transition Elements I (49) diphosFe' OCHzPh Me Me (50) Scheme 16 bipyridine ligands promote the thermally forbidden [4 + 41 ene reaction wherein the allylic ether serves as the enophile and the 1,3-diene as the ene component to give (49).A further illustration of the use of the iron tricarbonyl moiety as a diene protecting group has been furnished. The synthesis of 3,14-dihydroxytrichothecenes begins with a tricarbonyl(4-methoxy- 1-methylcyclohexadienyl)iron cation as an A ring synthon and the Fe(CO) group is used to protect the dienol ether during epoxidation and osmylation reactions (Scheme 17).57 In the synthetic route 'OCOPh 1. OSO 2. Na,S,O, I F e C 0 '1 OCOPh 'OCOPh (52) (51) Scheme 17 decomplexation of (51) followed by hydrolysis of the resultant dienol ether afforded the key tricyclic intermediate (52).Iron-diene tricarbonyls may be readily acylated under Friedel-Crafts conditions and the acylated product has been shown to be a promising synthetic intermediate.58 Oxidation of the intermediate (53) leads to an E,E-2,4-diene-l,6-dione while photocyclization gives a 2-acyl-3-cyclopentenol in good yield (Scheme 18).57 A. J. Pearson and Y. S. Chen J. Org. Chem. 1986 51 1939. 58 M. Franck-Neumann M. Sedrati and M. Mokhi Angew. Chern. 1986,98 1138. 216 D. Parker Ac Ac RCOCl -Fe(CO) AICI AcCHrCMe-C(Me)=CHAc -(CO)3Fe 2. OOH-Me& R Me Me Me Me PAC Me OH Scheme 18 The mechanism of the reaction of iron and manganese hydridocarbonyl complexes with 1,3-dienes has been studied.The 2-enyl metal products of 1,4-addition of the metal hydride to the 1,3-diene were formed and CIDNP studies suggested that the process may involve a radical-pair mechanism.59 A judicious choice of solvent and temperature is always required for the ultrasonic activation of organic reactions. The application of ultrasound in promoting the reaction of Fe,(CO) with 1,3-dienes has been demonstrated.60 Some progress has been made towards the problem of efficiently introducing trifluoromethyl groups into organic substrates. The low temperature reaction of Cd(CF3)* with copper(1) salts generates in situ a rather unstable trifluoromethylcop- per species which reacts with aryl iodides for example to give trifluoromethylphenyl derivatives in high yield.6' In related work the metathesis of copper(1) salts with fluorinated vinylcadmium or zinc reagents has provided a convenient method of preparation of fluorinated vinyl copper reagents.62 The copper(1)-catalysed photobicyclization of the diene (54) led to the expected bicycle (55) and provided a key step for the synthesis of robustadials e.g.(56) whose structure had previously been incorrectly assigned.63 The unusual [Slradialene (58) has been synthesized in one step from the ate complex of the copper carbenoid (57),64 and copper acetylacetonate salts have been shown to catalyse the Michael addition of P-dicarbonyls to @-unsaturated enones in a similar manner to the related nickel salts.65 A new synthesis of alkenes has been established using molybdenum complexes.66 Reaction of the 0x0-molybdenum complex (59) with diazo compounds gives the metalloazine (60).These complexes are susceptible to nucleophilic attack at the carbon end of the coordinated diazo sub-unit. Reaction with conventional phos- 59 M. J. Thomas T. A. Shackelton S. C. Wright D. J. Gillis J. P. Colpa and M. C. Baird J. Chem. Soc. Chem. Cornmun. 1986 1138. 60 S. V. Ley M. R. C. Low and A. D. White J. Organornet. Chem. 1986 302 C13. 61 D. M. Wiemers and D. J. Burton J. Am. Chem. Soc. 1986 108 832. 62 D. J. Burton and S. W. Homsen J. Am. Chem. SOC.,1986 108 4229. 63 K. Lal E. A. Zarate W. J. Youngs and R. G. Salomon J. Am. Chem. Soc. 1986 108 1311. 64 M. Iyoda H. Otani M. Oda Y. Kai Y. Baba and N. Kasai J. Chem. Soc.Chem. Cornmun. 1986 1794. 65 P. Kocovsky and D. Dvorak Tetrahedron Lett. 1986 41 5015. 66 J. A. Smegal I. K. Meier and J. Schwartz J. Am. Chem. Soc. 1986 108 1322. Organometallic Chemistry -Part (i) The Transition Elements J + Me M*:e Me Me Me Me (58) phoranes produces alkene nitrogen gas free phosphine and regenerates the starting molybdenum compound (Scheme 19). This alkene synthesis parallels conventional Wittig chemistry except that hydrazine is effectively oxidized to nitrogen to balance the reduction of the carbonyl to the alkene in order that the triphenylphosphine and the molybdenum complex may be recycled. OMo(S2CNR2) OMO( NNCR'RZ)(S2CNR2) R = Me Et (59) (60) OMO(NNCR'R~)(S~CNR,)~ + Ph3P=CR3R4 + R'R2C=CR3R4 + N + PPh + OMo(S,CNR,) Scheme 19 The old Reppe reaction involves the cyclotetramerization of ethyne to produce cyclooctatetraene using nickel catalysts although its intimate mechanism has not been clearly defined.A thoughtful carbon-13 n.m.r. labelling study has shown that benzene or cyclobutadiene intermediates are not involved nor are any processes which do not leave the original connectivity in the alkyne intact. A zipper-type mechanism was postulated to account for these observation^.^^ The reaction of cyclopropabenzene with cyclooctadiene nickel phosphine complexes gives the dinickel complex (61). This reacts with carbon monoxide to give the cyclopentanone (62) which may be converted into the tetrakismethano[24]annulene (63).68The McMurry reaction has gained wide acceptance in a short period and it has been harnessed in the synthesis of the pentacyclo-tetracosatetraene (65) from the diketone (64) and (65) forms stable square-planar silver( I) complexe~.~~ Trichloromethyl-titanium has been developed as a non-basic and highly selective Grignard analogue which reacts stereoselectively with carbonyl compounds,70 while ruthenium tri- 67 R.E. Colborn and K. P. C. Vollhardt J. Am. Chem. SOC.,1986 108 5740. 68 R. Mynott R. Neidlein H. Schwager and G. Wilke Angew. Chem. 1986 98 374. 69 J. E. McMurry G. J. Haley J. R. Matz J. C. Clardy and J. Mitchell 1.Am. Chem. SOC.,1986 108 515. 'O M. T. Reetz S. H. Kyung and M. Hullrnann Tetrahedron 1986 42. 2935. 218 D. Parker TiCI,/ Zn-Cu P dme oo-o-a=oo chloride under reducing conditions (Zn/ MeOH) catalyses the dimerization of alkyl acrylates to hexenedioate~.~~ There are several groups seeking to utilize C02 as a C building block in organic synthesis.The coupling of C02and butadiene is mediated by Feo complexes opening up a new route to a,@-dicarboxylic a~ids.’~ The intermediate iron ally1 (66) may be protonated coupled to a second equivalent of C02,or dimerized to give a Clo di-acid (Scheme 20). Using nickel or palladium catalysts C02reacts with butadiene to give a C9 six-ring la~tone,~~ while a one-step synthesis of vinyl carbamates is catalysed by ruthenium( 111) complexes involving co-addition of C02 terminal alkynes and amines via a metal-vinylidene intermediate.74 Scheme 20 6 Oxidation Reduction C-H Activation and Miscellaneous A general procedure for the catalytic asymmetric epoxidation of allylic alcohols has been rep~rted.~’ The key modification is the introduction of 3 8 or 4 8 molecular 71 R.J. McKinney and M. Colton Organometallics 1986 5 1080. 72 H. Hoberg K. Jenni C. Krueger and E. Raabe Angew. Chem. In?. Ed. En& 1986 25 810. 73 A. Behr R. He K. D. Juszak C. Krueger and Y. H. Tsay Chem. Ber. 1986 119 991. 74 P. Mahe P. H. Dixneuf and S. Leidrer Tetrahedron Lett. 1986 27 6333. 75 R. M. Hanson and K. B. Sharpless J. Org. Chem. 1986 51 1922. Organometallic Chemistry -Part (i) The Transition Elements sieves principally to take up adventitious water so that less than 10% of the chiral titanium tartrate catalyst is required.The search continues for further high valent 0x0 complexes for alkene oxidation some 0x0 complexes of osmium act as selective oxidants for cyclohexene oxidation in the presence of iod~sylbenzene.’~ Significant mechanistic information in many metal-catalysed oxidations is still lacking although the mechanism of the manganese( 111) acetate oxidation of alkenes has been examined in some Efficient asymmetric hydrogenation of alkenes has been mostly achieved with organorhodium catalysts but a chiral BINAP-ruthenium complex (67) catalyses the hydrdgenation of dehydroisoquinolines to give quinolines in greater than 95YO enantiomeric Hydrogenation of the 2-enamide (68) gives N-acyl isoquino- line derivative (69) with complete enantioselectivity.Homogeneous transfer hydro- genation using tributylammonium formate as a source of hydrogen has been used for the awkward reduction of phenyl fluoroalknesulphonates to the corresponding arenes in the presence of Pd( PPh3)4.79 O.’-” 4 du/O I ‘0 A heteropolytungstic acid has been used as a catalyst for the liquid-phase activation of alkanes at room temperature.80 Using acetonitrile as solvent and under constant illumination the reaction involves an initial electron-transfer from the alkane to the catalyst which is in an excited state giving a radical cation that loses a proton and is then trapped by the acetonitrile solvent. The catalyst turnover ratios are rather low. Illumination of the rhenium complex CpRe( PPh3)2H2 is accompanied by loss of triphenylphosphine to give a species which catalyses Hf D exchange between benzene and methane.81 A thermally induced C-H activation of benzene involves 76 C.M. Che K. W. Cheng and T. C. W. Mak J. Chem. SOC.,Chem. Commun. 1986 200. 77 W. E. Fristad J. R. Peterson A. B. Ernst and G. B. Urbi Tetrahedron 1986 42 3429. 78 R. Noyori M. Ohta Y. Hsiao M. Kitamura T. Ohta and H. Takaya J. Am. Chem. SOC.,1986 108,7117. 79 Q. Y. Chen Y. B. Ibe and Z. Y. Yang J. Chem. SOC.,Chem. Commun. 1986 1452. 80 R. F. Renneke and C. L. Hill J. Am. Chem. SOC.,1986 108 3528. W. D. Jones and J. A. Maguire Organornetallics 1986 5 590. 220 D. Parker the relatively stable fourteen-electron iridum complex IrCI[ P( Pr)3]2showing again that high energy metal-ligand fragments are not the only species which may promote CH activation.82 Transition metal complexation and hence stabilization of reactive intermediates was a feature of early organotransition metal chemistry.A further rare example of a thermally stable mononuclear benzyne complex (70) has been reported83 and the related unusual zirconacene-cyclohexyne complex (7 1) has also been character- i~ed.~~ The ferrocenylmethyl group has been demonstrated to be a highly lipophilic C02Me E.% C02Me (72) (73) and chromophoric group for the masking of peptide bonds.85 It may be introduced by the reductive alkylation of amino-acids with ferrocenecarboxaldehyde and is conveniently removed with trifluoroacetic acid.The palladium(0)-catalysed azidation of allyl acetates proceeds smoothly with sodium azide in the presence of Pd( PPh3)4 giving trans isomers exclusively.86 Finally the nickel-promoted 1,3-migration of an sp2 centre in the vinylcyclobutene (72) gives the cyclohexadiene (73),8’ while the Claisen rearrangement of allyl vinyl ethers is efficiently catalysed by PdC12( MeCN) at ambient temperatures and proceeds via the expected chair transition state.88 82 H. Werner A. Hohn and M. Dziallas Angew. Chem. Int. Ed. Engl 1986 25 1090. 83 S. L. Buchwald R. T. Lumm and J. C. Dewan J. Am. Chem. Soc. 1986 108 7441. 84 S. L. Buchwald B. T. Watson and J. C. Huffmann J. Am. Chem. SOC.,1986 108 7411. 85 H. Eckert and C. Seidel Angew. Chem. fnt. Ed.EngL 1986 25 159. 86 S. Murahasi Y. Tanigawa Y. Imada and Y. Taniguchi Tetrahedron Lett. 1986 27 227. 87 J. L. van der Baan and F. Bickelhaupt Tetrahedron Lett. 1986 27 6267. 88 D. DiFrancesco and A. R. Pinhas J. Org. Chem. 1986 51 2098.

ISSN:0069-3030    

DOI:10.1039/OC9868300201

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

9 Organometallic Chemistry Part (ii) The Main-Group Elements By A. T. HUTON Department of Pure and Applied Chemistry The Queen's University Belfast BT9 5AG 1 Introduction In scope and coverage this year's report is similar to last year's,' though this time somewhat more emphasis has been placed on the organometallic chemistry of the elements of Groups I and IV mainly at the expense of Group 11. Next year's report will redress the balance particularly with respect to organo-zinc -cadmium and -mercury chemistry. A glance at the references cited in this report will confirm that the health of main-group organometallic chemistry is confined largely to the research groups in Germany with whom excellence in this field has been traditionally associated. 2 Groups I and I1 In principle the hydrides of alkali metals should be ideal synthetic reagents for the metallation of active hydrogen compounds hydrogen is the only by-product and the course of the reaction can be conveniently followed by gas evolution.Unfortu- nately however the alkali metal hydrides are normally not very reactive. Now the synthesis of 'superactive' alkali metal hydride metallation reagents LiH NaH and KH by hydrogenation of BUM (M = Li Na K) in hexane in the presence of TMEDA has been described.2 Precipitated n-butylpotassium (Bu"K) prepared by metal-metal exchange between Bu"Li and potassium t-amylate has been shown to dissolve in hexane (after addition of TMEDA) to give a homogeneous solution which is an effective metallation reagent,3 while simple mixing of Bu'OK Bu"Li and TMEDA in hexane or pentane at temperatures below -40 "Cgives an extremely efficient metallating agent.This has resulted in the first successful direct metallation of ethene (to form vinyl potassium); typical products are obtained with l-bromo- octane and after addition of LiBr in THF with benzaldehyde and diphenyl disul- hide.^ ' A. T. Hutton Annu. Rep. hog. Chem. Sect. B Org. Chem. 1985 82 223. ' P. A. A. Klusener L. Brandsma H. D. Verkruijsse P. von R. Schleyer T. Fried] and R. Pi Angew. Chem. Int. Ed. Engl. 1986 25 465. R. Pi W. Bauer B. Brix C. Schade and P.von R. Schleyer J. Organomet. Chem. 1986 306 C1. L. Brandsma H. D. Verkruijsse C. Schade and P. von R. Schleyer J. Chem. Soc. Chem. Commun. 1986 260.221 222 A. 7'.Hutton Reductive metallation has been used as a general preparative method for hydrocar- bon allylmetallic compounds allyl phenyl sulphides are the ideal substrates for a particularly versatile preparative method for allylic anions because of their great ease of preparation and their smooth reductive lithiation using lithium naphthalenide or l-(dimethylamin~)naphthalenide.~ The great importance of the counterion in determining the structure of a carbanion is clearly revealed both by calculations performed for allenyl anions and the results of the first X-ray structure analysis of an allenylsodium derivative viz. Na(tmeda),+ Bu'-C=C=C(Me)-CEC-Bu'. Na+ favours the allenyl structure (1) having a strongly localized charge; the free anion and the Li+ salts on the other hand are better described by the resonance structures (1) f* (2) *(3).The different behaviour of the organolithium and organosodium compounds is due to the stronger interaction of the anion with the smaller Li+ ion.6 Me Me Me Attention has been drawn to the use of the complex-induced proximity effect (CIPE) as a rationale for a number of novel reactions of organolithium compound^.^ The importance of such complexation has been recognized for some time but recent work suggests that proximity in a transition state related to the initial complex can be dominant over classical effects in determining the course of a reaction. CIPE processes are notable in the formation and reactions of a variety of carbanionic synthetic equivalents ranging from a-lithioamines allyl anions and electrophilic nitrogen to enolates and the regio- and stereo-control provided in these reactions is a matter of continuing interest.The CIPE proposal should be a useful guide for correlating observations devising new reactions and designing mechanistic probes. Recent reports which illustrate CIPE processes in novel reactions include the carbenoid anion behaviour of dilithio derivatives of thioacetal alcohols (ring-closure by oxyanion-facilitated CH bond insertion),8 the selective vulnerability towards lithium bases of a yCH bond syn to a functional group in an a,P-unsaturated amide system,' the transient introduction of a complexing group to bring the lithium base into proximity for proton abstraction e.g.in tetrahydroisoquinoline alkyla- tions," and the deprotonation of the chelating enamine derived from cyclohexanone and N,N,N'-trimethylethylenediamine which leads to complete formation of the vinyl carbanion rather than the expected allyl carbanion (see equation l)." An ' T. Cohen and B.-S. Guo Tetrahedron 1986,42 2803. C. Schade P. von R. Schleyer M. Geissler and E. Weiss Angew. Chem. Inr. Ed. Engb 1986 25 902. ' P. Beak and A. I. Meyers Acc. Chem. Rex 1986 19 356. ' R H Ritter and T Cohen. J Am Chem Ync. 1986. 108. 1718 M. Majewski J. R. Green and V. Snieckus Tetrahedron Lett. 1986 27 531. "' A. R. Katritzky and K. Akutagawa Tetrahedron 1986 42 2571. " G. Stork C. S. Shiner C.-W. Cheng and R. L. Polt J. Am. Chem. Soc. 1986 108 304. Organometallic Chemistry -Part (ii) The Main-Group Elements 223 equally surprising result is that chelating enamines derived from aldehydes unbranched at the a-position in which the competition now involves removal of either the a-or the P-vinyl hydrogen lead to p-rather than the expected a-deprotonation (see equation 2)." It seems very likely that these remarkable deproton- ations of chelating enamines arise from critical geometric constraints in the relevant Me transition states.The oxygen- and nitrogen-assisted lithiation and carbolithiation of non-aromatic compounds has been reviewed the discussion covers the properties of non-aromatic organolithium compounds capable of intramolecular coordination to oxygen and nitrogen.I2 The compounds (4) react with Bu'Li to give considerable amounts of the 'anti-Michael' adducts (5) (equation 3) and a single-electron-transfer mechanism has been proposed for these reactions; in contrast both compounds (4) behave as Michael acceptors towards Bu"Li.l3 R H But \/ 1. 2Bu'Li 2. H,O I *R CH (3) R = Ph,Me,Si (4) \CO,H H /c=c\cO,H \CH ' (5) The structural variety of organolithium compounds has been further expanded by the 1,3-diboratacyclobutadiene(6),for which n.m.r. spectroscopic results under- line the importance of the resonance structures for the description of the electron distribution. Compound (6) crystallizes as a dimer in which a planar layer of four Li atoms bridges two four-membered rings in a sandwich structure. The rings are eclipsed (a B atom lying above a C atom in each case) and strongly puckered; the separations of the Li atoms in the Li layer are in part shorter than those found in the Li tetrahedra of tetrameric lithium cornpo~nds.'~ The first isolable crystalline compound containing the bishomoaromatic anion bicyclo[3.2.l]octa-2,6-dienide the TMEDA adduct of bicyclo[3.2.l)octa-2,6-dienyllithium,has C symmetry in solution but in the solid state the lithium is bonded unsymmetrically to all five sp2 carbon atoms.The lithium occupies an almost central position below the seven- membered ring such that not only the allylic but also the olefinic part of the carbanion l2 G. W. Klumpp Red. Trau. Chim. Pays-Bas 1986 105 1-21 containing 151 refs. l3 K. J. H. Kruithof A. Mateboer bl.Schakel and G. W. Klumpp Red. Trau. Chim. Pays-Bas 1986 105 62. 14 G. Schmidt G. Baum. W. Massa and A. Berndt Angew. Chem. Inr. Ed. Engl 1986 25 1111. 224 A. T. Hutton SiMe3 SiMe3 is engaged in metal-ligand bonding. A coordination number of seven rarely observed for solvated lithium bound to a pure hydrocarbon is thus a~hieved.'~ An X-ray structure determination has shown that the 'ketene iminate' PhCH=C=N-and not the carbanion PhCH-CEN is present in [(a-cyanobenzyl- lithium.trneda),.C,H,] as structure (7). The 'anions' are planar (measurements at -35 "C located the H atom) and it is interesting that the bond lengths in the CCN groups deviate considerably from those in ketene imines such as (8) because in .Ph ...* :C' 'I4 comparison enolates have practically the same bond lengths as enol ethers.This difference is probably due to the different stabilization of the negative charge whereas a carbonyl group is predominantly mesomeric in a nitrile group the inductive field effect also plays a prominent role.' Another organolithium com- pound without Li-C bonding is (Ph,P),CHLi-tmeda which as shown by X-ray structure analysis is a monomer containing a slightly puckered CP2Li four- membered ring (9). The transannular Li-C distance of 3.054(6) A precludes any bonding interaction." Again the crystal structure of the a-sulphinyl 'carbanion' [PhC(Me)S(O)Ph]Li shows no interaction between the benzylic carbon atom and H C 4-\ Ph2P PPh2 \/ l5 N. Hertkorn F. H. Kohler G.Muller and G. Reber Angew. Chem. Int. Ed. Engl 1986 25 468. G. Boche M. Marsch and K. Harms Angew. Chem. Int. Ed. EngL 1986 25 373. " D. J. Brauer S. Hietkamp and 0.Stelzer J. Organomet. Chem. 1986 299 137. Organometallic Chemistry -Part (ii) The Main-Group Elements the Li atom; the benzylic C atom is not planar and the salt is present as a dimer with a central Li202 unit." The stereoselectivity in reactions of a series of a-lithiosulphinyl carbanions with aldehydes (to give p-hydroxysulphoxide products) has been unambiguously estab- lished steric effects and intramolecular chelation of the associated cation are the important factors contributing to the observed ~utcome.'~ One approach to asym- metric homoaldol reactions may be provided by the surprising finding that a-deprotonation of an a-chiral 2-alkenylcarbamate proceeds with retention and the resultant lithium compound (10) racemizes only very slowly at -78 "C.Accordingly the lithium in (10) must be very strongly bonded to the chiral carbon centre despite the possibility of resonance in the anion. Furthermore lithium-titanium exchange of (10) with TiC1(NEt2) proceeds with inversion to give a species that can add to carbonyl compounds with 1,3-chirality transfer.20 For the first time q3-allyllithium entities as found in allyl-transition metal com- plexes have been shown to exist in the solid state. The X-ray structure of [1,3- diphenylallyllithium~Et20],,shows that the q3-allyllithium units aggregate to form polymeric chains and that the Li atoms lie practically symmetrically above and below the almost planar ally1 groups which are inclined at 120" to each other.The structure in solution is thought largely to correspond with this crystal structure.21 Monolithiated organic compounds can often be converted further into syntheti- cally useful dilithiated derivatives and the first lithium substituent often determines the position of the second metallation by activation of H atoms in close spatial proximity. A combination of X-ray and n.m.r. analysis of 2-lithio- 1-phenylpyrrole (11) has shown that the position of the second lithiation may be predicted. The X-ray structure revealed a dimer [(1 1)-tmeda] with the closest contact to Li shown by the H marked by an asterisk. Using 6Li-'H two-dimensional heteronuclear Li 18 M.Marsch W. Massa K. Harms G. Baum and G. Boche Angew. Chem. Int. Ed. Engl. 1986,25 1011. 19 D. R. Williams J. G. Phillips F. H. White and J. C. Huffman Tetrahedron 1986 42 3003. 20 D. Hoppe and T. Gamer Angew. Chem. Int. Ed. Engl. 1986 25 160. 21 G. Boche H. Etzrodt M. Marsch W. Massa G. Baum H. Dietrich and W. Mahdi Angew. Chem. In?. Ed. Engl. 1986 25 104. 226 A. T. Hutton Overhauser n.m.r. spectroscopy (2D HOESY) it was shown that the solution structure of (11) was similar to that in the crystal with the shortest Li-H distance being to the H marked by an asterisk (the most intense cross peak was between 6Li and this 'H). Experimentally it is indeed this H which undergoes substitution by Li to form the dimetallated product.22 0-OLi OLi (12) X = H or F (13) OH (14) X = H or F (15) Although mono-lithiated fluoro compounds capable of undergoing a-,p- and/or y-elimination have been known for a long time the reagents (12) and (13) [>go% enantiomeric excess (R)-form] are the first poly-lithiated derivatives of this type.They exhibit an unexpected stability toward fluoride elimination and offer accessibil- ity to a variety of new fluorinated organic compounds with additional functional groups. They can be prepared using Bu"Li in THF at low temperatures and converted with carbonyl compounds or alkylating reagents into (14) or (15) respectively in yields of 50'/0.~~ It has also been shown that addition of excess lithium powder to cyclooctyne in ether (-35 "C 2 h) results in the formation of a yellow solution of cis-dilithiocyclooctene while acyclic alkynes react much more slowly with lithium (20 "C,48 h) to give trans-dilithioalkenes which are insoluble in ether.Only trans-addition is observed; the long-known cis-addition of lithium to diphenylacetylene and now to cyclooctyne however suggests a sequential cis-trans isomerization as has found to be the case for unsubstituted 1,2-dilithioeth~lene.~~ Liz[ (C5Me4)2CH2] the dilithium salt of the novel permethylated ring-connected [ ( C5Me4)2CH2]2-dianion has been prepared as a colourless pyrophoric powder from C5Me4H2 via (C5Me4H),CH2 and subsequent reaction with Bu"Li (equation 4);it has been used as a bridging ligand between transition metal fragments.25 2Bu"Li CHZCIZ 2C,Me4H2 -2LiC,Me,H -22 W.Bauer G. Miiiler R. Pi and P. von R. Schleyer Angew. Chem. Int Ed. Engl. 1986 25 1103. 23 D. Seebach A. K. Beck and P. Renaud Angew. Chem. Inf. Ed. Engl. 1986 25 98. 24 A. Maercker T. Grade and U. Girreser Angew. Chem. Int. Ed. Engl. 1986 25 167 25 H. J. Scholz and H. Werner J. Organomef. Chem. 1986 303 C8. 232 A. T. Hutton 88%) and its transoid isomer (22; 12%). The same reaction using the germanium analogue of (20) did not give the corresponding germole but only 2,3-dimethyl- butadiene as the sole identifiable product.58 In the presence of a catalyst derived from the co-sublimation of AlCl with FeC1 (lolo) a series of permethylcyclosilanes (Me,Si), n = 5-12 rearranged to form isomeric branched cyclopentasilanes or cyclohexasilanes remarkably in each reac- tion a single isomeric product was obtained in nearly quantitative yield.Conforma- tional analyses of these branched cyclosilanes have been perf~rmed.~~ Alkylthiosilanes RSSiMe, have been found to be excellent initiators for the group- transfer polymerization of acrylic acid esters.60 The molecular and electronic structures of penta- and hexa-coordinate silicon compounds have been comprehensively reviewed.61 The reactivity of anionic pentacoordinated silicon complexes towards nucleophiles e.g. PhMgBr has been studied and this has led to new synthetic methods for various silanes while the reaction of Grignard reagents with dianionic hexacoordinated (pyrocatechol) silicon complexes has provided the way to synthesize organosilicon compounds directly from silica The chemistry of the penta-coordinated bi- and tri-cyclic organo- silicon and -tin compounds R2M(CH2CH2CH,),E and RM(CH2CH2CH2)3N (M = Si Sn; R = C1 Br I Me; E = NMe 0 S) has been reviewed the compounds which have 'diptych' and 'triptych' structures exhibit intramolecular E (or N) + M donor-acceptor interactions of varying strengths depending on the nature of the substituents R bonded to the metal centre.63 Until recently the investigation of cyclopentadienyl chemistry of main-group elements was restricted to Group IV species and some other isolated examples.This situation has changed radically during the last decade; a variety of new cyclopen- tadienyl compounds is their often- or usually-observed fluxionality and this aspect edge of the possible bonding modes in a-bonded (7')species as well as in v-bonded ( qn)complexes has increased.One of the most interesting features in 7'-cyclopen- tadienyl compounds is their often- or unusually-observed fluxionality and this aspect has been reviewed with respect to compounds of the main-group 111 IV and V elements.64 Recent developments have shown that drastic differences in fluxional behaviour exist among the cyclopentadienyl compounds of main-group elements and these differences may be ascribed to the nature of the main-group element the other ligands bonded to the main-group element and the substituents on the cyclopentadienyl ring. These factors influence the rate of prototropic shifts and the proportion of allylic and vinylic isomers present in equilibrium enormously; further- more they determine specifically the activation energy for the circumambulatory migration of the relevant main-group metal.The migrations are characterized as 58 J.-P. Beteille G. Manuel A. Laporterie H. Iloughmane and J. Dubac Organornetallics 1986 5 1742. 59 T. A. Blinka and R. West Organometallics 1986 5 128 and 133. 60 M. T. Reetz R. Ostarek K.-E. Piejko D. Arlt and B. Bomer Angew. Chern. Int. Ed. Engl. 1986,25 1108. 61 St. N. Tandura M. G. Voronkov and N. V. Alekseev Top. Curr. Chem. 1986 131,99-189 containing 1008 refs. 62 A. Boudin G. Cerveau C. Chuit R. J. P. Corriu and C. Reye Angew. Chem. Inf. Ed. Engl. 1986 25 413 and 414.'' A. Tzschach and K. Jurkschat Pure Appl. Chern. 1986 58 639. 64 P. Jutzi Chern. Rev. 1986 86 983-996 containing 94 refs. 228 A T. Hutton 1,4-addition of benzylzinc bromide or allylzinc bromide respectively to 5-benzy- lidenebarbituric acids followed by hydr~lysis.~~ It has been shown that the bromina- tion (pyridinium hydrobromide perbromide) or iodination (iodine) of allenic or propargylic organomercury halides in pyridine proceeds with rearrangement to afford the corresponding propargylic or allenic halides respectively. This procedure provides a convenient new route to 3-bromo- and 3-iodo-l,2-alkadienes useful in organic ~ynthesis.~~ The synthesis of organometallics by decarboxylation reactions both thermal and radical-initiated has been reviewed; much of this is relevant to the organic chemistry of Zn Cd and Hg.35 3 Group 111 A review on the high-resolution metal-n.m.r.spectroscopy of organometallic com- pounds has highlighted the use of 25Mg n.m.r. for the characterization of organomag- nesium compounds and the relationship between 27Al n.m.r. shift and coordination number of organoaluminium Conclusions from 27Al n.m.r. spectro- scopy invoking an equilibrium between complexes with four- and five-coordinate A1 atoms in the compound [Et2A10CH2(2-C5H4&)l2 have been shown to be incorrect. The false impressions were caused by background signals emphasizing the fact that caution is necessary when n.m.r. spectra of dilute samples of broad quadrupolar metal nuclei are recorded.37 rr-Complexes of aluminium with olefins have long been regarded as intermediates in many reactions of organoaluminium compounds but only now has a compound with aluminium-olefin T-bonds been characterized by X-ray structure analysis.Treatment of the active species AlCl (generated at elevated temperature) with MeCECMe in a low-temperature reaction led upon warming from -196 "C to room temperature to formation of dimeric 1,4-dichlor0-2,3,5,6-tetramethyl-1,4-dialumina-2,5-cyclohexadiene. The structure shows that two non-planar 1,4-dialuminacyc- lohexadiene moieties twisted through 90" with respect to each other are coupled via four aluminium-olefin .rr-bonds to give the dimer (mean rr-bonded A1-C distance 2.354 A).38 All simple organoaluminium compounds which have so far been characterized by single-crystal X-ray diffraction methods have been shown to be dimeric in the solid state with three-centred two-electron carbon bridge bonds or have chain structures as exhibited by Me2A1(C,H,) and Al(CH,Ph) .However steric interac- tions in trimesitylaluminium (16; M = Al) prepared by metal exchange between dimesitylmercury and aluminium metal give rise to a monomeric structure (16) which is planar around the A1 centre with the three mesityl groups disposed in a propeller-like fashion about the trigonal axis. The reactivity of this compound is also altered from that of other organoaluminium compounds because of the structural 33 Y. Frangin C. Guimbal F. Wissocq and H. Zamarlik Synthesis 1986 1046.34 R. C. Larock and M.-S. Chow Organometallics 1986 5 603. 35 G. B. Deacon S. J. Faulks and G. N. Pain Adu. Organomet. Chem. 1986 25,237-276 containing 169 refs. 36 R. Benn and A. Rufinska Angew. Chem. Int. Ed. Engl. 1986 25 861-881. containing 181 refs. 37 R. Benn A. Rufinska E. Janssen and H. Lehmkuhl Organometallics 1986 5 825. 38 H. Schnockel M. Leimkuhler R. Lotz and R. Mattes Angew. Chem. Int. Ed. Engl. 1986 25 921. Organometallic Chemistry -Part (ii) The Main-Group Elements effects of the mesityl group reduced reactivity towards hydrolysis oxidation and complex formation is found.39 Trimesitylgallium has been found to have virtually exactly the same structure (16; M = Ga).,’ An attempt has been made to introduce Ga+ cations in between the parallel rings of [2.2]paracyclophane.However an X-ray structure of the 1 :1 complex with Ga[GaBr,] showed that the Ga+ cations are not accommodated within the cyclo- phane cages but are approximately centrically ( v6)-bonded to the arene rings from their outer sides (Ga- -.ring plane 2.72 A) giving rise to zig-zag chain-like polydecker columns (17). These are interconnected by [GaBr,]- anions each of which provides one bromine atom to bridge two Ga’ centres thereby forming a highly symmetrical three-dimensional network.41 Dimethylgallane best synthesized by the reaction between GaMe3 and NaGaH, has now been characterized by its spectrmcopic and chemical properties and the predominant vapour species at low pressure has been established by electron diffraction as the dimer Me,Ga( p-H),GaMe Although the structure of cyclopentadienylindium(1) in the solid state has long been known to comprise zig-zag polymeric chains of In( q5-C5H5) units with very long In-‘centroid’ distances (3.19 A) the presence of an octahedral cluster has now been established for the permethylated derivative In( v’-C5Me5).The v’-C,Me units are arranged on the exterior of an octahedral In core with an In-‘centroid’ distance of 2.302 A. The volatility of h6(C5Me5)6 however suggests that the octahedral cluster has only marginal stability and monomeric species are probably formed in the gas phase.43 The synthesis and reactions of fulvalenedithallium (18) have been reported; it is obtained as an air-sensitive chocolate-brown solid from the reaction of an ethyl ether/ hexane solution of dihydrofulvalene with thallium ethoxide.44 It has been shown that room temperature reaction of simple aliphatic ketones with an aqueous solution of TlC13 leads to mono-oxoalkylthallium( III) derivatives 39 J.J. Jerius J. M. Hahn A. F. M. M. Rahman 0.Mols W. H. Ilsley and J. P. Oliver Organomeraflics 1986 5 1812. 40 0. T. Beachley jun. M. R. Churchill J. C. Pazik and J. W. Ziller Organomeraflics 1986 5 1814. H. Schmidbaur W. Bublak B. Huber and G. Muller Organometallics 1986 5 1647. P. L. Baxter A. J. Downs M. J. Goode D. W. H. Rankin and H. E. Robertson J. Chem. Soc. Chem. 41 42 Commun. 1986 805. 43 0.T. Beachley jun. M. R.Churchill J. C. Fettinger J. C. Pazik and L. Victoriano J. Am. Chem. SOC. 1986 108 4666. 44 W. C. Spink and M. D. Rausch J. Organomet. Chem. 1986 308 C1. 230 A. T Hutton T1 I T1 (18) of type C12T1CH2C(0)CH2R followed by formation of the selectively a-monochlori- nated ketones MeC(0)CHClR it is not clear as to why the chlorination site of the final product is not the same as the thallation site of the intermediate though it is known that de-thallation can involve rearrangement of the product.45 4 Group IV The organic chemistry of silicon has been succinctly described in a monograph which includes a discussion of the applications of organosilicon compounds in industry and medicine,46 while a review of the chemistry of silenes (=Si=C=) covers their synthesis physical properties calculations concerning their properties and their addition reactions dimerization and molecular rearrangement^.^^ There has been a review on the synthesis of ylides by the desilylation of a-trimethylsilyl onium salts,48 while silyl-substituted cyclopropanes which are emerging as versatile synthetic reagents have been reviewed as Another review focuses on vinylsilane- and alkynylsilane-terminated cyclization reactions.’’ As a result of the direct attachment of the silicon atom to the participating T bond the chemistry of vinyl- and alkynyl-silane terminators is similar.Vinylsilane-terminated cyclizations are of value for the synthesis or carbocycles as well as oxygen and nitrogen heterocycles and their utility for the synthesis of complex target structures alkaloids in particular has been amply demonstrated.Continued evaluation of the useful cyclization chemistry of vinyl- and alkynyl-silanes seems likely the combination of these 7r nucleophiles with other initiating electrophiles as well as the use of these organosilanes to terminate polyene cyclizations that form two or more rings are obvious areas for future development. The chemistry of organometallic compounds with highly sterically hindered organosilicon ligands such as (Me3S&C or (Me2PhSi)3C attached to a variety of metal centres has been reviewed and these include a range of new boron compounds such as (Me,PhSi),CBF(OH) and (Me,PhSi),CB(p-H),Li(thf) ,which have inter- esting structures.It is worth noting that each of the three metal-carbon bonds in the Me-SiMe2-C(SiMe3)2-M systems may participate in reactions at the metal ~entre.~’ The synthesis properties and reactivities of stable compounds featuring double bonding between the main-group IV elements e.g.,the disilenes (R2Si=SiR2) 45 J. Glaser and I. Toth J. Chem. Soc. Chem. Commun. 1986 1336. 46 S. Pawlenko ‘Organosilicon Chemistry’ Walter de Gruyter Berlin and New York 1986. 41 A. G. Brook and K. M. Baines Adu. Organomer. Chem. 1986 25 144 containing 209 refs. 4R E. Vedejs and F. G. West Chem. Rev. 1986 86 941-955. 49 L. A. Paquette Chem. Rev. 1986 86 733-750 containing 146 refs. so T. A. Blumenkopf and L. E. Overman Chem. Reo. 1986 86 857-873 containing 105 refs.” J. D. Smith Pure Appl. Chem. 1986 58 623. Organometallic Chemistry -Part (ii) The Main-Group Elements 231 digermenes ( R2Ge=GeR2) and distannenes (R,Sn=SnR,) have been reviewed,52 as have derivatives of divalent Si Ge Sn and Pb (silylenes germylenes etc.) as ligands in transition-metal complexes.53 Silabenzene silaethene ( H2Si=CH2) 1,4- disilabenzene and related compounds such as borabenzene and boraethene have been commented on briefly.54 'Thermal elimination of lithium chloride' reactions continue to be popular result- ing e.g. in the synthesis of the very stable free silanimine (19) which is an orange crystalline solid melting at 97-99 "C without decomposition to give a deep-red liquid. This stability is due to the good steric shielding of the Si=N bond.Neither in solution nor as a solid does (19) exhibit the often common tendency to undergo dimerization though it is very sensitive to water and air.55 A Y"'" (19) The application of difunctional organosilicon compounds to organic synthesis can be seen in the simultaneous use of a silicon atom as an activating influence and a link between reagent and substrate. This forms the basis of a method which reduces P-hydroxy-ketones to anti-1,3 -diols with diastereoisomeric excesses exceeding 95% the reducing agent is an organosilane e.g. Pr',SiHCl which is initially attached to the hydroxy group of the P-hydroxy-ketone and then induced to react with the carbonyl group by a Lewis acidic catalyst e.g. SnC14. The reaction is presumed to involve intramolecular transfer of hydrogen from the silicon atom to the carbonyl carbon.56 The utility of trimethylsilylation in organic synthesis is well recognized and a large number of methods have been described for the introduction of the trimethylsilyl group.Now trimethylsilylazide ( Me3SiN3) has been shown to react very rapidly with primary or secondary alcohols at room temperature to give high yields of trimethylsilyl ethers.57 The double C-methylation of main-group IV metalloles causes a stabilization toward the [4 + 21 dimerization reaction and an attempt to produce stable monomeric 3,4-dimethylmetalloles with a Si-H or Ge-H bond has resulted in the first.stable C-methylated silole having a Si-H bond. Flash vacuum pyrolysis of the starting silacyclopentene (20) was used in reaction (5) to obtain the silole (21; FVP -C,H 0+ 0 R = Me Ph Si R/si-R/\ Pi\ H RH (20) (21) (22) 52 A.H. Cowley and N. C. Norman Prog. Inorg. Chem. 1986 34 1-63 containing 156 refs. 53 W. Petz Chem. Reu. 1986 86 1019-1047. 54 G. Maier Pure Appl. Chem. 1986 58 95. 55 M. Hesse and U. Klingebiel Angew. Chem. In?. Ed. Engl. 1986 25 649. 56 S. Anwar and A. P. Davis J. Chem. Soc.,Chem. Commun. 1986 831. 57 D. Sinou and M. Emziane Synthesis 1986 1045. 232 A. T. Hutton 88%) and its transoid isomer (22; 12%). The same reaction using the germanium analogue of (20) did not give the corresponding germole but only 2,3-dimethyl- butadiene as the sole identifiable product.58 In the presence of a catalyst derived from the co-sublimation of AlCl with FeC1 (lolo) a series of permethylcyclosilanes (Me,Si), n = 5-12 rearranged to form isomeric branched cyclopentasilanes or cyclohexasilanes remarkably in each reac- tion a single isomeric product was obtained in nearly quantitative yield.Conforma- tional analyses of these branched cyclosilanes have been perf~rmed.~~ Alkylthiosilanes RSSiMe, have been found to be excellent initiators for the group- transfer polymerization of acrylic acid esters.60 The molecular and electronic structures of penta- and hexa-coordinate silicon compounds have been comprehensively reviewed.61 The reactivity of anionic pentacoordinated silicon complexes towards nucleophiles e.g. PhMgBr has been studied and this has led to new synthetic methods for various silanes while the reaction of Grignard reagents with dianionic hexacoordinated (pyrocatechol) silicon complexes has provided the way to synthesize organosilicon compounds directly from silica The chemistry of the penta-coordinated bi- and tri-cyclic organo- silicon and -tin compounds R2M(CH2CH2CH,),E and RM(CH2CH2CH2)3N (M = Si Sn; R = C1 Br I Me; E = NMe 0 S) has been reviewed the compounds which have 'diptych' and 'triptych' structures exhibit intramolecular E (or N) + M donor-acceptor interactions of varying strengths depending on the nature of the substituents R bonded to the metal centre.63 Until recently the investigation of cyclopentadienyl chemistry of main-group elements was restricted to Group IV species and some other isolated examples.This situation has changed radically during the last decade; a variety of new cyclopen- tadienyl compounds is their often- or usually-observed fluxionality and this aspect edge of the possible bonding modes in a-bonded (7')species as well as in v-bonded ( qn)complexes has increased. One of the most interesting features in 7'-cyclopen- tadienyl compounds is their often- or unusually-observed fluxionality and this aspect has been reviewed with respect to compounds of the main-group 111 IV and V elements.64 Recent developments have shown that drastic differences in fluxional behaviour exist among the cyclopentadienyl compounds of main-group elements and these differences may be ascribed to the nature of the main-group element the other ligands bonded to the main-group element and the substituents on the cyclopentadienyl ring.These factors influence the rate of prototropic shifts and the proportion of allylic and vinylic isomers present in equilibrium enormously; further- more they determine specifically the activation energy for the circumambulatory migration of the relevant main-group metal. The migrations are characterized as 58 J.-P. Beteille G. Manuel A. Laporterie H. Iloughmane and J. Dubac Organornetallics 1986 5 1742. 59 T. A. Blinka and R. West Organometallics 1986 5 128 and 133. 60 M. T. Reetz R. Ostarek K.-E. Piejko D. Arlt and B. Bomer Angew. Chern. Int. Ed. Engl. 1986,25 1108. 61 St. N. Tandura M. G. Voronkov and N. V. Alekseev Top.Curr. Chem. 1986 131,99-189 containing 1008 refs. 62 A. Boudin G. Cerveau C. Chuit R. J. P. Corriu and C. Reye Angew. Chem. Inf. Ed. Engl. 1986 25 413 and 414. '' A. Tzschach and K. Jurkschat Pure Appl. Chern. 1986 58 639. 64 P. Jutzi Chern. Rev. 1986 86 983-996 containing 94 refs. Organometallic Chemistry -Part (ii) The Main-Group Elements 1,5-sigmatropic rearrangements which can proceed either with retention or with inversion of configuration depending on the circumstances. Last year's report' suggested that a new approach to the main-group IV metal-locenes which had resulted in the synthesis of decamethyl-germanocene and -stannocene pointed a possible path to the (then unknown) analogous silicon compound.65 Indeed the reduction of (Me5C5)2SiC12 with naphthalene-lithium -sodium or -potassium in THF has now been reported to afford decamethyl- silicocene the first molecular compound of divalent silicon that is stable under normal conditions and the first .ir-complex with silicon as the central atom.The colourless crystalline silicocene Si( q5-C5Me,)2 readily undergoes sublimation and is thermally stable (m.p. 171 "C) but is extremely air-sensitive (presumably under- going oxidation). Two conformers are present in the crystal structure in the ratio 1:2. Whereas in the first conformer the two C5Me5 rings are staggered and their planes strictly parallel in the second conformer the rings are staggered and form an interplanar angle of 25.3" probably due to intermolecular interactions and packing effects in the crystal.Interestingly the colours of the decamethylmetallocenes of this group proceed from colourless (Si) through light-yellow (Ge) and dark-yellow (Sn) to orange-red (Pb).66 The molecule with the longest Si-Si bond is now (hexa-t-buty1)disilane (23). The X-ray structure determination of (23) shows an unusually long Si-Si bond of 2.697 A which is about 0.35 8 greater than that usually found in normal disilanes (ca. 2.34 A). This distance apparently results (despite a staggered conformation) from mutual repulsion of the But groups. The air- and moisture-stable compound (23) is formed via a radical intermediate upon reaction of nitrosyl cations with (tri-t-buty1)silyl-sodium or -potassium (equation 6).67 Two neighbouring very long +2NO' 2But,SiNa (or K) 2{But,Si}' + Bu',Si-SiBu' (6) -2N0 -2Na(or K)' (23) Si-Si bonds are found in the diiodotrisilane (24) [2.581(1) and 2.644(1) A Si-Si-Si = 115.8(1)0].68 The great steric crowding in the molecule significantly (24) lengthens the Si-C and Si-I bonds as well and also increases the Si-Si-Si and Si-C-C bond angles.A linear correlation between the average number of bulky substituents per Si atom (n) and the length of the Si-Si bond (d) has made it possible to classify substituents according to their steric effect [d(Si-Si) = (0.186n + 2.14) A].680n the other hand the weak and highly reactive central Si-Si 62 Full paper P. Jutzi and €3. Hielscher Orgnnornetallics 1986 5 1201. 66 P. Jutzi D. Kanne and C. Kriiger Angew.Chem. Int. Ed. Engl. 1986 25 164. 67 N. Wiberg H. Schuster A. Simon and K. Peters Angew. Chem. In?. Ed. Engl. 1986 25 78. 68 M. Weidenbruch B. Flintjer K. Peters and H. G. von Schnering Angew. Chem. Int. Ed. Engl. 1986 25. 1129. 234 A. T. Hutton bond in the tetrasilabicyclo[ 1.1.O]butane (25) which undergoes extremely facile ring-inversion is surprisingly short at 2.373(3) A. This distance is typical for a cyclic Si-Si bond but was expected to be particularly long in (25) owing to the high p-character of the bond and in analogy to the bonding in bicycl~butanes.~~ / \ But But (25) R = 2,6-Et,C,H3 A highly efficient method of uniting inorganic and organic matter requires ‘bireac- tive’ molecules containing a silicon functionality for bonding to inorganic material on the one hand and a carbon functionality for anchoring to an organic counterpart on the other.The 3-chloropropyltrialkoxysilanes,(R0)3SiCH2CH2CH2C1, and their derivatives epitomize such molecules owing to their bifunctionality they are capable of binding to inorganic (especially siliceous) systems as well as to organic polymers. They are key intermediates in the commercial production of organofunctionalized silanes and polysiloxanes and were originally used as coupling agents mainly in glass-fibre reinforced thermosetting or thermoplastic resins (e.g.,for boat building) in organic sealants containing inorganic fillers and in casting moulds prepared from foundry sand and organic binders. More recently the benefit of silanes to the rubber industry has been established since sulphur derivatives of the 3-chloropropyltrialkoxysilanes have been found to be useful as coupling agents in silica-reinforced rubber articles (e.g.special tyres) or as essential ingredients of equilibrium cure systems for sulphur-curable elastomers. Other applications are to be found in the fields of dental materials coatings and adhesives and catalysis and even in the immobilization of enzymes on glass spheres for use in commercial enzyme reactors. In all cases organofunctionalized silanes guarantee a reliable and permanent union between two otherwise ‘incompatible’ material systems. Along with silicones organosilicates and silylating agents they have become the fourth important class of commercially-used organosilicon compounds and an interesting review of their synthesis and applications was most ~elcorne.~’ Several papers at the ‘Symposium on the Biogeochemistry of Silicon and Related Group IV Organometallics in Fresh Water Ecosystems’ at the 192nd ACS National Meeting at Anaheim in September 1986 noted that organosilicon compounds are not so inert in the environment as thought.Polydimethylsiloxane or silicone as it is widely called in commerce is by far the most widespread organosilicon compound in the environment and has been found to settle out of water into sediment layers and stay there. It has been found that inorganic mercury( 11) salts can be methylated in the presence of polydimethylsiloxane by thermal energy in aqueous solution and that there is the potential for producing methylmercury which could bioaccumulate in fish and other aquatic organisms and which is highly toxic to humans.Organosi- latranes and several other organosilicon compounds also transfer a variety of organo 69 R. Jones D. J. Williams Y. Kabe and S. Masamune Angew. Chem. Int. Ed. Engl. 1986 25 173. 70 U. Deschler P. Kleinschmit and P. Panster Angew. Chem. Inr. Ed. Engl 1986 25 236. Organometallic Chemistry -Part (ii) The Main-Group Elements 235 species to mercury. Fortunately the most reactive methylsiloxane with mercury salts hexamethyldisiloxane has extremely low water solubility and is highly volatile and consequently is not a component of the aquatic environment. Also temperatures of 60-80°C were required to yield significant methyl transfer to mercury which would not appear to be environmentally relevant.Even at these higher temperatures the polydimethylsiloxanes which comprise most of the material that can be found in the environment are markedly unreactive relative to hexamethyldisiloxane. The symposium concluded that the silicone trace-components of aquatic sediments are extremely unlikely to contribute significantly to environmental methylmercury levels but pointed out that these compounds which were previously considered to be inert in the environment do have the potential to react.71 Organotin chemistry continues to be lively both in the organic synthesis and structural areas. Recent results on the use of tin(rr) compounds in highly diastereo- and enantio-selective synthesis have been summari~ed,~~ and the use of transition- metal catalysts in organotin chemistry has been re~iewed.'~ Hexaorganoditins are finding increasing applications in reduction reactions as organic radical sources or as precursors of tin-metal derivatives and they also show interesting bactericidal and fungicidal activity.An easy high yield route to these &Sn2 compounds now exists in the reduction of bis(triorganotin)oxides (R3Sn)20 by Ti Mg K or Na 1,l-Distannyl-1-alkenes of the type RR'C=C(SnMe3)2 can now be readily prepared from Me,SnLi and geminal dibromoalkenes; hydro- stannation of the geminal distannylalkenes gives tristannylalkanes and bromodes- tannylation using N-bromosuccinimide occurs readily as does halogenodemethyla- tion at tin using dimethyltin dihalides.Palladium-catalysed coupling reactions between geminal distannylalkenes and organic halides are also possible.'' The cross-coupling of organotin reagents with organic electrophiles catalysed by pal- ladium provides a novel method for generating a carbon-carbon bond and this area has been reviewed.76 The organotin compounds may be prepared by several routes can bear a variety of functional groups and moreover are not very sensitive to air or moisture. This versatile reaction takes place under mild conditions and is tolerant of a wide variety of functional groups on either coupling partner and so is ideal for use in the synthesis of elaborate organic molecules. A simple example is reaction (7) in which a wide variety of R and R groups may be employed.When [L,PdOl R-COCl + Bu",Sn-CEC-R -R-CO-CEC-R' + Bu",SnCl (7) the coupling reaction is carried out in the presence of carbon monoxide instead of a direct coupling CO insertion takes place stitching the two coupling partners together and generating a ketone (equation 8). 71 192nd American Chemical Society National Meeting Anaheim California 7-12 September 1986 Abstracts of Papers GEOC 115-119 and 126138; see also Chem. Eng. News Vol. 64 No. 39 (29 Sept. 1986) p. 73. 72 T. Mukaiyama Pure Appl. Chem. 1986 58 505. 73 T. N. Mitchell J. Organomet. Chem. 1986 304,1-16 containing 68 refs. 74 B. Jousseaume E. Chanson and M. Pereyre Organometallics 1986 5 1271. 7s T. N. Mitchell and W.Reimann Organometallics 1986 5 1991. 76 J. K. Stille Angew. Chem. Int. Ed. Engl. 1986 25 508-524 containing 125 refs. 236 A. T. Hutton IPdol RX + R'SnR + CO -R-CO-R' + R",SnX (8) The highly stereoselective acid-catalysed cyclization of an epoxystannane is a key step in a simple synthesis of an aromatic 6,11,17-triketo~teroid.~' A competing 1,3-rearrangement of allyl stannanes has been demonstrated to occur under the normal thermal homolytic allyl transfer reaction conditions which limits the substitu- tion patterns in these processes and two methacrylyl stannanes have been described which allow the direct transfer of the methacrylyl moiety to alkyl halides under mild condition^.^^ For the nucleophilic alkyllithiums RLi the stannocene molecule provides two sites of attack the protons of the cyclopentadienyl ligands and the central tin atom.While unsubstituted stannocene undergoes metallation of cyclopentadienyl protons decamethylstannocene is attacked only at the central tin atom and the reaction products strongly suggest the formation of a [ (ql-Me5C5),Sn(R)Li] intermediate. In the presence of Me1 the intermediate is trapped yielding tin(1v) compounds; otherwise loss of Me5C5Li takes place to give substituted diorganotin species [ R2Sn] .79 The cyclopentadiene rings in decaphenylstannocene ( Slosymmetry) are exactly parallel thus violating the VSEPR model and the question has been raised as to where the lone pair resides seeing as it is not stereochemically active. Fenske- Hall MO calculations now predict that the tin lone pair in (q5-Ph5C5),Sn resides in the HOMO a Sn 5s-like orbital and is not (as was earlier suggested) delocalized onto the ring system of the ligands.80 The X-ray structure and solution behaviour of the organotin(1v) compound (26) derived from the reaction of 2-Me2NC6H4CH(SiMe3)Li with PhMeSnBr has been studied.The compound (26) contains two chiral centres which are formed stereo- specifically during the reaction and which have either the Rc,Rs or the SC,SSn @n='ph 'Me \ I Br '' SiMe combination of configurations at the benzylic C and five-coordinate Sn centres.81 Li[CH( PPh,),] reacts with SnCl or PbCl in THF to yield the homoleptic complexes [M{CH(PPh,),},] (M = Sn or Pb) X-ray crystallographic studies reveal similar structures with a monomeric pyramidal MCP core i.e.each complex contains two distinctly diflerent bis(dipheny1phosphino)methanide ligands one binding as a 77 D. N. Jones and M. R. Peel J. Chem. SOC.,Chem. Commun. 1986 216. 78 J. E. Baldwin R. M. Adlington D. J. Birch J. A. Crawford and J. B. Sweeney J. Chem. Soc. Chem. Commun. 1986 1339. 79 P. Jutzi and B. Hielscher Organometallics 1986 5 2511. 80 R. L. Williamson and M. B. Hall Organometallics 1986 5 2142. " J. T. B. H. Jastrzebski G. van Koten C. T. Knaap A. M. M. Schreurs J. coon and A. L. Spek Organometallics 1986 5 155 1. Organometallic Chemistry -Part (ii) The Main-Group Elements monodentate ligand through carbon (its P atoms remaining uncoordinated) the other binding as a bidentate chelating ligand through two P atoms.' The crystal structures of (Bu',Sn) and (Am',Sn) show that the four-membered tin ring of (Bu',Sn) is planar and the molecules are highly ordered in the crystal; the ring of (Amt2Sn) is puckered.In both compounds the tin-tin bonds are longer than in other cyclostannanes which is probably caused by the size requirements of the organyl group^.'^ Hexakis(trimethylgermyl)benzene c6(GeMe3) has been synthesized from the reaction of C6Br6 with Me3GeC1 and magnesium; the X-ray structure shows that the benzene ring is very slightly puckered and the six germanium atoms are located alternately above and below the average ring-plane. The mean bond-distance between aromatic carbons 1.418 A is significantly longer than that in benzene (1.39 A).84 Interactions of basic organic compounds especially unsaturated hydrocarbons with transition-metal centres form the starting point for various catalytic processes.Thus any comparable catalytic activity of a main-group element requires the ability to form .rr-complexes. Surprisingly crystallographic evidence has not previously been presented for an interaction between a main-group metal and the wsystem of an ordinary carbon-carbon double-bond and the compound ( 77,-Me4C5H)MezSi( q5-Me4C5)Ge+GeC13- (27) provides the first example of this type of bonding since its diene is dihapto-coordinated to the germanium atom.85 The parent permethylated silyl-bridged dicyclopentadienyl ligand Me,Si( Me4C5H)2 was obtained from reaction of Me4C5HLi with MezSiC1,; with C2H4(Me2SiC1)2 the 1,2-disilylethane-bridged dicyclopentadienyl ligand C2H4{ Me,Si( Me,C,H)} is formed.86 1' GeCl; 5 Groups V and VI Despite their potential importance as precursors to semiconductors such as gallium arsenide and indium phosphide relatively little is known about organometallic compounds featuring bonding between the heavier main-group I11 and V elements.A flurry of such compounds has now appeared. For example a product of the 82 A. L. Balch and D. E. Oram Organornefaflics 1986 5 2159. 83 H. Puff C. Bach W. Schuh and R. Zimmer J. Organomet. Chem. 1986 312 313. 84 W. Weissensteiner I. I. Schuster J. F. Blount and K. Mislow J. Am. Chem. Soc. 1986 108 6664. 85 F. X. Kohl R.Dickbreder P. Jutzi G. Muller and B. Huber J. Organomet. Chem. 1986 309,C43. 86 P. Jutzi and R. Dickbreder Chem. Ber. 1986 119 1750. 23 8 A. T. Hutton reaction of PhAsH with (Me,SiCH,),Ga is the novel organoarsenic-organogallium cluster [(PhAsH)( R,Ga)( P~As)~( RGa),] (R = Me3SiCH2) which contains a As7Ga core; the known compound (PhAs) is also isolated.87 Silylarsines R2AsSiMe3 (R = Me3SiCH2 or mesityl) have been used to synthesize (arsino)gallanes and e.g. the dimeric bis( arsino)gallane shown in equation 9 displays fluxional properties R=Me3SiCH 4R,AsSiMe3 + 2GaC1 [(R,As)~G~CI],+ 4Me3SiC1 (9) above room temperature due to rapid exchange of the endocyclic (bridging) and exocyclic (terminal) bis[ (trimethylsilyl)methyl]arsino groups.88 The first crystal structure of a dimeric arsenic-gallium compound that of [(Me3SiCH2),AsGaPh2], shows that the four-membered As2Ga2 ring is strained though dissociation does not occur in The reaction of GaC1 with three equivalents of Bu',AsLi affords the mononuclear perarsenido gallium compound Ga(AsBu',) as a red air-sensitive crystalline solid while the reaction of GaCl with one equivalent of Bu',AsLi and two equivalents of MeLi results in another four-membered As2Gaz ring-compound viz.[Bu',AsGaMe,] .90 The synthesis properties and reactivities of stable compounds featuring double bonding between main-group V elements e.g. diphosphenes (RP=PR) phos-phaarsenes (RP=AsR) phosphastibenes (RP=SbR) and diarsenes (RAs=AsR) have been reviewed.52 Diels-Alder adducts have been prepared in a one-pot pro- cedure by [2 + 41 cycloaddition of the perfluoro-2-arsapropene F3CAs=CF2 to 1,3-dienes; the arsapropene was produced in situ by thermal (70-80 "C) elimination of Me,SnF from Me3SnAs(CF3) .91 The exchange reactions of tetramethyl-diphos- phine -diarsine -distibine and -dibismuthine have been studied (equation 10); the Me,E + Me4Ef2 2Me,EE'Me (10) (E,E' = P As Sb Bi) tetramethyldipnictogens Me,E2 (E = P As Sb Bi) also undergo exchange reactions with dimethyldichalcogenides Me2A2 (A = S Se Te) to produce the corresponding (dimethy1pnicto)methylchalcogenides Me,EAMe.These latter compounds have been fully characterized by n.m.r. (including 12'Te) Raman and mass spec-tro~copy.~~ The first stable compound containing an arsenic-carbon triple bond is 2-(2,4,6-tri-t-butylpheny1)-1-arsaethyne (30) which is pale yellow and crystalline melting at 114-116 "C.It was prepared from the acid chloride (28) and the arsenide (29) R-COC1 + LiAs(SiMe,) --* [R-CO-As(SiMe,),] + R-CEAs (11) (28) (29) (30) (R = 2,4,6-But3C6H2) 87 R. L. Wells A. P. Purdy A. T. McPhail and C. G. Pitt J. Chem. SOC.,Chem. Commun. 1986 487. 88 C. G. Pitt A. P. Purdy K. T. Higa and R. L. Wells Organornetallics 1986 5 1266. 89 R. L. Wells A. P. Purdy A. T. McPhail and C. G. Pitt J. Organomef. Chem. 1986 308 281. 90 A. M. Arif B. L. Benac A. H. Cowley R. Geerts R. A. Jones K. B. Kidd J. M. Power and S. T. Schwab J. Chem. Soc. Chem. Commun. 1986 1543. 91 J. Grobe and D. Le Van J.Organomef. Chem. 1986 311 37. 92 A. J. Ashe 111 and E. G. Ludwig jun. J. Organomef. Chem. 1986 303 197; 1986 308 289. Organometallic Chemistry -Part (ii) The Main-Group Elements which is readily accessible from tris(trimethylsily1)arsane (equation 1 l).93One of the first lithium organoarsenides to be structurally characterized is [Li(thf)-{As( But)As( produced from the reaction of LiAs( with MgBr2 (2 :1) in THF and involving As-As bond formation and As-C bond cleavage. It is a dimer with two Li atoms bridging two -AS(BU')AS(BU')~ groups and with a planar Li2As2 The crystal structure of 2SbC13.C6H6 a prototype of the Menshutkin complexes shows that two independent SbC13 molecules with a benzene molecule between them form a molecular complex.The metal atoms are acentrically q2-bound on either side of the benzene ring plane with Sb...ring plane distances of 3.30 and 3.22 A similar to the Sb....rr interactions in other Menshutkin complexe~.~~ BiC13 BiC13 BiC13 (31) (32) The arene complexes of bismuth (3 1) and (32) display fascinating structure^.^^ They were prepared by simply dissolving BiC13 in mesitylene or hexamethylben- zene/ toluene respectively followed by crystallization. The layer structure of the 1:1 half-sandwich complex (31) is characterized by q6-coordination of the mesityl- ene to the metal atom; this is the first structurally characterized arene complex of bismuth. The novel 'inverted' sandwich structure of (32) also displays q6-coordina- tion but this time ring-shaped Bi4ClI2 structural units in the crystal are linked through the Bi(arene)Bi bridges to form a three-dimensional network.It is significant that no stereochemical activity of the lone pair in the sense of ligand-free polyhedral corners is recognizable either in (31) or (32). Here -and in the T6-bonding -the stabilization of the 6s' level (inert-pair effect) manifests itself. Chemical transformations involving tellurium were until recently very rare. However the explosive development of selenium chemistry in the last decade has called attention to the potential of tellurium reagents and a number of interesting transformations based on tellurium-containing species are now known; several of these were mentioned in last year's report.' It is therefore appropriate that the applications of tellurium reagents in organic synthesis and the transformations of organotellurium compounds exhibiting potential synthetic utility have been reviewed;97 this article also contains a useful section on the experimental procedures for preparation of the more important organotellurium reagents.93 G. Mark1 and H. Sejpka Angew. Chem. Inf. Ed. Engl. 1986 25 264. 94 A. M. Arif R. A. Jones and K. B. Kidd J. Chem. SOC.,Chem. Commun. 1986 1440. 95 D. Mootz and V. Handler Z. Anorg. Allg. Chem. 1986 533 23. 96 A. Schier J. M. Wallis G. Miiller and H. Schmidbaur Angew. Chem. Znf. Ed. Engl. 1986 25 757. 97 N. Petragnani and J. V. Comasseto Synthesis 1986 1-30 containing 119 refs.

ISSN:0069-3030    

DOI:10.1039/OC9868300221

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

10 Synthetic Methods By P. A. CHALONER School of Chemistry and Molecular Sciences University of Sussex Brighton BNl 9QJ 1 Introduction Despite the arrival of a new reporter the format of this report remains essentially the same as that of the past few years with a broad division into two sections. The first details reactions in which new carbon-carbon bonds are made or broken and new carbon skeleta constructed and the second deals with functional group transfor- mations. The first section is further sub-divided according to the type of transforma- tion (coupling of separate fragments cyclization cycloaddition etc.) and the latter into oxidative reductive and non-redox conversions. As always such a review must be extremely selective and whilst every attempt has been made to include contributions of general interest and applicability the author expresses her regret that some valuable material must be excluded.2 C-C Connection and Disconnection Connection of Separate Fragments.-Enolutes and their Equivalents. Again this year enolates figure strongly in C-C bond-forming methodology and again stereoselec- tive reactions have proved among the most interesting. Enantioselective deproton- ation of ketones by a chiral lithium amide base such as (1) (R' = H alkyl or Ar; R2-R" = H or alkyl; X = H OMe or NR2) has been achieved for 4-alkyl- cyclohexanones trimethylsilyl enol ethers being formed with up to 98% enantiomer excess on quenching with Me,SiCl.' Similar results were found with 2,6-dialkyl- cyclohexanones.* Ultrasound has been used to accelerate the generation and C-ethoxythiocarbonylation of en~lates,~ and as later sections will reveal this technique has found many new applications this year.Alkylation of chiral amide enolates (Scheme 1) may be achieved in an extremely stereoselective manner the product being hydrolysed to give an asymmetrically R. Shirai M. Tanaka and K. Koga J. Am. Chem. SOC.,1986 108 543. N. S. Simpkins J. Chem. SOC. Chem. Commun. 1986 88. M. A. Palominos R. Rodriguez and J. C. Vega Chem. Left. 1986 1251. 241 I? A. Chaloner ,OMOM OMOM I,. II I 111 .. -. ... R.qN3 NCYN5 NC NC O< i.,-.';OM 0' <OMOM OL OMOM OMOM R' R2 x NC COOH 80-90% e.e. Reagents i BuLi THF; ii R'X; iii R'X; iv HCI H,O; v K2C0, MeOH Scheme 1 I-I Me vii R'R~CHCOOH Reagents i BuLi; ii R'X; iii BuLi; iv R'X; v MeI; vi R3M; vii H30+ Scheme 2 dialkylated 2-cyanoacetic acid.4 Successive lithiations and alkylations of the tetrahy- drofolate coenzyme model (2) also provided convenient syntheses of dialkylated acids and ketones (Scheme 2).5 Ally1 derivatives have been shown to react readily with enolate anions in the presence of palladium( 0) complexes the reaction proceeding via cationic 73-allyl palladium complexes.Two examples of this reaction have shown useful degrees of enantioselectivity. Racemic (3) reacted with the anion of pentane-2,4-dione in the presence of (4) to give (5) in 97% chemical and 90%S optical yield (Scheme 3). The presence of the -CH20H groups in the catalyst is crucial and their function is thought to be to coordinate the incoming nucleophile.6 The palladium-catalysed allylation of chiral enamines (6),prepared from a proline derivative occurred with 100% chirality transfer (Scheme 4>.7 T.Hanamoto T. Katsuki and M. Yamaguchi Tetrahedron Lett. 1986 27 2463. ' M. W. Anderson R. C. F. Jones and J. Saunders J. Chem. SOC. Perkin Trans. I 1986 205 and 1995. T. Hayashi A. Yamamoto T. Hagihara and Y. Ito Tetrahedron Lett. 1986 27 191, ' K. Hiroi K. Suya and S. Sato J. Chem. SOC.,Chem. Commun. 1986 469. Synthetic Methods Fe &PPh2 phPPh OCOMe CH (COMe)2 Reagents i Na[CH(COMe)2] [{( q3-C3H5)PdCI},] Scheme 3 3 . .. I II -Reagents i [Pd(PPh,),] CHCI,; ii H@ Scheme 4 ,OSiMe OMe Reagents i TMSOTf -78 "C; ii TiCI, -78 "C; iii PDC Scheme 5 Two particularly facile preparations of spirocyclic ketones have been reported.In the first a cycloalkanone enolate is generated using potassium t-butoxide and ultrasound and reacts in a one-pot process with a,w-dibromoalkanes. The method is versatile giving good to excellent yields for a range of ring sizes.' Scheme 5 shows an alternative strategy; the initial step involves reaction of the silyl enol ether with the acetal displacing one methoxy group. This is followed by attack of the alkyltin moiety on the aldehyde accelerated by a Lewis acid with oxidation to give the final product.' There has been continued progress and extensive interest in the area of diastereoselective aldol condensations.It was known that p-silyl enolates could be alkylated with high diastereoselectivity and control of three contiguous chiral centres 'T. Fujita S. Watanabe M. Sakamoto and H. Hashimoto Chem. Znd. (London) 1986 427. T. V. Lee K. A. Richardson and D. A. Taylor Tetrahedron Lett. 1986 27 5021. 244 P. A. Chaloner has now been achieved (Scheme 6) in the reaction of (7). The outcome of the aldol reaction depends on the geometry of the starting enolate which is readily controlled. The product was used in a stereospecific synthesis of ally1 silanes." The boron enolate formed in situ from 3-pentanone and BC13 reacted with benzaldehyde to give an aldol with 95% syn-stereoselectivity. Similar results were obtained using ROBC12 prepared in situ." One of the best diastereofacial selectivities reported this year (Scheme 7) involved the titanium enolate of (8) which gave (9) and (10) in the ratio of 99:l on reaction with propanal.12 SiMe2Ph R' SiMe2Ph PhMeu:Me -1 ,COOMe RZ R' + I (7) ..... II 111I SiMelPh & ,COOMe 1 R' ' + J. R2 'OH R From (7) A:B = 89:ll;from (7a) A:B = 6:94 Reagents i R2CH0 -78 "C; ii LNH4]C1; iii LDA THF; iv Me2NCH(OMe),; vi PhS02CI; vii collidine A Scheme 6 OSi Mez( C Me3) Me OSiMe2(CMe3) ".a"i; i,ii,iii ~tfl CY + OH (9) (8) Reagents i LDA THF; ii CITi(OCHMe2)3; iii EtCHO (4 equiv.) Scheme 7 lo I. Fleming and J. D. Kilburn J. Chem. SOC.,Chem. Commun. 1986 305; I. Fleming and A.K. Sarkar J. Chem. Soc. Chem. Commun. 1986 1199. " H.-F. Chow and D. Seebach Helu. Chim. Acto 1986 69 604. I* C. Siege1 and E. R. Thornton Tetrahedron Left.. 1986 27 457. Synthetic Methods One route to chiral aldol products involves the use of a chiral auxiliary as a temporary appendage to one partner in the reaction (Scheme 8). Thus chiral a-halogenoimide enolates react with aldehydes to give (11) as essentially the sole product. Removal of the auxiliary and cyclization gave a chiral epoxide.I3 In the related reaction of the tin enolate of a thiocyanate derivative the ultimate product was an optically pure 2-methylamino-3-hydroxy carboxylic acid (Scheme 9).14 N-Methylephedrine was the chosen auxiliary in the reaction of (12) (Scheme 10); anti :syn ratios in the product ranged from 10 1 to greater than 30 1 which was a considerable improvement over the analogous reaction in the absence of the titanium Reagents i Bu,B (Me,CH),NEt 0 "C; ii C,H,,CHO -78 "C; iii PhCH,OLi Scheme 8 OSnX NCS i ii /111 iv v vi vii NHMe Reagents i [Sn(OTf),]; ii RCHO; iii Mg[OMe] MeOH; iv [Me,O][BF,]; v H,O; vi KOH; vii H30+ Scheme 9 MezN4%.Me (12) Reagents RCHO TiCI, PR, CH,CI Scheme 10 l3 A. Abdel-Magid L. N. Pridgen D. S. Eggleston and I. Lantos J. Am. Chem. Soc. 1986 108 4595. D. A. Evans and A. E. Weber J. Am. Chem. Soc. 1986 108 6757. 246 P. A. Chaloner salt and phosphine. Enantiomer excesses in the hydrolysed product were up to 94% without purification of the intermediates but optically pure material was readily obtained by flash chromatography of the diastereoisomers before hydr~lysis.'~ The chiral boron enolate of 3-pentanone synthesized from (13) (iPC = isopinocampheyl) in the presence of base gave up to 82% enantiomer excess in a syn-product from its reaction with acetaldehyde.16 n A,,B(iPC)OTf (13) An alternative approach to enantioselective aldol reactions involved the use of a chiral Lewis acid such as (14) as catalyst; in its presence 3,3-dimethyl-2-butanone reacted with 2,2-dimethylpropanal to give (15) in 84% enantiomer excess.l' The chiral base (16) was used in the reaction of a tin(Ir) thioester enolate with an aldehyde in optical yields varying from 55 to 80%.18 Such thioester enolates prepared by the addition of a tin(I1) thiolate to a ketene also reacted readily with aldimines (17) to give 3-alkylamino thioester derivatives with high anti :syn ratios (Scheme 11 ).19 RH rHphz (17) Reagents i [Sn(SCMe,)2] THF -78 "C; ii [Sn(OTf),]; iii (17) Scheme 11 Two new practical syntheses of Reformatsky reagents have been described (Scheme 12).The first involves the use of ultrasound in the reaction of (18) (R2= H or Me; R3 = F or CF,) at the nitrile group of (19). Subsequent hydrolysis and cyclization gave fluorinated P-keto- y-butyrolactones.20 The best activating system l5 C. Palazzi L. Colombo and C. Gennari Tetrahedron Lett. 1986 27 1735. 16 1. Paterson M. A. Lister and C. K. McClure Tetrahedron Lett. 1986 27 4787. 17 M.T. Reetz F. Kunisch and P. Heitmann Tetrahedron Lett. 1986 27 4721. 18 T. Mukaiyama N. Yamasaki R. W. Stevens and M. Murakami Chem. Lett. 1986 213. 19 N. Yamasaki M. Murakami and T. Mukaiyama Chem. Lett. 1986 1013. 20 T. Kitazume Synthesis 1986 855. Synthetic Methods Reagents i Zn ultrasound THF; ii H2S04 HzO 25 "C Scheme 12 thus far reported for zinc is a laminated zinc/silver-graphite obtained from CgK/ZnC12/Ag[OCOMe]. This allowed the reaction between ethylbromoacetate and cyclohexanone to proceed in high yield at temperatures as low as -78 "C over twenty minutes.21 Triphenylmethyl perchlorate was used to activate silyl enol ethers (20) towards Michael reaction with enones. The anti :syn ratio in the product was typically 80 :20 at room temperature but could be improved by cooling.22 The first product of this reaction is an enolate anion and this may be used for a further aldol condensation in a tandem reaction (Scheme 13).The product y-acyl-8-hydroxy ketone derivative (21) was produced with good stereoselectivity uia a transition state dominated by steric effects.23 i ii Me,CMe2SiwR3 - R' \ (20) Me 121 1 Reagents i [Ph,C][ClO,]; ii aOH ;iii R4CH0 Scheme 13 An enantiaselective Michael reaction of ethyl acetoacetate with esters of 2- carboalkoxy-a$-unsaturated acids was achieved (Scheme 14) using the chiral enamine (22) synthesized from ethyl acetoacetate and the t-butyl ester of valine. The final product was obtained in up to 93% enantiomer excess.24 Allyl Alkynyl and Alkenyl Anions and their Equivalents.Mixed metal allyl anions RLiMg prepared from allyl magnesium chloride and a lithium amide base may be used for the conversion of esters into enones. A successful reaction is assured since 21 R. Csuk A. Furstner and H. Weidmann J. Chem. SOC.,Chem. Commun. 1986 775. 22 T. Mukaiyama M. Tamura and S. Kobayashi Chem. Lett. 1986 1017. 23 S. Kobayashi and T. Mukaiyama Chem. Lett 1986 221. . 24 K. Tornioka K. Yasuda and K. Koga Tetrahedron Lett. 1986 27 715 and 4611. P. A. Chaloner Me2CH3. R' GCOOR2 COOR2 I,II ~ J& +% COOR' EtOOC COORZ 111 IV (22) Reagents i LDA; ii HCl; iii 20%HCI MeCOOH A; iv CH2N2 J&OOMe Scheme 14 R'AZnBr R' + '& -2; R4 MgBr BrZn R4 R5 \ MgBr Reagents i R'CHO BF,.Et,O (23) Scheme 15 the product is enolized by the strong base and hence unavailable for further rea~tion.~' gem-Dimetallic compounds (23) were also formed on reaction of allyl zinc halides with alkenyl Grignard reagents via a carbometallation process (Scheme 15).Compound (23) underwent condensation with aldehydes or reacted with suc- cessive portions of two electrophiles.26 A facile and stereoselective preparation of allyl stannanes using an ultrasound- accelerated Barbier-type reaction between tributyltin chloride and an allyl chloride has been described; cross-coupling occurred under conditions in which both com- ponents were capable of self-~oupling.~~ Three groups have separately reported the synthesis of a-methylene- y-lactones (25) (Scheme 16) from ethoxycarbonyl allyl stannane (24) and aldehydes.28 The reaction of E-1-phenyl-3-chloro-1-propene with Bu,SnY/ -Ry& COOEt -6 COOEt R (24) (25) Reagents i RCHO BF,.Et20 CH2C12; ii CF,COOH CH2C12 Scheme 16 25 C.Fehr and J. Galindo Helu. Chim. Acta 1986 69 228. 26 P. Knochel and J. F. Normant Tetrahedron Lett. 1986 27 1039 and 1043. 27 Y. Naruta Y. Nishigaichi and K. Maruyama Chern. Lett. 1986 1857. 28 J. E. Baldwin R. M. Adlington and J. B. Sweeney Tetrahedron Lett. 1986 27 5423; K. Uneyama K. Ueda and S. Torii Chem. Lett. 1986 1201; J. Nokami T. Tamaoka H. Ogawa and S. Wakabayashi Chem. Lett. 1986 541. Synthetic Methods 249 aldehydes in the presence of tin(o) (generated in situ from tin(r1) chloride and aluminium powder) gave threo-products (26) with between 90 and 99% ~electivity.~~ Compound (24) also reacted with 1-bromoadamantane in the presence of a radical initiator to give (27) in up to 70% yield.30 Ph Enantiomerically pure 2-2-butenyldiisopinocampheylboranes may be prepared from 2-2- butenyl potassium and P-methoxy diisopinocampheyl borane [derived from (+)-a-pinene] and react with aldehydes to give erythro P-methyl homoallyl alcohols with greater than 99% diastereoselection and more than 95% enantioselec- tivity.The E-isomer (28) gave exclusively a threo product with about 90% enan- tioselectivity (Scheme 17). Since (-)-a-pinene is also readily available this route may be used to yield all four possible stereoisomers of the product with excellent selection.31 Enantioselective (53-84% e.e.) allylation of prochiral aldehydes was achieved using allyl bis(2-methylpropyl)aluminium in the presence of (16) and tin(r1) trif~ate.~~ OH OH 95 5 Reagents i RCHO -78 "C; ii H202 Scheme 17 0R' 0R' Reagent Lewis acid Scheme 18 The reaction of allyl silanes with aliphatic acetals in the presence of a Lewis acid (Scheme 18) was extremely regiospecific and highly syn-selective irrespective of the geometry of (29) or the Lewis acid used.However with aryl aldehyde acetals 2-(29) gave mainly anti-products whilst the E-isomer gave a syn-selective reaction. 29 K. Uneyama H. Nanbu and S. Torii Tetrahedron Lett. 1986 27 2395. 30 J.E. Baldwin R. M. Adlington D. J. Birch J. A. Crawford and J. B. Sweeney J. Chem. Soc. Chem. Commun. 1986 1339. 31 H. C. Brown and K. S. Bhat J. Am. Chem. SOC.,1986 108 5919. 32 T. Mukaiyama N. Minowa T. Oriyama and K. Narasaka Chem. Lett. 1986 97. Z? A. Chaloner The diastereoselection depended on the electronic demand of substituents on the aryl ring and various plausible transition states were proposed.33 A practical and highly stereocontrolled synthesis of 1,3-dienes from allyl silanes is shown in Scheme 19.34 i ii iii vi OH 100O/o Iv R- 75-0 2?o Reagents i BuLi THF; ii [Ti(OCHMe,),] -78 "C; iii RCHO -78 "C; iv Me,COK 25 "C; v H2[S04] THF; vii 30°C 3 h Scheme 19 The hydroboration of alkynes is known to proceed with excellent stereospecificity to yield alkenyl boranes.The hydroboration/ halogenoboration sequence of Scheme 20 allows the preparation of both stereoisomers of the disubstituted alkenyl bromides.35 Analogous reactions were used in the stereospecific synthesis of trisub-stituted alkenes by coupling of alkenyl boranes with alkenyl halides in the presence of palladium(0) catalysts.36 Alkenyl copper compounds produced by alkenylcupration of alkynes have also found further applications (Scheme 21) since they may be readily coupled with alkyl allyl and acyl halides. Their reaction with enones is very much improved by Reagents i R2BHBr.SMe2 Et20 0 "C; ii MeONa MeOH 25 "C; iii Br, CH,Cl, -40 "C; iv MeONa MeOH -40 "C; v BHBr,.SMe, CH,CI,; vi MeOH Scheme 20 33 A.Hosomi M. Ando and H. Sakurai Chem. Lett. 1986 365. 34 Y. Ikeda and H. Yamamoto Bull. Chern. SOC.Jpn. 1986 59 657. 35 H. C. Brown N. G. Bhat and S. Rajagopalan Synthesis 1986 480. 36 M. Satoh N. Miyaura and A. Suzuki Chem. Lett. 1986 1329; N. Miyaura M. Satoh and A. Suzuki Tetrahedron Lett. 1986 27 3745. Synthetic Methods 25 1 . .. ... I II 111 BuLi (BwuLi Bu Reagents i CuBr.SMe2 Et20 -40 "C; ii C2H2 -25 "C 30 min; iii C2H2 0 "C 10 min; iv MeI HMPA Et,O -50 "C -* 0 "C; v Me,SiCI; vi cyclohexenone; vii H20 Scheme 21 the presence of trimethylchlorosilane and this was also found to be the case with other organocopper compounds and other unsaturated carbonyl compounds.37338 The efficiency of the conversion of alkenyl iodides into alkenyl chromium com- pounds using chromium(I1) chloride was initially found by Kishi to be strongly dependent on the source of the chromium(I1) salt.However addition of O.l-lo/~ nickel(11) chloride removed this dependence and allowed coupling with aldehydes to occur under very mild conditions with a high tolerance for other functional groups.39 Numerous papers this year have reported the coupling of 1-alkynes with alkenyl and more particularly aryl and heteroaryl halides in the presence of base copper salts and a palladium(0) catalyst. Among the more interesting examples was the reaction of (30) the product being cyclized to give an indole derivative (Scheme 22).40 Alkynylzinc compounds reacted again under palladium(0) catalysis only with E-alkenyl halides giving (31) in excellent stereoisomeric purity (Scheme 23).4' R Reagents i RCECH [Pd(PPh3)2C1,] Et,N 100 "C; ii EtONa EtOH Scheme 22 R R Br RCH=CHBr+ClZnC_C-SiMe -** +w %Me3 E+Z (31) Reagent [Pd( PPh,),] Scheme 23 37 H.Furber R. J. K. Taylor and S. C. Burford J. Chem. SOC.,Perkin Trans. I 1986 1809. 38 A. Alexakis J. Berlan and Y. Besace Tetrahedron Lett. 1986 27 1047. 39 H.Jin J. Uenishi W. J. Christ and Y. Kishi. J. Am. Chem. Soc.. 1986 108 5644. 40 T. Sakamoto Y. Kondo and H. Yamanaka Heterocycles 1986 24 31 and 1845. B. P. Andreini A. Carpita and R. Rossi Tetrahedron Lett. 1986 27 5533. P. A. Chaloner The 'new' metal for this year was vanadium and alkynylvanadium compounds underwent oxidative nucleophilic addition to aldehydes to give qp-alkynyl ketones (32) (Scheme 24).42Allenyl boronic and chiral allenyl boronates& have been used in very highly diastereoselective and enantioselective additions to carbonyl groups (Scheme 25).1 I1 R-CrC-Li -R-C=C-VCl -R-CZC-COR' (32) Reagents i VCI, CH2CI, -78 "C; ii R'CHO CH2C12 -78 "C Scheme 24 OH H R02C OH Reagents i CH,=C=CHB(OH),; ii H,O,; iii PhMe; iv OCH0 ROzCXOH H Scheme 25 Miscellaneous. There have been further reports of new reagents for carbonyl alkenyla- tion. [ClW(O)=CH,] converted 1-phenylethanone into 2-phenylpropene4' and the tungsten Wittig reagents [R'R'C= W(OCH2CMe3)4] reacted with esters and lac- tones at room temperature and amides at 50°C.These species should prove more versatile than the Tebbe reagent since numerous substitution patterns can be obtained and by varying the other ligands at tungsten reagents of different chemoselectivities were The cyclic pentavalent phosphorus compound (33) may be opened to (34) and thus represents an extremely stable reagent for ketone methyleneation needing 42 T. Hirao D. Misu and T. Agawa Tetrahedron Lett. 1986 27 933. 43 N. Ikeda K. Omori and H. Yamamoto Tetrahedron Lett. 1986 27 1175. 44 N. Ikeda I. Arai and H. Yamamoto J. Am. Chem. Soc. 1986 108 483. 4s T. Kauffmann R. Abeln S. Welke and D. Wingbermiihle Angew. Chem. Int. Ed. Engl. 1986 25 909 and 910. 46 A. Aguero J. Kress and J. A. Osborn J. Chem. SOC.,Chem. Commun. 1986 531. Synthetic Methods 253 neither base nor solvent for successful reaction?' A Wittig-like synthesis of 1,l-diiodoalkenes was achieved using Ph,P=CI, formed at 0 "C from triphenylphos- phine and carbon tetraiodide.It reacts readily with aldehydes but not with ketones in the presence of zinc The scope of Peterson reactions has been extended (Scheme 26).49,50 2 -BuCHYCHMe PhS SiMe Li %Me3 Reagents i LiNp TNF -78 "C; ii MeCHO THF -78 "C-* 0 "C Scheme 26 MeO? 8'20Me MeO? #''OMe COH (35) Reagent MeMgI Scheme 27 Many workers continue to report examples of the addition of organometallic reagents to carbonyl compounds. Amongst the most interesting examples are those in which enantioselective reaction is achieved using an appropriate chiral auxiliary.The reaction of Grignard reagents with the chiral a-ketoacetal (35) gave up to 98% optical yield (Scheme 27). The presence of the methoxy groups was critical to successful reaction suggesting that these may be involved in chelation of the incoming n~cleophile.~~ The chirally modified methyltitanium reagent (36) reacted with aldehydes in between 31 and 90% enavtiomer excess,52 whilst (37) proved a useful 47 H. Daniel and M. Le Corre Tetrahedron Lett. 1986 27 1909. 48 F. Gavifia S. V. Luis P. Ferrer A. M. Costero and J. A. Marco J. Chem. Rex (S) 1986 330. 49 D. J. Ager J. Chem. SOC.,Perkin Trans. I 1986 183 and 195. 50 S. Hackett and T. Livinghouse J. Org. Chem. 1986 51 879. Y. Tamura H. Kondo H. Annoura R. Takeuchi and H. Fujioka Tetrahedron Lett.1986,27,81and 21 17. 52 M. T. Reetz T. Kukenhohner and P. Weinig Tetrahedron Lett. 1986 27 5711. P. A. Chaloner catalyst for the enantioselective reaction of aldehydes with dialkyl zinc corn pound^.^^ Addition of a methyltitanium reagent of reduced Lewis acidity to (38) was not chelation-controlled giving (39) with more than 99% selectivity (Scheme 28).54 Homoenolate anions may be generated readily from the mixed acetal (40) and could be coupled with aryl halides under palladium(0) catalysis. A homo-Refor-matsky reaction occurred in the presence of titanium tetra~hloride.~~ Cerium homoenolates prepared from P-bromoesters by contrast gave lactones (41) (Scheme 29).56 Me3CMezSi0\ //0 M e3 CMe SiOMOH ..m -Me--Me Me H Et H Et (38) (39) Reagent [MeTi(OCHMe,)J Scheme 28 fyoR C1,Ti.Ph LOOR R1 RZ -COOMe BrCe Reagents i ZnCI,; ii PhI; iii [Pd{P(C,H4-4-Me),},C12]; iv TiCI4; v PhCHO Scheme 29 The continuing search for more selective reagents has again led to the employment of some of the more 'exotic' metals. Two groups have reported the iodomethylation of carbonyl compounds [e.g. (42)] which occurs both in the presence of samarium metal and samarium iodide (Scheme 30). a-Halogenoketones yielded cyclopro- 53 M. Kitamura S. Suga K. Kawai and R. Noyori J. Am. Chem. SOC.,1986 108 6071. 54 M. T. Reetz and M. Hullmann J. Chem. SOC.,Chem. Commun. 1986 1600. 55 E. Nakamura and I. Kuwajima Tetrahedron Lett. 1986 27 83; E. Nakamura H. Oshino and I.Kuwajima J. Am. Chem. Soc. 1986 108 3745. 56 S. Fukuzawa T. Fujinami and S. Sakai J. Chem. Soc. Chem. Cornmun. 1986 475. Synthetic Methods (42) Reagents CH,I, Sm THF 0°C Scheme 30 pan01s.~' Organ~tin,~~ vanadium,59 and manganese6' reagents have all been shown to react selectively with acyl halides to give ketones. [RMnX] will also react with aldehydes in the presence of ketones with greater than 99% selectivity for the aldehyde. Tris(trimethylsily1amido)methyl uranium has been recommended as a highly selective nucleophilic methylating agent.61 Organozincates R,ZnMgBr or R,ZnLi have proved excellent reagents for regioselective Michael attack on enones; only one group is generally transferred.62 Enantioselective addition of a chiral cuprate to cyclohexenone could be achieved in up to 92% enantiomer excess (Scheme 31); the structure (43) was proposed for the transition state.63 Asymmetric 1,4-addition to N-enoyl sultams (44) occurred with excellent diastereoselectivity; the products were converted into chiral P-hydroxy Ph&.p.-NMe, Reagents i MeI THF -78 "C; ii N THF -78 "C; ;I OH Me iii CuI THF Me,S -35 "C; iv BuLi MeI -78 "C; v cyclohexenone -78 "C Scheme 31 X = I or THF; S = THF; (43) R = Et Bu or Me3COCH 57 T. Imamoto T. Takeyama and H. Koto Tetrahedron Lett. 1986,27,3243; T. Tabuchi J. Inanaga and M. Yamaguchi Tetrahedron Lett. 1986 27 3891. 58 J.-B. Verlhac and J.-P. Quintard Tetrahedron Lett. 1986 27 2361. 59 T. Hirao D. Misu K. Yao and T. Agawa Tetrahedron Lett.1986 27 929. 60 G. Cahiez J. Rivas-Enterrios and H. Granger-Veyron Tetrahedron Lett. 1986 27 4441 and 4445. 61 A. Dormond A. Aaliti and C. Moise Tetrahedron Lett. 1986 27 1497. 62 R. A. Kjonaas and E. J. Vawter J. Org. Chem. 1986 51 3993; W. Tuckmantel K. Oshima and H. Nozaki Chem. Ber. 1986,119 1581; R. A. Watson and R. A. Kjonaas Tetrahedron Lett. 1986,27 1437. 63 E. J. Corey R. Naef and F. J. Hannon J. Am. Chem. SOC.,1986 108 7114. 256 P. A. Chaloner esters (Scheme 32). 1,4-Hydride addition using L-Selectride was also very stereoselec- The asymmetric synthesis of a-substituted carbonyl compounds has been achieved by attack of an organoaluminium compound on an a$-unsaturated chiral acetal. The regioisomeric products could be readily separated and cleaved (Scheme 33).65 V I--+ so2 SiMe2Ph (44) 1 ii iii OH SiMe2Ph 92->98% e.e.Reagents i RLi Cur PBu, EtAICI,; ii LiOH H20 THF; iii CH2N2; iv H[BF4]; v 3-CI-C,H4C03H Scheme 32 CONMe2 Rlq$-CONMe2 R2 li H 5' 4-RI+O R3 YONMe2 *CONMe2 R2 I ii iii ~2 = H 5' F3 A R'Y R' COOH R2 Reagents i RiAl 5-25 "C; ii 03,MeOH; iii [Mn04]-Scheme 33 64 W. Oppolzer R. J. Mills W. Pachinger and T. Stevenson Helu. Chirn.Acta 1986,69 1542; W. Oppolzer and G. Poli Tetrahedron Lett. 1986 27 4717. 65 K. Maruoka S. Nakai M. Sakurai and H. Yamamoto Synthesis 1986 130. Synthetic Methods Further work on the reductive coupling of ketones to give pinacols has appeared.For example magnesium in graphite is effective for reaction of both aldehydes and ketones and gives excellent yields even in the case of benzophenone which is a poor substrate under McMurray conditions.66 The similarly hindered compound (46) was prepared uia the tin derivative (45) (Scheme 34).67 II 4 / Q$g '0 Reagents i [(Me,(PhS)Sn},] hv; ii NaOH H20 Scheme 34 Transition metal-catalysed reactions have continued to dominate the fields of carbonylation and carboxylation. Of particular interest have been the new double carbonylations reported for aryl and benzyl halides in the presence of [co,(co)8] yielding a-keto acids.68 Compound (47) prepared from 1-butene Et2NH and [ Pd( MeCN),C12] in a carbon monoxide atmosphere reacted with piperidine to give (48).Chromatography on silica promoted amine elimination giving (49) in a surpris- ingly high 75% yield.69 Aryl benzyl alkenyl and ally1 iodides and triflates were homologated to aldehydes using Bu3SnH-CO with palladium(0) as a ~atalyst,~' the Et2N' COCON ) 'COCON ) reaction being tolerant of a wide range of functional groups. Electroreductive carboxylation of aryl and benzyl halides using palladium(0) or nickel(o) catalysts gave a clean and convenient synthesis of carboxylic acids.71 Electrochemical reduc- tion of 3-halogeno-/3-lactams in an atmosphere of C02 yielded 3-carboxy-/3-lactams which are otherwise rather difficult to prepare.72 66 R. Csuk A. Fiirstner and H. Weidmann J. Chem. SOC.,Chem. Commun. 1986 1802. 67 H. Fobbe and W.P. Neumann J. Organomet. Chem. 1986 303 87. 68 F. Francalanci E. Bencini A. Gardano M. Vicenti and M. FOB J. Organomet. Chem. 1986,301 C27. 69 F. Ozawa M. Nakano I. Aoyama T. Yamamoto and A. Yamamoto J. Chem. SOC.,Chem. Commun. 1986 382. 70 V. P. Baillargeon and J. K. Stille J. Am. Chem. SOC.,1986 108 452. 71 S. Torii H. Tanaka T. Hamatani K. Morisaka A. Jutand F. Huger and J.-F. Fauvarque Chem. Lett. 1986 169; J. F. Fauvarque A. Jutand and M. Francois Noun J. Chim. 1986 10 119. 72 M. A. Casadei F. M. Moracci and A. Inesi J. Chem. SOC.,Perkin Trans. 2 1986 419. P. A. Chaloner Homoallyl alcohols such as (50) were efficiently prepared by reductive coupling of allylic acetates with carbonyl compounds using palladium(o)/samarium( 11) iodide (Scheme 35).The reaction is thought to involve samarium iodide-induced elec- trophilic substitution of an allyl palladium complex.73 Ring-opening of P-epoxysulphones sulphoxides and esters (51) with Grignard reagents has been achieved at -60 "C without loss of chirality using a copper catalyst (Scheme 36). Such epoxides are generally extremely labile and undergo facile base-promoted eliminative fission to allyl Reagents SmI, [Pd( PPh,),] THF 0 "C (SO) Scheme 35 O h R +R'MgBr -+ KTR OH R = SO,Ph SOPh or COOEt R' = Ph or alkyl Reagents CuI Et20 THF -60 "C 1 min Scheme 36 -SiMe2Ph I + (PhMe2Si)3MnMgMe -Me(CHJ9 Me(CHh (52) Reagents THF 0 "C Scheme 37 Alkenyl and allyl silanes such as (52) were synthesized by cross-coupling of alkenyl and allylic compounds with trisilylmanaganese methyl magnesium (Scheme 37).The reagent is prepared from PhMezSiMgMe and Liz[MnCl4]. The reaction is stereospecific for E-substrates but usually only stereoselective for the 2-analogues. Stereospecific synthesis of 2-products was accomplished at -95 0C.75p-Ketosilanes and p-ketophosphonates were synthesized from a-halogenoketones uia a novel Umpolung approach (Scheme 38). This route is complementary to the Arbusov process and also allows the synthesis of fluoroalkyl phosphonate derivatives which are insufficiently nucleophilic for the Arbusov reaction.76 73 T. Tabuchi J. Inanaga and M. Yamaguchi Tetrahedron Lett. 1986 27 1195. 74 R. Tanikaga K. Hosoya and A. Kaji J. Chem. Soc. Chem.Commun. 1986 836. 75 K. Fugami K. Oshima K. Utimoto and H. Nozaki Tetrahedron Lett. 1986 27 2161 76 P. Sampson G. B. Hammond and D. F. Weimer J. Org. Chem. 1986 51 4342. Synthetic Methods 0 0 0 iv,v,vi LB~ t-Ph ), Ph SiMe3 Reagents i Li[N(SiMe3)2] THF -65 "C; ii [Me,C]Li -65 "C; iii (EtO),P(=O)CI -100 "C; iv Li[N(SiMe,)2] THF -78 "C; v Me,SiCI -78 "C; vi BuLi -78 "C Scheme 38 Aryl derivatives of dimethyl malonate (53) are not readily available from car- banionic routes but may be obtained by a ceric ammonium nitrate-catalysed radical reaction (Scheme 39). The site-selectivity observed in the reactions with toluene and methoxy benzene suggest that the intermediate the [ *CH(COOMe)2] radical is ele~trophilic.~~ In another radical reaction (Scheme 40) ketones were coupled with electron-deficient alkenes in the presence of samarium iodide.78 C6H6 + CH,(COOMe) + PhCH(COOMe) (53) Reagents [ NH,],[Ce( NO,),] MeOH 25 "C Scheme 39 R2 Reagents i CH2=CHCOOEt; ii ROH Scheme 40 Cyc1ization.-Free-radical cyclizations continue to attract considerable attention.The well-established formation of radicals by halide abstraction was used to initiate the cyclization of silyl enol ethers such as (54) to give (55) (Scheme 41) as a 1 1 mixture of diastereoi~omers.~~ A photochemical process (Scheme 42) was used to initiate reaction of (56) to give a carbapenam.80 The phenylseleno group may also be abstracted by triphenyltin radicals; Scheme 43 shows a new synthesis of cyclopen-tanes using an ester enolate rearrangement in conjunction with radical cyclization.81 Intramolecular aromatic cyclization of alkenyliodonium salts (57) occurs readily on heating (Scheme 44); intermolecular arylation may also be accomplished.** The 77 E.Baciocchi D. Dell'Aira and R. Ruzziconi Tetrahedron Lett. 1986 27 2763. ?a S. Fukuzawa A. Nakanishi T. Fujinami and S. Sakai J. Chem. SOC.,Chem. Commun. 1986 624. 79 H. Urabe and I. Kuwajima Tetrahedron Lett. 1986 27 1355. J. Knight P. J. Parsons and R. Southgate J. Chem. SOC.,Chem. Commun. 1986 78. A. Y. Mohammed and D. L. J. Clive J. Chem. SOC.,Chem. Commun. 1986 588. 82 M. Ochiai Y. Takaoka K. Surni and Y. Nagao J. Chem. SOC.,Chem. Commun. 1986 1382. €? A. Chaloner Reagents i Bu3SnH AIBN C6HS;ii HCl MeOH Scheme 4.1 0dx-oa (56) Reagents C6H6 hv Scheme 42 02C( CH2)$e P h 11 111 .....iz(sep' C02SiMe2CMe3 602Me C02Me Reagents i CICO(CH,),SePh py Et,O ii. LDA. THF. -78 "C; iii (Me3)CMe2SiCI HMPA. THF; iv [Bu,N]F; v CH2N2;vi Ph3SnH AIBN Scheme 43 SiMe3 'IPh BFL Reagents i PhIO BF,.Et,O CHIC], 0 "C; ii CD30D 60 "C Scheme 44 Synthetic Methods 26 1 Pummerer type reaction of a-acyl sulphides with [ PhI(OCOCF,),] generates the cation (58) which is readily cyclized (Scheme 45).83A cationic cyclization of (59) to (60) initiated by SnCl, presumably involves the same type of intermediate. The reaction is extremely stereospe~ific.~~ Enantioselective cyclization of unsaturated aldehydes such as (61) was catalysed with up to 90% e.e.using a chiral Lewis acid (Scheme 46) but the success of the reaction is strongly dependent on substrate structure.85 rOCOCF3 PhI 13 + H -. SMe -QINX -aNxre QL E LoSMe I I I Ph Ph J Reagents [ PhI(OCOCF,),] CICH,CH,CI 25 "C Ph Scheme 45 Reagent Scheme 46 83 Y. Tamura Y. Yakura Y. Shirouchi and J. Haruta Chem. Pharm. Bull. 1986 34 1061. 84 L. E. Overman A. Casteiiada and T. A. Blumenkopf J. Am. Chem. Sac. 1986 108 1303 85 S. Sakane K. Marouka and H.Yamamoto Tetrahedron 1986.42 2203. P. A. Chaloner Pyrrolidine synthesis has been accomplished by palladium-catalysed cyclization of enynes such as (62) (Scheme 47). Compounds (63) and (64) do not interconvert by isomerization and the proportions of each product depended on the substituent R and the ligand L.The best selectivity for (64) is obtained with a diimine ligand such as (65).86Related pyrrolidines (66),were obtained by reaction of a trimethylene methane nickel complex with imines (Scheme 48); in this instance the palladium analogue gave much poorer result^.^' (62) (63) (64) Reagents Pd(OCOMe), L Scheme 47 Reagent [Ni{P(OEt),},] (66) Scheme 48 I CY Ph Ph Reagents i 0 "C;ii 25 "C; iii 100 "C; iv PhNC Scheme 49 B. M. Trost and S.-F. Chen J. Am. Chem. Soc. 1986 108 6053. 87 M. D. Jones and R. D. W. Kemmitt J. Chem. Soc. Chem. Commun. 1986 1201. Synthetic Methods 263 A new route to pyrroles shown in Scheme 49 involves a template synthesis with alkenyl carbene complexes and isonitriles.With aryl isonitriles as the substrates a further cyclization yielded S-carbolines.88 Cycloadditions and Annu1ations.-Reactions Forming Six-membered Rings. A com-mercial microwave oven has been used to reduce the time required for Diels-Alder Claisen and ene reactions.89 Enantioselective Diels- Alder reactions such as the conversion of (67) into (68) were promoted by chiral Lewis acids including (69) and (70).90*91 i ii ql q) iii iv a 7 O\ B,o Ph 0'' '0 HO 0 HO 0 QM~ (67) (68) 70-9 0'/' 98% e.e. \/ \/ MPh Reagents i BH3 THF MeCOOH 20 "C; ii (69); iii ;iv H20 Scheme 50 Ph HO HO Ph Ph ,Ph P h"P h (69) [MoO,(acac),] was used to catalyse the [4 + 21 cycloaddition of (71) to the aldehyde (72) in up to 58% yield (Scheme 51).The reaction was largely but not entirely stereoselective and the product was converted into the Prelog-Djerassi acto one.^^ A new and facile synthesis of 1,2-dimethylenecyclohexaneand [6,6] and [6,7] fused-ring systems was achieved by a double elimination from (74) (Scheme 52). Compound (73) may thus be regarded as a 2,2'-biallyl radical ~ynthon.~~ 88 R. Aumann and H. Heinen Chem. Ber. 1986,119,3801; R. Aumann H. Heinen C. Kriiger and Y.-H. Tsay Chem. Ber. 1986 119 3141. 89 R. J. Giguere T. L. Bray S. M. Duncan and G. Majetich Tetrahedron Let?. 1986 27 4945. 90 T. R. Kelly A. Whiting and N. S. Chandrakumar J. Am. Chem. SOC.,1986 108 3510. 91 K. Narasaka M.Inoue and N. Okada Chem. Lett. 1986 1109. 92 Y. Yamamoto H. Suzuki and Y. Moro-Oka Chem. Lett. 1986 73. 93 A. Hosomi K. Otaka and H. Sakurai Tetrahedron Lett. 1986 27 2881. P. A. Chaloner BzOk+l.-Bzon (71) (72) Reagent [MoO,(acac),] Scheme 51 MeOOC SiMe gCOOMe + SiMe3 xNMe2 + MeOOC MeOOC. X N M e (73) (74)I i ii iii MeOOC MeOOC. Reagents i MeI MeCN; ii CsF MeCN; iii CH2=CHCOOMe Scheme 52 There has continued to be considerable interest in cycloaddition reactions medi- ated by cobalt complexes including pyridine syntheses from dienes and nit rile^^^ and alkynes and nit rile^.'^ The cobalt-catalysed one-step assembly of aromatic steroids (Scheme 53) could be halted at the intermediate (75).96 Et YMe OMe i ii -HO Reagents i [C~CO(CO)~] hv xylene 1 h; ii decane A 20 h Scheme 53 94 B.Potthoff and E. Breitmaier Synthesis 1986 584. 95 G.Vitulli S. Bertozzi R. Lazzaroni and P. Salvadori J. Organomet. Chem. 1986 307 C35. 96 S. H. Lecker N. H. Nguyen and K. P. C. Vollhardt J. Am. Chem. Soc. 1986 108 856. Synthetic Methods 265 The annulation of methanoylcyclohexanones with enamines gave mixtures of the alcohol (76) and the ene-dione (77). Conversion of (76) into (77) was accomplished in CF,COOH giving (77) in 84% yield overall (Scheme 54). This reaction is distinctive in that the new ring is attached to the a and P-carbon atoms rather than the a-carbon and the carbonyl. It represents an example of a small but growing number of reactions in which a six-membered ring is created from two three-carbon fragment^.^' 111 Scheme 54 Reactions Forming Fiue-membered Rings.The 1,3-dipolar cycloaddition of the pyridinium ylide (78) to dimethyl acetylene dicarboxylate yielded (79) after hydrogen transfer to the dipolarophile (Scheme 55). The yield was enhanced and the reaction time greatly reduced by conducting the reaction under ultrasonic irradiati~n.~~ Pyrrolidines were prepared from phenylthioamines as shown in Scheme 56; the COOMe0,-COPh -\@COOMe COPh - COOMe WCOOMe COPh (78) (791 Reagent i Me00C-CEC-COOMe Scheme 55 'uCooMe Me,SiCH2-N-CH2SPh -i ii iii I CHzPh i Ph Reagents i AgF MeCN; ii R-C_C-COOMe; iii DDQ Scheme 56 97 W. L. Meyer M. J. Brannon A.Memtt and D. Seebach Tetrahedron Lett. 1986 27 1449. 98 M. T. GandPsegui and J. Alvarez-Builla J. Chem. Res. (S) 1986 74. 266 P. A. Chaloner intermediate is the dipolarophile (80).99Trimethylenemethane palladium(o) formed in situ underwent cycloaddition to (81) (Scheme 57) in the synthesis of 3-methylene cyclopentenes.loo Cyclopentannulation has been accomplished using methyl 3-phenylsulphonyl orthopropanoate (Scheme 58). The final cyclization of the silyl enol ether was accomplished using Me,SiOTf as the Lewis acid.'" A new synthesis of cyclopen-tenones and cyclohexenones from amides has been noted (Scheme 59). The cycliz- ation of an alkenyl lithium compound onto a carboxamide is unprecedented.lo2 (81 1 R3 R' R',R' are electron-withdrawing groups Reagents i MeCOO SiMe3 ;ii Pd(OCOMe)2 P(OCHMe,),; iii flash vacuum pyrolysis R3 Scheme 57 OSiMe3 I ... ... + m 1 11 111 PhSO ___ IV -C(OMe)3 I SOzPh Reagents i BuLi THF HMPA -78 "C; ii cyclohexenone -78 "C; iii Me3SiC1 Et,N -78 "C -* $25 "C; iv Me3SiOTf CH2CI2 -78 "C Scheme 58 Me& Me3Si 1 ii iii -Ia -M~+ I Et2N Ph Ph Reagents i LDA PhCH2CONEt2 THF; ii [Me,C]Li; iii [NH,]CI H20 Et20 Scheme 59 99 A. Padwa W. Dent H. Nimmesgern M. K. Venkatramanan and G. S. K. Wong Chem. Ber. 1986 119 813. 100 B. M. Trost J. M. Balkovec and S. R. Angle Tetrahedron Lett. 1986 27 1445. 101 S. De Lombaert I. Nemery B. Roekens J. C. Carretero T. Kimmel and L. Ghosez Tetrahedron Lett. 1986,21 5099.102 H. Sawada M. Webb A. T. Stoll and E. Negishi Tetrahedron Lett. 1986 27 775. Synthetic Methods Other Ring Sizes. Copper complex containing zeolites were successful catalysts for alkene cyclopropanation by ethyl diazoacetate (Scheme 60). The activity of the catalyst depended on the sodium exchange level and this promoter gave lower amounts of polymer than the more conventional cataly~ts.''~ Two stereoselective syntheses of p-lactam derivatives have been reported (Scheme 61). In the first the product obtained is largely cis suggesting that the reaction does not involve a ketene cycloaddition.'04~'05 78 22 Reagents N2CHCOOEt zeolite NaCuX-57 A Scheme 60 0 Reagents i Et3N CH2C12 5-10 "C; ii py 25 "C Scheme 61 Rearrangements and Fragmentations.-The Claisen rearrangement of (82) gave a synthesis of the unusual 5,6-unsaturated 8-membered lactones (Scheme 62).Although a reasonable chair transition-state could be envisaged for the trans-isomer w" I _.* *Yo 0 Ox0SePh (82) II 0 Reagents DBU xyfene Mg[SO,] A Scheme 62 103 J. C. Oudejans J. Kaminska A. C. Kock-van Dalen and H. van Bekkum Red. Trav. Chim. Pays-Bas 1986 105 421. 104 S. D. Sharma S. Kaur and U. Mehra Indian J. Chern. Sect. B 1986 25 141. lo' D. K. Dutta R. C. Boruah and J. S. Sandhu Heterocycles 1986 24,655. P. A. Chaloner the cis-analogue was thought to react via a boat transition-state.lo6 A Claisen rearrangement was also the key step in the regiospecific synthesis of P,y-unsaturated ketones from ally1 alcohols (Scheme 63).'07 The [2,3] Wittig rearrangement followed by a Peterson alkenylation sequence has provided an extremely stereoselective synthesis of dienynes (Scheme 64).Both products were produced from the same precursor and were formed with more than 95% selectivity."* CHO i or ii iii iv R2 R R' R' R' R5 R3 / R2 0 Reagents i RCOCHN, BH3 Et,O; ii NaH; iii R q ;iv PCC; v Me,SiCI Et,N DMF; vi Na[IO,] Scheme 63 -SiMe3 SiMe3 97% E 95% E 96% threo SiMe3 I J' Reagents i BuLi THF -85 "C; ii BF,.Et,O CH,CI,; iii KH THF Scheme 64 Tsuchihashi's group have reported further preparations of chiral synthons bearing alkynyl groups via organoaluminium promoted pinacol type rearrangements (Scheme 65).'09 The Lewis acid promoted rearrangement of a,P-epoxy oximes was found to lead to the synthesis of diketospiroalkanes.The diketospiranes produced by this route 106 R. W. Carling and A. B. Holmes J. Chem. SOC.,Chem. Commun. 1986 325. 107 J. L. C. Kachinsky and R. G. Salomon J. Org. Chem. 1986 51 1393. 108 K. Mikami T. Maeda and T. Nakai Tetrahedron Lett. 1986 27 4189. 109 K. Suzuki T. Ohkuma M. Miyazawa and G. Tsuchihashi Tetrahedron Lett. 1986 27 373. Synthetic Methods Me& OH >99% threo Reagents i Me,AI CHCI, C,H,; ii Li[AlH,] -100°C Scheme 65 were isomeric with those from the rearrangement of the corresponding a$-epoxyketones (Scheme 66)."' Opening of the cyclopropyl derivative (83) with [Hg(OR),] is extremely regio- and stereoselective (Scheme 67).After reduction with Li[AlH4] the overall transfor- mation achieved was that of an allyl alcohol into a 2-methyl-1,3-diol; this process complemented the hydroboration of a secondary allyl alcohol."' II 111 IV -Reagents i BF3.Et20;ii Na[BH,]; iii TiCI,; iv PCC Scheme 66 Reagents i [Hg(OR),]; ii NaCI; iii Li[AIH,] Scheme 67 'lo R. D. Bach M. W. Tubergen and R. C. Mix Tetrahedron Lett. 1986 27 3565. "' D. B. Collum W. C. Still and F. Mohamadi J. Am. Chem. SOC.,1986 108 2094. 270 l? A. Chaloner 3 Functional Group Modifications Oxidation.-Additions to C=C. There have been numerous reports of new methodology for the conversion of alkenes into epoxides. Two groups separately have reported the use of hydrogen peroxide with a tungstic acid or pertungstate catalyst in a buffered medium.Allylic alcohols were particularly reactive.Il2 Epoxida- tion of such substrates by Me,COOH in the presence of [Bu2SnO] was generally found to be somewhat more selective than reactions using [VO(a~ac),].''~ Elec- trophilic alkenes underwent stereo- and regiospecific epoxidation using RLi-Me,COOH with the esters of chiral alcohols reacting with up to 65% diastereofacial selectivity.' l4 The enantioselective epoxidation of allyl alcohols by the Sharpless reaction has again been much in evidence this year and has been re~iewed."~ A particularly elegant demonstration of the power of this process is shown in Scheme 68 in which both enantioselective epoxidation and kinetic resolution are employed to synthesize the four stereoisomers of secondary allyl alcohols all with excellent selectivity."6 The well-known conversion of alkenes into cis-diols by osmium(v1rI) oxide may be achieved in an enantioselective manner in the presence of chiral amines such as (84) and (85) (Scheme 69)."' Novel reagents containing iodine(rI1) such as (86) convert alkenes via an electrophilic process into dioxygenated derivatives.' '*In the presence of PhIO sodium azide was added to alkenes to give vicinal diazides as the major product^."^ Oxymercuration of (87) yields (88) but demercuration of these intermediates could be induced to follow a different course from those of simple alkenes.The amount of threo product was increased in non-polar solvents giving excellent selectivity.By comparison conventional demercuration with Na[ BHJ-EtOH was extremely sensitive to the amount of hydride present and stereoselection was usually modest.'20 Other Oxidations. Chemoselective oxidation of primary alcohol groups in diols was achieved by zirconocene-catalysed hydrogen transfer to cyc1ohexanone.l2' Selective oxidation of secondary alcohols in the presence of primary ones could by contrast be accomplished using [NH4I2[Ce( NO,),]-Na[ Br03],122 Me,COOH in the presence or of a range of molybdenum c~mplexes,'~~ K2[FeO,] and a phase-transfer 112 D. Prat and R. Lett Tetrahedron Lett. 1986,27,707;J. Prandi H. B. Kagan and H. Mimoun Tetrahedron Lett. 1986 27 2617. 113 S. Kanemoto T.Nonaka K. Oshima K. Utimoto and H. Nozaki Tetrahedron Lett. 1986 27 3387. 114 C. Clark P. Hermans 0. Meth-Cohn C. Moore H. C. Taljaard and G. van Vuuren J. Chem. SOC. Chem. Commun. 1986 1378. 115 A. Pfenninger Synthesis 1986 89. 116 Y. Kitano T. Matsumoto and F. Saio J. Chem. SOC. Chem. Commun. 1986 1323; Y. Kitano T. Matsumoto Y. Takeda and F. Sato J. Chem. SOC.,Chem. Commun. 1986 1732. 117 M. Tokles and J. K. Snyder Tetrahedron Lett. 1986 27 3951; T. Yamada and K. Narasaka Chem. Lett. 1986 131. 118 N. S. Zefirov V. V. Zhdankin Yu. V. Dan'kov V. D. Sorokin V. N. Semerikov A. S. Koz'min R. Caple and B. A. Berglund Tetrahedron Lett. 1986 27 3971. 119 R. M. Moriarty and J. S. Khosrowshahi Tetrahedron Lett. 1986 27 2809. 120 F.H. Gouzoules and R. A. Whitney J. Org. Chem. 1986 51 2024. 12' T. Nakano T. Terada Y. Ishii and M. Ogawa Synthesis 1986 774. 122 S. Kanemoto H. Tomioka K. Oshima and H. Nozaki Bull. Chem. SOC.,Jpn. 1986 59 105. 123 K. Yamawaki T. Yoshida T. Suda Y. Ishii and M. Ogawa Synthesis 1986 59; Synth. Commun. 1986 16 537. Synthetic Methods 271 .. ... II 111 I Me3si+R1 OH + Me3si-YR1 ~ Me3SiyR1 iv Me3Si R OH OH ,/ *" ii iii / EE = ethoxyethyl Reagents i Me,COOH [Ti(OCHMe,),] L-(+)-DIF'T; ii CH,=CHOEt H+; iii R2MgBr CuI; iv Me,COOH [VO(acac),]; v KH THF then HCI; vi H2[S04] MeOH Scheme 68 catalyst.'24 Silver ferrate was a better oxidant and needed no phase-transfer agent whilst barium ferrate was advocated as a safe versatile and non-pollutant oxidant for a wide range of alcohols.'25 Oxidative deprotection of alcohols occurred with (89); this is a particularly mild reagent leaving even a sensitive p-lactam functionality intact (Scheme 70).'26 Further stereoselective a-oxidations of enolates have been reported this year.Dibenzyl peroxycarbonate was used in the oxidation of (90) to the carbonate of the hydroxycarbonyl compound in >99 :1diastereomer ratio (Scheme 71) and a-amino 124 K. S. Kim Y. H. Song N. H. Lee and C. S. Hahn Tetrahedron Lett. 1986 27 2875. 125 H. Firouzabadi D. Mohajer and M. E. Moghaddam Synth. Commun. 1986 16 211 and 723. I26 F. P. Cossio J. M. Aizpurua and C. Palomo Can. J. Chem. 1986 64 225. I? A. Chaloner Q I aNpxy H '1 Ph-I ,OH a::: OMS (84) (85) (86) Hg0C0Me 1i &COOMe i_ COOMe -&cooMe Me0 H Me0 H (87) (88) threo erythro = 95 5 Reagents i [Hg(OCOMe),] MeOH ii HS(CH,),SH Et,N MeOH Scheme 69 R' R2 R' R2 0 II CI-Cr-OSiMe3 II 0 (89) R' = PhO R2 = Ar R3 = H Me$i or (Me3C)Me2Si Reagent (89) Scheme 70 Reagents i Li[ N(NMe,),]; ii (PhCH20COOS2 Scheme 71 Synthetic Methods and a-hydrazino derivatives were prepared ~imi1arly.l~' An alternative approach is the oxidation of an achiral enolate by a chiral camphonyl sulphonyl oxaziridine (Scheme 72).Ketone ester and amide enolates were all successfully oxidized in some cases giving excellent optical yields particularly from Z-enolates.'28 i ii Ph-COOMe -Ph Scheme 72 In the area of sulphide oxidations new protocols have been developed for simple reactions and further progress has been made in the area of enantioselective oxidations.Selectivity for sulphoxides was excellent using 0,-[NH,][Ce( NO,),] (which involves a radical process).129 Chiral systems have ranged from the well- known [Ti(OCHMe2),]-(+)-DET130 to Na[IO,]-bovine serum albumin'31 and Na[ IO,]-[A-Ni( l,10-phen),]-montmorillonite.'32 Tartaric acid derivatives could also be used as chiral auxiliaries for PhIO generating (91) in sit^',^ as an oxidant. In all these instances selectivity for the sulphoxide was good and excellent optical yields were obtained in favourable cases. 0 Reduction.-Hydrogenation of Carbon- Carbon Multiple Bonds.Hydridic reduction of @-unsaturated carbonyl compounds generally causes reduction of the carbonyl group rather than the double bond but a number of contrary examples have been described this year. Unsaturated esters were reduced by dibaH (Dibal) in the presence of methylcopper( 11) as the catalyst,134 and an alternative strategy using magnesium 127 M. P. Gore and J. C. Vederas J. Org. Chem. 1986,51 3700; D. A. Evans T. C. Britton R. L. Dorow and J. F. Dellaria 1. Am. Chem. Soc. 1986 108 6395 L. A. Trimble and J. C. Vederas J. Am. Chem. SOC.,1986 108 6397. 128 F. A. Davis M. S. Haque T. G. Ulatowski and J. C. Towson J. Org. Chem. 1986 51 2402; F. A. Davies and M. S. Haque J. Org. Chem. 1986 51 4083. 129 D. P. Riley and P.E. Correa J. Chem. SOC.,Chem. Commun. 1986 1097. 130 H. B. Kagan PYlosphoncs Sulfur 1986 27 127. 131 S. Colonna S. Banfi R. Annunziata and L. Casella J. Org. Chv. 1986 51 891. 132 A. Yamagishi J. Chem. SOC.,Chem. Commun. 1986 290. 133 T. Imamoto and H. Koto Chem. Lett. 1986 967. 134 T. Tsuda T. Hayashi H. Satomi T. Kawamoto and T. Saegusa J. Org. Chem. 1986 51 537. 274 P. A. Chuloner in methanol is sufficiently mild that even a sensitive thioacetal group survived (Scheme 73).13' Conjugate reduction by transfer of hydrogen from dimethylphenyl benzimidazoline promoted by aluminium trichloride was found to be suitable for reduction of enones and unsaturated esters but not enal~.'~~ Chloroalkenones could be reduced to a-halogenoketones with modest chemical efficiency but in good optical yield with fermenting Baker's yeast (Scheme 74).137 Reduction of a-alkynyl ketones to truns-enones could be effected with chromium( 11) sulphate or chloride; less than 2% of the cis-isomer could be detected and a number of sensitive functional groups were t~lerated.'~~ n n Reagents Mg MeOH 10°C Scheme 73 82% e.e.syn :anfi = 8.1 1 Reagents Baker's yeast K[H,PO,] [NH4][H2P0,] Ca[C03] Mg[S04] glucose H20 Scheme 74 Hydrogenation ofCurbony1 Compounds. In the past catalytic hydrogenation of enones and enals has been more noted for double bond than for carbonyl reduction. The first catalyst generally capable of promoting the formation of ally1 alcohols has now been reported cis-[H,Ir(PEt,Ph),]'.Selectivities were in the region of 9&96% though the conditions required were fairly severe (30 atm HZ 100 "C,10-22 h).'39 A number of reactions have been added to the armoury of reliable procedures for the selective reduction of aldehydes in the presence of ketones including the use of Na[ BH,]-[Bu4N]Br-CH2C12-H,0'40 and Li[OMe]-HSi(OR)3.141 Reduction of the ester group in (92) (to a primary alcohol) was achieved without epoxide opening using sodium borohydride in ethanol for five minutes followed by rapid quenching with 0.4 molar hydrochloric acid. Under similar conditions one of the 135 I. K. Youn G. H. Yon and C. S. Pak Tetrahedron Left. 1986 27 2409. 136 H. Chikashita and K. Itoh Bull. Chem. SOC.Jpn. 1986 59 1747. 137 M. Utaka S.Konishi and A. Takeda Tetrahedron Lett. 1986 27 4737. A. B. Smith P. A. Levenberg and J. Z. Suits Synthesis 1986 184. 139 E. Farnetti M. Pesce S. KaSpar R. Spogliarich and M. Graziani J. Chern. Soc. Chem. Cornrnun.,1986 746. 140 C. S. Rao A. A. Deshmukh and B. J. Patel Indian J. Chem. Sect. B 1986 25 626. 141 A. Hosomi M. Hayashida S. Kohra and Y. Tominaga J. Chem. SOC.,Chem. Cornrnun. 1986 1411. Synthetic Methods R' nitrile groups in (93) was reduced to the primary amine.I4' Selective reduction of P-ketoesters to P-ketoalcohols was accomplished as shown in Scheme 75; the intermediate is thought to be the en01ate.l~~ Two new reducing agents K[ Ph3BH] and potassium dialkoxymonoalkyl borohy- dride (94) (synthesized from cyclic boronic esters) have shown excellent selectivity for reduction of 2-methylcylohexanone to the less stable cis alcoh01.'~~'~~ K[ Ph3BH] also shows unusual and useful chemoselectivity; cyclohexanone was reduced in the presence of cyclopentanone with 97% selectivity.Reagents i KH THF 0 "C; ii AIH3 THF 25 "C Scheme 75 98% selective Reagent [Me,N][HB(OCOMe),] Scheme 76 Numerous workers continue to report diastereoselective reductions of hydroxy- ketones and their derivatives (for example Scheme 76).'46 This type of P-chelation control is still probably the most popular directing effect but other routes to stereoselection are becoming more widely used. Thus in the stereoselective reduction of a#-dialkoxyketones (95) (Scheme 77) the reaction was a-chelation controlled; Zn[ BH4I2 gave the best re~u1ts.l~~ A highly selective synthesis of 2-alkenyl-l,3-diols 142 J.Mauger and A. Robert J. Chem SOC.,Chem. Commun. 1986 395. 143 K. Isobe K. Mohri H. Sano J. Taga and Y. Tsuda Chem. Pharm.Bull. 1986,34 3029. 144 N. M. Yoon K. E. Kim and J. Kang J. Org. Chem. 1986 51 226. 145 H. C. Brown W. S. Park J. S. Cha B. T. Cho and C. A. Brown J. Org. Chem. 1986 51 337. 146 D. A. Evans and K. T. Chapman Tetrahedron Lett. 1986.27 5939. 147 H. Iida N. Yamazaki and C. Kibayashi J. Org. Chem. 1986 51 3769. P. A. Chaloner OCH20Me OCHZOM i ii iii or iv Bno+R BnO+ Bnos:Me + MeOCH20 MeOCH20 OH MeOCH20 OH (951 64:36->99 1 Reagents i Na[BH,]; ii vitride; iii Zn[BH4],; iv Li[AIH4] Scheme 77 (Scheme 78) used a trimethylsilyl directing group the product being used in the total synthesis of a~enaciolide.'~~ Chiral methyl malates and related systems have been prepared by microbial asymmetric reduction (Scheme 79)'49 but there has been a general trend towards the use of isolated enzyme preparations for reduction.1-Hydroxypropanone was reduced to (R)-1,2-propane diol in 98% optical yield using glycerol dehydrogenase isolated from Enterobacter aerogenes or Cellurnonas sp. these enzymes providing somewhat different specificities from those shown by HLADH or yeast alcohol dehydr0gena~e.l~' Me3%Y Me3Si me351 v Y >99 1 Reagent Li[Et,BH] Scheme 78 H0' HO-syn:anti = 39:61 >99% e.e. Reagents i Cundidu ulbicans; ii BH,.Me,S Na[ BH,]; iii CF,COOH Scheme 79 Other Reductions.Hydrogenolysis of functional groups attached to aryl allyl and alkyl groups has received much wider attention over the last year. The most widely applicable route involves oxidative addition to palladium(o) followed by attack or transfer of hydride. Examples are shown in Scheme 80.'5','52In related procedures K. Suzuki M. Shimazaki and G. Tsuchihashi Tetrahedron Letr. 1986 27 6233. I49 H. Akita H. Matsukura and T. Oishi Chem. Pharm. Bull. 1986 34 2656. 1so L. G. Lee and G. M. Whitesides J. Org. Chem. 1986 51 25. Y. Akita A. Inoue Y. Mori and A. Ohta Heterocycles 1986 24 2093. N. Ono I. Hamamoto A. Kamimura and A. Kaji J. Org. Chem. 1986 51 3734. Synthetic Methods 277 .c 0 Reagents i H, [Pd(PPh,),] K[OCOMe] DMF; ii Na[BH,] [Pd(PPh3),] THF A Scheme 80 propargyl acetates and carbonates have been reduced to allenes with good selectivity (Scheme 81).'53*'54By contrast the deoxygenation of (96) was achieved without isomerization to the allene by protection as a cobalt carbonyl adduct followed by reduction with diborane methyl sulphide and trifluoroacetic acid.'55 Reduction of carbonyl groups to hydrocarbons was accomplished by hydrogenation in the pres- ence of rhodium(r) and /3-~yclodextrin.'~~ Reagents i [Pd2(dba)J [NH4][HC00] THF; ii [Pd(PPh,),] (Me,CH),CHOH SmI Scheme 81 The reductive cleavage of chiral acetals such as (97) may be effected with very high diastereoselectivity (-98 :2) using either dibaH or Et3SiH-TiC1 followed by KF (Scheme 82).The ethers produced were readily cleaved to chiral alcohols using PCC-K2[C03].'57 153 J. Tsuji T. Sugiura M.Yuhara and I. Minami J. Chem. SOC.,Chem. Commun. 1986 922. 154 T. Tabuchi J. Inanaga and M. Yamaguchi Tetrahedron Lett. 1986,21 5237. 15s D. F. McComsey A. B. Reitz C. A. MaryanofT and B. E. Maryanoff Synth. Commun. 1986 16 1535. 156 H. A. Zahalka and H. Alper Organometallics 1986 5 1909. 157 K. Ishihara A. Mori 1. Arai and H. Yamamoto Tetrahedron Lett. 1986 27 983 and 987. 278 P. A. Chaloner +HO OH Ox0 @ Et +y.Et / / BU BU (97) Reagents dibaH -20 "C CH,CI Scheme 82 HO NOCHzPh HO NH2 HO NHz Bu Bu Bu -Bu + BuLBu syn 1 anti = 52:48 96 4 PhCH20 N NHOCH2Ph NHOCHzPh + Ph\OH Ph>OH ph%oCoMe 99 1 Reagents Li[AlH,]; ii PhMe,SiH CF,COOH Scheme 83 Diastereoselective reduction of the 0-benzyl oximes of p-hydroxyketones may be achieved using either Li[AlH4] or PhMe,SiH-CF,COOH (Scheme 83).In the second example the stereoisomeric oxime derivative gave much less successful results reinforcing the thesis that the stereoselection is sterically rather than chelation ~ontrolled.'~~~'~~ Non-redox Conversions.-Substitution at sp3-Hybridized Carbon. The ready availabil- ity of chiral epoxy alcohols by the Sharpless reaction has encouraged studies of their further transformations. Their opening with sodium azide supported on zeolite clay is generally regioselective for attack remote from the hydroxyl group and the reagent is easy to prepare manipulate and separate from the products.'60 Opening with trimethylsilyl azide in the presence of titanium( IV) isopropoxide was rather regioselective for attack on the less-substituted carbon atom of the epoxide.Conversion of epoxides into chlorohydrins with titanium( IV) chloride is stereo- specific and regioselective; it is particularly valuable in that it tolerates acetal protecting groups normally labile to aqueous acid.'62 The problems of esterification and macrolactonization using alkyl halides continue to attract attention. 2,4,6-Trimethylbenzoic acid may be esterified by alkyl halides in the presence of a solid-liquid phase-transfer catalyst such as Aliquat 336. Similar K. Narasaka Y. Ukaji and S.Yamazaki Bull. Chem. SOC.Jpn. 1986 59 525 159 M. Fujita H. Oishi and T. Hiyarna Chem. Lerr. 1986 837. 160 M. Onaka K. Sugita and Y. Izumi Chem. Lett. 1986 1327. 161 D. Sinou and M. Emziane Tetrahedron Lert. 1986 27 4423. 162 C.-L. Spawn G. J. Drtina and D. F. Wiemer Synthesis 1986 315. Synthetic Methods conditions suffice for hydrolysis thus providing a convenient alternative to the strongly acidic media usually associated with reactions of such hindered species.'63 This and numerous other related reactions were also achieved in the presence of the tetraethylammonium salt of pyrrolidone.'64 Dimethylcarbonate has been used as a versatile inexpensive and safe methylating agent for 2-alkylimidazoles thiols and phenols under phase-transfer condition^.'^' Mercury(11) chloride/iodine is a useful reagent for the regiospecific synthesis of a-iodocarbonyl compounds avoiding the use of enol derivatives.'66 The bromina- tion of enantiomerically pure acetals of alkyl aryl ketones is very stereoselective (Scheme 84).The product acetals could be hydrolysed to a-bromoketones by methane sulphonic acid in methanol without ra~emization.'~' MeOOC COOMe MeOOC. ,COOMe MeOOC ,COOMe 90:10-94:6 Reagents Br, HBr CCI, 15 "C Scheme 84 Substitution at sp2-HybridizedCarbon. The halogenation of phenols phenol ethers and aromatic amines may be made extremely regioselective for the 4-isomer using [Me,SCl]+Cl-. The observed selectivity is related to a late arenium ion-like transition state with a bulky halogenating agent.16* 2-Substitution of N-monoalkyl aro- matic amines could be accomplished by the protection lithiation sequence of Scheme 85 which can be performed as a one-pot process.'69 Phenyl ethers and amines cannot be synthesized by the normal Williamson process; the copper-catalysed reactions of organobismuth compounds developed by Barton's group provide a convenient alternative."' Many more examples of the enantioselective formation and hydrolysis of acid derivatives catalysed by enzyme preparations have been reported this year.Some R Reagents i BuLi THF; ii CO,; iii [Me,C]Li THF; vi E+; v HCI H20,0°C; vi A Scheme 85 163 A. Loupy M. Pedoussaut and J. Sansoulet J. Org. Chem. 1986 51 740. 164 T. Shono 0. Ishige H. Uyama and S.Kashimura J. Org. Chem. 1986 51 546. 165 M. Lissel S. Schmidt and B. Neumann Synthesis 1986 382. 166 J. Barluenga J. M. Martinez-Gallo C. Najera and M. Yus Synthesis 1986 678. 167 G. Castaldi S. Cavicchioli C. Giordano and F. Uggeri Angew. Chem. Znt. Ed. Engl. 1986 25 259. 168 G. A. Olah L. Ohannesian and M. Arvanaghi Synthesis 1986 868. 169 A. R. Katritzky W.-Q. Fan and K. Akutagawa Tetrahedron 1986 42 4027. 170 D. H. R. Barton J.-P. Finet. J. Khamsi and C. Pichon Tetrahedron Lett. 1986 27 3615 and 3619. 280 P. A. Chaloner of these involve simple hydrolyses of racemic esters (Scheme 86),'713'72 whilst others are selective hydrolyses of meso diesters giving rise to highly functionalized chiral building blocks and potentially at least allowing conversion of all the material into one enantiomer (Scheme 87).'73As in all other areas of asymmetric synthesis standards are rising and most of the reported enantiomer excesses are greater than 90% crucial to any large scale or commercial application.The use of enzymes in all areas of synthesis has been reviewed.'74 Ph\rCI i_ Phycl Ph + FCl I OH OKPr 0 OKPr 0 t) 30O/O 100% e.e. 43O/O 100% e.e. R'. ,COOH R' .COOMe R' R' 7-52 '/o 3 1-8 1Yo up to 90% e.e. up to 61% e.e. Reagents i Lipoprotein lipase Ammo p Na2[HP04] K[H2P04] pH 7; ii pig-liver esterase Scheme 86 OCH2Ph P hC H 20, I MeCOO OCOMe OH OCOMe THPO OH 95% s Reagents i lipase E.C. 3.1.1.34; ii 4-Me-C,H4S03H DHP 25 "C; iii K2[C03] MeOH Scheme 87 Addition to C-C Multiple Bonds.Asymmetric hydroboration of heterocyclic alkenes with diisopinocampheyl borane (iPC,BH) gives alcohols in up to 100% enantiomer excess. iPCBH2 may generally be used to produce the other enantiomer of a desired alcohol but optical yields are usually 10wer.'~' p-Halogenoalkenyl ketones have been prepared from the corresponding alkynones (Scheme 88). By a change in the conditions both stereoisomers could be obtained with good selectivity and a related compound was used in an approach to 171 H. Kutsuki I. Sawa J. Hasegawa and K. Watanabe Agric. Biol. Chem. 1986 50 2369. 172 S. Ramaswamay R. A. H. F. Hui and J. B. Jones J. Chem. Soc. Chem. Commun. 1986 1545. 173 D. Breitgoff K. Laumen and M. P.Schneider J. Chem. Soc. Chem. Commun. 1986 1523. 174 J. B. Jones Tetrahedron 1986 42 3351. 175 H. C. Brown and J. V. N. V. Prasad J. Am. Chem. Soc. 1986 108 2049. Synthetic Methods 28 1 Reagent i 0Yo 85 O/o 11 65 % 9Yo Reagents i NaI CF,COOH 25 "C; ii NaI MeCOOH 25 "C Scheme 88 pa1yt0xin.l~~ Bromination of alkynes by [Bu,N][ Br,] gave truns-dibromoalkenes with excellent stereoselectivity under particularly mild condition^.'^^ Miscellaneous. Mild and selective methods continue to be sought for the conversion of acetals and thioacetals into carbonyls and routes not requiring aqueous conditions figure prominently. A combination of phenyl dichlorophosphate and sodium iodide may be used at near neutral pH in benzene,'78 whilst iodine in methanol cleaved carbohydrate acetals without the loss of glycosidic bonds.'79 Iron( 111) chloride on silica promotes acetal cleavage much more rapidly than that of triphenylmethyl or t-butyldimethylsilyl ethers and so could be used for selective deprotection of (98).180 The use of bromine in tetrachloromethane or tris(pyridyl)iron(111) perchlorate under acidic conditions provided mild high-yielding and convenient methods for dethioacetalization.'81.'82 (98) (99) w 0 NC' 'NHR (100) (101) Reagents RNH, KCN MeCOOH ultrasound Scheme 89 '76 M.Taniguchi S. Kobayashi M. Nakagawa T. Hino and Y. Kishi Tetrahedron Lett. 1986 27 4759 and 4763. 177 J. Berthelot and M. Fournier Can. J. Chem. 1986 64 603. 178 H.-J. Liu and S. Y. Uu Synth.Commun. 1986 16 1357. 179 W. A. Szarek A. Zamojski K. N. Tiwari and E. R. Ison Tetrahedron Lett. 1986 27 3827. 180 K.S. Kim Y. H. Song €3. H. Lee and C. S. Hahn J. Org. Chem. 1986 51,404. 18' M. Murase E. Kotani and S. Tobinaga Chem. Phann. Bull, 1986 34 3595. 182 R. Caputo G. Ferreri and G. Palumbo Tetrahedron 1986 42 2369. P. A. Chaloner The t-butyldimethylsilyl group has been widely used for the protection of alcohols and the related t-butyldiphenylsilyl function is now reported by Over- man's group to be equally useful in the blocking of primary amino groups. The derivatives RNHSiPh,(CMe,) are stable to chromatography basic hydrolytic alkylating and acylating reagents. They could be smoothly cleaved by dilute acid or ~yridine-HF.'~~ Amines may also be protected with #3-trimethylsilylethane sul- phony1 chloride; (99) was stable to refluxing CF,COOH 6M-HC1 [Bu,N]F BF, and 40% HF being cleaved only by CSF-[BU,N]F.'~~ Two groups have reported the enantioselective synthesis of cyanohydrins.Cataly- sis by the peptide cycle(S-Phe-S-His) was the more successful giving optical yields of up to 82%.lX5In crystalline cyclodextrin complexes up to 33% optical yields were achieved.'86 An intriguing use of ultrasound in this area has been noted; under ultrasonic irradiation (100) was converted into the Strecker product (lOl) whereas without such irradiation only the cyanohydrin was formed (Scheme 89).lg7 183 L. E. Overman M. E. Okazaki and P. Mishra Tetrahedron Lett. 1986 27 4391. 184 S.M. Weinreb D. M. Demko T. A. Lessen and J. P. Demers Tetrahedron Lett. 1986 27 2099. Y. Kobayashi S. Asada I. Watanabe H. Hayashi Y. Motoo and S. Inoue Bull. Chem. SOC.Jpn. 1986 59 893. H. Gountzos W. R. Jackson and K. J. Harrington Aust. J. Chem. 1986 39 1135. 187 J. C. MenCndez G. G. Trigo and M. M. Sollhuber Tetrahedron Lett. 1986 27 3285.

ISSN:0069-3030    

DOI:10.1039/OC9868300241

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

11 Polymer-supported Catalysts and Reagents By P. HODGE Department of Chemistry University of iancaster Lancaster LA 1 4YA 1 Introduction Since Merrifield reported his method of ‘solid-phase peptide synthesis’ in 1963,’ there has been considerable interest in carrying out organic reactions on polymer supports. Several books and reviews have been published The supported species may be either a catalyst a reagent or the substrate. A very large number of each type have been reported in the last 20 years and there is clearly insufficient space in this Report to cover all the aspects. The Report must therefore be selective. It will consider the practical advantages of PS” catalysts and reagents their prepar- ation some general features of PS reactions and selected examples of PS catalysts and reagents likely to be of interest to synthetic organic chemists.It will concentrate on recent developments. PS transition metal complex catalysts will not be considered as this topic is sufficiently large and specialized to justify a Report of its own.8 Reactions using PS substrates will not be considered because these have a more limited range of applications in organic synthesis than PS catalysts and reagenk4v9 The subject of this Report involves both organic chemistry and polymer chemistry. Readers not familiar with the latter may find the texts listed in ref. 10 useful. 2 Practical Advantages of PS Catalysts and Reagents The features of PS catalysts and reagents which usually prompt the initial studies are the practical advantages which result from the easy separation of the supported and the non-supported species.The separation is easiest if the polymer is crosslinked R. B. Merrifield J. Am. Chem. SOC.,1963 85 2149. ‘Polymers as Aids in Organic Chemistry’ N. K. Mathur C. K. Narang and R. E. Williams Academic Press New York 1980. ‘Polymer-supported Reactions in Organic Synthesis’ ed. P. Hodge and D. C. Sherrington Wiley Chichester 1980. J. M. J. FrCchet Tetrahedron 1981 37 663. A. Akelah and D. C. Sherrington Chem. Rev. 1981 81 557. A. Akelah and D. C. Sherrington Polymer 1983 24 1369. ’ ‘Polymeric Reagents and Catalysts’ ed. W. T. Ford ACS Symposium Series 308 Washington 1986. * P. E. Garrou Chapter 5 in ref. 7; F. R. Hartley ‘Supported Metal Complexes’ D. Reidel Publishing Co.Dordrecht 1985; F. Ciardelli G. Braca C. Carlini G. Sbrana and G. Valenti J. Mol. Cutal. 1982 14 1; D. C. Bailey and S. H. Langer Chem. Rev. 1981 81 110. J. M. J. FrCchet Chapter 6 in ref. 3. ‘Contemporary Polymer Chemistry’ H. R. Allcock and F. W. Lampe Prentice-Hall Englewood Cliffs New Jersey 1981; ‘Textbook of Polymer Science’ by F. W. Billmeyer 3rd Edition Wiley New York 1984. * Throughout this Report ‘Polymer-supported’ is abbreviated to PS. 283 284 P. Hodge (and therefore insoluble in all media) and in the form of beads at least 50 p in diameter. Separation can then be achieved simply by filtration using common laboratory equipment. Somewhat larger beads are easily separated by decantation and can also be used in columns.The separation of polymeric and non-polymeric species is less easy if the polymer is linear and therefore soluble. Separation must then be achieved by selective precipitation or by membrane filtration. This Report unless noted otherwise will therefore just consider catalysts and reagents prepared from crosslinked polymers. Work with linear polymers has been reviewed." The advantages resulting from an easy separation include the following. (i) Product isolation is simplified. This may make it possible to avoid exposing reaction products to water to avoid chromatographic separations or to allow the rapid isolation of unstable products. (ii) If the use of an excess of a reagent results in a greater reaction yield then an excess can be used without causing separation problems.(iii) The polymer is easily recovered and can possibly be re-used. If the polymer can be re-used successfully it becomes economically feasible to prepare complex and sophisticated catalysts or reagents. (iv) It may be possible to automate the whole reaction procedure. This has obvious attractions to industry. The practical advantages are likely to be most useful in the preparation of valuable materials on a small scale for example in the preparation of certain pharmaceuticals and of labelled compounds. They are also likely to be valuable in asymmetric synthesis since attaching complex chiral species to polymers provides a 'handle' which permits their easy removal from the chiral reaction products and also allows the complex species to be re-used.3 Preparation of Functionalized Polymers A number of PS catalysts and reagents are available commercially and the range is increasing steadily. However on most occasions the polymer required for a particular application will need to be synthesized. In most cases the functionalized polymers used have been derivatives of cross- linked polystyrenes. Polystyrenes are particularly attractive as supports because they are readily available they are hydrophobic (and hence compatible with many organic solvents) and the unfunctionalized phenyl residues do not usually interfere in subsequent reactions. Other hydrophobic polymers are beginning to be investi- gated.I2 When hydrophilic supports are required polymers prepared from monomers such as acrylamide N,N-dimethylacrylamide or 2-hydroxyethyl methacrylate (HEMA) may be used.The two main approaches to the synthesis of functionalized crosslinked polymers are as follows. *'(a) K. Geckeler V. N. R.Pillai and M. Mutter Adv. Polym. Sci. 1981 39 65; (6) D. E. Bergbreiter Chapter 2 in ref. 7. 12 P. Hodge B. J. Hunt and I. H. Shakhshier Polymer 1985. 26,1701; A. A. H. Al-Kadhumi P. Hodge and F. G. Thorpe ibid. 1985 26,1695; F.Anwar C. Bain M. Bakhshaee and D. C. Sherrington J. Chem. SOC.,Chem. Commun. 1984 1363; D. Lindsay and D. C. Sherrington Reactive Polymers 1985 3 327. Polymer-supported Catalysts and Reagents 285 By Copolymerization.-This approach involves copolymerizing the appropriate func- tional monomer any monomer used as a diluent and a crosslinking agent.An example is the preparation of a polymer containing triphenylphosphine residues by the free radical-initiated copolymerization of p-styryldiphenylphosphine,styrene and di~inylbenzene.'~ To obtain products in the form of beads suspension copoly- merizations must be carried out. By careful control of the conditions including the feedstock composition the vessel and the stirrer shapes the stirrer speed and the types and amounts of suspending agents products of quite different size and morphology can be ~btained.'~ With only a small amount of crosslinking agent (1YO or 2% of divinylbenzene for polystyrenes) and no additives (compare below) a microporous polymer is obtained. On drying the polymer matrix collapses to leave a product with only very small pores.With a relatively large amount of crosslinking agent (>20% of divinylbenzene for polystyrenes) and the addition of porogens (for example toluene amyl alcohol or linear polystyrene) macroporous polymers are obtained. These are rigid and do not collapse when they are dried but remain in an expanded porous form. In general considerable experimentation is needed to optimize the polymerization conditions for a particular feedstock. As a result this approach to functionalized polymers is not often used by organic chemists. Finally it should be noted that with this approach the distribution of the functional monomer in the final product will depend on the reactivity of ratios of the various monomers and that some functional groups may subsequently prove to be inaccess- ible to low molecular weight reactants.By Chemical Modification of Preformed Polymers.-Several unsubstituted cross-linked polystyrenes of good physical form are available commercially and many PS catalysts and reagents have been prepared by chemical modification of these prod- ucts. The reactions used for the chemical modification must be essentially free of sidz reactions and reaction sequences must be short for there is no way of removing the products of side reactions which are bound to the polymers. Many groups can be introduced into crosslinked polystyrenes by electrophilic aromatic substitution reactions. Some important examples are given in Scheme 1 together with some important transformations of the products.Polystyrene reacts directly with n-butyl lithium and N,N,N',N' -tetramethylethyl-enediamine to give lithiated polystyrene but the maximum degree of functionaliz- ation obtained is only CQ. 25% and it is a mixture of m- and p-isomers." Essentially quantitative para-lithiation can be achieved by bromination with bromine and thallic acetate followed by treatment of the product with n-butyl lithium." These lithiated polystyrenes (6) react with a wide range of electrophiles to give useful products see Scheme 2. Another much-used sequence is chloromethylation of polystyrene then reaction of the products with nucleophiles. Chloromethyl ether was originally used for the chloromethylation'6 but it contains highly carcinogenic impurities.A more l3 D. C. Sherrington D. J. Craig J. Dalgleish G. Domin and J. Taylor Eur. Polym. J. 1977 13 73. 14 R. Arshady and A. Ledwith Reactive Polymers 1983,1 159; D. C. Shemngton Macromol. Synfh. 1982 8 69; Appendix section of ref. 3. IS M. J. Farrall and J. M. J. Frichet J. Org. Chem. 1976 41 3877. 16 K. W. Pepper H. M. Paisley and M. A. Young J. Chem. SOC. 1953 4097. 286 P. Hodge CHZCI Q co vii Ref. d,f CHO COzH (5) Reagents i C1S03H in CH,Cl,; ii Br, Tl(OAc),; iii CICHz AlCl,; iv 2-chloroben- zoyl chloride AlCI,; v KOBut/H20 (3 1); vi ClCH20CH, SnCI,; vii NaHCO, DMSO; viii Na,Cr,O, HZSO References (a) J. R. Millar D. G. Smith W. E. Marr and T. R. E. Kressman J. Chem. Soc. 1963 218; (b) See ref. 15 in text; (c) R.Kalir M. Fridkin and A. Patchornik Europ. J. Biochem. 1974 42 151; (d) C. R. Harrison P. Hodge J. Kemp and G. M. Perry Makromol. Chem. 1975 176 267; (e) See refs. 16 and 17 in text; (f) H. W. Gibson and F. C. Bailey J. Polym. Sci. Chem. Ed. 1975 13 1951. Scheme 1 satisfactory procedure uses dimethoxymethane thionyl chloride and zinc chloride.” Some of the nucleophiles which have been used are shown in Scheme 3. Often the reactions are best carried out using phase-transfer catalysis. ’* Further less expensive chemical modifications of readily available polymers are required as routes to functional polymers. One recent approach involves phase- 17 J. P. C. Bootsma B. Eling and G. Challa Reactive Polymers 1984 3 17. 18 J. M. J. Frichet M.D. de Smet and M. J. Farrall J. Org. Chem. 1979 44 1774. Reagents i LiPPh,; ii Bu"Li TMEDA; iii Ph,PCI; iv CO,; v MgBrz then BunSnCl3 then LiAIH,; vi (MeS),; vii As(OEt) then H20 References (a) H. M. Relles and R. W. Schluenz J. Am. Chem. Soc. 1974; 96 6469. (6) See ref. 15 in text. (c) S. V. McKinley and J. W. Rakshys J. Chem. SOC.,Chem. Commun. 1972 134. (d) See ref. 100 in text. (e) See ref. 88 in text. (f)See ref. 48 in text Scheme 2 transfer-catalysed Wittig reactions between aldehydes and PS phosphonium salts [(13) in Scheme 3].19 Another involves reacting a commercial crosslinked poly- methacrylic acid (14) (a weak acid cation-exchange resin) with benzyltrimethyl- ammonium hydroxide followed by reaction of the PS salt (15) with appropriate alkyl bromides iodides or tosylates see Scheme 4.20The ester linkage is relatively unreactive as it is in effect a PS pivalate ester.It should be noted that the distribution of functional groups introduced by chemical modification will depend on many factors e.g. the rate of the chemical reaction compared to the rate of diffusion of the reagent into the polymer beads and the effect of functional groups already introduced on the ease of introduction of other functional groups in the vicinity. The groups may be evenly distributed or 19 P. Hodge and J. Waterhouse Polymer 1981 22 1153. 20 P. Hodge and M. Houghton unpublished results. 288 P. Hodge Q CH20R I sf. --CH-CHZ--CH2C1 Rex _--CH-CH2 -___ (1) 0 CH26Ph~ CH~NU c1-(13) Reagents i NR,; ii N&-OR; iii Various nucleophiles Nu-; iv PPh References (a) S.L. Regen and D. P. Lee J. Am. Chem. SOC 1974,96 294. (b) W. M. MacKenzie and D. C. Shemngton J. Chem. SOC.,Chem. Commun. 1978 541. (c) See ref. 18 in text. (d) See ref. 19 in text Scheme 3 Me -FH Me Me I PhCH,NMe I I ...C-CH2.. ...C-CH,... RCH,Br ...C-CH,... . b -+ ICO2H I c02- IC02CH2R PhCH2&’Me (14) (15) Where R = functional group Scheme 4 clustered but in general they will all be accessible in subsequent reactions. Clearly the distribution obtained will differ from that obtained by direct copolymerization. 4 Some General Features of PS Reactions Selection of Reaction Conditions.-The reaction conditions used with PS catalysts and reagents are not necessarily the same as those used with their low molecular weight counterparts.The choice of reaction solvent is particularly important. PS catalysts and reagents are usually prepared in the form of crosslinked beads with diameters of 50-100 p. If the beads were only functionalized on the surface their maximum capacities would be of the order of 0.01 mmol g-’. It is clear that Polymer-supported Catalysts and Reagents 289 for applications in synthetic organic chemistry the beads need to be functionalized throughout their volume. They will then have maximum capacities of several mmol g-’. Because the vast majority of the functional groups are within the beads low molecular weight substrates must diffuse into the beads to react.To obtain adequate diffusion rates with microporous beads (see section on copolymerization above) they must be swollen by the reaction solvent. The extent of swelling with a given solvent will depend on the support polymer the functional groups present and on the concentration and distribution of both. The reaction solvent must not only swell the beads initially but throughout the reaction as the original bound functional groups are transformed into others. The choice of solvent is less important with macroporous polymers (see section above on copolymerization) since functional groups in the porous regions should be accessible in most solvents. However the high percentage of crosslinking in macroporous polymers generally means they have lower capacities than microporous polymers.The choice of solvent is also important because the substrate will not in general be evenly distributed between the polymer phase and the surrounding solution. Ideally the substrate will concentrate in the polymer beads and this may lead to enhanced reaction rates but the substrate may also tend to stay in the surrounding solution so leading to decreased reaction rates. These effects may well change as the reaction proceeds. Apart from its influence on diffusion rates and on the distribution of the substrate between the polymer and the surrounding solution the reaction solvent will also influence the rates of reactions as in low molecular weight systems. The factors are so complex that in general the best solvent for a particular reaction system should be determined by experiment.The rates of many PS reactions are limited by diffusion. Many PS reactions are therefore slower than their low molecular weight counterparts and longer reaction times and/or higher reaction temperatures are often necessary. Microenvironment in the Vicinity of PS Reactive Groups.-In the presence of the reaction solvent the functional groups in most PS catalysts or reagents will be surrounded by the reaction solvent. The reactivity of the group will therefore generally be the same as its low molecular weight counterpart. The microenvironment may differ however if the substrate accumulates in the polymer beads and/or other groups in the polymer interact strongly with the functional group before or during reaction.The latter is most likely to be the case if charged groups are present and/or hydrogen-bonding is possible. Such ‘polymer effects’ have been observed in a few cases.21-22 There is no clear evidence that functional groups bound to polystyrenes have different steric requirements than their low molecular weight counterparts. They are not expected to since in most cases the functional groups are bound at the para-position. Steric effects may be found with functional groups bound closer to the polymer backbone as for example the acyl groups in addition polymers prepared from maleic anhydride. 21 C. R. Harrison P. Hodge B. J. Hunt E. Khoshdel and G. Richardson J. Org. Chem. 1983,48 3721. 22 C. Yaroslavsky A. Patchornik and E.Katchalski Tetrahedron Lett. 1970 3629; G. L. Baker S. J. Fritschel and J. K. Stille. J. Org. Chem. 1981 46.2960. 290 P. Hodge Ease of Intrapolymeric Reactions.-This has been a topic of interest with PS reactions for many years. The subject has been reviewed recently.23 It will be useful here to draw together the main conclusions. There are two main types of situation (i) those where the functional groups react together and then separate and (ii) those where the functional groups react and then remain bound together. Consider the former type first. In general there is no reason why two functional groups (potentially capable of reacting together) bound to a linear polymer chain existing as a random coil should not be able to react together however! low the degree of functionalization.The introduction of crosslink-ing will tend to limit the movements of bound functional groups but with the low degrees of crosslinking present in microporous polymers this does not significantly limit intrapolymeric reactions. At high levels of crosslinking (>20% with poly- styrenes) a small proportion of the functional groups particularly in polymers with a few uniformly distributed groups will not be able to react with others. For these ‘permanent site isolation’ will have been achieved. This can be useful with PS catalysts; the classical example is a PS titanocene hydrogenation catalyst.24 Titanocene itself dimerizes and the catalytic activity is lost but with the PS catalyst prepared from a highly crosslinked polymer and relatively lightly loaded a significant proportion of the titanocene sites were permanently isolated from the others with the result that the catalytic activity was higher and a significant amount remained over long periods.When intrapolymeric reactions do take place because the polymer chains reduce the mobility of the functional groups the reactions are usually slower than with their low molecular wieght counter parts. Consequently it is possible to have what might be termed ‘kinetic site isolation’. This has been exploited in selectively binding difunctional substrates to polymers by just one of the two possible groups.25 With 2-l0% crosslinked polystyrenes in swelling solvents reduced mobility results in 1 to 10 minute life-times of PS ester eno1ates,26a benzyneTb and a glycine active ester.26c The second type of situation is similar to the first but is more complicated and less predictable because each reaction leads in effect to a further crosslink.The distribution of these crosslinks and their effect on the swelling properties of the polymers can limit the extent of further reaction. In most cases the crosslink is probably formed between nearby groups on the same section of polymer chain. 5 Selected Examples of PS Catalysts These are the most attractive type of PS reactant because a relatively small amount of polymer can be used chemically to transform a relatively large amount of substrate into product. In principle it should be possible to re-use the recovered catalyst but 23 W.T. Ford Chapter 11 in ref. 7. 24 W. D. Bonds C. H. Brubaker E. S. Chandrasekaran C. Gibbons R. H. Grubbs and L. C. Kroll J. Am. Chem. SOC.,1975,97 2128. 2s C. C. Leznoff Acc. Chem. Res. 1978 11 327. 26 (a) Y. H. Chang and W. T. Ford J. Org. Chem. 1981 46 3756 and 5364; (b) S. Mazur and P. Jayalekshrny J. Am. Chem. Soc. 1979,101,677; (c) J. Rebek and J. E. Trend J. Am. Chem. SOC.,1979 101 737. Polymer-supported Catalysts and Reagents 29 1 unfortunately this aspect has not usually been pursued to any significant extent. A complex PS catalyst that retained significant activity through ten or more reaction cycles would probably justify its synthesis for laboratory applications. It was originally anticipated that PS catalysts would display useful substrate selectivity based on size because the substrates need to diffuse into the polymer to react.However the need to use good swelling solvents with microporous polymers and the highly porous nature of macroporous polymers generally militate against significant size selectivities. PS Acids.-The simplest PS acids are the various commercially available strong acid cation exchange resins containing residues (2) (see Scheme 1).These have long been utilized to catalyse such reactions as esterification ester hydrolysis and acetal and ketal f~rmation.~ A milder catalyst for these reactions2' and for enamine formation28 is the hydrochloride form (16) of poly(viny1pyridine). The activity of the sulphonic acid resins (2) can be increased considerably either by combination with aluminium tri~hloride~~ or by fluorination to give acid (17).30 Commercial products similar to the latter are Nafion resins (18).Olah and his co-workers have shown that these can be used to catalyse esterificati~n,~'~ dehydration^,^'^ hydrations of alkyne~,~'" and many other reac- Friedel-Craft alkylations31d and acylation~,~'~ tions. c1-rn = 1,2,3 ... (16) n = 5 to 13.5 x = ca. 1000 Various PS Lewis acids have been described.32 Aluminium tribromide in a poly- styrene matrix catalyses the alkylation of aromatic compounds in good yields and is reported to be superior to the original aluminium trichloride analogue.33 Even more effective are polystyrene resins which have been reacted with PCl3/A1Cl3 or PBr,/A1Br3 .33,34 PS Bases.-The simplest are the hydroxide forms of anion exchange resins (11) (see Scheme 3).These have been used to catalyse ester hydrolyses condensations 27 J. Yoshida J. Hashimoto and N. Kawabata Bull. Chem. SOC.Jpn. 1981 54 309. 28 Reilly Tar and Chemical Co. Indianapolis Indiana. Product Bulletih R-8050. 29 V. C. Magnotta and B. C. Gates J. CufuL 1977 46 266. 30 J. Klein. F. Doscher and H. Widdecke. Roc. Svmn Mucromol. Strussbourg 1981 403. 31 (a)G. A. Olah T. Keumi and D. Meidar Synthesis 1978 929; (b) G. A. Olah A. P. Fund and R. Malhotra Synthesis 1981 474; (c) G. A. Olah and D. Meidar Synthesis 1978 671; (d) G. A. Olah D. Meidar R. Malhotra J. A. Olah and S. C. Narang J. CutuL 1980 61 96; (e) G.A. Olah R. Halhotra S. C. Narang and J. A. Olah Synthesis 1978 672. 32 E. C. Blossey L. M. Turner and D. C. Neckers J. Org. Chem. 1975 40 959. 33 J. Schliiter and H. Widdecke paper presented at EUCHEM Conference at Cirencester September 1984. 34 H. Widdecke J. Klein and K. Struss Erdol U. Kohle Compendium 1982/83 199. 292 P. Hodge Michael reactions,35 and numerous other reaction^.^ The polymers shown in formula (19) also serve as catalysts for Michael reaction^.^^ Chiral anion-exchange resins have been prepared by quaternizing the cinchona alkaloids (20)-(23),36*37 N-meth~lephredrine,~~ or amino acid derivatives3* with chloromethylated polystyrenes (l) and various anionic forms of these have been used as catalysts for Michael reactions.CH=CH2 0-x QH I+ CH2NMe2 I ,CHOH CH2CH2OH I X-= C1- F- OH-HC0,-(19) Conjguration at Alkaloid C-8 C-9 X (20) Cinchonidine S R H (21) Cinchonine R S H (22) Quinine S R OMe (23) Quinidine R S OMe Polyvinylpyridine (24) which is commercially available catalyses acylation~.~~ PS 4-dimethylaminopyridine (2q40p41 and several related polymers incorporating spacer groups for example polymer (25),42have been prepared and successfully e~terification,~~"'~~ used as catalysts for acylation~,~~~ transesterification:' enol acetate formation:' O-alkylation;' and O-~ilylation.~' I I Me (24) n = 1 (25) n = 7 35 E. D. Bergmann and R. Corrett 1. Org. Chem. 1958,23 1507. 36 P. Hodge E. Khoshdel and J. Waterhouse J.Chem. SOC.,Perkin Trans. 1 1983 2205. 37 N. Kobayashi and K. Iwai Makromol. Chem. Rapid Cornmun. 1981 2 105. 38 S. Banfi M. Cinquini and S. Colonna Bull. Chem. SOC.Jpn. 1981 54 1841. 39 F. LeGoffic S. Sicsic and C. Vincent Tetrahedron Lett. 1976 17 2845. 4o M. Tomoi Y. Akada H. Kakiuchi Makromol. Chem. Rapid Commun. 1982 3 537. 41 F. M. Menger and D. J. McCann J. Org. Chem. 1985 50 3928. 42 (al M Tornoi. M Goto and H. Kakiuchi Makromol. Chem. Rapid Commun. 1985 6 397; (b) F. Guendouz R. Jacquier and J. Verducci Tetrahedron Lett. 1984 25 4521. 43 S. Shinkai H. Tsuji Y. Ham and 0. Manabe Bull. Chem. SOC.Jpn. 1981 54 631. Polymer-supported Catalysts and Reagents 293 Various PS chiral amine catalysts have been prepared from the cinchona alkaloids (20)-(23)44 and from other chiral ami11es.4~ Catalysts derived via acylation of the 9-hydroxyl group of these alkaloids generally give very poor asymmetric induc- tion,44eJ but polymer (26) catalysed the addition of methanol to phenylketene to give the S-isomer of ester (27)in an enantiomeric excess of 32%.44f Better asymmetric induction is obtained if the P-hydroxy amine unit is retained and this has prompted the utilization of the vinyl group for the preparation of PS Thus Kobayashi copolymerized the alkaloids with acrylonitrile and used the copolymer products (28) as catalysts for Michael additions.44a-b A copolymer prepared from quinidine (23) gave an enantiomeric excess of 42% of the R-isomer in Scheme 5 whilst a similar Copolymer prepared from quinine (22) gave an enantiomeric excess of 30% of the S-enantiomer.44b Optical yields of up to 57% were obtained in additions of thiols to en one^.^^ Ph-EH-CO,Me I Me &"\ 4c\ 0-Cinchonine NH 0 (27) I &O-Cinchonine o-+ /NH 0 CN alkaloid CH2=CH mH2CH2COMe \c=o -C02Me m C 00 2 M e + Me/ 0 Scheme 5 Other catalysts have been prepared by the addition of PS thiols (29) to the vinyl groups of cinchona alkaloids.44' In Michael additions these catalysts (30) gave lower optical yields than the corresponding free alkaloids.However low molecular weight 44 (a) N. Kobayashi Br. Polym. J. 1984,16,205; (b)N. Kobayashi and K. Iwai J. Am. Chem. Soc. 1978 100 7071; (c) P. Hodge E. Khoshdel J. Waterhouse and J. M. J.Frtchet J. Chem. Soc. Perkin Trans. 1 1985 2327; (d)P. Hodge E. Khoshdel and P. Stratford unpublished results; (e) K. Hermann and H. Wynberg Helu. Chim. Acra 1977 60,2208; (f)T. Yamashita H. Yasueda N. Nakatani and N. Nakamura Bull. Chem. Soc. Jpn. 1978 51 1183 and 1247. 45 (a) K. Kondo T. Yamano and K. Takemoto Makromol. Chem. 1985 186 1781; (b) T. Yamashita E. Kagigaki N. Takahashi and N. Nakamura Makromol. Chem. 1983 184 675. 46 N. Kobayashi and K. Iwai Macromolecules 1980 13 31. 294 P. Hodge catalysts prepared by the addition of simple aliphatic thiols to the vinyl groups of the alkaloids gave essentially the same optical yields as the PS catalysts.4c This indicates that the polymer itself did not have an adverse effect on the optical yields and that to make meaningful studies of 'polymer effects' carefully chosen model compounds must be used.Catalysts (31) prepared by the addition of polymethylhy- drosiloxane to the vinyl groups of the alkaloids gave enantiomeric excesses in Michael additions for example Scheme 5 essentially the same as those obtained with the free alkaloids.44d Various PS L-prolines have been used as catalysts for Robinson cy~lizations.~~" Me I -+Si-O j;-I CH2CH2Q (30) Where QCH=CH represents (20)-(23) PS Oxidation Catalysts.-It has been known for a long time that various oxometal ions containing tungsten molybdenum or vanadium when bound to anion exchange resins (1 1) or other polymers serve as PS catalysts for the epoxidation of olefins by hydrogen peroxide or alkyl hydro peroxide^.^^ More recently the PS arsonic acid and PS tellurinic acid (32)49 have been shown to catalyse epoxidations.The latter is particularly interesting as low molecular weight analogues appear to have no catalytic activity and the activity of the PS catalysts depends greatly on the polymer structure and increases with increased crosslinking. The PS seleninic acid (33)" also catalyses epoxidation but the epoxides are usually hydrolysed to truns-diols. Certain PS porphyrin-manganese( 111) complexes catalyse epo~idations.'~ TeOzH Se02H The PS arsonic acid ( and PS seleninic acid (33)" catalyse Baeyer-Villiger reactions. The latter also catalyses the t-butyl hydroperoxide oxidation of activated 47 See for example G. G. Allan and A.N. Neogi J. Catal. 1970 19 256; T. Yokoyama M. Nishizawa T. Kimura and T. M. Suzuki Bull. Chem. SOC.Jpn. 1985,58 3271; K. Zhang G. S. Kumar and D. C. Neckers J. Polym. Sci. Polym. Chem. Ed. 1985 23 1213. 48 S. E. Jacobson F. Mares P. M. Zarnbri J. Am. Chem. SOC.,1979 101 6946. 49 W. F. Brill J. Org. Chem. 1986 51 1149. 50 R. T. Taylor and L. A. Flood J. Org. Chem. 1983 48 5160. 5' A. W. van der Made J. W. H. Srneets R. J. M. Nolte and W. Drenth J. Chem. Soc. Chem. Comrnun. 1983 1204. 52 S. E. Jacobson F. Mares and P. M. Zambri J. Am. Chem. SOC., 1979 101 6938. Polymer-supported Catalysts and Reagents 295 alcohols to aldehydes and ketones.50 Certain PS porphyrin-cobalt(111) complexes53 and phthalocyanine-Co” complexes54 catalyse the aerial oxidation of thiols.Kawabata et al. have reported several novel oxidizing reagents which can be electrically recycled in situ and are therefore catalysts.’’ Thus the bromide form of a particular ion exchange resin (1 1) was used to catalyse electrochemical epoxida- ti on^,^^^ a polyvinylpyridinium hydrobromide was used to catalyse the oxidation of primary and secondary alcohol^,^' and a mixture of polyvinylpyridinium hydro- bromide and hydrosulphate catalysed the electrochemical oxidation of aromatic alkyl side ha ins.''^ PSPhase-transfer Catalysts.-Reactions using PS phase-transfer catalysts have been studied extensively and the s~ope~~,’~ and mechanisms7 of the reactions have been reviewed. The reactions proceed in three-phase mixtures consisting of aqueous salt solution organic solution and insoluble polymer and the method has been called triphase catalysis.For displacement reactions such as the reactions of alkyl halides with -CN or -0COMe in liquid-liquid systems as expected PS quaternary ammonium and PS quaternary phosphonium salts are generally more active catalysts than PS crown ethers and PS (polyethylene glyco1)s. The use of ‘spacer arms’ between the active site and the polymer backbone often increases a~tivity.~’ Hence polymers such as (34) are the best types for displacement reaction^.^' Since in PS phase-transfer catalysis both the organic substrate and the reactive anion need to diffuse into the polymer beads to react the hydrophobic-hydrophilic balance of the catalyst is very important.For polystyrenes carrying quaternary ‘onium sites loadings of 10-20% of the phenyl residues are often ~ptimal.’~ Alkylations of active nitriles and ketones with aqueous NaOH or KOH as base proceed readily with commercial anion- exchange resins (1 1);’ PS(polyethy1ene glycol)s,61 or PS crown ethers6’,62 as catalysts. PS(polyethy1ene glyco1)s (12; R = polyethylene glycol) are also active catalysts for dehydrohalogenations by aqueous base.63 Other catalysts investigated are PS sulph~xides~~ and PS crypt and^.^^ Attempts to achieve asymmetric syntheses using PS chiral phase-transfer catalysts have generally been unsuccessful.66 Surprisingly since two solid-phases are involved examples are known of the catalysis of solid-liquid reactions by insoluble PS phase-transfer catalysts.’ 53 L.D. Rollman J. Am. Chem. Soc. 1975 97 2132. 54 W. M. Brouwer P. A M. Traa T. J. W. de Weerd P. Piet and A. L. German Angew. Makromol. Chem. 1984 128 133. 55 (a) J. Yoshida J. Hashimoto and N. Kawabata J. Org. Chem. 1982 47 3575; (b) J. Yoshida R. Nakai and N. Kawabata J. Org. Chem. 1980,45 5269; (c) J. Yoshida K. Ogura and N. Kawabata J. Org. Chem. 1984 49 3419. 56 S. L. Regan Angew. Chem. Inr. Ed. Engl. 1979 18 421. 57 W. T. Ford and M. Tomoi Ado. Polym. Sci. 1984 55 49. 51 See for example M. Tomoi S. Shiiki and H. Kakiuchi Mocrornol. Chem. 1986,187,357; and M. Tomoi E. Ogawa Y. Hosokama and H. Kakiuchi J. Polym. Sci.,Polym. Chem. Ed. 1982 20 3421. 59 Ref. 57 pp. 67-68.60 T. Balakrishnan and W. T. Ford J. Org. Chem. 1983 48 1029 and Tetrahedron Lett. 1981 22 4377. 61 Y. Kimura P. Kirszensztejn and S. L. Regen J. Org. Chem. 1983 48 385. 62 F. Montanari and P. Tundo J. Org. Chem. 1982,47 1298. 63 Y. Kimura and S. L. Regen J. Org. Chem. 1983,48 195. 64 (a) V. Janout H. Hrudkova and P. Cefelin Collect. Czech. Chem. Commun. 1984 49 2096; (b) S. Kondo K. Ohta and K. Tsuda Makromol. Chem. Rapid Commun. 1983 4 145. 65 F. Montanari and P. Tundo Tetrahedron Lett. 1979 20 5055. 66 J. Kelly and D. C. Sherrington P-lymer 1984 25 1499 and references cited therein. 296 P.Hodge I I n = lor7 (35) R = Me (34) (36) R = H II n = 1,2,3 ... R = H or Me Closely related to PS phase-transfer catalysis is the use of PS solvents and co-s~lvents.~~ Thus polymers (35),67 (36),67 (37),68 and (38)640catalyse displacement reactions under triphase conditions.Polymers (35)69and (37)6*have also been shown to be active under biphase conditions. Other PS Catalysts.-The cyanide forms of polymer (1 1) and other anion-exchange resins catalyse the conversion of aromatic aldehydes into ben~oins.~' Chiral anion- exchange resins result in asymmetric synthesis in some case^.^'" When dimethyl sulphoxide is the solvent 2-and 4-methoxybenzaldehydes give the corresponding benzils PS thiazolium salts of the type (39) in combination with a base such as triethylamine have a wider range of application than PS cyanide. Thus as Q R Ph-As=O I R = Me or -CH2CH,0H Ph (39) (40) 67 S.L. Regen and A. Nigam J. Am. Chem. Soc. 1978 100 7773; S. L. Regen A. Nigam and J. J. Besse Tetrahedron Lett. 1978,19,2757; M. Tomoi,M. Ikeda and H. Kakiuchi Tetrahedron Lett. 1978,19,3757. 68 V. Janout and P. Cefelin Tetrahedron Lett. 1986 27 3525. 69 G. Nee and J. Seyden-Penne Tetrahedron 1982 38 3485. 70 (a) J. Castells and E. Dunach. Chem. Lett.. 1984 11 1859; (b) S. Xie. J. Tu. F. Ji. J. Zhang and W. Huang Zhongshan Duxue Xuebo Zirun Kexuebun 1984 11. [Chem. Abs. 102 13129721. Polymer-supported Catalysts and Reagents 297 R' I RCHO + RCH=CHCOMe --* RCOCHCH,COMe Scheme 6 well as catalysing the formation of benzoins they catalyse the formation of acyloins and the additions of aldehydes to enones (Scheme 6).71 PS-triphenylarsine oxide (40) catalyses the conversion of isocyanates into carb~diimides.~~ Many PS photosensitizers have been in~estigated.~~ The best and most intensively studied example is Rose Bengal covalently bound to crosslinked chloromethylated polystyrene (l).73" When used in non-polar solvents in the presence of oxygen it is an excellent source of singlet oxygen.The topic has been reviewed recently.73b 6 Selected Examples of PS Reagents For the purposes of this report PS reagents are considered to be functional polymers used in one-step processes in at least stoicheiometric amounts to transform low molecular weight substrates into products. Because they need to be used in st'oicheiometric amounts to be useful they generally need to have capacities that is millimoles of reactive functional groups per gram as high as is practicable.They will usually be more expensive than analogous low molecular weight reagents and ideally the spent reagent should be capable of recycling. Unfortunately this aspect has rarely been pursued to any significant extent. PS Reagents where the Reactive Groups are Ionically Bound.-The most readily available PS reagents are the various anionic forms of strong base anion-exchange resins (1 1). The commercial chloride forms can be converted into the desired anionic forms either by direct anion exchange or in the case of anions such as fluoride for which the resins generally have a low affinity by conversion of the chloride form into the hydroxide or bicarbonate form followed by neutralization of this with the appropriate acid.The various anionic forms are in effect PS lipophilic quaternary ammonium salts and if the resin is of the macroporous type the anions often react successfully in solvents such as hexane ether or dichloromethane. These PS reagents are therefore an alternative to phase-transfer catalysis. The reagents may show some substrate selectivity based on the size and/or polarity of the They also have the potential to be regioselective. PS oxidizing agents derived from polymer (1 1) include the HCr04- form which oxidizes primary and secondary alcohols to aldehydes or ketones,75 and the 10 71 S. Shinkai Y. Hara and D. Manabe J. Polym. Sci. Polym. Chem. 1982 20 1097; C. S. Sell and L. A. Dorman J.Chem. SOC. Chem. Commun. 1982 629; K. Karimian F. Mohanazedeh and S. Rezai J. Heterocycl. Chem. 1983 20 1119; T.-L. Ho and S.-H. Liu Synth. Commun. 1983 13 1125; B.-H. Chang and Y. L. Chang J. Chin. Chem. SOC.,1983 30,55. 72 C. P. Smith and G. H. Temme J. Org. Chem. 1983,48 4681. 73 (a) See J. Paczkowski and D. C. Neckers Macromolecules 1985 18 1245; (b) D. C. Neckers Chapter 6 in ref. 7. 74 G. Cainelli M. Contento F. Manescalchi and L. Plessi J. Chem. SOC.,Chem. Comrnun. 1982 725. 75 G. Cardillo M. Orena and S. Sandri Terrahedron Lett. 1976 17 3985; G. Cainelli G. Cardillo M. Orena and S. Sandri J. Am. Chem. Soc. 1976 98 6737. 298 P. Hodge form which can be used to cleave 1,2-diols or oxidize ~ulphides.~~ The BH form reduces aldehydes and ketones to and the Fe(CO) form reduces acid chlorides to aldehydes.78 PS nucleophiles studied include F-,79%80a -Br-,80a I-,80a HCO 292o RC0;,20,80b C032-,80c Ar0-,80d SCN-,80e RS-,80f ArS-,80f RCOS-,80g CN-,80e and -CH(CO,Me)PO(OEt) .81 In most cases these have been reacted with alkyl halides or mesylates or acid chlorides in displacement reactions but the F-form has also been used to remove silyl protecting groupss2 and the phosphonate has been used in Horner-Wittig reactions.81 The Br3- and IC12- forms have been used to brominate or chlorinate olefins and ketones.83 Crosslinked polyvinylpyridine is commercially available and various salts ( 16) similar to those above have been prepared and studied.The chlorochromate form has been used to oxidize primary and secondary alcohols to aldehydes and ketones but a substantial excess of reagent is required.84 The Cr20:- form of a synthetic crosslinked polyvinylpyridine proved to be a better reagent than that prepared from the commercial resins.85 PS pyridinium hydrobromide perbromide brominates olefins and ketones.86 One interesting feature of PS reagents which has yet to be fully exploited is that if two separate reagents prepared from crosslinked polymers are mixed together the reactive groups do not come into contact (apart from the negligible amounts at the surface of the beads).Hence reagents which are mutually antagonistic can be used in combination in the same reaction vessel. Thus the conversion shown in equation 1 can be achieved using PS 104-in combination with PS BH4-,87 and that shown in equation 2 by polymer (2) in combination with PS cyanomethylphosphonate.81 I1 II II -C-C-+ -C C-+ -CH CH-II I1 II II OHOH 0 0.OH OH RCH:) + RCHO + RCH=CHCN 0 76 C. R. Harrison and P. Hodge J. Chem. Soc. Perkin Trans. I 1982 509. 77 A. R. Sande M. H. Jagadale R. B. Mane and M. M. Salunke Tetrahedron Lett. 1984 25 3501. 78 G. Cainelli F. Manescalchi and A. U. Ronchi J. Org. Met. Chem. 1984 276 205. 79 C. L. Borders D. L. MacDonell and J. L. Chambers J. Org. Chem. 1972 35,3549; S. Colonna A. Re G. Gelbard and E. Cesarotti J. Chem. Soc. Perkin Trans. I 1979 2248. 80 (a)G. Cainelli and F. Maneschalchi Synthesis 1976,472; (6)G. Cainelli and F. Maneschalchi Synthesis 1975,723; (c) G.Cardillo M. Orena G. Porzi and S. Sandri Synthesis 1981,793; G. Cardillo M. Orena and S. Sandin J. Org. Chem. 1986 51,713; (d) G. Gelbard and S. Colonna Synthesis 1977 113; T. Iverson and R. Johansson Synthesis 1979,823; (e) C. R. Harrison and P. Hodge Synthesis 1980 299; (f)G. Cainelli M. Contento F. Manescalchi and L. Plessi Gazz. Chim. Ital. 1982 112 461; (g) G. Cainelli M. Contento F. Manescalchi and M. S. Mussatto Synthesis 1981 302; G. Cainelli M. Contento F. Manescalchi L. Plessi and M.Panunzio Gazz. Chim. Ital. 1983 113,528. 81 G. Cainelli M. Contento F. Manescalchi and R. Regnoli J. Chem. Soc. Perkin Trans. I 1980 2516. 82 G. Cardillo M. Orena S. Sandri and C. Tomasini Chem. Ind. 1983 643. 83 (a) A. Bongini G. Cainelli M.Contento and F. Manescalchi Synthesis 1980 143; (b) A. Bongini G. Cainelli M. Contento and F. Manescalchi J. Chem. SOC.,Chem. Commun. 1980 1278. 84 J. M. J. FrCchet J. Warock and M. J. Farrall J. Org. Chem. 1978 43,2618. 85 J. M. J. Frichet P. Darling and M. J. Farrall J. Org. Chem. 1981 46 1728; T. Brunelet G. Gelbard and A. Guyot Polym. Bull. 1981 5 145. 86 J. M. J. FrCchet M. J. Farrall and L. J. Nuyens J. Macromol. Sci. Chem. 1977 A-11,507. 87 M. Bessodes and K. Antonakis Tetrahedron Lett. 1985 26 1305. Polymer-supported Catalysts and Reagents 299 PS Reagents where the Reactive Groups are Covalently Bound.-Polymer-supported reagents where the reactive groups are covalently bound are less readily available than those where the reactive groups are anions but a greater variety of reactions can be carried out.PS Oxidizing Agents. Reagents used to oxidize alcohols include PS thioanisole and chlorine,88a N-chl0ronylon-66,~~~ and a PS carbodiimide in combination with dimethyl sulphoxide.g8' Primary halides and tosylates have been oxidized to aldehydes by a PS amine oxideg9 and benzyl chloride has been oxidized to benz-aldehyde by a PS ~ulphoxide.~' PS aromatic peroxy acids prepared from polymer (5) have been used successfully to oxidize di- and tri-substituted olefin to epoxides but monosubstituted olefins only reacted ~luggishly.~' Sharpless oxidation of geraniol using a PS tartrate gave the 2S,3S-epoxide with up to 66% enantiomeric excess.92 PS aromatic peroxy acids oxidize sulphides including penicillin and cephalosporins to sulphoxides and s~lphones.~~ Several PS selenium-containing oxidants have been prepared.94 Unlike their low molecular weight analogues they are odourless and non-toxic.The selenium-containing polymers are easily recovered. PS Reducing Agents. Many PS reducing agents convert aldehydes and ketones into alcohols. The simplest are the complexes of borane with PS aminesg5 and with PS dimethyl~ulphide.~~ Prochiral ketones have been reduced by the complexes formed from PS chiral amino alcohols and diborane and in favourable cases optical yields of up to 80% have been ~btained.~' Reagents of this general type can reduce aldehydes in the presence of ketones.98 The activity of lithium aluminium hydride has been modified by PS chiral amino alcoh01s,~~~ a PS chiral dihydr~xybiphenyl,~~~ and a PS chiral bornane di01.'~' The latter gave the best results with acetophenone being reduced to 1-phenylethanol in up to 61% enantiomeric excess.The PS tin hydride (8) not only reduces aldehydes and ketones to alcohols but also reduces bromides and iodides to hydrocarbons."' Finally in this section aromatic disul- phides are reduced to thiophenols by treatment with PS phosphine (7) in aqueous tetrahydrofuran containing a catalytic amount of hydrochloric acid."' nn (a) G. A. Crosby and M. Kato J. Am. Chem. SOC. 1977,99 278; (b) H. Schuttenberg G. Klump,.U. Kaczmar S. R. Turner and R. C. Schulz J. Macromol. Sci. Chem. 1973 A7,1085; (c) N. M. Weinshenker and C.-M.Shen Tetrahedron Lett. 1972 13 3285. 89 J. M. FrCchet M. J. Farrall and G. Darling Reactive Polymers 1982 1 27. 90 J. A. Davies and A. Good Makromol. Chem. Rapid Commun. 1983 4 777. 91 C. R. Harrison and P. Hodge J. Chem. SOC.,Perkin Trans. 1 1976 605; J. M. J. FrCchet and K. E. Haque. Macromoleculev. 197C. U. 170. 92 M. J. Farrall M. Alexis and M. Trecarten Nouu. J. Chim. 1983 7 449. 93 C. R. Harrison and P. Hodge J. Chem. SOC. Perkin Trans. 1 1976 2252. 94 R. Michels M. Kato and W. Heitz Makromol. Chem. 1976 177 2311; N. Hu Y. Aso T. Otsubo and F. Ogura Chem. Lett. 1985 603. 95 F. M. Menger H. Sinozaki and L. C. Lee J. Org. Chem. 1980 45 2724; T. Yamashita H. Mitsui H. Watanabe and N. Nakamura Makromol. Chem. 1980 181 2563.96 G. A. Crosby U.S. Pat. 3 928 293 (Chem. Abstr. 1976 84 106499~). 91 S. Itsuno K. Ito A. Hirao and S. Nakahama J. Chem. Soc. Perkin Trans. 1 1984 2887. 9R S. Itsuno T. Wakasugi K. Ito. A. Hirao and S. Nakahama Bd/.Chem. SOC., Jpn. 1985 58 1669. 99 (a) P. Lecavalier E. Bald Y. Jiang J. M. J. Frechet and P. Hodge Reactive Polymers 1985 3 315; (b) H. Suda S. Kanoh N. Umeda M. Ikka and M. Motoi Chem. Lett. 1984 899; (c) J. S. Lui K. Kondo and K. Takemoto Makromol. Chem. 1983 184 1547. 100 N. M. Weinshenker G. A. Crosby and J. Y. Wong 1. Org. Chem. 1975,40 1966. 101 R. A. Amos and S. M. Fawcett J. Org. Chem. 1984 49 2637. 300 P. Hodge (41) n = 1 (42) n = 4 (43) n = 7 Other PS Reagents.PS alkoxides'02 and PS( 1,8-diazabicyclo[ 5,4,0]~ndec-7-ene),'~~ PS DBU (41) have both been used to carry out elimination reactions. Other bases investigated are in effect PS-butyl lithium,'04" PS-phenyl lithium,'04b and PS-trityl lithium.'04c All of these have been used for hydrogen-lithium exchange and some for halide-lithium exchange. Salts formed from the PSDBUs (41) to (43) arid carboxylic acids react with alkyl halides to give This procedure has been extended to the cyclization of a-bromo acids to 1a~tones.l~~ PS Wittig reactions were some of the first PS organic reactions to be studied and many examples have been reported the attraction being the easy separation of the PS phosphine oxide (which can be regenerated) from the olefinic prod~ct~.'~~~'~~ The Wittig reactions are generally carried out by reacting lightly crosslinked PS phosphines (7) with alkyl halides.A wide variety of bases have been used to generate the PS ylides from the phosphonium salts. In the case of salts prepared from allylic or benzylic halides aqueous sodium hydroxide or solid potassium carbonate have been used as the base under phase-transfer conditions.'08 In the relatively few cases studied lightly crosslinked polymer supports give E-and 2-olefins in similar proportions to the corresponding low molecular weight Wittig reactions. Interest- ingly however highly crosslinked supports show a marked tendency to give more of the E-alkene.lo7 When unstabilized ylides are generated using organolithium bases the presence of the lithium halide produced depresses the proportion of 2-olefin obtained.In PS reactions the lithium halide is easily washed away from the PS ylide before the carbonyl compound is added."' Dichloro- and dibromo-methylene phosphorus ylides prepared from PS phos- phine (7) and carbon tetrahalides have been used to prepare 1,l-dichloro- and 102 I. Artaud and P. Viout Polym. Commun. 1986 27 26; I. Artaud and P. Viout J. Chem. Soc. Perkin Trans. 1 1985 1257. 103 M. Tomoi Y. Kato and H. Kakiuchi Mukromol. Chem. 1984 185 2117. 104 (a) M. L. Hallensleben Angew. Mukrornol. Chem. 1973 31 147; (b) D. Braun and E. Seelig Chem. Ber. 1964,97,3098; (c) B. J. Cohen M. A. Kraus and A. Patchornik J. Am. Chem. SOC.,1977,99,4165. 105 M. Tomoi T. Watanabe T.Suzuki and H. Kakiuchi Mukromol. Chem. 1985 186 2473. 106 This topic has been reviewed. P. Hodge Chapter 2 in ref. 2; W. T. Ford Chapter 8 in ref. 7. 107 See for example M. Bernard and W. T. Ford J. Org. Chem. 1983 48 326; M. Bernard W. T. Ford and E. C. Nelson J. Org. Chem. 1983 48 3164. 108 S. D. Clarke C. R. Harrison and P. Hodge Tetrahedron Lett. 1980 21 1375. 109 W. Heitz and R. Michels Liebigs Ann. Chem. 1973 227. Polymer-supported Catalysts and Reagents -dibromo-olefins.' lo Wittig-type reactions using PS triphenylarsine have recently been reported." ' PS sulphur ylides prepared under phase-transfer conditions from sulphonium salts (44) react with aldehydes and ketones to give high yields of epoxides."2 The PS phosphine (7) has found numerous other app1i~ations.l'~ In combination with carbon tetrachloride it has been used to convert alcohols or thiols into alkyl chlorides,21 carboxylic acids into acid chlorides,2' mixtures of acids and amines into amides," primary amides into nitriles,' l4 and secondary amides into imino- chlorides.' l4 In combination with bromine or(better) carbon tetrabromide alcohols are converted into alkyl bromides.' '' In combination with diethyl azodicarboxylate esters can be prepared from acids and alcohols."6 Finally with diethyl peroxide diols can be cyclodehydrated to give epoxides tetrahydrofurans or tetrahy-dropyrans.' l7 s+ OH QN/N-N R' 'R (45) HO SCH2Li HgOCOCFs An alternative to Merrifield's solid-phase peptide synthesis has the growing peptide chain in solution and uses PS acylating agents.l18 Many such reagents have been described the most useful of which are esters of PS o-nitrophenols e.g.(4) and (45),119" and PS hydroxybenztriazole (46)."9b I LO P. Hodge and E. Khoshdel Reactive Polymers 1985 3 143. 111 W. Tao and X. Hu Huaxue Shiji 1984 6,207 Chem. Abs. 1984 101 192101g. 112 M. J. Farrall T. Durst and J. M. J. Frichet Tetrahedron Lett. 1979 20 203. 113 A review P. Hodge B. J. Hunt E. Khoshdel and J. Waterhouse Nouu. J. Chem. 1982 6 617. 114 C. R. Harrison P. Hodge and W. J. Rogers Synthesis 1977 41. 115 P. Hodge and E. Khoshdel J. Chem SOC.,Perkin Trans. I 1984 195. 116 R. A. Amos R. W. Emblidge and N. Havens J. Org. Chem. 1983,48 3598. 117 J.W. Kelly P. L. Robinson and S. A. Evans J. Org. Chem. 1985 50 5007. 118 For leading references see A. Patchornik E. Nov K. A. Jacobson and Y. Shai Chapter 10 in ref. 7; Y. Shai K. A. Jacobson and A. Patchornik J. Am. Chem. SOC.,1985 107 4249. 'I9 (a) M. Fridkin A. Patchornik and E. Katchalski J. Am. Chem. Soc. 1966 88 3164; (b) R. Kalir A. Warshawsky M. Fridkin and A. Patchornik Eur. J. Biochem. 1975 59 55. 302 P. Hodge Finally homologation of alkyl iodides can be achieved by treatment with PS phenylthiomethyl lithium (47) prepared from polymer (9) then with NaI/ Me1 in N,N-dimethylformamide.88" PS carbodiimides88c~'20 and PS ynamines have been used to prepare acid anhydrides and peptide bonds.'21 PS phenylmercury tri- fluoroacetate (48) cleaves dithio-acetals and -ketals smoothly.'22 The potassium salt of PS thiol (29) efficiently regenerates olefins from 1,2-dibromide~.'~~ 7 Conclusions Many PS catalysts and PS reagents have been investigated.Those referred to in this Report are simply examples. Much is now known about the preparation of reactive crosslinked polymers the selection of reaction conditions for their use and the way in which the PS reactions differ from their low molecular weight analogues. However much remains to be done to establish the extent to which the polymers can be recycled. Thus even modest physical losses and chemical side-reactions which would not otherwise be important can after perhaps only 10 reaction cycles significantly reduce the capacity and usefulness of the polymers.In many cases so far the polymer may have simply served as a 'handle' on the reactive species but with a better understanding of reactive macromolecules more sophisticated PS systems may be prepared in which the polymer enhances the reactivity and selectivity of the bound groups. Such polymers are likely to have controlled microenvironments with specific hydrophobic and/or hydrophilic regions and ordered regions resulting from particular conformations of the polymer or the presence of mesogenic groups into which one or more types of reactive groups are carefully located. 120 Y. Wohlman S. Kivity and M. Frankel J. Chem. SOC.,Chem. Comrnun. 1967 629. 12' J. A. Moore and J. J. Kennedy J. Chern. SOC.,Chem. Cornmun. 1978 1079. 122 V.Janout and S. L. Regen J. Org. Chem. 1982 47 2212. 123 V. Janout and P. Cefelin Tetrahedron Left. 1983 24 3913.

ISSN:0069-3030    

DOI:10.1039/OC9868300283

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

12 Enzyme Chemistry By D. GANl Department of Chemistry The University Southampton SO9 5NH 1 Introduction Annual Reports last reviewed enzyme chemistry in 1985.' This review follows the same format and thus the main objective is to highlight some of the more important findings published in 1986 rather than to provide exhaustive coverage ofthe literature. Again emphasis is placed upon papers describing structural and mechanistic aspects of enzymic catalysis rather than those describing the isolation and/or purification of the proteins. Over the past year many reviews have bcen published in the area of enzyme chemistry. Battersby has reviewed studies largely from the Cambridge Group on the biosynthesis of vitamin B12.2 Breslow has surveyed the use of artificial enzymes and enzyme models3 and Kuhn Schewe and Rapoport4 have reviewed the stereochemistry of the reactions of the lipoxygenase enzymes and their metabolites.The use of enzymes in synthesis has been reported by Jones;' other reviews will be cited in context. 2 Racemase Enzymes Proline racemase operates by a two-base mechanism and is not pyridoxal 5'-phosphate dependent. The enzyme has been studied in detail by Knowles and his co-workers.6-'2 Following on from earlier work by Abeles13 who showed that there are two forms of the free enzyme Knowles was able to demonstrate that the proline racemase system shows three kinetic regimes -unsaturated saturated and oversatur- ated -depending upon the concentration of substrate. At low concentrations of substrate the initial rates for racemization under equilibrium conditions increased ' D.Gani Annu. Rep. hog. Chem. Sect. B ch. 11 Enzyme Chemistry. A. R. Battersby Acc. Chem. Res. 1986 19 147. R. Breslow Ado. Enzymol Relat. Areas Mol. Biol. 1986 58 1. H. Kuhn T. Schewe and S. M. Rapoport Adv. Enzymol. Relat. Areas Mol. Biol. 1986 58 273. J. B. Jones Tetrahedron 1986 42 3351. L. M. Fisher W. J. Albery and J. R. Knowles. Biochemistry 1986 25 2529. ' L. M. Fisher W. J. Albery and J. R. Knowles Biochemistry 1986 25 2538. * L. M. Fisher J. G. Belasco T. W. Bruice W. J. Albery and J. R. Knowles Biochemistry 1986,25,2543. J. G. Belasco W. J. Albery and J. R. Knowles Biochemistry 1986 25 2552. lo J. G. Belasco T. W. Bruice W. J. Albery and J.R. Knowles Biochemistry 1986 25 2558. " J. G. Belasco T. W. Bruice L. M. Fisher W. J. Albery and J. R. Knowles Biochemistry 1986 25 2564. W. J. Albery and J. R. Knowles Biochemistry 1986 25 2572. '3 G. Rudnick and R. H. Abeles Biochemistry 1975 14 4515. 303 304 D. Gani with increasing substrate concentration. When the concentration of substrate was increased still further the enzyme showed saturation kinetics and the initial rate was unaffected by substrate concentration. At high substrate concentration the enzyme entered the oversaturated regime where an increase in substrate concentra- tion led to a decrease in the reaction velocity after the initial phase where the rates were the same. Given that all trivial explanations for the observation of an oversatur- ated regime can be discounted Knowles suggested6 that at high substrate concentra- tion the amounts of free E and E2 were small and thus the interconversion of the free enzyme from the product releasing form (E2) to the substrate binding form (E,) became rate-limiting Scheme 1.k2 EIP r EZP Scheme 1 Using the tracer perturbation method which involves measurement of the time- dependent distribution of radiolabelled substrate and product initially at equili- brium when the system is perturbed by the addition of a large amount of one of the unlabelled substrates Knowles was able to estimate the rate constant for the enzyme intercon~ersion.~ Furthermore it was shown that the enzyme is bound-state saturated and thus the rate determining step for interconversion does not involve k4 and k-4 for the saturated regime but rather steps 1-3.In a further two papers’.’ using [2-2H]- and [2-3H]-substrates Knowles showed that the transition state that involves the protonation and deprotonation of proline the TS of step 2 (Scheme 2) must be at least partially rate-limiting. To test for the concertedness of step 2 a double fractionation experiment was undertaken.’ The results indicated that the on/off rates for the substrate and product were faster than the racemization step and that either the racemase reaction proceeded in a concerted manner or that the Substrate Product J H Step 1 --b c- Scheme 2 Enzyme Chemistry 305 reaction was stepwise and involved catalytic groups such as thiols with ground-state fractionation factors of about 0.5.The fractionation factors of the protons bound to the essential catalytic groups of proline racemase were determined using two competitive deuterium wash-out experiments." The results allowed Knowles and co-workers to conclude that two thiol groupsI4 of cysteine residues mediate enzymic racemization. These findings confirmed earlier proposals by Abeles.13 In order to probe the nature of the interconversion of the two unliganded forms of proline racemase,' a number of experiments including competitive deuterium wash-out were conducted under oversaturating conditions where it has been shown that this interconversion was rate lirnitir~g.~?~ The results supported a stepwise mechanism for the interconversion of the free enzyme forms in which a proton is abstracted from a bound water molecule to give a reaction intermediate possessing a hydroxide ion bound to the diprotonated form of the enzyme Scheme 3.H H H I 0 I 0 H' Scheme 3 E2 Finally Albery and Knowles collated the results from their studies of proline racemase to allow the construction of the complete free energy profile of the reaction for the unsaturated saturated and oversaturated regimes.12 The pyridoxal 5'-phosphate-dependent enzyme alanine racemase has been the subject of much attention from Walsh and his co-workers. The biosynthetic enzyme encoded by the alr gene of Salmonella typhimurium has now been purified and characterized" and compared to the catabolic enzyme encoded by the dad B The two enzymes share 43% amino acid sequence homology" and active- site decapeptides of each enzyme which contain lysine are identical.The biosynthetic enzyme was inhibited through treatment with both D-and L-P-haloalanines to give a ternary inactivated enzyme ~omplex'~ similar to that of the catabolic enzyme,19 Scheme 4. Walsh has also studied alanine racemase from Gram-positive bacteria.*' Recently these studies have been extended to the enzyme from Bacillus stearothermophilus where the gene has now been cloned and expressed in E. coli21 Investigation of the time-dependent inhibition of the enzyme with both antipodes of ( 1-aminoethy1)phos-phonate the phosphonate analogues of alanine reyealed that inhibition was due l4 R.J. Szawelski C. W. Wharton and S. White Biochem. SOC.Trans. 1982 10 232. l5 N. Esaki and C. T. Walsh Biochemistry 1986 25 3261. 16 S. A. Wasserman E. Daub P. Grisafi D. Bolstein and C. T. Walsh Biochemistry 1984 23 5182. l7 B. Badet D. Roise and C. T. Walsh Biochemistry 1984 23 5188. l8 N. G. Galakatos E. Daub D. Botstein and C. T. Walsh Biochemistry 1986 25 3255. 19 D. Roise K. Soda T. Yagi and C. Walsh Biochemistry 1984 23 5195. 20 B. Badet and C. Walsh Biochemistry 1985 24 1333. 21 K. Inagaki K. Tanizawa B. Badet C. T. Walsh H. Tanaka and K. Soda Biochemistry 1986,25,3268. 306 D. Gani H H H 1 1 T' -N+ Me H I H Scheme 4 to the formation of non-covalent slowly dissociating enzyme-inhibitor complexes.22 Interestingly the time-dependent loss of activity by this inhibitor appears to be general for alanine racemases from Gram-positive bacteria" but not from Gram- negative bacteria to which the racemases are not s~sceptible.'~"~~~~~~~ 3 Other mridoxal Phosphate-dependent Enzymes The identification of structure (l) Scheme 4 as the heat hydrolysis-denatured product of the inactivated complexes formed from ~acemase,'~~'~ tran~aminase,~~ and decarb~xylase~~ enzymes and P-nucleofuge-substituted alanines (2; X = F C1 OSO or OAc) tends to suggest that the depicted inactivation mechanism is general.However it should be pointed out that these suicide substrates all lack a distal enzyme-binding group after the elimination of HX has occurred and thus there may be less translationary restriction than for suicide inhibitors containing additional active-site binding groups e.g.(S E ) -4-amino-5-fluoropent-2-enoic acid.26 These suicide substrates may be unable to dissociate in order to become involved in enamine condensation with the coenzyme aldamine and thus could potentially act 22 B. Badet K. Inagaki K. Soda and C. T. Walsh Biochemistry 1986 25 3275. 23 E. Wang and C. Walsh Biochemistry 1978 17 1313. 24 H. Veno J. J. Likos and D. E. Metzler Biochemistry 1982 21 4387. 25 J. J. Likos H. Veno R. W. Feldhaus and D. E. Metzler Biochemistry 1982 21 4377. 26 R. B. Silverman B. J. Invergo and J. Mathew J. Med. Chem. 1986 29 1840. Enzyme Chemistry as Michael acceptors for enzyme-bound nu~leophiles.~~~~~ Clearly the structures of several more inactivated ternary complexes need to be determined before a single inactivation mechanism can be assumed general.Recently Grigg has presented a new perspective of pyridoxal chemistry relevant to enzymic inhibiti~n.~’ Churchich has studied homogeneous porcine brain glutamate decarboxylase.28 The enzyme catalyses a slow decarboxylative transamination reaction with L-glutamic acid at ca. lop4times the rate of normal a-decarboxylation to give succinic acid semialdehyde and presumably inactive apoenzyme-PMP. Treatment of the inactive enzyme with phosphopyridoxyl-ethanolaminephosphate restores activity through formation of pyridoxal5’-phosphate. This reaction (Scheme 5)is mechanisti- cally interesting and shows similarities to observations reported by Riva and co- worker~.~~.~’ Gani has shown that L-methionine decarboxylase from the fern species Dryopteris felixmas has a wide substrate specificity and catalyses the decarboxylation of H H H 1 1 TEnz Me -NH, Active Ct H H Scheme 5 27 P.Armstrong D. T. Elmore R. Grigg and C. H. Williams Biochem. SOC. Trans. 1986 14 404. 28 S. Y. Chai and J. E. Churchich Eur. J. Biochem. 1986 160 515. 29 F. Eva D. Carolti A. Giartosio and C. Turano J. Biol. Chem. 1980 285,9230. 30 D. Carolti F. Riva R. Santucci F. Ascoli and P. Fasella Eur. J. Biochem. 1982 124 589. 308 D. Gani L-methionine with retention of configuration at C-2.31Christen and co-workers have shown that chicken mitochondrial aspartate aminotransferase catalyses the stereo-specific exchange of the c-4'-pro-s hydrogen of [4'-3H]-pyridoxamine 5'-phosphate with solvent in the absence of ketoacid substrate.32This result will be of particular use in investigating the acid-base properties of C-4' and the modulating effects of the active-site environment independently of aldimine and/or ketimine formation.Gehring has investigated the mechanism of the mitochondrial chicken heart enzyme using cryoenzymological methods.33In the cryosolvent (80% methanol) the kinetic parameters for the overall reaction with the substrates cysteine sulphinate and oxaloacetic acid were essentially unaltered. At -44 "C mixing PLP-holoenzyme and substrate resulted in the formation of an intermediate absorbing at 430nm (probably the external aldimine) which decayed in a biphasic process.Quinoid formation was not observed indicating that protonation at C-4' is not rate-limiting (Step 3 Scheme 6) and /or that the equilibrium strongly favours the aldimine. Further analysis of the kinetic data indicated that hydrolysis of the ketamine is probably rate-limiting (step 4 Scheme 6). "r"" NH2 L RljjCo; Step 1 Step 2 PLP-Holoenzyme-Substrate -+ H H 430 nm 490 nm 11~:~ RDS "r" NH2 RYco2-i. Step 4 H\ RDS He "H PMP-Holoenzyme-Product H 340 nm Scheme 6 " D. E. Stevenson M. Akhtar and D. Gani Tetrahedron Lett. 1986 27 5661. 32 H. P. Tobler P. Christen and H. Gehring J. Biol.Chem. 1986 261 7105. 33 H. Gehring Eur. J. Biochem. 1986 159 291. Enzyme Chemistry 309 The differential inhibition of the porcine heart enzyme with D-and L-hydrazinosuccinate has been studied recently.34 The inhibition of L-enantiomer was found to involve a two-step inactivation mechanism in contrast to that for the D-antipode and resulted in a lower inhibition constant. Morino and co-workers have identified the 4’-H internal aldimine ‘H-n.m.r. chemical shift value for both cytosolic and mitochondrial aspartate amin~transferase.~’ Remarkably the resonance for 4’-H of the cytosolic holoenzyme showed no variation with pH whereas the chemical shift of the mitochondrial holoenzyme varied considerably with pH reflecting significant differences in the respective coenzyme microenvironments.Comparison of the tryptophan synthase and tryptophanase reactions has been investigated by Miles.36 These workers were interested in establishing why the synthase although capable of catalysing several similar p-elimination and P-replace- ment reactions to tryptophanase was not apparently able to catalyse the elimination of indole from L-tryptophan the physiological reaction for tryptophanase Scheme 7. Careful examination of the tryptophanase-free synthase both in the and p2 complexes revealed that L-tryptophan was indeed converted into indole pyruvate and ammonia. H H H + Scheme 7 In a further mechanistic study to assess substrate binding using ‘’F-n.m.r. spectro- scopy Miles showed that D-and ~-5-fluorotryptophan tryptophan and (3s)-2,3-dihydro-5-fluorotryptophanare all slowly isomerized by racemization-epimerization reaction^.^' These reactions occur lo3-10’ times more slowly than the &replacement and p-elimination reactions.Possible mechanisms for proton translocation during the racemization-epimerization process a single base swinging door or a two-base system vide supra are discussed in the light of recent findings with other PLP- dependent enzymes.38 34 R. Yamada Y. Wakabayashi A. Iwashima and T. Hasegawa Biochim. Biophys. Actu 1986,871 279. 35 Y. Morino F. Nagashima S. Tamase M. Yamasaki and T. Higaki Biochemistry 1986 25 1917. 36 S. A. Ahmed B. Martin and E. W. Miles Biochemistry 1986 25 4233. 37 E. W. Miles R. S.Phillips H. J. C. Yeh and L. A. Cohen Biochemistry 1986 25 4240. S. A. Ahmed N. Esaki H. Tanaka and K. Soda Biochemistry 1986 25 385. 310 D. Gani Recently Matthews has studied synergism in the folding of b double mutant of the a subunit of tryptophan synthase from E. COZ~.~~ Using ultraviolet difference spectroscopy and urea-induced unfolding techniques two single inactive mutant proteins Tyr-175 + Cys and Gly 211 + Glu and the active double mutant Cys- 175/Glu-211 were examined. The sum of the changes in stability for the single mutants was found not to be equal to the change observed for the double mutant. As an equality would be expected only if the residues at positions 175 and 211 did not inter-react Matthews concluded that a structural interaction occurred.Kinetic studies revealed that the synergism occurs only after the final rate-limiting step of domain association. Nihira and co-workers have studied the catalytic role4' of an essential tyrosine residue4' in tryptophanase using chemical modification techniques. It appears that the tyrosine is involved in coenzyme binding probably through an H-bonding interaction with the pyridine heteroatom. Although the modified holoenzyme is able to catalyse transaldimination in the presence of substrate C" -H labilization does not occur. 4 Carboxylation Reactions Transcarboxylase is a biotin-dependent enzyme which catalyses the reversible forma- tion of (S)-methylmalonyl CoA from propionyl CoA (using oxaloacetic acid as a source of carbon dioxide) in two steps involving the intermediacy of carboxybiotin Scheme 8.The reaction is unique among biotin-dependent enzymes in that it is not driven by ATP and bicarbonate. The kinetic mechanism is two-site ping-pong and the reaction has an overall equilibrium constant of about 1. COSCoA COSCoA 0 Transcarbox ylase M,i-H + ,&/co2- + Me+-CO; + via H -02c H Scheme 8 In order to gain insight into the mechanism of the carboxylation of pyruvate to oxaloacetate catalysed by the enzyme Knowles measured the deuterium ["( V/ K)] and l3C [13( V/K)] isotope eff e~ts.~~ By comparison of the slopes of double-reciprocal plots of the initial rates obtained using [2H,]pyruvate and unlabelled material as substrates D( V/K)was found to be 1.39.The I3C kinetic isoWpe effect for carboxy- lation was found to be 1.0227 when measured using the competitive method. These results together suggested concerted or balanced stepwise mechanisms for the carboxylate reaction. In order to determine whether the removal of the proton from 39 M. R. Harte N. B. Tweedy and C. R. Matthews Biochemistry 1986 25 6356. 40 T. Kakizono T. Nihira and H. Taguchi Biochem. Biophys. Res. Commun. 1986 137 964. 41 T. Nihira T. Toraya and S. Fukui Eur. J. Biochem. 1981 119 273. 42 S.J. O'Keefe and J. R. Knowles Biochemistry 1986 25 6077. Enzyme Chemistry 311 pyruvate and the addition of the carboxyl group occur in the same or different steps Knowles made use of the double-isotope fractionation test.This method predicts that the ‘3C-isotope effect for carboxylation will decrease in magnitude when protium is replaced by deuterium in the methyl group of pyruvate if the overall reaction occurs via a stepwise mechanism. Such a decrease would occur because the C-C bond formation step would be less rate-limiting in a system where the free energy at the transition state for C-H bond cleavage was increased. A concerted mechan- ism however would predict no change in the observed I3C isotope effect. Knowles observed that the value of 13( V/ K) dropped from 1.0227 (for undeuteriated sub- strate) to 1.0141 (for deuteriated pyruvate) and thus the results clearly indicated that the reaction was stepwise. The stereochemistry of the carboxylation of phosphoenolpyruvate catalysed by phosphoenolpyruvate carboxykinase from both chicken liver and Ascaris (helminth) muscle has been investigated by Nowak using (2)-3-fluorophosphoenolpyruvate.43 Analysis of the carboxylated products which had not incorporated deuterium through enolization using 19F-n.m.r.spectroscopic techniques showed that carboxylation had occurred at the 3-si face of enzyme-bound substrate. These results parallel those obtained by Roseu using specifically labelled [3-’H,3H]-phosphoenolpyruvate and the enzyme from pigeon liver. Frey and co-workers have studied the stereochemical course of the phosphoenol- pyruvate carboxykinase reaction using inosine 5‘4 3-thiotriphosphate) (ITP,S) as the ~ubstrate.~’ Incubation of the rat liver cytosolic enzyme with (Rp)-[ y-1802] ITP,S and oxaloacetate gave (Sp)-thio[180]phosphoenolpyruvate.Thus the reaction proceeded with overall inversion at the phosphorus atom as for the mitochondria1 enzyme46 indicating that an odd number of phosphoryl transfers (probably one) were involved in the reaction.The catalytically essential cysteine residue in phos- phoenolpyruvate carboxylase has been tentatively identified through protection studies with the substrate analogue 2-pho~pholactate.~~ The oxygen dependence of vitamin K-dependent carboxylase has been studied by S~ttie.~~ The carboxylase reaction of ribulose 1,5-bisphosphate carboxylase/oxy- genase has been investigated by Schloss using deuteriated and tritiated substrates for the enzymes from spinach and Rhodospirillum r~brum.~~ With the spinach enzyme isotope effects at high pH on V,, and V/K did not vary with C02 concentration from K to 100 times K,.This result was interpreted in favour of a mechanism whereby Cot adds to the ene-diol of ribulose bisphosphate in a Theorell-Chance- type bimolecular manner after abstraction of the C-3 proton of the sugar bisphos- phate. The isotope effect on V,, was found to be pH-dependent 2 at high pH up to about 9 at low pH. Inhibition by the substrate analogue xylulose 1,5-bisphosphate was also pH-dependent. In contrast to the spinach enzyme both V,, and V/K 43 S. H. Hwang and T. Nowak Biochemistry 1986,25 5590. 44 I. A. Rose E. L. O’Connell P. Noce M. F. Utter H. G. Wood J. M. Willard T. G. Cooper and M. Benziman J.Biol. Chem. 1969 224 6130. 45 J. M. Knopka H. A. Lardy and P. A. Frey Biochemistry 1986 25 5571. 46 K. F. Sheu H. T. Ho L. D. Nolan P. Mankovitz,J. P. Richard M. F. Utter and P. A. Frey Biochemistry 1984 23 1779. 47 S. Ishijima K. hi and H. Katsuki J. Biochem 1986 99,1299. 48 J. J. McTigue and J. W. Suttie FEBS Lett. 1986 200 71. 49 D. E. Van Dyk and J. V. Schloss Biochemistry 1986 25 5145. 312 D.Gani were found to be pH-dependent for the enzyme from R. rubrum. From this data Schloss suggested that both enzymes contain an essential base of about pK 7.5 probably imidazole of histidine or e-NH2 of lysine which abstracts the C-3 proton in the first step of the reaction. Pierce and coworkers have shown that the enzymic reaction proceeds via the ordered addition and enolization of ribulose bisphosphate followed by reaction with gaseous C02.50 The inability to detect an enzyme-C02 complex directly by 13C-n.m.r.spectroscopy in these studies supports the view that a Theorell-Chance type mechanism (no Michaelis complex for C02) occurs.49 5 Coenzyme BIz-dependent Rearrangements The stereochemical course of the reaction catalysed by coenzyme B12-dependent 2-methyleneglutarate mutase (Scheme 9) has been investigated by Buckel.'l H Isomerase Mutase -___, MeIco; Me CO; D2O D2O c CO2H (2s) Scheme 9 In order to determine the absolute configuration of biologically active 3-methyl- itaconic acid the racemic material was incubated with a cell-free extract of Clos-trzdiurn barkeri until half was consumed.Re-isolated methylitaconic acid gave a specific optical rotation of [a12 + 3.58" indicating by comparison with published values that the absolute configuration at C-3 was (S). The (R)-antipode was synthesized using the light-inactivated cell free extract; AdoCbl-dependent enzymes are light sensitive. This preparation contained an isomerase activity which was able to convert 2,3-dimethylmaleic acid into (3R)-3-methylitaconic acid [a]',"-3.53" via si-face protonation. Thus the biologically active isomer possessed (3R) -absolute stereochemistry. To determine the stereochemical course of the rearrange- ment of (3 R)-3 -methylitaconate to 2-methyleneglutaride the cell-free extract in J. Pierce G. H. Lorimer and G. S.Reddy Biochemistry 1986 25 1636. 5' G. Hartrampf and W. Buckel Eur. J. Biochem. 1986 156 301. Enzyme Chemistry 313 deuterium oxide was incubated with 2,3-dimethylmaleic acid. The resulting deuteri- ated 2-methyleneglutaric acid was isolated purified and oxidized with nitric acid to give deuteriated succinic acid. Comparison of the CD spectrum of the succinic acid with published data revealed that the sample possessed (2s)-absolute stereochemistry and thus the migration of the acryloyl group had occurred with inversion of configuration at C-3 of the substrate. This stereochemical result is similar to that for glutamate mutase but differs from that of methylmalonyl CoA mutase. Retey has recently investigated some of the unusual side reactions observed with methylmalonyl CoA m~tase.~~ Using homogeneous enzyme preparations and prepar- ations contaminated with methylmalonyl CoA epimerase Retey was able to show that the previously observed high wash-out of labels3 from methyl- and ethyl-malonyl CoA substrates54 and low wash-in of solvent label resulted from three combined factors.Infidelity of the mutase with respect to radical abstraction of the 3-pro-R and 3-pro-S H-atoms high intramolecular isotopic discrimination and contamination with the epimerase Scheme 10. Thus where a deuterium atom only occupies the preferred 3-pro-R position the isotope effect and steric preference work against each other and a significant amount of substrate is turned over uia abstraction of the 3-pro-S protium atom.Some of the label in this product then occupies the acidic position of methylmalonyl CoA which is rapidly exchanged with solvent protium. If deuterium occupies the 3-pro-S position where both steric preferences and the isotope effect favour the removal of the 3-pro-R hydrogen the deuterium will end up almost entirely in an exchangeable position. R I 5 *H *H COSCoA *H ,COSCoA *H-hCO; eco; *H OH *H OH R \ I *H major Przzi!tion 2 pathway 2 5 OH COSCoA pro-S-H migration C0; *-__-_ *-----*H-* minor pathway *H OHs QH Solvent proton R.=5’-deoxyadenosyl-5’-radical exchange Scheme 10 52 K. Wolfe M. Michenfelder A. Konig W. E. Hull and J. Retey Eur. J. Biochem. 1986 156 545. 53 A. Gaudemer J.Zylber N. Zylber M. Baran-Harszac W. E. Hull M. Fountaoulakis A. Konig K. Wolfe and J. Retey Eur. J. Biochem. 1981 119 279. 54 J. Retey E. H. Smith and B. Zagalak Eur. 1. Biochem. 1978 83 437. 314 D. Gani Leadlay has recently studied the subunit structure of the mutase from Propionibac-terium sherma n ii. 6 Redox Reactions The chemistry and structure of NAD(P)-dependent alcohol dehydrogenase have been reviewed by Biellmann.56 Recent work by Biellmann5’ has examined the effect of the modified coenzyme 3-benzoylpyridine-adeninedinucleotide upon the catalytic properties of horse liver alcohol dehydrogenase. In the modified system only primary alcohols are accepted as substrates. Kroneck has studied the flavin-dependent alcohol oxidase of yeast.58 This enzyme converts lower alcohols and oxygen into the corresponding aldehydes and hydrogen peroxide.Kinetic data obtained using methanol and deuteriomethanol as substrates under both single and multiple turnover conditions allowed a four-step mechanism to be proposed (1) formation of a Michaelis complex between the enzyme and the alcohol; (2) partially rate-limiting scission of the substrate C-H bond; (3) reaction of the reduced enzyme-aldehyde complex with dioxygen; and finally (4) dissociation of the product from the reoxidized enzyme complex at a rate slow enough to affect the overall reaction rate. The C-H bond cleavage appears to occur homolyti- ally.^^,^^ Ghisla has investigated the kinetic properties of acyl CoA dehycrogenase from pig kidney using a range of deuteriated butyryl CoA substrates labelled at C-2 and C-3 and in both positions.60 In turnover catalysis isotope effects of 2 3.6 and 9 were observed for each substrate respectively while in the reductive half-reaction the corresponding values were 2.5 14 and 28.No intermediates were apparent during the reduction of oxidized enzyme to the presumed reduced enzyme crotonyl CoA complex indicating a high degree of concertedness during C-2-H and C-3-H bond rupture. The results are compatible with a mechanism in which simultaneously the C-2 hydrogen is removed as a proton and the C-3 hydrogen is transferred to the flavin as hydride. Dihydroorotate dehydrogenase61 and dihydroorotate oxi- dase62,63appear to catalyse reactions via a stepwise hydride-transfer mechanism.Glutathione reductase is a disulphide-containing flavoprotein for which the X-ray crystal structure has been determined.64965 Lively and McFarland have studied the structure of the EH2 intermediate that is formed on reaction of the flavoprotein with NADPH using resonance Raman spectroscopy.66 The EH2 species is important as it is kinetically competent for the reaction with glutathione. The EH intermediate is an oxidized flavin and furthermore s5 F. Francalanci N. K. Davis J. Q. Fuller D. Murfitt and P. L. Leadlay Biochem. J. 1986 236 489. 56 J. Biellmann Acc. Chem. Res. 1986 19 321. 57 J. Samama D. Hirsch P. Gaulas and J. Biellmann Eur. J. Biochem. 1986 159 375. 58 J. Geissler S. Ghisla and P. M. H. Kroneck Eur.1.Biochem. 1986 160 93. 59 B. Sherry and R. H. Abeles Biochemistry 1985 24 2594. 60 B. Pohl T. Raichte and S. Ghisla Eur. J. Biochem. 1986 160 109. 61 P. Blattrnann and J. Retey Eur. J. Biochem. 1972 30 130. 62 R. A. Pascal N. Trang A. Cerami and C. T. Walsh Biochemistry 1983,22 171. R. A. Pascal and C. T. Walsh Biochemistry 1984 23 2745. 64 G. E. Schulz R.H. Schirmer and E. F. Pai J. Mol. Bid. 1982 160 287. 65 E. F. Pai and G. E. Schulz J. Biol. Chem. 1983 258 1752. 66 C. R. Lively and J. T. McFarland Biochem. Biophys. Res. Commun. 1986 136 22. Enzyme Chemistry the most likely structure involves charge transfer donation of electrons from the thiolate anion of Cys-63 to the N-5 flavin heteroatom (cf. ref. 1). Dihydrolipoamide dehydrogenase a related protein has now been purified from Halobacterium h~lobiurn.~~ This enzyme is not (unusually) associated with 2-oxoacid dehydrogenase multienzyme complex.Recently Walsh has described a new member of the disulphide-containing flavoprotein group that includes lipoamide dehydrogenase and glutathione and mercuric reductase which reduces the macrocyclic disulphide trypanothione to the dithiol. The new enzyme trypanothione reductase shows considerable active-site peptide amino-acid homology with glutathione reductase.68 Walsh and co-workers have also investigated the interaction of the EH form of mercuric reductase with Hg2+.69 Although the substrate (Hg2+) is bound very tightly by the active-site thiol groups of the reduced enzyme no reduction of the substrate occurs unless additional reducing equivalents are provided.Lindskog has recently published the results of rapid-scan stopped-flow studies of the pH-dependence of the reaction between the enzyme and NADPH.70 Rate constants and isotope effects are reported. Mercuric reductase is the second enzyme in the microbial mercury detoxification pathway. The first organomercurial lyase catalyses the protonolysis of carbon mercury bonds Scheme 11. 0rganornercurial lyase R-Hg-X R-H+HgZ+ Mercuric reductase HgZ+ -* Hg O NADPH NADP’ Scheme 11 Walsh has overproduced the lyase to the level of 3% of the soluble cell protein in E. coli by a construction using the l7 promoter. The homogeneous enzyme is a monomer (M 22 400) and requires no detectable cofactors or metal ions.71 The enzyme is able to catalyse protonolysis of the C-Hg bond in a wide range of organomercurial salts including primary secondary and tertiary alkyl vinyl allyl and aryl mercurials to give the hydrocarbon and mercuric ion at turnover rates in the range 1-240 min-’.Walsh has studied the mechanism of the enzymic reaction using a wide range of structurally diverse organomercury substrate^.^ The protonoly- sis products are summarized in Scheme 12. The results indicate that the enzyme operates via an SE2 mechanism and thus is novel in this respect. Ferry Walsh and co-workers have also investigated the mechanism of the 5-deazaflavin coenzyme F,,,-dependent formate dehydrogenase rea~tion,’~ Scheme 67 M.T. Danson A. McQuatties and K. J. Stevenson Biochemistry 1986 25 3880. 68 S. L. Shomes A. H. Fairlamb A. Cerami and C. T. Walsh Biochemistry 1986 25 3519. 69 S. M. Miller D. P. Ballou V. Massey C. H. Williams and C. T. Walsh J. Biol. Chem. 1986 261 8081. 70 L. Sahlman A. Lambeir and S. Lindskog Eur. J. Biochem. 1986 156 479. 71 T. P. Begley A. E. Walts and C. T. Walsh Biochemistry 1986 25 7186. 72 T. P. Begley A. E. Walts and C. T. Walsh Biochemistry 1986 25 7192. 73 N. L. Schauer J. G. Ferry J. F. Homek W. Orme-Johnson and C. Walsh Biochemistry 1986,25,7163. 316 D. Guni HgCl H Scheme 12 13. The enzyme is specific for the si-face hydride transfer to C-5 of F420 and thus joins three other F,,,-recognizing methogen enzymes in this stereospecificity.While catalysis probably occurs via hydride-transfer from formate to the enzyme to generate an EH2 species and then by hydride-transfer back out to coenzyme F420 the formate-derived hydrogen exchanges with solvent hydrogen before transfer to F42p The kinetics of hydride-transfer from formate revealed that the step was not rate- limiting suggesting that an internal electron transfer may be. Villafranca has determined kinetically the order of substrate binding for the dopamine P-hydrolylase reaction using a range of substrates of differing structure including unlabelled and [2,2-2H2]tyramine.74 The results suggested that the reaction occurred via a ping-pong mechanism in which tyramine binds to the enzyme after the release of oxidized ascorbate.Subsequently oxygen binds to form a ternary complex. Benkovic and co-workers have studied iron-binding in phenylalanine hydroxylase (the enzyme which catalyses the conversion of phenylalanine into tyrosine) using e.p.r. spectro~copy.’~ It appears that iron can be bound in two environments which are both populated in the crude enzyme. The two environments are not interconvert- ible. Benkovic has also reported on studies of phenylalanine hydroxylase from Chromobacterium viol~ceum.~~ This pterin-dependent enzyme is a copper-containing 74 P. F. Fitzpatrick M. R. Harpel and J. J. Villafranca Arch. Biochem. Biophys. 1986 249 70. 75 L. M. Bloom S. J. Benkovic and B. J. Gamey Biochemistry 1986 25 4204. 76 S.0. Pember J. J. Villafranca and S. J. Benkovic Biochemistry 1986 25 6611. Enzyme Chemistry F420 Fo R=H monooxygenase which contains 1 mole of Cu2+ per mole of enzyme. The enzyme shows some features in common with the mammalian iron-containing enzyme such as the intermediacy of the 4a- hydrate of 6-methyltetrahydropterin suggesting that the mechanism of oxygen activation is similar for both enzymes. The copper-containing monooxygenase tyrosinase has been reported to catalyse 7-an unusual oxidative decarboxylation of 3,4-dihydroxymandelate. ' ' A mechanism for the reaction has been proposed. Muller has investigated the role of active-site residues in the p-hydroxybenzoate hydroxylase reaction by chemical modification and sequence determination.Residues 343-5 Ser-Trp-Trp were previously assigned erroneo~sly.'~ Ghisla and co-workers have described the preparation and properties of 6-substituted flavins as active-site probes for flavin enzymes" and Ghisla and Massey have reviewed the use of such probes.*' Severin et al. have reviewed the chemistry of the dehydrogenases of a-ketoacids.81 Finally Walsh has studied reactions cata- lysed by the flavoenzyme cyclohexanone oxygena~e.~~~ In the oxidation of a chiral boronic acid the chiral secondary alcohol is produced with complete retention of configuration Scheme 14.82 It appears that enzyme-bound FAD-4a-OOHS3 is the actual oxygenation agent in this versatile and probably prototypic biological Bayer- Villiger catalyst. The enzyme is also reported to catalyse the oxidation of organoselenides to ~elenoxides.~~ Enzymically-formed allylic selenoxide rearranged in a 2,3-sigmatropic 77 M.Sugumaran Biochemistry 1986 25 4489. 78 R. A. Wijnands W. J. Weijer F. Muller P. A. Jekel W. J. H. \-an Berkel and J. J. Beinlema Biochemistry 1986 25 421 1. 79 S. Ghisla V. Massey and K. Yagi Biochemistry 1986 25 3282. S. Ghisla and V. Massey Biochem. J. 1986 239 1. S. E. Severin L. S. Khailova and V. S. Gomazkova Adu. Enz. Re& 1986 25 347. 82 J. A. Latham and C. Walsh J. Chem. Soc. Chem. Commun. 1986 527. 83 C. C. Ryerson D. P. Ballou and C. Walsh Biochemistry 1982 21 2644. 84 J. A. Latham B. P. Branchaud Y. J. Chen and C. Walsh J. Chem. SOC.,Chem. Commun. 1986 528. 318 D.Gani Scheme 14 manner to give after hydrolysis racemic alcohols. It is not clear that the initial oxidation at selenium is non-enantioselective since selenoxides readily racemize through hydrate formation and this process could outcompete the 2,3-sigmatropic rearrangement rate. The oxygenating component of 2,5-diketocamphane 1,2-monooxygenase from Pseudornonas putida has been purified to homogeneity by Tr~dgill.~~ This enzyme is also a simple flavoprotein and operates in a similar manner to the cyclohexanone oxygenase enzyme. 7 Ammonia-lyase and Dehydrase Enzymes Over the past few years advances in genetic techniques have allowed the convenient determination of the primary structure of enzymes using relatively simple gene nucleic acid sequencing techniques.Very recently the application of these techniques and the comparison of deduced amino-acid sequences have produced exciting results. Aspartase (L-aspartate ammonia-lyase) catalyses the reversible deamination of L-aspartic acid to give ammonia and fumaric acid. The enzyme is thought to follow a carbanion (E 1cb)-type mechanism in which an active-site thiolate86 (from Cys-140 or -43087) abstracts the pro-R-hydrogen as a proton from C-3 before rate-limiting C- N bond cleavage.88 Studies of the binding affinity of transition-state intermediates has suggested that fumarase which catalyses an analogous process with the same stereospecificity but with water instead of ammonia also follows the same mechanistic pathway.88 However no catalytically essential active-site thiolates have been implicated.Compari~on~~.~~ of the deduced amino-acid sequence from two genes for each enzyme has shown that there is a striking degree of homology. Alignment of the sequences shows that the active-site cysteine residues of L-aspartase are replaced by serine and alanine in fumarase Figure lag9 Clearly aspartase and fumarase have evolved from a common gene; it will be interesting to compare the other chemically related members of the group for example 3-methylaspartase. Gani" has shown that this enzyme can utilize substrates containing halogens in place of the methyl group of mesaconic acid the best substrate for the retrophysiological amination reaction and that chiral highly functionalized aspartic acids can be prepared in good yield.The observed suicide inhibition shown by bromofumaric acid has been rationalized (Scheme 15) in terms of the alkylation 85 D. G. Taylor and P. W. Trudgill J. Bacferiol. 1986 165 489. 86 N. Ida and M. Tokushige J. Biochem. 1985 98 793. 87 J. S. Takagi N. Ida M. Tokushige H. Sakamotom and Y. Shimura Nucl. Acids Res. 1985 13 2063. 88 D. J. T. Porter and H. J. Bright 1.Biol. Chem. 1980 225 4772; I. I. Nuiry J. D. Hermes P. M. Weiss C. Chen and P. F. Cook Biochemistry 1984 23. 5168. 89 S.A. Woods J. S. Miles R. E. Roberts and J. R.Guest Biochem. J. 1986 237 547. 90 T. Takagi and M. Kisumi J. Bacreriol 1985 161 1. 91 M. Akhtar M. A. Cohen and D. Gani J. Chem. SOC. Chem. Commun. 1986 1290. 56 Clt G 55 59 i15 114 119 175 173 178 235 233 238 295 293 298 355 353 WLASGPRCGlGEIVlPENEPGSSlMPGKVNPTQSEALTMl~AQ N DlTuVTIMA A &IS GP R d N L LQ AIG S S IMPmK V N P~P~~VflFl;t?lll~G 358 415 413 418 466 461 411 (ReproducedbypermissionfromBiochem.J. 1986,237,547) Figure 1 Alignments of amino acid sequences for the Fume CitG and AspA proteins. The sequences have been aligned for maximum homology based on the DIAGON comparisons. Identical residues shared in two or more of the sequences are boxed. The asterisks mark the methionine histidine and cysteine residues that are conserved in all three sequences the arrows denote the reactive cysteine residues in AspA. The polypeptides are numbered from the residue immediately following the N-terminal methionine D.Gani 320 Enz -Enzl Scheme 15 of an enzyme-bound nucleophile at the active-site by the enzymic amination product 3-bromoaspartic acid. Viola92 has recently shown that L-aspartase contains an activation binding-site for L-aspartate distinct from the active-site. Other substrate analogues which are not substrates can bind to the activation site. The mechanism of the argininosuccinate lyase reaction has been investigated by Rau~hel,~~ Scheme 16. No primary deuterium isotope effect was observed for either V,, or V/K for (2S,3R) -[3-2H,]argininosuccinate while a primary "N isotope effect on V/K of 0.9964 was observed. The "N isotope effect on the equilibrium constant was 1.018. A deuterium solvent isotope of 2.0 was observed on V,,,.The data is consistent with a carbanion mechanism where the C-3 proton abstraction step is not rate-limiting. The inverse "N primary isotope effect and the solvent deuterium isotope effect suggest that protonation of the guanidino group and C-N bond cleavage are kinetically significant. Raushel has also used a new method for the determination of dissociation rates of enzyme-substrate complexes to study the lyase reaction.94 The method which is referred to as 'Dynamic Isotope Exchange Enhancement' involves measuring the 92 W. E. Karsten R. B. Gates and R. E. Viola Biochemistry 1986 25 1299. 93 S. C. Kim and F. M. Raushel Biochemistry 1986 25,4744. 94 S. C. Kim and F. M. Raushel J. Biol. Chem. 1986 261 8163.Enzyme Chemistry Scheme 16 rate of exchange of a labelled product back into substrate during catalysis of the forward reaction when the forward reaction is kept far from equilibrium by the enzymic removal of the non-exchanging product. The values of the ratio of the exchange rate and the net rate for product formation at various concentrations allow estimation of the relative rates of product dissociation from binary and ternary enzyme complexes. Application of this technique led to the conclusion that argininosuccinate-lyase has a random kinetic mechanism. The calculated lower limit for arginine release from enzyme-fumarate-arginine was 0.35 of V,, for arginosuc- cinate formation while the rate of release from the binary complex enzyme-arginine was 210 times V,,,.Schwab has investigated the stereochemical course of the hydration-dehydration reaction catalysed by p-hydroxydecanoyl thioester dehydrase. Synfacial elimina- tion-addition is ~bserved.~’ Schwab has also determined the fate of the N-acetylcys- teamine thioester of 3-decynoic acid a suicide inhibitor for the enzyme,96 Scheme 17. H H I Scheme 17 95 J. M.Schwab A. Habib and J. B. Klassen J. Am. Chem. SOC.,1986 108 5304. 96 J. M. Schwab C. Ho W. Li C. A. Townsend and G. M. Salituro J. Am. Chem. SOC.,1986 108 5309. 322 D. Gani Thorpe and co-workers have disclosed that the flavoprotein medium-chain acyl CoA dehydrogenase from porcine kidney exhibits an intrinsic hydrolase activity towards crotonyl-CoA which leads to the formation of ~-3-hydroxybutyryl-CoA.~~ The hydrolase activity which is FAD or FAD analogue-dependent is about 10-fold lower than the dehydrogenase activity.The activity is not due to contamination. It is proposed that both the activities utilize the same active-site and share some common mechanistic features Scheme 18. R RH I II Dehydrogenase H tH COSCoA *. COSCoA I ‘kH Me H Me -H + \:B-H-B- R R I 0 0 H\. COSCoA H COSCoA M e n H HO +H-B- :B- Scheme 18 8 Proteases and Related Enzymes The seine proteases are a relatively well-studied group of enzymes. Over recent years a detailed picture of the active-site and catalytic mechanism of these enzymes has emerged. Bryan et aL98 working with subtilisin have tested the proposed role of Am-155 as the potential hydrogen-bond donor for the tetrahedral active-site serine-substrate intermediate by replacing asparagine with the isosteric residue leucine using site-directed mutagenesis.Kinetic experiments with the mutant sub- tilisin containing the modified oxyanion hole revealed that K for substrate was unaltered but K,, was 200-300 times lower. These results are consistent with the proposed role of Asn-155 Scheme 19. Meyer et al. have studied the X-ray structure of the product complex of acetyl-Ala- Pro-Ala with porcine pancreatic elastase at 1.65 8 res01ution.~~ Unfortunately the 97 S. Lau P. Powell H. Buettner S. Ghisla and C. Thorpe Biochemistry,1986 25 4184. 98 P. Bryan M.W. Pantoliano S.G. Quill H. Hsiao and T. Poulos Roc. Natl. Acud. Sci. USA 1986 83 3743. 99 E. F. Meyer R. Radpakrishnan G. M. Cole and L. G. Presta J. Mol. Biol. 1986 189,533. Enzyme Chemistry 323 Asn-155 \ N Ser-221 R NH Substrate A Scheme 19 peptide was not present in productive binding mode in the crystal. Abeles"' has synthesized peptidyl fluoromethyl ketones that are specific inhibitors of the serine proteases a-chymotrypsin and porcine pancreatic elastase. By analogy with the corresponding aldehydes it is believed that the fluoromethylketones react with the hydroxyl group of the active-site serine residue to form stable hemiacetals. "F-N.m.r. spectroscopic studies of chymotrypsin-bound trifluoromethyl ketone inhibitors clearly indicate that the carbonyl carbon is tetrahedral at the active-site of the enzyme.Abeles rationalized the observed potency of the transition-state inhibitors (the trifluoro- and difluoro-methyl ketones are better than monofluoro- etc.) in terms of the degree of hydration of the carbonyl group and the pK of the hemiacetal hydroxyl. This latter consideration is important for binding at the anionic hole Scheme 19. Stein has studied the mechanism of inactivation of human leukocyte elastase using the chloromethylketone MeO-Suc-Ala-Ala-Pro-Val-CH2Cl.101 The kinetic data for inactivation suggested that a Michaelis complex was formed initially which reacted reversibly to give a covalent hemiketal. Further reaction via nucleophilic attack by the active-site histidine at the chloromethyl group then gave the fully inactivated enzyme.Abelesio2 has also examined the inactivation of chymotrypsin by 3-benzyl-6- chloro-2-pyrone using X-ray diffraction analysis at 1.9 A resolution. Analysis of the inactivator-enzyme complex showed that the oxygen of active-site Ser- 195 is covalently attached to C-1 of (2)-2-benzylpentenedioicacid that the benzyl group of the inactivator is held in the hydrophobic specificity pocket of the enzyme and that the free carboxylate forms a salt bridge with active-site His-57 (Scheme 20). Bachovchin et ~1"~ have used "N-n.m.r. spectroscopy to examine the H-bonding interactions in the active-site of a-lytic protease. The enzyme was isolated from a histidine-requiring mutant of Lysobacter enzymogenes grown on [i5N-irnidazoZe]his-tidine and thus His-57 the central residue in the catalytic triad was "N-enriched.Spectroscopic analysis of the resting enzyme revealed (in contrast to X-ray diffraction data) that a strong H-bond links the active-site histidine and serine residues. In addition the "N-chemical shifts demonstrated that protonation of the histidine imidazole ring at low pH in the transition-state or similar complexes triggers the 100 B. Imperiali and R. H. Abeles Biochemistry 1986 25 3760. lo' R. Stein and D. A. Trainor Biochemistry 1986 25 5414. 102 D. Ringe J. M. Mottonen M. H. Gelb and R. H. Abeles Biochemistry 1986 25 5633. 103 W. W. Bachovchin Biochemistry 1986 25 7751. 324 D. Gani ___ ~ph H+ 00 I I Ser-195 specificity pocket -on,\ 00Po I H Ser-195 His-57 I IN$ N H Scheme 20 disruption of the aspartate- histidine H-bond.The results suggest a catalytic mechan- ism involving directed movement of the imidazole ring of His-57. Zinc-dependent carbopeptidase A has also been subjected to directed mutagenesis experiments. Replacement of Tyr-248 by phenylalanine has revealed that the phenolic hydroxyl is not required for catalysis although it is probably important for ligand binding. 104,105 Lipscomb has examined the X-ray structure of the enzyme-2- benzyl-4-oxo-5,5,5-trifluoropentanoic acid (trifluoromethyl ketone inhibitor) com- plex.'06 The inhibitor is bound as its hydrate vide supra. The structure has also yielded the first direct interaction of Arg-127 with a zinc-bound oxygen of an inhibitor.Lipscomb has also shown that the Co2+reconstituted enzyme (which has a co-ordination structure essentially identical to the native enzyme as determined by X-ray diffraction) has the same co-ordination environment in crystals and in sol~tion.'~' The stereospecificity of the formation of thiohemiacetal inhibitor complexes has been studied with the cysteine protease papain.'" Both D-and L-N-acetyl phenyl- alanyl [l-'3C]glycinal react stereospecifically with papain and each gives one diastereomer of the thiohemiacetal only. The 13C-n.m.r. chemical shifts are 75.1 and 74.7 p.p.m. respectively. Storer has shown also using 13C-n.m.r. spectroscopy that '3CN-labelled benzoylamidoacetonitrile forms a covalent adduct with the thiol group of cysteine-25 in the active-site of papain.'" It is proposed that the adduct is a thioimidate.104 S. J. Gardell C. S. Craik D. Hilvert M. S. Ordea and W. J. Rutter Noture (London) 1985 317 551. 105 D. Hilvert S. J. Gardell W. J. Rutter and E. T. Kaiser J. Am. Chem. Soc. 1986 108 5298. I06 D. W. Christianson and W. N. Lipscomb J. Am. Chem. Soc. 1986 108 5003. L. C. Kuo W. N. Lipscomb and M. W. Makinen J. Am. Chem. Soc. 1986 108 5003. 108 N. E. MacKenzie S. K. Grant A. I. Scott and J. P. G. Malthouse Biochemistry 1986 25 2293. 109 J. Brisson P. R. Carey and A. C. Storer J. Biol. Chem. 1986 261. 9087. Enzyme Chemistry 325 9 Phosphoryl Transfer Reactions Sowadski has reported on the refined structure of alkaline phosphatase (phos- phomonoester hydrolase EC 3.1.3.1) from E.coli at 2.8 8 resolution."' Alkaline phosphatase is a metalloenzyme that forms an isologous dimer with two reactive centres 32 8 apart. Despite some similarities with the a/P class of proteins the enzyme does not have a characteristic binding cleft at the carboxyl end of the parallel sheet but rather an active pocket that contains a cluster of three functional metal sites. Alkaline phosphatase is a non-specific phosphomonoesterase that hydrolyses small phosphomonoesters as well as the phosphate termini of DNA. The active pocket barely accommodates inorganic phosphate; thus the organic portion of substrates must occupy exposed positions on the surface of the enzyme.Two metal sites M-1 and M-2 3.9 8 apart are occupied by zinc. The third M-3 5 8 and 7 8 away from the other sites is occupied by magnesium or zinc. The imidazole side-chain of histidine residues are ligands to the zinc sites M-1 (three) and M-2 (one). Ligand assignment indicates that sites M-1 M-2 and M-3 correspond to the spectroscopically deduced sites A B and C respectively. The inhibitor arsenate a product analogue binds between Ser-102 and M-1 and M-2. Arg-166 is within H-bonding of the arsenate site. This structural arrangement suggests that despite the lack of protein acid and base functions metals can activate both nucleophiles Ser- 102 and water necessary for double in-line nucleophilic displace- ment on phosphorus Scheme 21.has also studied the metal sites using n.m.r. spectroscopic techniques. The entire primary structure has been rep~rted."~ Enz' Enz+ Enz+ Enz+ R = alkyl or aryl,or H Scheme 21 Hall and Williams have recently studied leaving-group dependence in the phos- phorylation of E. coli alkaline phosphatase using a range of monophosphate ester~."~ The results of these kinetic studies indicate that the leaving groups (alkoxides or phenoxides) bind in a lipophilic site and that the leaving group in the enzyme- substrate complex points away from the surface of the enzyme. Arguments are also advanced to exclude a dissociative mechanism (involving metaphosphate) for the enzyme-catalysed substitution at phosphorus. 110 J. M. Sowadski M.D. Handschumacher H. M. K. Murthy B. A. Foster and H. W. Wyckoff J. Mol. Biol. 1985 186 417. 111 J. E. Coleman K. Nakamura and J. F. Chlebowski J. Eiol. Chem. 1983 258 386. 112 P. Gettins and J. E. Coleman J. Biol. Chem. 1983 258 396. 113 R. A. Bradshaw F. Cancedda L. H. Ericsson P. A. Neuman S. P. Piccoli M. J. Schlesinger K. Schriefer and K. A. Walsh Roc. Natl. Acad. Sci. USA 1981,78 3413. 114 A. D. Hall and A. Williams Biochemistry 1986 25 4784. 326 D. Gani Of related interest Dunaway-Mariano has investigated the regiospecificity and stereospecificity of proton-transfer in the yeast inorganic pyrophosphatase-catalysed rea~tion.''~ The enzyme was shown only to catalyse the hydrolysis of Rp enantiomers of substrate complexes [ e.g.Co(NH3)4PPS]. The reported results are accommodated by a reaction mechanism involving enzyme-mediated proton transfer to the pro-R 0-atom of the incipient phosphoryl leaving-group of the P',p-bidentate Mg(H,O),PP-complex Scheme 22. -+ Em-? H I / H-&Enz Pro-R Scheme 22 Frey'16 has shown that the transfer of the terminal thiophosphate group of chirally labelled [ y-'702180]ATPS in the mevalonate-5-diphosphate decarboxylase reaction proceeds with overall inversion of configuration of phosphorus Scheme 23. Culp et a!."' have shown that the active-site residue of bovine intestinal 5'-nucleotide phosphodiesterase is threonine.' l7 This is the first reported example of the involvement of threonine in covalent phosphoryl enzyme intermediates.Potter' l8 has shown the enzyme-catalysed reaction proceeds with retention of configuration at phosphorus as is expected for double-transfer reactions. The crystal structure of RNase A complexed with d(pA) has been examined by McPherson et a/.at 2.5 8,re~olution."~ The analysis reveals many important interac- tions and explains why the protein can cover or protect 11-12 base segments within long strands of nucleic acid. Over the recent past many groups have turned their attention to the mode of action of E. coli DNA polymerase I. The enzyme has five activities and catalyses polymerization pyrophosphorolysis pyrophosphate exchange 3' +5' exonu-cleolytic degradation and 5' .-+ 3' exonucleolytic degradation. Polymerization pyrophosphorolysis and PPi exchange are associated with the polymerase activity and indeed pyrophosphorolysis and PP exchange are reverse reactions.Limited proteolysis of DNA Polymerase I (Pol I) results in cleavage of the protein into a 115 I. Lin W. B. Knight A. Hsueh and D. Dunaway-Manano Biochemistry 1986 25 4688. 116 P. Iyengar E. Cardemil and P. A. Frey Biochemistry 1986 25 4693. 117 J. S. Culp H. J. Blytt M. Itermodson and L. G. Butler J. Biol. Chem. 1985 260 8320. J. E. Cummins and B. V. L. Potter Biochem. SOC.Trans. 1986 14 1289. 119 A. McPherson G. D. Brayer and R. D. Morrison J. Mol. BioL 1986 189 305. Enzyme Chemistry m N 328 D. Gani large (Klenow) fragment and a small fragment. The Polymerase and 3’ -+ 5’ exonu-clease activities are associated with the Klenow fragment (KF) while 5’ --* 3’ exonu- clease activity is displayed by the small fragment.Only the mechanistic properties of the Klenow fragment will concern us here. Polymerization proceeds in the 5’ -+ 3’ direction and requires a template strand a 3’-hydroxy primer terminus and 2’-deoxynucleoside 5’-triphosphates. Synthesis of the chains antiparallel to the template is a direct consequence of the initial antiparallel orientation of the primer strand to the template Scheme 24. P/ Template DNA Scheme 24 The 3’ -+ 5’ exonuclease activity is thought to edit-out mismatched base-pairs at the primer terminus before further polymerization (see Kornberg’” for further background). The amino-acid sequence of the protein has been reported12‘ and the X-ray crystal structure of the complex with thymidine monophosphate has been obtained at 3.3 8 resolution.’22 Brody and Fre~’~~ have shown that the polymerase reaction occurs with overall inversion of configuration at the a-P-atom of the incoming dNTP while Benk~vic’~~ has shown that the 3’ -+ 5’ exonuclease activity (hydrolysis of the phosphate diester) also proceeds with overall inversion.Thus both processes probably involve direct one-step phosphoryl transfers. Benkovic has also investigated the mechanism of activities associated with poly- merization. Using the Klenow fragment it was shown that dTTP and corresponding a-thiotriphosphate (dTTPa S) were incorporated at equal initial rates during tem- 120 A.Kornberg ‘DNA Replication’ Freeman San Francisco 1980. 121 C. M. Joyce W. S. Kelley and N. D. F. Grindley J. Biol. Chem. 1982 257 1958. 122 D. L. Ollis P. Brick R. Hamlin N. G. Xuong and T. A. Steitz Nature (London) 1985 313 762. 123 R. S. Brody and P. A. Frey Biochemistry 1981 20 1245. 124 A. P. Gupta and S. J. Benkovic Biochemistry 1984 23 5874. Enzyme Chemistry 329 plate-directed synthesis thus indicating that a chemical step was not rate-1imiti11g.l~~ Further positional isotope exchange experiments showed that no label from [u-~*O~] dATP (labelled in the bridging position) entered a non-bridging position at the &phosphorus atom at dATP during template-directed reaction catalysed by Pol I indicating that PPi release rapidly follows the chemical step.The stereochemical course of PP exchange was found to occur with overall retention of configuration. Thus PPi attack on the elongated primer must occur with inversion of configuration since polymerization is known to proceed with inversion vide supra. Several groups have examined the mechanism of the idling-turnover reaction described below.'26-128 In previous studies conversion of a fraction of the available dNTP pool into a corresponding dNMP pool indicated that both the polymerase and 3' +5' exonuclease activities were expressed during the course of DNA syn- thesis. It was suggested that the extent of action of the 3'-5' exonuclease in producing nucleoside monophosphate could reflect the degree of proof-reading accompanying replication.In the absence of the correct following dNRP the rate of nucleoside monophosphate appearance was enhanced and the enzyme was forced to 'idle' at the primer terminus until the dNTP pool was depleted. Experiments conducted in this idling-mode have allowed the evaluation of the base misinsertion frequency12' and ongoing mechanistic studies are providing detailed insight. Ben- kovic has shown that when the idling reaction is conducted in a pool of [3H]dATP correctly template-matched 32P-deoxyadenosine is excised from the primer terminus and is replaced with tritiated material.'26 This result suggests that a mode of excision/incorporation rather than misincorporation/excision operates Scheme 25. 5'-G*A* A 3'-C?TAA Pathway A dAM P" dA'TP Pathway B dA'MP ' = 3H P * ~ 32 -G*A*A -CITAA -C'ITAA Scheme 25 The 3-[32P]end-label from the excision was traced to two products the expected exonuclease hydrolysis product [32P]dAMP and also [32P]dATP.The formation of the [32P]dATP was shown to occur via the attack of PPi on the terminal phos- phodiester linkage of the primer strand by PPi derived from the nucleoside triphos- phate pool. The pyrophosphorolysis reaction which occurs at extremely low PPi concentrations (0.1 pM),and the 3' --* 5' exonucleolytic degradation of DNA operate at similar rates. Benkovic has also shown that the DNA substrate does not dissociate from the enzyme during the switch in activity from exonuclease -P polymerase demanded by 125 V. Mizrahi N. Henrie J.F. Marlier K. A. Johnson and S. J. Benkovic Biochemistry 1985 24 4010. '26 V. Mizrahi P. A. Benkovic and S. J. Benkovic Proc. Nail. Acad. &I. USA 1986 83 231. 330 D. Gani excision/incorporation reaction in the idling-turnover mode.'27 Also the rate of pyrophosphorolysis was found to depend significantly upon the DNA sequence within the duplex region upstream of the primer-template junction. Evidence for the misincorporation/excision during idling-turnover was also presented. Mildvan has studied the conformation and interactions of substrate and ribonu- cleotide templates bound to the Klenow fragment using n.0.e. technique^.'^^ Finally Papanicolaou et al. have compared Pol I to the Klenow fragment and report that the differences are more profound than thought previously.Apparently the 3'-5' exo/pol activity ratios and hence error rates are subject to multiple influences which could cause mutational hot-spots in vivo whenever processive replication is inter- rupted.13' 10 Other Enzymes The application of site-directed mutagenesis to the study of the mechanism of tyrosyl tRNA synthetase was discussed in some detail last year.' Fersht and co-workers have continued to apply these techniques as is described in several recent publica- tion~.'~~-' Finally Baldwin and co-w~rkers'~~'~~ and others14' have studied the properties of isopenicillin N synthetase in some detail. Specifically the stereospecificity of carbon-sulphur bond'36 and p-lactam ring formation'37 has been determined as well as the structure reactivity profiles for ~nsaturated'~~ substrates.and alleni~'~~ Demain and co-w~rkers'~~ have now detected enzymic activity in cell-free extracts of Cephalosporium acremonium which catalyses the formation of 8-(L-W aminoadipy1)-L-cysteine the first intermediate in penicillin and cephalosporin bio- synthesis. The isolated yields are similar to those reported by Ba1d~in.l~~ The biosynthesis of p-lactam antibiotics has been reviewed re~ent1y.l~~ 127 V. Mizrahi P. A. Benkovic and S. J. Benkovic hoc. Natf. Acad. Sci. USA 1986 83 5769. lZ8 A. R. Fersht J. P. Shi and W. C. Tsui J. Mol. Biof. 1983 165 655. 129 L. J. Ferrin and A. S. Mildvan Biochemistry 1986 25 5131. I30 C. Papanicolaou P. Lecomte and J. Ninio J. Mol.Biof. 1986 189 435. 131 T. N. C. Wells and A. R. Fersht Biochemistry 1986 25 1881. 132 M. D. Jones D. M. Lowe T. Borgford and A. R. Fersht. Biochemistry 1986 25 1887. 133 C. K. Ho and A. R. Fersht Biochemistry 1986 25 1891. 134 A. R. Fersht R. J. Leatherbarrow and T. N. C. Wells Nature (London) 1986 322 284. 135 T. N. C. Wells C. K. Ho and A. R. Fersht Biochemistry 1986 25 6603. 136 J. E. Baldwin R. M. Adlington B. P. Domayne-Hayman H. Ting and N. J. Turner J. Chem. SOC. Chem. Commun. 1986 110. 137 J. E. Baldwin R. M. Adlington N. G. Robinson and H. Ting J. Chem. SOC. Chem. Cornmun. 1986,409. 138 J. E. Baldwin R. M. Adlington A. Basak S. L. Flitsch A. K. Forrest and H. Ting J. Chem. Soc. Chem. Cornmun.,1986 273. 139 J.E. Baldwin R.M. Adlington A. Basak and H. Ting J. Chem. SOC. Chem. Commun. 1986 1280. 140 J. M. Castro P. Liras J. Cortes and J. F. Martin FEMS Microbiol. Lett. 1986 34 349. 141 G. Banko S. Wolfe and A. L. Demain Biochem. Biophys. Res. Commun. 1986 137 528. 142 R. M. Adlington J. E. Baldwin M. Lopez-Nieto J. A. Murphy and N. Patel Biochem. J. 1983,213,573. 143 J. A. Robinson and D. Gani Nut. Prod. Rep. 1985 2 293.

ISSN:0069-3030    

DOI:10.1039/OC9868300303

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

13 Arachidonic Acid Metabolites By P. BARRACLOUGH Department of Medicinal Chemistry The Wellcome Research Laboratories Langley Court Beckenham Kent BR3 3BS 1 Introduction This report will emphasize developments during 1986 while summarizing the salient points of earlier work where necessary. Since the last review in Annual Reports (in 1981) monographs have appeared covering the synthesis,’.2 general chemi~try,~ and biochemistry4 of prostaglandins (PG’s) and thromboxanes. In addition reviews describe asymmetric syntheses of the primary PG’s,’ routes to PG’s from sugars,6 syntheses of 13-azaprostanoids and their actions at thromboxane receptors,’ general aspects of PG’s thromboxanes and le~kotrienes,~.~ autooxidation mechanisms of polyunsaturated lipids,” and the synthesis and biological activity of prostacyclin analogues,”*‘2 PG lac tone^,'^ and PG ana10gues.l~ In the past five years there has been a reduction in the number of publications dealing with the chemistry of the primary PG’s and their analogues much of the recent work being focused on shorter and more efficient synthetic routes.During this period however there has been an increasing interest in the leukotrienes and the more recently discovered metabolites such as lipoxins punaglandins and clavul ones. ‘New Synthetic Routes to Prostaglandins and Thromboxanes’ ed. S. M. Roberts and F. Scheinmann Academic Press 1982. * ‘Prostaglandins and Thromboxanes’ ed. R. F. Newton and S. M. Roberts Butterworth Scientific 1982. Adv. Prostaglandin Thromboxane Leukotriene Res.Vol. 11 ed. B. Samuelsson R. Paoletti and P. Ramwell Raven Press New York 1983. Methods in Enzymology Vol. 86 Prostaglandins and Arachidonate Metabolites ed. W. E. M. Lands and W. L. Smith Academic Press 1982. A. D. Baxter and S. M. Roberts Chem. Znd. 1986 510. R. J. Ferrier and P. Prasit Pure Appl. Chem. 1983 55 565. ’ E. W. Collington H. Finch P. Hallett P. Hunt T. Parkhouse D. Reynolds L. M. Smith and C. J. Wallis in ‘Second SCI-RSC Medicinal Chemistry Symposium’ Special Publication No. 50 The Royal Society of Chemistry London 1984 p. 299. * S. M. F. Lai and P. W. Manley Nat. Prod. Rep. 1984 1 409. R. H.Green P. F. Lambeth R. F. Newton S. M. Roberts in ‘Aliphatic and Related Natural Product Chemistry’ A Specialist Periodical Report Vol.3 ed. F. D. Gunstone The Royal Society of Chemistry London 1983 p. 107. 10 N. A. Porter Acc. Chem. Res. 1986 19 262. R. C. Nickolson M. H. Town and H. Vorbruggen Med. Res. Rev. 1985 5 1. 12 ‘Innovative Approaches in Drug Research’ ed. A. F. Harms Elsevier Science 1986 p. 223. l3 G. L. Bundy D. C. Peterson J. C. Cornette W. L. Miller C. H. Spilman and J. W. Wilks J. Med. Chem. 1983 26 1089. 14 P. W. Collins J. Med. Chem. 1986 29 437. 33 1 P.Barraclough Finally the importance of the area as a whole was highlighted by the Nobel Awards in medicine to S. Bergstrom B. Samuelsson and J. R. Vane and their Nobel lectures were published in 1983.'59'6~'7 2 Primary Prostaglandins and their Metabolites A new simple stereocontrolled route" (Scheme 1) to PGF2 (1) employs radical cyclization-trapping methodology to convert iodide (2) into trimethylsilylketone (3).1 + (Me C )M e S i0' (Me3 C)Me S i0' 0 Reagents i Bu,SnCI NaBH,(CN) CH,=CH( SiMe3)C0.CSH,, hv THF Scheme 1 The selective deprotection of the THP ether (4)to alcohol (5) is the key step in a synthesis" of PGD2(6) which starts from a Corey lactone intermediate. Deprotec- tion is effected cleanly in the presence of the silyl ether functionality by simply heating at 135 "C in a sealed tube. 0SiMez(CMe3) OH dMe OR OSiPhz(CMe3) (4) R = THP (5) R = H lC S. Bergstrom Angew. Chem. Int. Ed. Engl. 1983 22 858. '6 B. Samuelsson Angew. Chem. Int. Ed. Engl. 1983 22 805. J. R.Vane Angew. Chem. Int. Ed. Engl. 1983 22 741. l8 G. Stork P. M. Sher and Hai-Lin Chen J. Am. Chem. Soc. 1986 108 6384. l9 Y. Ogawa M. Nunomoto and M. Shibasaki J. Org. Chem. 1986 51 1625. Arachidonic Acid Metabolites New ways of obtaining the chiral PG precursor (7) are based on a highly enantioselective hydrolysis2' of diacetate (8) to alcohol (9) by electric eel acetylcholinesterase or lipase and on the conversion of epoxide (11) into alcohol (10) by a chiral lithium amide.2' OR1 l 0 4 I I I OP OR2 OSiMedCMe3) (7) P = Protecting (8) R' R2 = AC (11) Group (9) R' = H R2 = AC (10) R1= H R2 = SiMe2(CMe3) The three component coupling approach to PG synthesis employing intermediates such as (7) has been reviewed.22Several modifications to this strategy designed to circumvent enolate equilibration and elimination problems have appeared.Thus reaction of (7; P = CMe3) with the organolithium reagent (12) and subsequent alkylation with the iodide (13) in the presence of Ph3SnC123gave good yields of the PG precursor (15). ICH,CfC( CH2),X (13) X = C02Me Li -(:> (12) (14) x = 0 (15) An alternative variant24employs enone (16) for a PGE (17) synthesis. The extra a-oxygen functionality suppresses enolate equilibration by a combination of charge repulsion and angle strain. It is removed reductively after coupling. Oxime meth~dology~~ provides a means of coupling (18) the stannane (19) and the iodide OMe -7'0-6 -B HO OSiMe2(CMe3) (16) (17) PGEz (18) 20 D.R. Deardorff A. J. Matthews D. S. McMeekin and C. L. Craney Tetrahedron Lett. 1986 27 1255; K. Laumen and M. P. Schneider J. Chem. Soc. Chem. Commun. 1986 1298. 21 M. Asami Tetrahedron Lett. 1985 26 5803. 22 R. Noyori and M. Suzuki Angew. Chem. Int. Ed. Engl. 1984 23 847. 23 M. R. Binns R. K. Haynes D. E. Lambert and P. A. Schober Tetrahedron Lett. 1985 26 3385. 24 C. R. Johnson and T. D. Penning J. Am. Chem. Soc. 1986 108 5655. 2s E. J. Corey K. Niimura Y. Konishi S. Hashimoto and Y. Hamada Tetrahedron Lett. 1986 27 2199. P. Barraclough OMe Bu3Sn d:> (Me,C)Me Si 0 I I (19) (Me3C)MezSi0 OSiMez(CMe3) (20) (14) in a one-pot operation to give (20). Subsequent deoximination of (20) however required the use of a solid reagent obtained from TiCl and Dibal.Interestiqgly chiral oxime (18)’ required for the coupling was obtained from its racemate by a sequence utilizing a-cyclodextrin complexation. ‘The major urinary metabolite of PGD2 the diketo acid (25)’ was prepared26 by a route (Scheme 2) notable for its ‘conformational protection’ of an olefin and new OCOPh I! 111 .. ... (22) R = CH,OSiPh,( CMe,) (23) R = ( E)-CH=CHCO(CH,),CO,Me (24) R = CH,CH,CO(CH,),CO,Me (25) (26) Reagents i PhCOCl C,H,N; ii Bu,NF THF; iii Me2CHN=C=N CHMe2 DMSO Cl,CHCO,H; iv (MeO)2P(0)CH2CO(CH2)2C02Me, NaH THF; v H,S K2C03 DMSO; Bu,P hv Scheme 2 26. E. J. Corey and K. Shimoji J. Am. Chem. Soc. 1983 105 1662. Arachidon ic Acid Metabolites 335 methodology for the selective reduction of the double bond of a a,P-enone.Thus alcohol (21) was cyclized to the internal ortho ester (22) preventing intramolecular radical addition to the (2)-double bond in the subsequent desulphurization step of stage v such as occurred for (26). 5,6-Dihydro-PGE3(27) was identified27,28 among the endogenous PG's extracted from ram seminal vesicles. Although this PG was not detected in human seminal fluid both 18,19-dehydro-PGE1 (29) and 18,19-dehydro-PGE (30),of unknown 18~9 double-bond geometry were characterized28 by g.1.c-m.s. 5,6-Epoxy PGF,,(31) has been from incubation of cis-5,6-epoxy-8,11,14-eicosatrienoic acid (32) with microsomes of ram seminal vesicles. The major urinary metabolite of PGE3 (28) in the rat has been identified3' as the tetranor-derivative (33).0 OH OH I OH I OH (27) 5,6-dihydro (29) 5,6-dihydro (28) 5,6-bond (30) 5,6-bond I OH OH Previously inseparable acetylenic PG's have been separated as their cobalt com- ple~es.~' C.d. spectroscopy has been employed32 to assign configuration at C-15 in prostanoids. 21 N. Samel 1. Jawing M. Lohmus A. Lopp G. Kobzar V. Sadovskaya T. Valimae and U. Lille Eesti NSV Tead. Akad. Toim. Keem 1986 35 75 (Chem. Abs. Select. 104 162513n). 28 E. H. Oliw H. Sprecher and M. Hamberg J. Biol. Chem. 1986 261 2675. 29 E. H. Oliw and G. Benthin Biochem. Biophvs. Res. Commun. 1985 126 1090. 30 U. Diczfalusy and M. Hamberg Biochim. Biophys. Acta 1986 878 387. 31 J.Fried and C. 0-Yang Tebahedron Lett. 1983 24 2533. 32 M. F. Ansell M. P. L. Caton A. F. Drake and K. A. J. Stuttle Tetrahedron Left. 1983 24 3017. P. Barraclough 3 Prostacyclin (PGI,) and Metabolites A one-pot pr0cedu1-e~~ for converting the acetylene (34) into PG12methyl ester (37) relies on the reductive demercuration of the vinylic mercury intermediate (35) occurring with retention of configuration to give (36) as shown in Scheme 3. MeozcTx I I II (Me3C)Me2Si0 OSiMe2(CMe3) OR OR (34) (35) X = Hg(OCOCF,) R = SiMe,(CMe,) (36) X = H R = SiMe,(CMe,) (37) X = R = H Reagents i Hg(OCOCF3)2,NEt,; ii NaOMe NaBH,; iii Bu,NF Scheme 3 The versatility of the three-component coupling approach described in Section 2 is well illustrated by a short synthesis34of 6-keto PGFI (41).This PG12 metabolite was obtained from reaction of enone (38) iodide (39) and nitro-olefin (40) with a subsequent two-step elaboration.A high field 'H n.m.r. spectroscopic analysis3' has indicated that PGI adopts a very narrow range of ring conformations if not the single conformation shown in (43). Some characterization of the side-chain conformations was also possible. I I HO OH (41) X = H (43) (42) X = OH 33 M. Suzuki A. Yanagisawa and R. Noyori Tetrahedron Lett. 1983 24 1187. 34 T. Tanaka A. Hazato K. Bannai N. Okamura S. Sugiura K. Manabe and S. Kurozumi Tetrahedron Lett. 1984 25 4947. 35 H. Beierbeck G. Kotovych and M. Sugiura Can. J. Chem. 1985 63 1143.Arachidonic Acid Metabolites CO2H Ho2c-2 I OH OH OH OH (44) (45) The biosynthesis and metabolism of the prostacyclin metabolite 6-keto PGEl (44) has been reviewed.36 Identification of 5-hydroxy-6-keto PGF1 (42) as a PG12 metabolite in isolated rabbit kidney suggested an epoxidation pathway” via (45). The complexities of human PG12 metabolism have been described. Direct analysis of urine revealed sixteen components of which ten were identified3’ and all shown to retain the 6-keto PGF structure. The characteristics of the P-450 enzymes prostacyclin and thromboxane synthases have been briefly reviewed.39 4 Thromboxanes Endoperoxides and Levuglandins The synthesi~~~,~~ of labile thromboxane A (TXA2) from TXB (46) by W. Clark Still in 1985 was achieved by the route shown in Scheme 4.Macrolactone formation proved necessary to ‘conformationally protect’ the (E)-double-bond from C-10 free-radical attack during the debromination step (v).The key cyclization step (47) to (48) was studied in much detail 81% conversion being obtained with the phosphite Mitsunobu reagent. X-Ray crystallography confirmed the structure of 1,15-anhydro TXA (49). This superb work provided convincing evidence that the bicyclic oxetane structure (50) proposed for TXA2 by Samuelsson was correct. Salts of TXA could be stored as isolated solids at -20°C for up to a week. Comparative hydrolysis studies42 of alkoxyoxetane (51) and TXA2 (50) indicate that they possess similar ring-cleavage rates suggesting that the presence of an additional ring in TXA contributes little to the reactivity of the system.The acid-lability of the TXA ring-system can be reduced markedly however by difluoro-substitution alpha to the ketal moiety. Thus biiyclic oxetane (52)43 had a rate of hydrolysis 10’ or lo2slower than that of TXA2 or diethyl acetal respectively. Semi-empirical MO calculations have been employedu to predict the stability of selected stabilized analogues and suggest a flattening of the chair conformation of these analogues and of TXA2 itself. 36 J. R.S. Hoult and P. K. Moore Trends Pharm. Sci. 1986 7 197. 37 P. Y.-K. Wong K. U. Malik B. M. Taylor W. P. Schneider J. C. McGiff and F. F. Sun J. Biol. Chem. 1985 260 9150. 38 A. R. Brash E. K. Jackson C. A.Saggese J. A. Lawson J. A. Oates and G. A. Fitzgerald J. Pharmacol. Exp. Ther. 1983 226 78. 39 V. Ullrich and H. Graf Trends Pharm. Sci. 1984 5 352. 40 S. S. Bhagwat P. R. Hamann W. Clark Still S. Bunting and F. A. Fitzpatrick Nature (London) 1985 315 511. 41 S.S. Bhagwat P. R. Hamann and W. Clark Still J. Am. Chem. Soc. 1985 107 6372. 42 J. Fried Z. Zhou and C.-K. Chen Tetrahedron Lett. 1984 25 3271. 43 J. Fried E. Ann Hallinan and M. J. Szwedo jun. J. Am. Chem. SOC.,1984 106 3871. 44 J. M. Williams J. Chern. Soc. Perkin Trans. 2 1984 1567. P. Barraclough . .. ... 1,11,111 -(50) (48) X = Br (49) X = H Reagents i 2-Thiopyridyl chloroformate NEt, 110"C; ii 2-chloro-1-methylpyridiniumiodide; iii NBS H,O 1% NaHCO,; iv EtO,CN=C=NCO,Et (MeO),P; v polymer-bound tin hydride; vi Me,SiOK THF Scheme 4 F Me =OMe Me (51) Diazoketone (53) has been prepared4' and as predicted from the putative enzyme mechanism demonstrated (equation 1) to be an irreversible inhibitor of TXA2 synthetase presumably by formation of complex (54).OH (53) (54) 'Biomimetic' cyclization of 1,2-dioxalane (55) produced the exo,exo-endoperoxide (56)46as shown in equation 2. The strong steric repulsion betweenthe C(14)H group and the nearby endoperoxide oxygen was believed to disfavour the alternative 45 J. L. Adams and B. W. Metcalf Tetrahedron Lett. 1984 25 919. 46 E. J. Corey C. Shih,".-Y. Shih and K. Shimoji Tetrahedron Lett. 1984 25 5013. Arachidonic Acid Metabolites 339 endo,endo pathway.Corey has ~peculated~~ that the differing stereochemical outcome for enzymatic and ‘biomimetic’ cyclizations may be due to the cyclooxygenase enzyme preventing an initially-produced carbon-radical intermediate assuming the same conformation or by forcing a conrotatory ring-closure. C02Me A CsHIi-CH=CH OH 14 (55) (56) Mechanistic studies of the endoperoxide (57)-( 58) rearrangement (equation 3) led to the prediction48 that PGH2 (59) would fragment (equation 4) to levuglandin (57) (58) HSa+ w (4) ((--H + Me w O--’; OH 0 0 (59) PGH2 (60) LGD (61) LGE D [LGD, (60)] and LGE2 (61). Decomposition of PGH2 in pH7.9 phosphate buffer did indeed produce these labile levulinaldehyde derivatives. However it is not yet known whether LGD and LGE2 are enzymatically produced endogeneous metabolites of PGH2.A key step (Scheme 5) in the total synthesis of LGE2 is the stereoselective 1,4-addition of cuprate (63) to enone (62) to yield ketone (64). Further details are given in a concise review by Sa10mon.~~ 5 Leukotrienes Lipoxins Hepoxilins and Trioxilins Leukotriene (LT) biosynthesis and its inhibition have been concisely reviewed.49 A chemoenzymatic synthesis5’ of LTB (65) was accomplished via the key chirons (68) and (70). The crucial stages in obtaining aldehydes (68) and (70) were the bsker’s yeast reduction of ketone (71) and a kinetic resolution of acetate (72) employing a microbial esterase of Klebsiella pneurnoniae. In a convergent enan- 41 E.J. Corey K. Shimoji and C. Shih J. Am. Chern. SOC.,1984 106 6425. 48 R. G. Salomon Acc. Chern. Rex 1985 18 294 and references therein. 49 G. W. Taylor and S. R.Clarke Trends Pharm. Sci. 1986 7 100. so C.-Q. Han D. DiTullio Y.-F. Wang and C. J. Sih J. Org. Chern. 1986 51 1253. €? Barraclough C02Me T-+ LiCu/ OSiMez(CMed I COzMe + C-8 epimer ; OSiMe2(CMed (64) Scheme 5 tioselective LTB4 synthesis5' two moles of each of aldehydes (69) and (70) could be obtained from 1 mole of D-mannitol as shown in Scheme 6 for (69). Stereoselective 2,3-sigmatropic rearrangement52 (Scheme 7) of ether (73) gave alcohol (74) which was converted into 2,E-dienynol (79 a useful LT precursor. The LTB4 metabolites (65) R = Me (68) R = Me (66) R = CH,OH (69) R = Et (67) R = C02H (Me3C)Ph2SiOyCHo (72) 51 Y.Le Merrer C. Gravier D. Languin-Micas and J. C. Depezay Tetrahedron Lett. 1986 27 4161. 52 A. D. Kaye G. Pattenden and S. M. Roberts Tetrahedron Lett. 1986 27 2033. Arachidonic Acid Metabolites (66) and (67) have been prepared53 by a route (Scheme 8) utilizing (R)-glycidol ether (76) to obtain aldehyde (77) for coupling with phosphonate (78). C02Et ~ i,ii,iii iv,v ~-Mannitol-0 -(69) 0{ PhCOIE zEt Reagents i LiC=CCO,Et BF,.Et20; ii PhCOCI; iii H,-Pt; iv CF3C02H HzO;v Pb(OAc) Scheme 6 Me& (73) (74) (75) Reagents i Bu"Li THF -30 "C Scheme 7 -wOSiPhz(CMe3) + 0 --+,OTHP I i-iv (76) (Me3C)PhzSiOTCH0 -wOSiPhz(CMe3) -(77) 0 I OSiPhz(CMe3) (78) Reagents i Bu"Li TMEDA -78°C; ii Ph,(Me,C)SiCl imidazole DMF; iii PPTSA MeOH; iv Cr0,.2(CsHsN) Scheme 8 Lipoxins hepoxilins and trioxilins are closely related families of metabolites.The lipoxins are formally produced via multiple lipoxygenation reactions. In 1983 K. C. Nicolaou Y.S. Chung P. E. Hernandez I. M. Taffer and R. E. Zipkin Tetrahedron Lett. 1986 27 1881. 342 P. Barraclough 02H / l5 OOH OH (79) 15-HPETE (80) LXA OH I OH I OH (81) LXB (82) OH C02H I OH OH (83) OH OH I COzH x-Y (84)X = H Y = OH (85) X = OH Y = H Samuel~son~~ isolated lipoxins (LX) A and B from human leukocytes treated with exogenous 15-HPETE (79) and calcium ionophore A-23187.Although the 5,6,15- and 5,14,15-triHETE structures for LXA and LXB respectively were established quickly some confusion existed with regard to their absolute stereochemistry and olefin geometry because of conflicting assignments. Partial isomerization during isolation and differing sources of natural material were complicating factors.55 LXA56 has structure (80). It is the active component of the leukocyte extract which also contains the 6-S epimer of LXA and the all-trans isomers (83). A meticulous study by Morris” has found LXB to correspond to a mixture of (81) (84) and (85). This work required the enantioselective synthesis of four LX isomers and a typical approach is shown in Scheme 9. 2-Deoxy-~-ribose (86) was the starting material for both acetylene (87) and epoxide (88) and the latter underwent the key coupling to afford alcohol (89).A putative biosynthetic precursor” to LXA and LXB ep0xid.e 54 C. N. Serhan M. Hamberg and B. Samuelsson Roc. Natl. Acad. Sci. 1984 81 5335. 55 J. Morris and D. G. Wishka Tetrahedron Lett. 1986 27 803 and references therein. ,f> C. N.Serhan K. C. Nicolaou S. E. Webber C. A. Veale S.-E.Dahlen,T.J. Puustinen,and B. Samuelsson J. Biol. Chem. 1986 261 16340. 57 C. N. Serhan M. Hamberg B. Samuelsson J. Morris and D. G. Wishka Roc. Natl. Acad. Sci. 1986 83 1983 Arachidonic Acid Metabolites 343 OCOPh + bC0,Me I 0' I OSiMe2(CMe3) (88) (87) li OSiMe2( C Me,) (89) Reagents i Bu"Li BF,.Et,O Scheme 9 (82) has been synthe~ized~~ by a stereoselective route.LXA activates protein kinase C59and stimulates superoxide anion generation while both LXA and LXB effect human natural killer cell function.57 In view of the current interest in lipoxins their remaining biosynthetic ambiguities may be resolved quickly. Hepoxilins and trioxilins are formed6' when 12-(S)-HPEPE (90) is incubated with rat pancreatic islets or bovine hemin. The gross structures of hepoxilin A and B and trioxilin A and B are (91) (92) (93) and (94) respectively. Hepoxilins A and B display insulin secretagogue activity. HOO'\c wo2H -2H (90) 12-(S)-HPEPE (91) Hepoxilin A4 ,I 0 (92) Hepoxilin B4 58 K. C. Nicolaou and S. E. Webber J. Chem. Soc, Chem.Commun. 1986 1816. 59 A. Hansson C. N. Serhan J. Haeggstrom M. Ingelman-Sundberg and B. Samuelsson Biochem. Biophys. Res. Commun.,1986 134 1215. 60 C. R. Pace-Asciak Prostaglandins Leukotrienes and Medicine 1986 22 1. 344 l? Barraclough OH H0‘,I/-u-v (93) Trioxilin A4 (94) Trioxilin B4 A number of metabolites have been isolated from rice plants suffering from rice blast disease (Pyricularia oryzae). Those characterized6’ and synthesized62 to date include epoxide (95) and trio1 (96). Hydroxy acids (97) and (98) which were isolated from the fungus-resistant rice plant ‘FUKUYUKI’ have been prepared63 as race- mates. OH (97) 6 Clavulones Punaglandins and Chlorovulones Although PGA2 esters were isolated from the gorgonian Plexaura homomalla over a decade ago it is only since 1982 that the above closely related series of eicosanoids have been isolated from marine sources and characterized.Clavulone I 11 and 111 obtained from the Okinawan soft coral Clavularia viridis were shown64 to have structures (99) (loo) and (101) respectively. The stereochemical assignments were confirmed6’ by total synthesis. Preliminary studies66 of clavulone biosynthesis using a C. viridis homogenate suggest the intermediacy of 8-(R)-HPETE (102) and pre-clavulone A (103). 61 T. Kato Y. Yamaguchi S. Ohnuma T. Uyehara T. Namai M. Kodama and Y. Shiobara Chem. Lett. 1986 6 577. 62 T. Kato Y. Yamaguchi S. Ohnuma T. Uyehara T. Namai M. Kodama and Y. Shiobara J. Chem. SOC.,Chem. Commun. 1986 743.63 A. V. Rama Rao and E. Rajarathnam Reddy Tetrahedron Lett. 1986 27 2279. 64 H. Kikuchi Y. Tsukitani K. Iguchi and Y. Yamada Tetrahedron Lett. 1983 24 1549. 65 H. Nagaoka T. Miyakoshi and Y. Yamada Tetrahedron Lett. 1984 25 3621. 66 E. J. Corey M. d’Alarcao S. P. T. Matsuda and P. T. Lansbury jun. J. Am. Chem. SOC.,1987 109 289. Arachidonic Acid Metabolites 345 0 COzMe OAc OAc (99) Clavulone I (100) Clavulone I1 HOO I NcozH -OAc (101) Clavulone 111 (102) (103) Punaglandins (PUGS) are halogenated eicosanoids isolated from the Hawaiian octocoral Telesto riisei. Revised structures (104) and (105) have been assigned67 to PUG 3 and 4 respectively. These revisions follow enantioselective syntheses of all possible diastereomers for configuration changes at C-5 C-6 and C-12.The struc-tures of PUG I (106) and PUG 2 (107) follow from these assignments although the C-7 configuration is not yet known. OH OH (104) 17,18-bond Punaglandin 3 (106) 17,18-bond Punaglandin 1 (105) 17,18-dihydro Punaglandin 4 (107) 17,18-dihydro Punaglandin 2 Chlorovulone bromovulone and iodovulone have also been isolated from Clavularia viridis and shown68 to have structures (108) (109) and (1 10) respectively. Both the punaglandins and chlorovulones have the same C-12 configuration which is opposite to that in clavulones. The C-10 chlorine atom thus seems67 to alter the 67 H. Nagaoka H. Miyaoka T. Miyakoshi and Y. Yamada J. Am. Chem. SOC.,1986,108,5019; M. Suzuki Y. Morita A. Yanagisawa R.Noyori B. J. Baker and P. J. Scheuer J. Am. Chem. Soc. 1986 108,5021. 68 K. Iguchi S. Kaneta K. Mori Y. Yamada A. Honda and Y. Mori J. Chem. SOC.,Chem. Commun. 1986 981. P. Barraclough 0 (108) X = CI Chlorovulone I (109) X = Br (110) x = I biosynthetic pathway. PUG 3 and 4 and chlorovulone inhibit leukaemia cell prolifer- ation ~ignificantly.~' The aldol condensation of cyclopentenone (1 12) and aldehyde (1 13) to give after dehydration ketone (1 14) is a key step (Scheme 10) in an enantioselective synthesis6' of PUG4. Cyclopentenone (112) was obtained from alcohol (111) by a multi-step sequence. Similarly alcohol (1 15) was elaborated to cyclopentenone (1 16) in a stereoselective synthesis6' of clavulone 11. The key intermediate (1 18) was obtained (Scheme 11) from aldol condensation of cyclopentenone (1 16) and aldehyde (1 17).Reagents i LDA -78 "C; ii Ac,O DMAP 60 "C Scheme 10 +C0,Me -(loo) OH (118) Reagents i 2 equiv. LDA THF -78 "C Scheme 11

ISSN:0069-3030    

DOI:10.1039/OC9868300331

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

14 Biosynthesis By T. J. SIMPSON Department of Chemistry University of Edinburgh West Mains Road Edinburgh EH9 3JJ 1 Introduction This Report will discuss biosynthetic studies on secondary metabolites and related work. Despite the fact that this has been and continues to be an area of intense activity the last Report was in 1980.’ Thus this Report can only give a highly selective and inevitably personalized view of the main developments over the past five years. Highlights have included the continuing impact of n.m.r. methods in biosynthetic studies2p3 and in particular the use of isotope-induced shifts in 13C n.m.r. to monitor the biosynthetic origins of hydr~gen~?~ and so obtain and ~xygen~.~ information on the oxidation levels of biosynthetic intermediates; the study of the isolation and mechanism of terpenoid cyclases;’ the use of tissue cultures as sources of enzymes for alkaloid biosynthesis; and the application of genetic engineering techniques to biosynthetic studies.The appearance of several new book^^-^ on biosynthesis and secondary metabolism emphasizes the continuing importance of these areas. An undoubted highlight has been the appearance of the review journal Natural Product Reports to replace several of the established Specialist Periodical Reports titles and comprehensive coverage of the areas discussed here are to be found in the regular articles appearing therein. 2 Polyketide Biosynthesis P-Hydroxydecanoyl thioester dehydrase which is the pivotal enzyme in the biosyn- thesis of unsaturated fatty acids in anaerobic micro-organisms mediates the conver- sion of acyl-carrier-protein thioesters of (R)-3-hydroxydecanoic acid (l) (E )-dec-2-enoic acid (2) and (Z)-dec-3-enoic acid (3).The allylic rearrangement which interconverts (2) and (3) has been shown by 2H labelling and 2H n.m.r. methods to ’ J. R. Hanson Ann. Rep. Bog. Chem. Sect. B 1980 77 289. * T. J. Simpson in ‘Modern Methods of Plant Analysis’ ed. H. F. Linskens and J. F. Jackson Springer- Verlag Berlin 1985 p. 1. C. Abell in ‘Modern Methods of Plant Analysis’ ed. H. F. Linskens and J. F. Jackson Spnnger-Verlag Berlin 1985 p. 60. J. C. Vederas Can. J. Chem. 1982 60,1637. D. E. Cane Acc. Chem. Rex 1985 220. ‘R. B. Herbert ‘The Biosynthesis of Secondary Metabolites’ Chapman and Hall London 1981.’ P. Mannitto ‘Biosynthesis of Natural Products’ Ellis Horwood Chichester 1981. K. H. G. Torsell ‘Natural Products Chemistry’ Wiley Chichester 1983. E. Haslam ‘Metabolites and Metabolism -A Comment on Secondary Metabolism’ Clarendon Press Oxford 1985. 347 348 T. J. Simpson be an overall suprafacial process in which 4-( pro-4R)-hydrogen of (2) is removed and the enzyme-catalysed protonation occurs at the si face at C-2 of (2)." This finding is consistent with a 'one-base' mechanism in which an active site histidine acts as the base. 3-[2-13C]Decynoyl-NAC which is known to act as a reversible inhibitor of the enzyme has been synthesized and incubated with the enzyme." 13C{lH} N.m.r. analysis of the incubation mixture allows direct observation of the enzyme-inhibitor complex.Lipoxins A and B are formed from human leukocytes exposed to 15-hydroxyeicosatetraenoic acid.12 Their structures (4) and (5) have been assigned by syntheses based on biosynthetic speculation^'^ and evidence for their formation via the (5S),(6S) epoxide (6) has been ~btained.'~ Other interesting papers discuss the possible routes for formation of the rethrolone segment of the pyrethroid in~ecticides;'~ and jasmonic acid (8) has been shown to be formed from linolenic acid via 12-oxo-phytodienoic acid (7) in tissue sections of several higher plant species.16 (CHACOzHro2H Me G M e / OH (6) 0 (7) (8) n n = 7; 9,14-dehydro = 1 Incorporation studies" with [1-13C]propionate and 13C-labelled acetates indicate that the antibiotic furanomycin (lo) a metabolite of Streptomyces threomyceticus is derived from the triketide precursor (9).Colletodiol (14) a macrocyclic dilactone isolated from Colletotrichium capsici and a Cytospora sp. has been shown by a LO J. M. Schwab and J. B. Klassen J. Am. Chem. SOC.,1984 106 7217. J. M. Schwab W. Li C.-K. Ho C. A. Townsend and G. M. Salituro J. Am. Ckem. SOC.,1984,106,7293. 12 C. N. Gerham M. Hamberg and B. Sarnuelsson Biochem. Biophys. Res. Commun. 1984 118 943. l3 J. Adams B. J. Fitzsimmons Y. Girard Y. Leblanc J. F. Evans and J. Rokach J. Am. Chem. SOC. 1985 107 464. 14 B. J. Fitzsimmons and J. Rokach Tetrahedron Lett. 1985 26 3939. 15 L. Crombie and S. J. Holloway J. Chem. SOC.,Perkin Trans.I 1985 1393. 16 B. A. Vick and D. C. Zirnmerman Plant Physiol 1984 75 458. 17 R. J. Parry and H. P. Buu J. Am. Chem. SOC.,1983 105 7446. Biosy n thesis 349 O'H (14) combination of 13C 'H and l80 labelling studies18 to be formed via the macrocyclic triene (13) which is itself formed via the triketide and tetraketide precursors (11) and (12). Oxidative ring-cleavage of preformed aromatic intermediates results in formation of many unusual structures. 13C-Labelling methods and studies with advanced intermediates have demonstrated the formation of astepyrone (1 5) in Aspergillus terreus" and of the mycotoxin botryodiplodin (18) in Penicillium roquefortii,20 via M&o -R&02H M$Me __* HO OH Ho 0 (16) R = OH ' (18) (15) (17) R = H orsellinic acid (16).The formation of patulin (19) via ring-cleavage of 6-methyl- salicylic acid (17) has been intensively studied for many years. Cell-free preparations of a patulin-minus mutant of Penicillium urticae convert isopatulin (20) into both (E)-and (2)-ascladiol (21). However only the (E)-isomer is further converted into patulin.21 '80-Labelling studies have shown that only the carbonyl oxygen is derived from acetate the others are introduced by oxidative processes.22 (17) -8' go / d H#' / -/ HOCH2 CH20H HO 0 0 OH 18 T. J. Simpson and G. I. Stevenson J. Chern. SOC.,Chern Cornmun. 1985 1822. 19 K. Arai T. Yoshimura Y. Hatani and Y. Yamamoto Chern. Pharrn. Bull. 1983 31 925. 20 F. Renauld S. Moreau and A.Lablanche-Combier Tetrahedron 1984 40 1823. 21 J. Sekiguchi T. Shimamoto Y. Yamada and G. M. Gaucher AppL Environ. Microbiol. 1983,45 1939. 22 H. Tijima H. Noguchi Y. Ebizuka U. Sankawa and H. Seto Chern. Pharm. Bull. 1983 31 362. 350 T. J. Simpson Comparison of the incorporation of 2H from [ 1-13C,2H3]- and [l-13C,2Hl]acetate into 6-methylsalicylic acid by both ’H n.m.r. and 2H-isotope-induced shifts in 13C n.m.r. show that there is no observable isotope-eff ect and so the necessary deproton- ations required for aromatization of the intermediates from cyclization of the enzyme-bound polyketide precursor must be enzyme-mediated and presumably stereo~pecific.~~ Full details of 14C and 13C-labelling studies on aspyrone (24) and asperlactone (25) have appea~ed.’~ 180-Labelling studies have shown surprisingly that no acetate- derived oxygen is retained in these metabolites.Alternative cyclizations of the epoxy-carboxylic acid (23) itself derived from the trienone (22) were proposed to HoY+Me 0 account for the co-occurrence of these compounds in Aspergillus rnelleu~.*~ This provides a simple model for the more complex epoxide-mediated cyclizations proposed to occur in monensin and other polyether antibiotics. The formation of cryptosporiopsonol (26) uia dihydroisocoumarin intermediates in Periconia mucros- pinosu26has been confirmed. Incorporation of [2-13C,2H3]acetate into mellein (27) in Aspergillus melleus was studied by both 2H n.rn.r. and edited 13C n.m.r. using a pulse sequence which allows only isotopically shifted signals to be ob~erved.~’ The simultaneous incorporation of two deuterium atoms at C-4 provides compelling evidence along with similar observations for brefeldin A,28 rnon~cerin,~~ and c1 AMe hMe & OH OH 0 23 C.Abell and J. Staunton J. Chem. SOC.,Chem. Commun. 1984 1005. 24 R. G. Brereton M. J. Garson and J. Staunton J. Chem. SOC.,Perkin Trans. 1 1984 1027 and preceding papers. 25 S. A. Ahmed T. J. Simpson J. Staunton A. C. Sutkowski L. A. Trimble and J. C. Vederas J. Chem. SOC.,Chem. Commun. 1985 1685. 26 G. B. Henderson and R. A. Hill J. Chem. SOC.,Perkin Trans. 1 1982 3037. 27 C. Abell D. M. Doddrell M. J. Garson E. D. Laue and J. Staunton J. Chem. SOC.,Chem. Commun. 1983 694.28 C. R. Hutchinson Acc. Chem. Res. 1983 16 7. 29 F. E. Scott T. J. Simpson L. A. Trimble and J. C. Vederas J. Chem. SOC.,Chem. Commun. 1984 756. Biosynthesis 351 colletodiol," that reductive modification of polyketide precursors takes place con- comitant with and not after chain elongation. The tetronic acid multicolic acid (28) is derived by oxidative modification of 6-pentylresorcylic acid. 180-Labelling studies establish details of the mechanism of ring cleavage and lactone ring f~rmation.~' Similar 180-labelling studies established that all the oxygens in griseofulvin (29) are acetate-derived to discount the proposed intermediacy of hydroquinone intermediates in formation of the grisan ring system.31 Biosynthetic studies of the chromanone ~~-D253cu (31) showed that the carbons of the hydroxyethyl side-chain become equivalent at some point in the biosynthesis.The cyclopropane intermediate (30) was proposed to account for this.32 1 OH (31) 2H-and 180-Labelling studies show that biosynthesis of palitantin (32) in Penicil-Zium brefeldianum does not involve aromatic intermediate^.^^ The origins of fulvic acid and citromycetin have long been a subject of speculation. In a careful study in Penicilfiumfrequentans it has been shown that citromycetin is in fact an artefact and the true metabolite is polivione (33).34 "0-Labelling studies35 show that the oxygen at C-4 is derived from the atmosphere to provide the first definitive evidence that this group of compounds are formed via a ring-cleavage process from a heptaketide-derived intermediate related to fusarubin (35).H02C OH 0 HO" CHZOH HO ' 0 0 (32) (33) 30 J. S. E. Holker E. O'Brien R. N. Moore and J. C. Vederas J. Cfiern.SOC.,Cfiern. Cornmun. 1983 192. 31 M. P. Lane T. T. Nakashima and J. C. Vederas J. Am. Cfiern.SOC.,1982 104 913. 32 C. R. McIntyre T. J. Simpson L. A. Trimble and J. C. Vederas J. Chem. Soc. Cfiern.Cornmun. 1984 706. 33 A. K. Demetriadou E. D. Laue and J. Staunton J. Cfiern. Soc. Cfiern. Cornmun. 1985 1125. 34 A. K. Demetriadou. E. D. Laue F. J. Leeper and J. Staunton J. Cfiern.Soc. Cfiern.Comrnun. 1985,762. 352 T. J. Sirnpson 5-Deoxyfusarubin (34) is a yellow pigment which has been isolated from a mutant strain of Nectria haematococca which normally produces fusarubin.The strain used was a double crossover-producing mutant designated Ann A*58.yelJl derived from the Ann A"58 mutant which showed higher production and excretion of red pigments into the medium and yelJl which produced yellow pigments rather than red. Thus it appears to lack the gene responsible for the late-stage oxidation at C-5 of f~sarubin.~~ MeOfypMe J,W. \ I1 0 OH OH 0 '1 (34) R = H COzH (35) R = OH (36) Gene cloning methods are beginning to make a major impact in secondary metabolite production and biosynthesis. One area where there has been particularly significant work relates to the antibiotic actinorhodin and related octaketide-derived isochromanequinone antibiotics.Actinorhodin (36) is produced by Streptomyces coelicolor. All of the genes for the biosynthesis of actinorhodin are clustered on one contiguous region of the bacterial genome which has been cloned in a low-copy-number vector (pIJ922) as one large (32.5 kilobase) segment of DNA.37 The resultant plasmid (pIJ2303) has been used to transform other Streptomyces e.g. S. paruulus thereby conferring on them the ability to produce a~tinorhodin.~~ In related work it was shown that introduction of a plasmid vector carrying the afsB gene of S. coelicolor into S. liuidans or strains of S. coelicolor which had lost the ability to produce actinorhodin caused high production of actinorhodin in both.3Y The afsB gene appears to consist of a ca.2 kilobase segment of DNA4' which controls biosynthe~is~' of the regulatory substance known as A factor which in turn controls expression of genes controlling cell differentiation and antibiotic production.This work has been taken further to induce the formation of new or hybrid antibiotic^,^^ by making use of the close structural relationships between actinor- hodin (36) and medermycin (37) a metabolite of Streptomyces uiolacember and granaticin (38) produced by Streptomyces sp. AM-7161. Transformation of Strep romyces sp. AM-7161 with the whole act gene cluster carried on vector pIJ2303 resulted in production of both actinorhodin (36) and granaticin (38). However when transformed with a partial act clone a new metabolite dehydrogranitirhodin (39) was produced as a result of cooperation between gene products in the pathway 35 A.K. Demetriadou E. D. Laue and J. Staunton J. Chem. SOC.,Chem. Commun. 1985 764. 36 D. Parisot M. Deuys and M. Barbier Phytochemistry 1985 24 1977. 37 D. J. Lydiate F. Malpardita and D. A. Hopwood Gene 1985 35 223. 38 F. Malpardita and D. A. Hopwood Nature (London) 1984 309,462. 39 S. Horinuchi and T. Beppu Agr. Biof. Chem. 1984 48 2131. S. Horinuchi 0.Hara and T. Beppu J. Bacteriol 1983 155 1238. 41 S. Horinuchi Y. Kumada and T. Beppu J. Bacteriol 1984 158 481. 42 D. A. Hopwood F. Malpardita H. M. Kieser H. Ikeda J. Duncan I. Fujii B. A. M. Rudd H. G. Floss and S. Omura Nature (London) 1985 314 642. Biosynthesis 353 NMe OH OH 0 Me Me (38) (37) '0 NMe I to actinorhodin and granaticin.In contrast when S. violuceoruber was transformed with vector pIJ2303 normal antibiotic production was switched off and a new compound mederrhodin A (40) was produced instead. Mevinolin (41) is representative of a group of compounds containing the decalin ring system which have provoked considerable interest due to their ability to block cholesterol biosynthesis and to act as antibiotics or show other biological activities. The incorporation of 13C- 'H- and "0-labelled acetates into mevinolin in Aspergillus terreus give results consistent with biogenesis of (41) by intramolecular cycloaddition of a C18-polyunsaturated acid or intramolecular anionic condensations of a partially reduced p~lyketide.~~ illicicolin Similar studies on nargenicin Al ,44 nodu~micin,~~ A,46the beta en one^,^^ tetrocarcin A,48and chl~rothricin~~ have been reported.43 R. N. Moore G. Bigam J. K. Chan A. M. Hogg T. T. Nakashima and J. C. Vederas J. Am. Chem. SOC.,1985 107 3694. 44 D. E. Cane and C.-C. Yang J. Anribior. 1985 28 423. 45 W. C. Snyder and K. L. Rinehart jun. J. Am. Chem. Soc. 1984 106 287. 46 M. Tanabe and S. Urano Tetrahedron 1983 39 3569. 47 H. Ockawa A. Ichihara and S. Sakamura J. Chem. SOC.,Chem. Cornmun. 1984 814. 48 T. Tamaoki and F. Tomita J. Antibiot. 1983 36,595. 49 0.Mascaretti C. Chang D. Hook H. Otsuka E. F. Kreutzer and H. G. Floss Biochemistry 1981 20 919. 354 T. J. Simpson Incorporation of 13C-labelled acetates and malonate into oxytetracycline (42) in Streptomyces rimosus have established the mode of folding of the precursor chain5’ and the involvement of an intact malonate as the starter unit.5’ The mycotoxin viridicatumtoxin (43) has a similar structure but a quite different mode of assembly.52 0’ NMe2 N’2 HO HO 0 0 0 OH (42 1 (43) The mycotoxin asteltoxin (44) is derived from a nonaketide precursor.Surprisingly the first three carbons in the precursor chain can be derived either from acetate and a methionine-derived methyl or from pr~pionate.’~ 180-Labelling results show the involvement of a tris-epoxide (45) in the rearrangement and cyclization responsible for the formation of the bisfuranoid system.54 Analogous results are reported for ~itreoviridin’~ and aurovertin B.56 Me Me (44) 0 (45 1 The pathway to aflatoxin B (46) continues to be actively studied.The intermediacy of averufin (47) has been firmly e~tablished.~~ The other highlight in this area has been Townsend’s detailed studies58359 of the mechanism of conversion of averufin via versiconal acetate into versicolorin A (48) using synthetic intermediates specifically labelled with I3C 2H and l8O. The origins of all the oxygen atoms in monensin (49) have been and these are consistent with its formation uia a tris-epoxide itself formed from the 50 R. Thomas and D. J. Williams J. Chem. SOC.,Chem. Commun. 1983 128. 51 R. Thomas and D. J. Williams J. Chern. SOC.,Chem. Commun. 1983 677. 52 A. E. de Jesus W. E. Hull P. S. Steyn F. R. van Heerden and R.Vleggaar J. Chem. SOC.,Chem. Commun. 1982 902. 53 P. S. Steyn and R. Vleggaar J. Chem. SOC.,Chem. Comrnun. 1984 977. 54 A. E. de Jesus P. S. Steyn and R. Vleggaar J. Chem. SOC.,Chem. Commun. 1985 1633. 55 P. S. Steyn and R. Vleggaar J. Chern. SOC.,Chem. Comrnun. 1985 1531. 56 P. S. Steyn and R. Vleggaar J. Chem. SOC.,Chem. Commun. 1985 1791. 57 T. J. Simpson A. E de Jesus P. S. Steyn and R. Vleggaar J. Chem. SOC.,Chem. Commun. 1982 631. 58 C. A. Townsend and S. B. Christensen Tetrahedron 1983 39 3575. 59 C. A. Townsend and S. B. Christensen J. Am. Chem. Soc. 1985 107 270. D. E. Cane T.-C. Liang and H. Hasler J. Am. Chem. SOC., 60 1982 104 7274. ’‘ A. A. Ajaz and J. A. Robinson J. Chem. SOC.,Chem. Commun. 1983 679. Biosyn thesis 355 HO 0 (46’ (47) HO 0 Me OH Me 1 1 OMe \OH COzH (49) Me Me..Me )Me OH Me C02H (50) triene (50),the synthesis of which has been reported.62 An important theoretical paper presents a unified stereochemical model which attempts to correlate the structures and stereochemistries of more than 30 different polyether antibiotics and to show how they can be biosynthesized via polyepoxide prec~rsors.~~ Amino acids such as valine can act as efficient carbon sources in the biosynthesis of monensin and other antibiotics as can butyrate and i~obutyrate.~~ The results of a number of 62 F. van Middlesworth D V. Patel J. Conaubauer P. Gannett and C. J. Sih J. Am. Chem. Soc. 1985 107 2996. 63 D.E. Cane W. D. Celmer and J. W. Westley J. Am. Chem. Soc. 1983 105 4110. 64 S. PopKil P. Sedmera M. Havrhek V. Krumphanzl and Z. Vanek J. Antibiotics 1983 36 617. 356 T. J. Simpson studies notably by Robinson and co-workers in S. cinnarnonensi~~~ and the nonactin producer Streptomyces griseus,66 but also by others has led to much information on the stereochemical and mechanistic details of the interconversions of these com- pounds being elucidated. These need to be appreciated in interpreting many of the biosynthetic results in this area. 18 0-Labelling studies on erythromycin have been reported in full.67 These results are consistent with the view that the oxidation level that is observed in the aglycone (51) is established during elongation of the carbon chain and exclude alternative oxidation or dehydration-rehydration mechanisms.These and other aspects of the biosynthesis of macrolides and polyether antibiotics particularly their relationship to fatty acid biosynthesis are discussed in an excellent review article.28 3 Terpenoids and Steroids Mevinolin (see above) is believed to act by inhibiting hydroxymethylglutaryl-CoA reductase the key enzyme in regulation of terpenoid biosynthesis. Full length cDNA clones have been obtained that revealed the complete amino acid sequence of the reductase (M.W. ca. 95K)from hamster cells.68 The cyclases responsible for the formation of several mono- and sesquiterpenoids in plants have been isolated and studied in detail. Enzyme preparations which mediate the formation of d -bornyl pyrophosphate (52) and I-bornyl pyrophosphate from geranyl pyrophosphate (GPP)have been isolated from SaIvia ~ficinalis~~ and 65 C.Gani D. O'Hagan K. Reynolds and J. A. Robinson J. Chem. SOC.,Chem. Commun. 1985 1002; K. Reynolds and J. A. Robinson ibid. 1985 1831. 66 C. A. Clark and J. A. Robinson J. Chem. SOC.,Chem. Commun. 1985 1568. 67 D. E. Cane H. Hasler P. B. Taylor and T.-C. Liang Tetrahedron 1983 39 3449. 68 D. J. Chin G. Gil D. W. Russell L. Liscum K. L. Luskey S. K. Basu H. Okayama P. Berg J. L. Goldstein and M. S. Brown Nature (London) 1984 308 613. 69 H. Gambliel and R.Croteau J. Biol. Chem. 1982 257 2335. Biosyn thesis 357 Tanacetum ~ulgare~~ respectively. Inter alia these have been used with [3H,32P]- and ['4C,'80]-labelled GPP as substrates to show that the migration of the pyrophos- phate anion during cyclization involves formation of a very tight ion-pair (53).In contrast a cell-free preparation from Foeniculum uulgare (fennel) yielded (-)-endo-fenchol (54) from GPP by direct attack of water on the presumed bicycloterpinyl cation pyrophosphate anion non-pair. Consistent with this hypothesis no label was found in (54) if [1-180]GPP was used in the sub~trate.~' All of the plant phosphatases that have been studied catalyse P-0 bond cleavage so fenchyl pyrophosphate cannot be an intermediate. Cell-free extracts from Streptomyces spp. have been used to study the cyclization of farnesyl pyrophosphate to pentalene (55) the parent hydrocarbon of the pentalenolactone antibiotic^.^^ Retention of both hydrogens from C-9 of FPP suggested that cyclization occurred at a single enzyme active-site with no kinetically free intermediates.The cyclization of FPP to humulene (56) and caryophyllene (57) in a cell-free system from Saluia oficinalis represents the first Me Me I (55) (56) (57) example of a soluble Cls-cyclase from a higher plant.73 Plant tissue cultures provide a good source of cell-free systems for biosynthetic studies as has been demonstrated by the use of extracts from callus cultures of Andrographis panicul~ta~~ to show inter alia that (2E,6E)-FPP and not the (22,6Z)-isomer is the precursor of 7-bisabolene (58). The detailed stereochemistry and mechanisms of enzymic cycliz- ations to form several classes of sesquiterpenes and monoterpenes have been excel- lently re~iewed.~ *H N.m.r.and 'H isotope-induced shifts in 13C n.m.r. have also been used to provide details of sequiterpenoid diterpenoid and triterpenoid biosynthesis. Incor- poration experiments with labelled acetates and mevalonates revealed the occurrence of hydrogen migrations to C-1 and from C-5 to C-6 during biosynthesis of alliaciolide 70 D. E. Cane A. Saito R. Croteau J. Shaskuo and M. Felton J. Am. Chem. SOC.,1982 104 5831. 71 R. Croteau S. Shaskus D. E. Cane A. Saito and C. Chang J. Am. Chem. SOC.,1984 106 1142. 72 D. E. Cane and A. M. Tillman J. Am. Chem. SOC.,1983 105 122. 73 R. Croteau and A. Gundy Arch. Biochem. Biophys.1984 233 838. 74 P. Anastasis I. Freer C. Gilmore H. Mackie K. H. Overton D. Picken and S. Swanson Can. J. Chem. 1984 62 2079. 358 T.J. Simpson (59) in Marasmius allia~eus;~~ and the retention of label at C-6 of illudin M (60) enriched from [S2H2 ,5-'3C]mevalonate in Clitocybe illudens indicated that there is no hydride rearrangement involving this centre as had been previously reported.76 The appearance of a 2H-'3C coupling in the 2H n.m.r. spectrum of the antiviral and antitumour metabolite aphidicolin (61) when enriched from [4-'H2 ,3-'3C]meval- onate in Cephalosporium aphidicola established that a P-hydrogen at C-9 migrated to C-8 during the bio~ynthesis.'~ Further studies using advanced intermediates have shown that biosynthesis may proceed via aphidicolan-16-01 (62).78 R (61) R = OH (62) R = H A number of important studies in relation to the biosynthesis of the gibberellins have appeared.A microsomal enzyme preparation from Marah macrocarpus removes the 19-( pro-R) hydrogen during the stereospecific oxidation of ent-kauren- 19-01 (63)79to the aldehyde. A cell-free system which converts kaurene into the 19-aldehyde has also been obtained from maize seedlings.80 The kaurenolides e.g. (64) are co-metabolites of gibberellins in Giberella fujikuroi. Both oxygen atoms from C-19 of ent-kaur-16-en-19-oic are retained in their formation.81 The diene (65) has been (63) R = CH,OH 0 (65) R = C0,H; 6,7-dehydro (64) implicated in this step which presumably proceeds via the 6p,7P-epoxide which is opened in a trans diaxial manner by the carboxyl group.Resuspended cultures of G. fujikuroi metabolized [3-'3C]mevalonate to 13C-enriched gibberellins plus I3CO2 which results from the loss of C-20.82 The formation of gibberellic acid (GA,) could 75 A. P. W. Bradshaw J. R. Hanson and I. H. Sadler J. Chem. SOC.,Chem. Commun.,1982. 292. 76 A. P. W. Bradshaw J. R. Hanson and I. H. Sadler J. Chem. SOC.,Perkin Trans. I 1982 2445. 77 M. J. Ackland J. R. Hanson A. H. Ratcliffe and I. H. Sadler J. Chem. Soc. Chem. Commun. 1982 165. 78 M. J. Ackland J. R. Hanson B. L. Yeoh and A. H. Ratcliffe J. Chem. SOC.,Perkin Trans. 1. 1985 2705. 79 P. F. Sherwin and R. M. Coates J. Chem. SOC.,Chem. Commun. 1982 1013. 80 E.S. Wurtele P. Hedden and B. 0.Phinney J. Plant Growth Regul. 1982 1 15. 81 M. H. Beale J. R. Bearder G.H. Down,M. Hutchison J. MacMillan and B. P. Phinney Fhytochemistry 1982 21 1279. 82 P. Lewer and J. MacMillan Phytochemistry 1984 23 2803. Biosyn thesis 3 59 be observed in vivo as well as 13C02 if the filtered medium was concentrated. The metabolism of gibberellins has been reviewed.83 The aromatase-catalysed oxidation of androst-4-ene-3,17-dione(66) to oestrone has been the subject of particularly interesting work. Using samples of (66) with chiral 19-methyl labelling Caspi et ul. have demonstrated that the initial C-19 hydroxylation occurs with retention of ~tereochemistry.~~ 2H and l80doubly labelled alcohol (67) and aldehyde (68) also have been converted into oestrone by human placental microsomes to give the results shown.85 Me ,o 0 HO \ =* 0 HCOOH (68) The formation of oleanane and urs- 12-ene pentacyclic triterpenes has been exten- sively studied using 13C and 2H labelled acetates and mevalonate in tissue cultures of Isodon juponicus;86 and the incorporation of [1,2-13C2]acetate into the side chains of a number of sterols has been studied using cell-tissue cultures of several higher plants.87 A number of compounds of mixed terpenoid-polyketide origins (meroterpenoids) have been studied.The phthalide (69) is converted into mycophenolic acid (70) by two separate pathways.88 13C-Labelling studies demonstrate that the mycotoxin austalide D (71) is also derived via (69).89 Austin (72) is formed by alkylation of 3,5-dimethylorsellinic acid by farnesyl pyrophosphate followed by extensive oxida- tive modification^.'^ Andibenin B and terretonin have been shown to be products of the same path~ay.~',~~ 83 J.MacMillan in 'Analysis of Plant Hormones and Metabolism of Gibberellins' ed. A. Crozier and J. R. Hillman Society for Experimental Biology Cambridge 1984 Vol. 23 p. 9. 84 E. Caspi T. Arunachalam and P. A. Nelson J. Am. Chem. Soc. 1983 105 6987. 85 M. Akhtar M. R. Calder D. L. Corina and J. N. Wright Biochem. J. 1982 201 569. 86 S. Seo Y. Tomita and K. Tori J. Am. Chern. SOC.,1981 103 2075. 87 S. Seo A. Uomori Y. Yoshimura and K. Takeda J. Am. Chern. SOC.,1983 105 6343. 88 L. Colombo C. Gennari D.Potenza C. Scolastico F. Aragozzini and R. Gualandris J. Chem. SOC. Perkin Trans. 1 1982 365. 89 A. E. de Jesus R. M. Horak P. S. Steyn and R. Vleggaar J. Chem. SOC.,Chem. Commun. 1983 716. 90 T. J. Simpson D. J. Stenzel R. N. Moore L. A. Trimble and J. C. Vederas J. Chem. SOC.,Chem. Commun. 1986 1242. 91 C. R. McIntyre T. J. Simpson R. N. Moore L. A. Trimble and J. C. Vederas J. Chem. SOC.,Chem. Commun. 1984 1498. 92 C. R. McIntyre T. J. Simpson D. J. Stenzel A. J. Bartlett E. O'Brien and J. S. E. Holker J. Chem. Soc. Chem. Commun. 1982 781. 360 T. J. Simpson Me0 (71) (72) 4 Shikimate Metabolism Studies of the mechanisms of the individual steps in the shikimic acid pathway have been greatly facilitated by the availability of the individual enzymes in large quantities from gene cloning methodology.For example purification of dehydroquinate syn- thase from E. coli K-122 has been reported93 and a plasmid-bearing strain that overproduces the enzyme 1000 fold has been constructed by subcloning the aroB gene into E. coli RB791 resulting in production of the enzyme as 5% of the total water-soluble protein.94 Studies of the steric course of the 5-enolpyruvyl-shikimic acid-3-phosphate (EPSP) synthase reaction have shown that (2E)-[3-2H ,3- 3H,]phospho-enol pyruvate is incorporated into chorismate (73) with the double bond configuration retained so that in the EPSP synthase reaction the addition step must have the opposite steric course to that of the elimination The subsequent rearrangement of chorismate to prephenate (74) catalysed by chorismate mutase has been shown using (E)-and (Z)-[9-’H1 ,9-3H,]chorismates to proceed via a chair-like transition as does the corresponding uncatalysed thermal Claisen I I OH OH (73) (74) 93 J.W. Trost J. L. Bender J. T. Kadonaga and J. R. Knowles Biochemistry 1984 23 4470. 94 K. Duncan and J. R. Coggins Biochern. Soc. Trans. 1984 12 275. 95 C. E. Grimshaw S. G. Sogo S. D. Copley and J. R. Knowles J. Am. Chem. Soc. 1984 106 1699; J. J. Lee Y. Asano T.-L. Shieh F. Speafico K. Lee and H. G. Floss J. Am. Chem. Soc. 1984 106 3367. 96 S. G. Sogo T. S. Widlanski J. H. Hoare C. E. Grimshaw G. A. Berchtold and J. R. Knowles J. Am. Chem. Soc. 1984 106 2071; Y. Asano J. J. Lee T.L. Shieh F. Speafico C. Kowal and H. G. Floss ibid. 1985 107 4314. Biosynthesis 361 rearrangement.97 The mechanism of the prephenate dehydrogenase reaction has been studied making elegant use of I3C isotope effects on the decarboxylation of both deuteriated and non-deuteriated substrate^.^^ It was concluded that the reaction proceeds by a concerted mechanism rather than a stepwise one in which dehydroge- nation precedes decarboxylation. Studies of the substrate specificity of chalcone synthase from Pteroselinum hortense (parsley) showed that malonyl CoA could not be replaced by malonyl acyl carrier protein but that butyryl- hexanoyl- and benzoyl-CoA could function efficiently as chain-initiating units whereas acetyl- and octanoyl-CoA were relatively poor sub- strate~.~~ An isoflavone synthase has been detected for the first time in a microsomal preparation from cell-suspension cultures of soybean (Glycine max) treated with a glucan phytoalexin elicitor from Phytophthoramegasperma.'OOCofactor requirements were consistent with a monooxygenase so a pathway to isoflavone (75) via epoxida-tion of the enol form of the flavanone leading to the spiro-cyclopropyl-cyclohexadienone (76) has been proposed..OH H HO H+ (76) (75) 'H and 13C labelled precursors have been used to obtain useful biosynthetic information on a number of flavonoid metabolites including phaseolin,"' psilotin,"' formon~netin,'~~ and pisatin.Io4 5 Alkaloids and other Amino Acid Derived Metabolites The mechanism whereby phenylalanine is converted into tropic acid (77) has been much studied.Incorporation of the four possible stereoisomers of [carboxyl-97 S. D. Copley and J. R. Knowles J. Am. Chem. Soc. 1985 107 5306. 98 J. D. Hermes P. A. Tipton M. A. Fisher M. H. O'Leary J. F. Morrison and W. W. Cleland Biochemistry 1984 23 6263. 99 R. Schiizm W. Heller and K. Hahlbrock J. Bid. Chem. 1983 258 6730. I00 M. Hagmann and H. Grisebach FEBS Letf. 1984 175 199. ini P. M. Dewick and M. J. Steele Phytochemistry 1982 21 1599. 102 E. Leete A. Muir and G. H. N. Towers Tetrahedron Lett. 1982 23 2635. 103 H. A. M. Al-hi and P. M. Dewick J. Chem. Soc. Perkin Trans. 1 1984 2831. 104 S. W. Banks and P. M. Dewick. 2. Naturforsch. Sect. C 1983 38 185.362 T. J. Simpson C,P3Hl]alanine into hyoscyamine in Datura stramonium indicated that the rearrangement involves a 1,2-migration of both hydrogen and the ~arboxyl."~ A highlight of the period has been the complementary work of two research groups on elucidating the details of the biosynthesis of the pyrrolizidine and olizidine alkaloids from putrescine and cadaverine respectively. Extensive use has been made of 2H- 13C- and "N-labelled precursors and n.m.r. analysis of enriched metabolites. For example on incorporation of [1,9-13C2]homospermidine (78) into retronecine (79) the 13C n.m.r. spectrum showed doublets for C-8 and C-9 to confirm that homospermidine is an intact precursor.lo6 [l-13C,1-amino-15N]cadaverine (80) has been incorporated inter alia into lupinine (81) and lupanine (82).Observation NH2 HO of 13C-"N couplings indicated the mode of incorporation of cadaverine into these precurs~rs.'~~~'~~ Incorporations of (R) and (S) [l-2Hl]cadaverine have also been rep~rted.'"".'~ Aspects of this work have been recently reviewed."' Observation of two sets of I3C-l3C couplings on incorporation of [4,5-13C,]lysine (83) into vertine (84) and lythrine (84; 10PH) confirms that lysine is incorporated via a symmetrical intermediate cadaverine."' Detailed and valuable information on alkaloid biosynthesis has been obtained using enzymes from cell-tissue cultures. Inter alia an O-methyl-transferase which converts scoulerine (85) into tetrahydrocolumbamine (86) has been isolated from 105 E.Leete 1. Am. Chem. Soc. 1984 106 7271. I06 J. Rana and D. J. Robins J. Chem. Rex (S) 1983 146. 107 J. Rana and D. J. Robins J. Chem. Soc. Chem. Commun. 1983 1325. I08 W. M. Golebiewski and I. D. Spencer J. Am. Chem. SOC.,1984 106 7925. 109 A. M. Fraser and D. J. Robins J. Chem. Soc. Chem. Commun. 1984 1477. 110 I. D. Spenser Pure Appl. Chem. 1985 57 453. 111 S. H. Hedges R. B. Herbert and P. C. Wormald J. Chem. Soc. Chem. Commun. 1983 145. Biosyn thesis 363 OH (86) R = Me suspension cultures of Berberis wilsoniae.112 Vinorine .synthase which catalyses the conversion of 16-epi-vellosimine into vinorine (87) in the presence of acetyl CoA has been isolated from cell cultures of RauwolJa serpent in^."^ The conversion of anhydro-vinblastine into vinblastine by a cell-free homogenate of a cell-line of Catharanthus roseus that did not produce dimeric indole alkaloids has been repor- ted,Il4 and a review of one group's studies on terpenoid alkaloid biosynthesis in different cell-lines of C.roseus has appeared."' Incorporation of [Me-2H3]mevalonic acid into echinulin (88) in Aspergillus arnstelodarni followed by degradation and *H n.m.r. analysis of the enantiotopic methyl of the resultant 2,2-dimethylbutan- 1-01 using a chiral shift reagent revealed HN,!,,Me I12 S. Muemmler M. Ruffer N. Nagakura and M. H. Zenk Plant Cell Rep. 1984 4 36. I13 A. Pfitzner and J. Stockigt Tetrahedron Lett. 1983 24 5197. I14 W. R. McLauchlin M. Hasan R. L. Baxter and A. I. Scott Tetrahedron 1983 39 3777.11s J. P. Kutney B. Aweryn L. S. L. Choi T. Honda P. Kolodziejczyk N. G. Lewis T. Sato S. K. Leigh K. L. Stuart B. R. Worth W. G. W. Kurz. K. B. Chatson and F. Constabel Tetrahedron 1983,39.3781. 364 T. J. Simpson Ph '1 that most of the label was present in the 2-pro-S-methyl group."6 [ indole-2-13C,2-15 NITryptophan has been incorporated into roquefortine (89) in Penicillium roquefor- tii and into oxaline (90) in P. o~alicum."~ Incorporation was confirmed by observa- tion of 13C-'5N coupling in both metabolites. The cyclodipeptide (91) labelled with 35S has been shown to be a precursor for the aranotin derivative (92) in Aspergillus terreus.' l8 Analysis of the 13C n.m.r. spectrum of streptonigrin (93) isolated from feeding [ U-'3C]-glucose to Streptomyces Jocculus showed that the metabolite was formed from the intact units indicated."' Further evidence has come from feeding [ l-'3C]erythr~~e'20 resulting in enrichment(*) of C-8 C-6 and (2-9'.Detailed studies with 13C- and "N-labelled arginines have unambiguously estab- lishedI2l the way in which the molecule is used to construct the streptolidine moiety of streptothricin F (94). The mechanism for the conversion of a-lysine into the P-lysine component of (94) has been studied'22 in both Clostridium and Streptomyces species and is in general agreement with results for P-lysine formation in tissue cultures of Andrographilis pani~ulata.'~~ A huge body of work has appeared on the biosynthesis of the p-lactams.A useful general review'24 and a more detailed one on the enzymology of penicillin biosyn- thesis have appeared.'25 The enzyme which catalyses the cyclization of the tripeptide 116 D. M. Harrison and P. Quinn J. Chem. SOC.,Chem. Commun. 1983 879. I I7 P. S. Steyn and R. Vleggaar J. Chem. SOC.,Chem. Commun. 1983 560. 118 G. W. Kirby D. J. Robins and W. M. Stark J. Chern. SOC., Chem. Commun.,1983 812. 119 S. J. Gould and D. E. Cane J. Am. Chem. SOC., 1982 104 343. I20 W. J. Gerwick S. J. Gould and H. Fonouni Tetrahedron Lett. 1983 24 5445. 121 K. J. Martinkus C.-H. Tann and S. J. Gould Tetrahedron 1983 39 3493. 122 T. K. Thiruvengadam S. J. Gould D. J. Aberhart and H.-J. Lin J. Am. Chem. SOC.,1983 105 5470. 123 J. Freer G. Pedrocchi-Fantoni D.J. Picken and K. H. Overton J. Chem. SOC.,Chem. Commun. 1981 80. 124 R. Southgate and S. Elson Fortschr. Chem. Org. Naturst. 1985 47 1. 125 J. A. Robinson and D. Gani Nat. Prod. Rep. 1985 2 293. Biosynthesis 365 0 Me0&c02H / H2N H2N Me Me0 HoQ9' 0LNH2 OMe (93) (94) L,L,D-a-aminoadipylcysteinylvahe isopenicillin-N synthetase has been purified to homogeneity by several groups.'26 The gene from Cephalosporium acremoniurn that codes for isopenicillin-N synthetase has been identified using a synthetic oligonucleotide probe corresponding to a portion of the N-terminal amino-acid sequence of the enzyme and has been cloned into E. c~li.'~~ The substrate specificity of the enzyme has been studied extensively using synthetic tripeptide analogues and this has led to the formation of many novel P-lactams.'28 Use of suitably deuteriated samples of LLD-ACV in competitive mixed-label experiments with isopenicillin-N synthetase and detailed analysis of the deuterium isotope effects has provided evidence that the p-lactam ring forms before the thiazolidine ring.129 Model studies provided good support for a free radical mechanism for thiazolidine ring forma- tion,13' and a penicillin synthesis has been reported which begins with a monocyclic P-lactam and forms the thiazolidine ring oxidatively using Fe2+ and ascorbic acid which are the same cofactors used in the enzymic ~eacti0n.l~' Other noteworthy work concerns the incorporation of '3C,'5N-labelled LLD-ACV into isopenicillin N;'32 the synthesis of valine with chiral methyl groups and incorporation into cephalosporin C;133the biosynthetic origins of nocardicin A;134and the origins of the C3 and C5 units of clavulanic acid.'35 126 C.-P.Pang B. Chakravarti R. M. Adlington H.-H. Ting R. L. White G. S. Jayatilake J. E. Baldwin and E. P. Abraham Biochem. J. 1984 222 789; J. Kupka J.-Q. Shen S. Wolfe and A. L. Demain Can. J. Microbiol. 1983 29 488; F. R. Ramos M. J. L6pez-Nieto and J. F. Martin Antimicrob. Agents Chemother. 1985 27 381. 127 S. M. Samson R. Belagaje D. T. Blankenship J. L. Chapman D. Perry P. L. Skatrud R. M. van Frank E. P. Abraham J. E. Baldwin S. W. Queener and T. D. Ingolia Nature (London) 1985,318,191. 128 See for example J. E.Baldwin R. M. Adlington A. E. Derome H.-H. Ting and N. J. Turner 1.Chem. SOC.,Chem. Commun.,1984 1211. 129 J. E. Baldwin R. M. Adlington S. E. Moroney L. D. Field and H.-H. Ting J. Chem. Soc. Chem. Commun. 1984 984. 130 C. J. Easton J. Chem. Soc. Chem. Commun. 1983 1349; C. J. Easton and N. J. Bowman ibid. p. 1193. 131 J. E. Baldwin R. M. Adlington and R. Bohlmann J. Chem. SOC.,Chem. Commun. 1985 357. 132 R. L. Baxter C. J. McGregor G. A. Thomson and A. 1. Scott J. Chem. SOC.,Perkin Trans. 1 1985 369. 133 C.-P. Pang R. L. White E. P. Abraham D. H.G. Crout M. Lustorf P. J. Morgan and A. E. Derome Biochem. J. 1984 222 777. 134 C. A. Townsend and A. M. Brown J. Am. Chem. SOC.,1983 105 913; C. A. Townsend and G. M. Salituro J. Chem. SOC.Chem. Commun. 1984 631. 135 S. W. Elson R. S. Oliver B. W. Bycroft and E. A. Faruk J. Antibiot. 1982 35 81; C. A. Townsend and M.-F. Ho J. Am. Chem. Soc. 1985 107 1065 1066. 366 T J. Simpson The cyclopentyl isocyanide (95) has been shown to be formed from tyr~sine.'~~ Two labelling patterns are observed (from 13C-enriched precursor) showing that ring-fission OCCUTS at both a and b. The lincomycins A (96) and B (97) contain respectively the propyl- and ethyl-hygric acid moieties (98) and (99). Incorporations of 2H-labelled tyrosine and dopa (100) indicate their formation from oxidative cleavage of dopa and methi~nine.'~~ (96) R = Pr" (97) R = Et (98) X = Me (99) X = H The 2-amino-3-hydroxycyclopentenonemoiety occurs in several antibiotics of disparate structure.Results of experiments on formation of asukamycin in Streptomy-ces nodosus indicate that this moiety is formed by intramolecular cyclization of 5-aminolaevulinic Interesting biosynthetic studies on showd~mycin,'~~ 136 J. E. Baldwin H. S. Bansal J. Chondrogianni L. D. Field A. A. Taka V. Thaller D. Brewer and A. Taylor Tetrahedron 1985 41 1931. 137 N. M. Brahme J. E. Gonzalez J. P. Rolls E. J. Hassler S. Mizsak and L. H. Hurley J. Am. Chem. Soc. 1984 106 7873. 138 A. Nakagawa T.-S. Wu P. J. Keller J. P. Lee S. Omura and H. G. Floss J. Chem. SOC.,Chem. Commun. 1985 519. 139 J. G. Buchanan A. Kumar R. H. Wightman S. J. Field and D. W. Young J. Chem. SOC.,Chem. Commun. 1984 1517. Biosynthesis 367 virginiamycin antibiotic^,'^' and naphthyrid~mycin'~~ elia~mycin,'~~ have appeared.[2-'3C,'5N]Aspartic acid is incorporated intact into 3-nitropropionic acid in Penicil-Zium atro~enetum.'~~ A large number of tremorgenic mycotoxins have structures based on substitution of indole with highly modified terpenoid residues e.g. penitrem A (101). Structural and biosynthetic work on these and other tremorgens has been reviewed.'@ Me 6 Porphyrins Hydroxymethylbilane (102) is now firmly established as the product of the enzyme deaminase which is cyclized by co-synthetase to uroporphyrinogen I11 (103). Kinetic pulse-labelling experiments with both I3C- and 14C-labelled porphobilinogen (PBG) (104) have shown that the order of binding of the four pyrrolic rings to deaminase is first ring A then B C and finally D.'45 Different forms of deaminase which differ in having 1 2 3 or 4 molecules of PBG bound per molecule of deaminase have been detected and ~eparated.'~~ In the presence of excess PBG these forms could complete the synthesis of hydroxymethylbilane.Battersby and co-workers have P A HOZC $-P A HOCH2 >-P A P P I4O R. J. Parry and J. V. Mueller J. Am. Chem. SOC.,1984 106 5614. 141 J. W. LeFevre and D. G. I. Kingston J. Org. Chem. 1984 49 2588. 142 M. J. Zmijewski jun. M. Mikolajczak V. Viswanatha and V. J. Hruby J. Am. Chem. SOC.,1982 104 4969. 143 R. L. Baxter E. M. Abbott S. L. Greenwood and I. J. McFarlane J. Chem. Soc. Chem. Commun. 1985 564. 144 P.S. Steyn and R. Vleggaar Fortschr. Chem. Org. Naturst. 1985 48 1. 145 A. R. Battersby C. J. R. Fookes G. W. J. Mateham E. McDonald and R. Hollenstein J. Chem. SOC. Perkin Trans. 1 1983 3031; J. S. Seehra and P. M. Jordan J. Am. Chem. SOC.,1980 102 6841. 146 P. M. Anderson and R. J. Desnick J. Biol. Chem. 1980 255 1993; A. Berry P. M. Jordan and J. S. Seehra FEBS Lett. 1981. 129 220. 368 T. J. Simpson demonstrated that the active site of deaminase from Euglena gracilis contains an essential lysine residue which is the likely point of attachment of the first molecule of PBG.14' A different conclusion was reached by Scott and co-workers who studied the 3H n.m.r. of a PBG-deaminase complex formed using 3H-labelled PBG with an activity of 132 Ci mmol-' and the deaminase from Rhodopseudornonas spheroides.14* The 3H n.m.r. of this complex showed inter alia a broad peak centred at 6 3.28 ppm which was attributed to an S-CHT-pyrrole residue indicating that the PBG was attached to a cysteine group! The spiro-pyrrolenine (105) is a likely intermediate in the conversion of hydroxymethylbilane into uro'gen 111. Two model systems (106) and (107) containing the previously unknown macrocyclic system of (105) have been synthesi~ed.'~' In vitro evidence for this fragmentation-recombination process has been provided by synthesis of the model pyrrolo-pyrrolenine (108) and its demonstrated facile rearrangement to (109) on mild acid treatment.l5' P A P AM" CN (106) X = x ,(lo71 X = CN H Me ,Me Bu'02C H Me The conversion of uro'gen I11 into cobyrinic acid during the biosynthesis of vitamin B, proceeds via the C-methylated products Factors I 11 and 111 the dihydro forms of which are believed to be the actual enzyme-active intermediates.This has been confirmed for Factor I1 by an isolation experiment under rigorously anaerobic condition^.'^' Post Factor I11 (110)the pathway requires five methylations decarboxylation of the C-12 side-chain insertion of cobalt ring contraction and loss of C-20 via acetic acid. In a fascinating series of biomimetic synthetic studies Eschenmoser and co-workers have studied the methylation of dipyrrocorphins and 147 G. J. Hart F. J. Leeper and A. R. Battersby Biochem. J. 1984 222 93. 148 J. N.S. Evans P. E. Fagerness N. E. Mackenzie and A. I. Scott J. Am. Chem. SOC.,1984 106 5738. 149 W. M. Stark M. G. Baker P. R. Raithby F. J. Leeper and A. R. Battersby J. Chem. Soc. Chern. Comrnun. 1985 1294. 1so A. R. Battersby H. A. Broadbent and C. J. R. Fookes J. Chem. Soc. Chem Comrnun. 1983 1240. 151 A. R. Battersby F. Frobel F. Hammerschmidt and C. Jones J. Chem. Soc. Chem. Comrnun. 1982,455. Biosynthesis 369 pyrrocorphins to obtain information on the likely biogenetic sequence.152 The actual sequence has been demonstrated in separate studies using pulse-labelling experi- ments with l3C-labe1led S-adenosyl methionine and unlabelled Factor 111in cell-free preparations from Clostridium tetanornorphurn153 or R. ~pheroides'~~ to be C-17 12 1 15 and finally C-5.Eschenmoser has also provided excellent biomimetic evidence for the ring-contraction process by demonstrating the interconversions shown in the scheme starting from the nickel or cobalt complexes of 20-methyl-20-hydroxydihy-drocorphin (1 11). The previously puzzling requirement for the introduction of the 10-methyl is explained by the ready tautomerization of the nor-methyl analogue (112) to the corresponding ketone which does not undergo ring-c~ntraction.'~~ Recent 180-labelling studies on bacteriochlorophyll biosynthesis have shown that the phytyl ester is formed by attack of the ring D propionate carboxyl group on the w-HJ-N M'NJ (111) R = Me (112) R = H I52 R. Wadischatka and A. Eschenmoser Angew. Chem. Int. Ed. Engl.1983 22,630; R. Wadischatka E. Diener and A. Eschenmoser ibid. p. 631;C. Leumann K.Hilpert J. Schreiber and A. Eschenmoser J. Chem. SOC.,Chem. Commun. 1983 1404. 153 H.C.Uzar and A. R. Battersby J. Chem. SOC., Chem. Commun. 1985 585. 154 A. I. Scott N. E. Mackenzie P. J. Santander P. E. Fagerness G. Muller E. Schneider R. Sedlmeier and G. Worner Bioorg. Chem. 1984 12 356. 155 V. Rasetti A. Pfaltz C. Kratky and A. Eschenmoser Proc. Natl. Acad. Sci. USA 1981 78 11; V. Rasetti K.Helpert A. Fassler A. Pfaltz and A. Eschenmoser Angew. Chern Znt. Ed. Engl. 1981 20 1058. 370 T. J. Simpson isoprenyl pyrophosphate with retention of both carboxylate oxygen^.'^^ The stereochemistry of formation of the ethyl group in bacteriochlorophyll a has been shown to occur by overall trans redu~tion'~' of the corresponding vinyl group with addition of hydrogen from the si face at C-8l and the re face at C-8*.I56 V. C. Emery and M. Akhtar J. Chem. SOC.,Chem. Commun. 1985 600. V. C. Emery and M. Akhtar J. Chem. SOC.,Chem. Commun. 1985 1646; A. R. Battersby A. L. Gutman C. J. R. Fookes M. Gunther and H. Simon ibid. 1981 645.

ISSN:0069-3030    

DOI:10.1039/OC9868300347

出版商:RSC    

年代:1986

数据来源: RSC

摘要:

Author Index Aaliti A. 255 Abbott E. M. 367 Abdallah A. A. 161 Abdel-Magid A. 245 Abdel-Megeed M. F. 174 Abe T. 111 Abe Y. 26 Abeles R. H. 303 314 323 Abell C. 347 350 Abelman M. M. 42 140 141 Abeln R. 252 Abelt C. J. 29 150 Aberhart D. J. 364 Abeywickrema A. N. 72 156 Abiko S. 93 Abraham E. P. 365 Achira K. 119 Ackermann K. 202 Ackland M. J. 358 Adams J. 153 342 348 Adams J. L. 338 Adcock W. 149 Adlington R. M. 69 70 116 236 248 249 330 365 Agarwal S. K. 197 Agawa T. 97 107 109 128 252 255 Ager D. J. 80 253 Agnero A. 81 Agosta W. C. 129 Aguayo J. B. 3 Aguero A, 252 Ahlberg P. 58 150 152 Ahlrichs R. 54 Ahmad S. 41 119 Ahmed S. A. 309 350 Aime S.9 Aissani A. M. 22 Aitken R. A. 123 Aizpurua J. M. 271 Ajaz A. A. 354 Akada Y.,292 Akai S. 161 Akase F. 156 Akelah A. 283 Akhtar M. 308 318 359 370 Akita H. 276 Akita Y. 276 Akutagawa K. 157 222 279 Alagona G. 27 Al-Ani H. A. M. 361 Albery W. J. 303 Albonico S. M. 26 Alekseev N. V. 232 Alexakis A. 90 109 212 251 Alexis M. 299 Mi H. 48 Ali M. 58 154 Al-Kadhumi A. A. H. 284 Alkhader M. A. 182 Allan G. G. 294 Allcock H. R. 283 Allen A. D. 51 Allen W. D. 24 Allerhand A. 3 Allspach T. 94 Almond H. R. 59 Alper H. 97 277 Alston P. V. 20 Altona C. 23 Alunni S. 21 Alvarez-Builla J. 265 Amatore C. 58 156 Amin M. R. 57 Amin S. 162 Amos R.A. 299 301 Anastasis P. 357 Andersen K. E. 185 Anderson D. J. 41 Anderson L. G. 214 Anderson M. W. 242 Anderson P. M.,367 Ando K. 114 Ando M. 80 142 250 Ando T. 22 53 Ando W. 24 Andreini B. P. 94 251 Andrieux J. 161 Anet F. A. L. 4 Angelici R. J. 155 Angermann A. 101 Angle S. R. 266 Ankner K. 101 Ann Hallinan E. 337 Annoura H. 108 253 Annunziata R. 273 AnGrbe B. 103 Ansell M. F. 335 371 Antonakis K. 298 Antonsson T. 135 Anwar F. 284 Anwar S. 99 231 Aoyagi S. 11 1 Aoyama I. 257 Apeloig Y. 19 149 Apitz-Castro R. 41 Appel R. 89 186 had D. 19 149 Aragozzini F. 359 Arai I. 104 252 277 Arai K. 349 Araki S. 81 Aramata A. 155 Arase A.88 Archelas A. 155 Arif A. M. 238 239 Arisol A. 204 Arlt D. 232 Armet O. 76 Armistead D. A. 42 Armitage 1. M. 8 Armstrong J. C. 151 Armstrong P. 307 Arnett E. M. 48 Arora P. K. 191 Arriau J. 26 159 Arrington H. S. 157 Arshady R. 285 Artaud I. 300 Arunachalam T. 359 Arvanaghi M. 154 279 Arya F. 38 Asada S. 282 Asahina M. 109 Asami M. 333 Asano Y. 360 Ascoli F. 307 Ashe A. J. 111 238 Asirvatham E. 137 Aslam M. 88 Asmus K.-D. 160 Aso Y. 299 Assercq J.-M. 136 Atherton E. 121 Atkins R. L. 154 Attina M. 154 Auburn P. R. 212 372 Aue D. H. 41 Aumann R. 202 263 Avasthi K. 129 Avent A. G. 12 Aviram K. 23 25 Aweryn B. 363 Azadi-Ardakani M.182 Azuma Y. 192 Baar M. R. 129 Baba Y. 216 Babayan A. T. 94 Babston R. E. 42 Bach C. 237 Bach R. D. 25 95 161 269 Bachi M. D. 67 116 Bachovchin W. W. 323 Bachrach S. M. 20 Baciocchi E. 91 259 Bader H. 190 Badet B. 305 306 Bagby B. 135 Baghdadchi J. 39 40 Baharmast R. 87 Bailey D. C. 283 Bailey T. R. 156 Baillargeon V. P. 156 257 Bain C. 284 Baines K. M. 230 Baird M. C. 216 Baird N. C. 18 19 21 147 Bakac A. 74 Baker G. L. 289 Baker J. 18 Baker M. G. 368 Bakhshaee M. 284 Balakrishnan T. 295 Balani S. K. 163 Balavoine G. 78 Balch A. L. 237 Bald E. 299 Baldisera L. 48 Baldwin J. E. 69 70 116 162 236 248 249 330 365 366 Balina G.179 Balkovec J. M. 105 266 Ball M. J. 93 Ballester M. 76 Ballesteros P. 129 Ballou D. P. 315 317 Ban Y. 140 Banait N. 49 Banfi L. 106 Banfi S. 273 292 Banjoko O. 155 Banko G. 330 Banks S. W. 361 Bannai K. 336 Barlsal H. S. 366 Bar R. 20 Baran-Harszac M. 313 Baranski A. 149 Barbeaux P. 77 Barbier M. 352 Barczynski P. 171 Barlet R. 87 Barluenga J. 81 95 279 Barone V. 24 Barra M. 155 Barrack S. A. 40 Barrett A. G. M. 122 Barrow P. 57 154 Bartlett A. J. 359 Bartlett N. 160 Bartlett W. J. 157 Bartoli G. 156 Bartoli J. F. 79 Barton D. H. R. 67 70 71 72 77 78 157 279 Barton J. W. 39 Bartroli J. 111 Bartsch R. A, 55 Barzaghi M.21 Basak A. 330 Basavaiah D. 94 Bashir-Hashemi A. 162 164 Basilevsky M. V. 20 Basselier J.-J. 154 Bassetti M. 95 Bassindale A. R. 59 Bastiaan E. W. 4 165 Basu A. K. 188 Basu S. K. 356 Batlaw R. 92 Battersby A. R. 303 367 368 369 370 Battioni P. 79 Battiste M. A. 52 Battye P. J. 40 Bau R. 168 Bauer T. 121 Bauer W. 221 226 Bauld N. L. 25 Baum G. 223 225 Baum J. C. 22 Baum M. W. 12 63 Bauta W. E. 124 Bax A, 5 11 Baxter A. D. 331 Baxter P. L. 229 Baxter R. L. 363 365 367 Baxter S. G. 151 Beachley 0. T. Jun. 229 Beak P. 133 161 183 222 Beal R. B. 133 Beale M. H. 358 Bearder J. R. 358 Beauchamp P. D. 41 Beck A. K. 226 Becker G. 94 177 Becker W.94 Beckhaus H.-D. 77 78 Beckwith A. L. J. 72 73 74 75 116 156 Bedford C. D. 96 Begley N. J. 42 Begley T. P. 315 Author Index Behr A. 213 218 Beierbeck H. 8 336 Beinlema J. J. 317 Bekaert A. 161 Belagaje R. 365 Belanger P. C. 77 Belasco J. G. 303 Bellan J. 175 Belletire J. L. 105 Belley M. 153 Bellucci G. 56 Bellville D. J. 25 Belotti D. 135 Benac B. L. 238 Bencini E. 257 Bender C. J. 19 Bender D. 166 Bender J. L. 360 Benedetti F. 59 Bengsch E. 12 Benkovic P. A, 329 330 Benkovic S. J. 316 328 329 330 Benn R. 13 228 Bennet A. J. 60 Benthin G. 335 Benziman M. 311 Beppu T. 352 Berchtold G. A. 197 360 Berg P. 356 Bergbreiter D. E. 284 Berglund B.A. 270 Bergman A. 43 Bergman J. 195 Bergmann E. D. 292 Bergstrom S. 332 Berlan J. 251 Bermel W. 12 Bernard M. 300 Bernardi A. 79 Bernardi F. 19 24 Bernasconi C. F. 58 61 62 Bernatchez M. 133 Berndt A. 223 Bernlohr W. 78 Berry A. 367 Berson J. A. 39 148 181 Berthelot J. 281 Bertozzi S. 264 Bertran J. 25 26 Bertsch A. 29 147 Bertz S. H. 103 Besace Y. 251 Besse J. J. 296 Bessodes M. 298 Best W. M. 180 Beteille J.-P. 232 Bethelot J. 154 Bhagwat S. S. 337 Bhandal H. 68 Bhat K. S. 84 100 249 Bhat N. G. 93 94 95 250 Bhat V. 161 Bhatnagar N. Y. 157 Author Index Biachini R. 56 Biali S. E. 51 Bickelhaupt F. 4 165 220 Bielecki A.15 Biellmann J. 314 Biere H. 187 Bieri J. H. 173 Bigam G. 353 Billmeyer F. W. 283 Bimanand A. Z. 38 Binger P. 177 Bingmann H. 196 Binns M. R. 333 Birch D. J. 69 236 249 Birney D. M. 148 Blackband S. J. 3 Blagg J. 156 Blain D. A. 151 168 Blakemore P. M. 204 Blanchard L. A. 127 Blankenship D. T. 365 Blattmann P. 314 Blinka T. A. 232 Block E. 41 88 Bloodworth A. J. 84 Bloom A. J. 91 121 Bloom L. M. 316 Bloom S. H. 134 Blossey E. C. 291 Blount J. F. 150 237 Blumenkopf T. A. 171 198 230 261 Blumenstein J. J. 51 Blytt H. J. 326 Boate D. R. 74 Boche G. 224 225 Bochvar D. A. 160 Bockman T. M. 92 Boeckman R. K. Jun. 128 Boekelheide V. 166 Boelens R.5 Bomer B. 232 Boese R. 151 Bogdanov G. N. 23 Boger D. L. 31 34 35 171 Bohlmann R. 365 Bohm M. C. 18 Boivin J. 78 Boldrini G. P. 101 Bolstein D. 305 Bolton G. L. 38 145 Bolton P. H. 16 Bolton R. 156 Bonds W. D. 290 Bongini A. 298 Bootsma J. P. C. 286 Borden W. T. 24 40 126 181 Borders C. L. 298 Bordwell F. G. 62 Borgford T. 330 Borghese A. 76 Bortolini O. 110 Boruah R. C. 267 Bosch E. 67 116 Bosco M. 156 Bosnich B. 212 Botstein D. 305 Bottaro J. C. 70 Bottoni A. 24 Bouchoux G. 26 Boudin A. 232 Boudreaux G. J. 81 Bouma W. J. 24 Bouquant J. 38 Bourdon F. 119 Bourne C. 205 Bovey F. A. 8 Bowen-Jenkins P. E. 19 Bowman N. J. 365 Bowry V.W. 75 Boyd D. R. 197 Braca G. 283 Bradley C. H. 3 Bradley F. C. 86 Bradshaw A. P. W. 357,358 Bradshaw R. A. 325 Braga A. L. 94 Brahme N. M. 366 Braish T. F. 122 Branca J. C. 62 Branchadell V. 26 Branchaud B. P. 317 Brand M. 83 95 Brandsma L. 221 Brannon M. J. 265 Brash A. R. 337 Brauer D. J. 224 Braun D. 300 Bray T. L. 263 Brayer G. D. 326 Breault G. A. 153 Brechot P. 86 Brecht A. 90 91 Breitgoff D. 280 Breitmaier E. 189 264 Brennan M. R. 183 Brereton R. G. 350 Breslow R. 69 303 Brevard C. 13 Brewer D. 366 Brick P. 328 Bridon D. 71 Bright H. J. 318 Brill W. F. 294 Brillembourg I. 179 Brinker U. H. 125 Brisson J. 324 Britton T.C. 112 273 Brix B. 221 Broadbent H. A. 368 Brode S. 54 Brody R. S. 328 Brokatzky-Geiger J. 196 Brook A. G. 230 Brothers P. J. 202 Brotherton C. E. 35 Brouwer W. M. 295 Brown A. B. 166 Brown A. M. 365 Brown C. A. 94 275 Browp F. K. 24 29 Brown H. C. 52 77 79 83 84 93 94 95 100 119 172 249 250 275 280 Brown J. D. 157 190 Brown M. S. 356 Brown P. A. 34 143 Brown R. 34 Brown R. D. 93 Brown S. L. 114 Brown S. S. D. 13 Brubaker C. H. 290 Bruckner D. 151 Bruhnke J. D. 87 Bruice T. C. 56 Bruice T. W. 303 Brunelet T. 298 Brus L. E. 21 Bryan P. 322 Bryce-Smith D. 159 Brycki B. 51 Brynolf A. 195 Bublak W. 166 229 Buchanan J. G. 366 Buchwald S.L. 158 220 Buck H. M. 25 Buckel W. 312 Buckner J. K. 27 Buettner H. 322 Bullen J. V. 57 154 Bumgardner C. 95 Buncel E. 61 155 Bunch J. E. 95 Bundy G. L. 331 Bunnell R. D. 61 Bunting S. 337 Burford S. C. 88 227 251 Burgemeister T. 93 Burke S. D. 42 Burmeister M.S. 127 Burton D. J. 43 216 Bush C. A. 8 Bush R. C. 155 Buss S. 19 Buszek K. R. 32 Butler L. G. 326 Butsugan Y. 81 Buu H. P. 348 Bycroft B. W. 365 Bye M. R. 183 Byrd R. A. 5 Cabri W. 79 Cacace F. 57 154 Cacchi S. 156 Cadogen J. I. G. 57 Cahiez G. 255 Caille J.-C. 136 Cainelli G. 297 298 Cairns P. M. 34 Calder M. R. 359 Caldirola P. 37 Cameron A. G. 42 140 Cameron D.K. 57 Cameron D. W. 161 Cameron L. 121 Camezind R. 161 184 Camici L. 180 Campbell C. L. 24 Campbell J.-A. 160 Campos P. J. 95 Cancedda F. 325 Cane D. E. 347 353 354 355 356 357 364 Canonne P. 133 Caple R. 270 Caporusso A. M. 90 Capponi M. 59 148 Caputo R. 281 Cardemil E. 326 Cardillo G. 297 298 Cardin D. J. 201 Cardozo M. C. 26 Carey J. T. 143 Carey P. R. 324 Carling R. W. 268 Carlini C. 283 Carlson R. G. 161 Carolti D. 307 Caron M. 60 Carpenter A. J. 185 Carpita A. 94 97 251 Carr G. 48 Carretero J. C. 136 266 CarriC R. 192 Carter E. A. 24 Casadei M. A. 257 Casella L. 273 Caspi E. 359 Castaldi G. 106 279 Castafier J. 76 Casteel W.J. Jun. 179 Castells J. 296 Casteiiada A. 198 261 Castognino E. 72 Castro J. M. 330 Catalfamo J. L. 41 Catani V. 94 Caton M.P. L. 335 Caubere P. 192 Cava M.P. 121 Cave R. J. 20 Cavell K. J. 87 Cavicchioli S. 106 279 Cazes B. 93 Ceccherelli P. 142 Cederbaum F. E. 91 142 Cefelin P;,295 296 302 Cekovii Z. 67 68 Celmer W. D. 355 Cerami A. 314 315 Cerdeira S. 155 Cerveau G. 232 Cerveny L. 201 Cesarotti E. 298 Cevasco G. 56 Cha J. K. 162 Cha J. S. 275 Cha Y. 35 Chadwick D. J. 185 Chai S. Y. 307 Chakravarti B. 365 Challa G. 286 Chaloner P. A. 201 Chamberlin A. R. 134 Chambers J. L. 298 Champion R. 93 Chan J. K. 353 Chan K.-S. 124 Chan T. H.80 153 Chan T. L. 125 Chandrakumar N. S. 31 137 263 Chandrasekaran E. S. 290 Chandrasekhar J. 21 152 Chandrasekharan J. 52 100 Chang B.-H. 297 Chang C. 353 357 Chang Y. H. 290 Chang Y. L. 297 Chanson E. 235 Chapman J. L. 365 Chapman K. T. 99 275 Chatani N. 92 Chatson K. B. 363 Chattopadhyay S. 85 Che C. M. 219 Chen B. C. 171 Chen C. 318 Chen C.-K. 337 Chen C.-W. 161 183 Chen H. H. 112 Chen H.-L. 69 332 Chen M.-H. 66 Chen Q.-Y. 87 156 219 Chen S.-F. 208 262 Chen Y. J. 317 Chen Y. S. 215 Chenard B. L. 96 132 Cheng C.-J. 11 Cheng C.-W. 222 Cheng K. W. 219 Cheng M.-C. 112 Cheou S. H. 97 Chern J.-W. 188 Chernishenko M. J. 183 Chianelli D. 191 Chiang Y.59 Chiba M. 119 Chihiro M. 137 Chikashua H. 274 Childs R. F. 150 Chin D. J. 356 Chiriac C. I. 185 Chlebowski J.-F. 325 Cho B. R. 55 Cho B. T. 100 275 Cho Y. 84 Choi L. S. L. 363 Author Index Chokotho N. C. J. 62 Chondrogianni J. 366 Chong J. M. 94 Chou C. H. 38 Chow A. 194 Chow H.-F. 244 Chow M.-S. 228 Christ W. J. 97 251 Christen P. 308 Christensen S. B. 354 Christianson D. W. 324 Christl M. 39 151 Christopfel W. C. 161 Chuche J. 38 Chuit C. 232 Chung S. K. 75 Chung Y. S. 341 Churchich J. E. 307 Churchill M. R. 229 Ciancaglione M. 37 Ciardelli F. 283 Cimiraglia R. 24 Cinquini M. 292 Cioslowski J. 149 Ciranni G. 57 Clardy J.C. 126 151 217 Clarembeau M. 77 Clark C. 270 Clark C. A. 356 Clark J. H. 106 Clark M. T. 154 Clark T. 82 Clarke S. D. 300 Clarke S. R. 339 Clark Still W. 337 Clavero C. 25 Cleland W. W. 54 361 Clemens R. J. 175 Clement A. 173 Clementi S. 21 Clennan E. L. 91 Clive D. L. J. 259 Closs G. L. 23 125 Coates R. M. 358 Coddens B. A. 25 Coggins J. R. 360 Cohen B. J. 300 Cohen D. 20 Cohen L. A. 309 Cohen M. A. 318 Cohen M. P. 29 Cohen T. 222 Colborn R. E. 217 Colbran S. B. 13 Cole G. M. 322 Cole T. E. 83 93 119 Coleman J. E. 325 Coleman R.S. 34 Collett M. J. 40 Collington E. W. 331 Collins P. W. 331 Collmann J. P. 202 Collum D. B. 127 269 Colombo L.11 1 246 359 Author Index Colonna P. 12 Colonna S. 273 292 298 Colpa J. P. 216 Colquhoun I. J. 13 Colton M. 218 Comasseto J. V. 82 94 239 Come J. H. 144 Comins D. L. 157 190 Compernolle F. 187 Conaubauer J. 355 Concellon J. M. 81 Condon B. D. 105 Conn C. 161 Constabel F. 363 Contelles J. L. 87 Contento M. 297 298 Cook B. R. 79 Cook C. 84 Cook K. S. 53 Cook M. 74 Cook P. F. 318 Cooksey C. J. 97 Cooper D. L. 20 147 Cooper M. S. 154 Cooper P. N. 84 Cooper T. G. 311 Copley S. D. 360 361 Cordell G. A. 9 Corey E. J. 120 138 139 255 333 334 338 339 344 Corina D. L. 359 Cornelisse J. 159 Cornette J. C. 331 Cornea P. E. 273 Corrett R.292 Corriu R. J. P. 232 Corsano S. 72 Cortes J. 330 Cosquer P. 192 Cossar J. 59 Cossio F. P. 271 Cossy J. 135 Costero A. M. 148 149 161 Courtneidge J. L. 97 Cousseau J. 95 Cowley A. H. 231 238 Coxon J. M. 52 Crahe M.-R. 95 Craig D. J. 285 Craik C. S. 324 Crandall J. K. 68 Craney C. L. 333 Crawford J. A. 69 236 249 Creary X. 39 Cremer D. 21 Cresswell W. M. 214 Crich D. 67 70 77 Crimmins M. T. 129 Cripe T. A. 62 Crombie L. 348 Crosby B. A. 299 Crossley M. J. 161 Croteau R. 356 357 Crout D. H. G. 365 Crowe W. E. 124 Crump S. L. 161 184 Csuk R. 105 247 257 Cullis P. M. 54 Culp J. S. 326 Cummins J. E. 326 Curini M. 142 Curran D. P. 66 67 Cutts P.W. 83 Dabbagh G. 103 Daher D. N. 122 Dai L.-X. 103 Daignealt S. 104 d’Alarcao M. 344 Dalgleish J. 285 Dalpozzo R. 156 Danheiser R. L. 43 130 Daniel H. 253 Daniels M. W. 53 Danion D. 194 Danion-Bougot R. 194 Danishefsky S. J. 32 Dan’kov Yu. V. 270 Dankwardt J. W. 162 Danson M. T. 315 Dao L. H. 49 Darling G. 299 Darling P. 298 Das I. 74 Da Settimo F. 90 Daub E. 305 Daub G. W. 42 Davies A. G. 97 Davies J. A. 299 Davies S. G. 31 114 137 156 205 Davidson A. H. 42 Davidson E. R. 17 Davis A. P. 99 231 Davis F. A. 85 112 120 273 Davis N. K. 314 Deacon G. B. 228 Deakyne C. A. 24 De Amici M. 37 Deardo& D. R. 333 De Brosse C.7 De Camp Schuda A. 81 Decker 0. H. W. 43 De Clerq P. J. 34 De Frees D. 148 Degueil-Castaing M. 74 De Hoff B. S. 42 141 Deinzer M. L. 160 De Jaso B. 74 de Jesus A. E. 354 359 Dekker L. 57 De Lasalle P. 101 Deleuze C. 12 Dell’Aira D. 259 Dellaria J. F. 112 273 De Loach J. A. 129 De Lombaert S. 136 266 Demailly G. 118 Demain A. L. 330 365 De Mare G. R. 25 Demars J. P. 120 de Mayo P. 39 de Meijere A. 86 Demers J. P. 282 Demetriadou A. K. 351 352 De Michaeli C. 37 Demko D. M. 120 282 Demuth M.,124 143 Denmark S. E. 130 Dent A. 57 154 Dent W. 266 Depezay J. C. 340 Derome A. E. 365 De Rosa M. 179 de Rossi R. H. 155 Desai M. C. 94 Desai R. C. 104 Desbene P.-L.154 Deschler U. 234 Deshmukh A. A. 274 Deslongchamps P. 60 De Smet M. D. 286 Desmond R. W. Jun. 132 Desnick R. J. 367 Deuys M. 352 de Vaal P. 159 de Vargas E. B. 155 Devroy W. F. 214 Dewan J. C. 204 220 Dewar M. J. S. 18 26 27 29 160 167 De Weerd T. J. W. 295 Dewick P. M. 361 de Wolf W. H. 4 165 De-Xiang W. 21 Dey A. K. 124 De Young D. J. 97 Dhanak D. 178 179 Dibble P. W. 161 183 Dickbreder R. 237 Diczfalusy U. 335 Diehl K. 159 Diener E. 369 Diercks R. 151 152 213 214 Dieter K. M. 18 Dieter R. K. 121 Dietrich H. 225 Dietze P. E. 53 Di Francesco D. 220 Di Furia F. 110 Dijkstra K. 5 Dilworth B. M. 122 134 D’Incan E. 106 Dingwall J.G. 176 Di Novi M. J. 177 Dippel J. 126 Disch R. L. 21 Dittmann K. 183 Di Tullio D. 339 Di Vona M. L. 50 Dixneuf P.H. 97 218 376 Dixon D. A. 19 23 24 Dobson B. 50 Doddi G. 50 Doddrell D. M. 350 Doering W. von E. 29 Doscher F. 291 Dogan B. M. 29 Dohner B. R. 55 Dolbier W. R. 43 Domayne-Hayman B. P. 330 Dombroski M. A. 133 Domin G. 285 Dondoni A. 156 185 Dordor-Hedgecock I. M. 114 205 Dorfmeister G. 186 Dorigo A. E. 25 Dorman L. A. 297 Dormans G. J. M. 25 Dormond A. 255 Dorow R. L. 112 273 Dotz K. H.,202 Doubleday C. Jun. 166 Dougherty D. A. 125 Dougherty T. K. 143 Douglas K. T. 47 Douglas T. A. 61 Dow R. L. 11 1 Dowd P. 125 Dowling M.37 Down G. H. 358 Downing J. 149 Downs A. J. 229 Doyama K. 98 135 Doyle M. P. 202 Doyle T. W. 37 Drake A. F. 335 Dreiding A. S. 32 175 Dreuth W. 86 294 Drtina G. J. 278 Du P. 24 181 Dubac J. 232 Duchatsch W. 168 Dufresne C. 77 Duggan M. E. 65 Duh H.-Y. 37 87 Dunach E. 296 Dunaway-Mariano D. 326 Duncan J. 352 Duncan K. 360 Duncan S. M. 263 Duran M. 24 25 Durst T. 301 Dutta D. K. 267 Duyne G. V. 126 Dvorak D. 216 Dyke H. 34 137 Dziallas M. 220 Eaborn C. 12 Easton C. J. 365 Eatock G. B. 26 Eberbach W. 196 Eberlein T. H. 192 Eberson L. 58 154 Ebert C. 21 Ebisawa Y. 17 Ebizuka Y. 349 Eckert H. 14 220 Eckert-Maksic M. 151 Edlund U.21 167 Edstrom E. D. 139 155 Edwards J. H. 204 Edwards M.R. 50 Edwards P. P. 13 Egert E. 126 Eggleston D. S. 245 Eisch J. J. 181 Eisen N. 41 Eisenberg D. 187 Eisenhart E. K. 34 Eisenhuth L. 94 Eisermann D. 87 Ejiri E. 169 Ekogha C. B. 98 Eliasson B. 167 Eling B. 286 El-Kheli M.N. A. 12 Ellaboudy A. S. 13 Ellis R. J. 59 Ellis R. W. 35 53 Elman B. 195 Elmore D. T. 307 Elson S. W. 364 365 El-Talbi M. R. 23 Emblidge R. W. 301 Emery V. C. 370 Emziane M. 231 278 Enders D. 108 Engelke R. 29 148 Enzell C. R. 10 Ephritikhine M. 79 Epiotis N. D. 19 Epling G. A. 158 Ercolani G. 50 Erickson K. L. 183 Ericsson L. H. 325 Ermer O. 29 149 Ernst A.B. 219 Ernst L. 94 Ernst R. R. 5 16 Ershov B. A. 171 Esaki N. 305 309 Eschenmoser A. 369 Espenson J. H. 74 Estreicher S. 21 Eswarakrishnan V. 88 Etemad-Moghadam G. 175 Etzrodt H. 225 Evans D. A. 99 111 112 178 245 273 275 Evans J. C. 95 97 Evans J. F. 342 348 Evans J. N. S. 368 Evans S. A. 301 Ezeani C. 155 Fassler A. 369 Author Index Fagerness P. E. 368 369 Faggiani R. 150 Fairlamb A. H. 315 Fan W.-Q. 157 279 Fantin G. 156 Farnetti E. 274 Faron K. L. 124 Farrall M. J. 285 286 298 299 301 Farrks J. 186 Faruk E. A. 365 Fasella P. 307 Fatiadi A. J. 88 Faulks S. J. 228 Fauvarque J.-F. 257 Fawcett S. M. 299 Feast W. J. 204 Fedorynski M.174 Fehr C. 248 Feigel M. 7 Feke S. C. 191 Felberg J. D. 35 Feldhaus R. W. 306 Feldhues M. 65 Feldman K. S. 127 144 Feliz M. 186 Feller D. 17 Felton M. 357 Feng J. 26 153 Fengl R. W. 111 205 Ferguson J. 166 Fernandez J. 26 159 FernLndez-Simon J. L. 81 Ferraz H.M. C. 122 Ferreira J. T. B. 94 Ferrer P. 149 161 253 Ferreri G. 281 Ferrier R. J. 331 Ferrin L. J. 330 Ferroudi D. 113 Ferry J. G. 315 Fersht A. R. 330 Fesik S. W. 8 Fessner W.-D. 168 Fettinger J. C. 229 Feutrill G. I. 161 Fiedler J. 166 Field L. D. 365 366 Field S. J. 366 Fife T. H. 60 Finch H.,331 Finet J.-P. 157 279 Fink J. 176 Finke R. G. 166 Finkelstein H. 194 Firouzabadi H.271 Fischer G. 196 Fischer K. 34 144 159 Fisher L. M. 303 Fisher M. A. 361 Fisher M. W. 161 Fisher R. 7 Fitjer L. 139 Fittschem C. 115 Author Index Fitzgerald G. A. 337 Fitzpatrick F. A. 337 Fitzpatrick P. F. 316 Fitzsimmons B. J. 342 348 Flament J.-P. 26 Flamm-ter-Meer M. A. 77 78 Fleischmann M. 91 Fleming I. 92 111 157 244 Fleming S. A. 123 Flintjer B. 233 Flitsch S. L. 330 Flood L. A. 294 Florio E. 158 Floris B. 95 Floss H. G. 11 352 353 360 Fluck E. 177 Flynn D. L. 161 FOB M. 257 Fobare W. F. 191 Fobbe H. 257 Fobore W. F. 32 Falling P. 89 Fogagnolo M. 156 185 Foland L. D. 43 Fonouni H. 364 Fontana F. 7 1 72 Fookes C.J. R. 367 368 370 Ford W. T. 290 295 300 Forester T. R. 53 Formosinho S. J. 22 Forrest A. K. 330 Forsblom I. 10 Forsythe D. A. 49 149 Fort Y. 192 Foster B. A. 325 Foster D.F. 114 Fountaoulakis M. 313 Fourneron J. D. 155 Fournier M. 281 Fouts C. P. 5 Fowler P. W. 21 Foxman E. M. 207 Fraenkel G. 194 Francalanci F. 257 314 Franck B. 199 Franck-Neumann M. 215 Francois M. 257 Frangin Y. 228 Frank H. 163 Franck R. W. 161 Frankel M. 302 Fraser A. M. 362 Fraser-Reid B. 67 FrCchet J. M. J. 283 285 286 293 298 299 301 Frechou C. 118 Freeman P. K. 160 Freer J. 357 364 Freissler A. 101 Frenking G. 18 24 25 Frey P. A. 31 1 326 328 Freyer A. J. 144 Fridkin M.301 Fried J. 335 337 Friedl T. 221 Friedrichsen W. 187 Friesen R. W. 136 Frigge H. 39 Fristad W. E. 219 Fritschel S. J. 289 Fritschi H. 126 208 Fritz G. 81 Fritz H. 77 78 166 196 Frobel F. 368 Frolow F. 195 Fuchs P. L. 122 Furstner A. 105 247 257 Fugami K. 258 Fuji K. 116 117 Fuji M. 108 Fujii I. 352 Fujinami T. 117 254 259 Fujioka H. 108 253 Fujisaki S. 154 Fujise Y. 141 165 Fujita E. 111 Fujita M. 278 Fujita T. 243 Fujiwara H. 8 Fujiwara J. 31 Fukazawa Y. 116 Fukuhara T. 79 Fukui S. 310 Fukumoto K. 34 43 137 141 Fukunaga T. 19 23 Fukuzawa S. 254 259 Fukuzawa S.-l. 117 Fulde P. 18 Fuller J. Q. 314 Fund A. P. 291 Funhoff D. J.H. 163 Funk R. L. 38 42 140 141 145 Furber H. 251 Furber M. 88 227 Furstoss R. 155 Furuhata T. 24 Furuta K. 31 Gadwood R. C. 140 Gaumann T. 89 Cairns R. S. 40 194 Gajewski J. J. 39 41 Galakatos N. G. 305 Galemmo R. A. Jun. 136 Galindo J. 248 Gallagher T. 178 Galle J. E. 181 Gallucci J. 194 Galpern E. G. 160 Gambliel H. 356 Gampe R. T. Jun. 8 GandPsegui M. T. 265 Gani C. 356 Gani D. 303 308 318 330 364 Gannett P. 355 Ganthier J. G. 119 Gao J. 24 Garcia B. 72 Gardano A. 257 Gardell S. J. 324 Gareil M. 156 Garner D. S. 24 Gamey B. J. 316 Garrou P. E. 283 Carson M. J. 350 Garst J. F. 87 92 Gasdanska J. R. 35 184 Gassman P. G. 32 141 Gastiger M.78 Gates B. C. 291 Gates R. B. 320 Gattini P. G. 156 Gaucher G. M. 349 Gaudemer A. 313 Gaulas P. 314 Gauss J. 21 Gavina F. 148 149 161 253 Gebreyes K. 88 Geckeler K. 284 Gedge R. 48 Gee S. K. 43 130 Geerlings P. 149 Geerts R. 238 Gehring H. 308 Geissler J. 314 Geissler M. 92 222 Gelb M. H. 323 Gelbard G. 298 Gellibert F. 108 Genet J. P. 113 Gennari C. 11 1 246 359 George C. F. 129 George I. A. 67 Gerham C. N. 348 German A. L. 295 Gerratt J. 20 147 Gersdorf J. 159 Gerson F. 86 168 Gerwick W. J. 364 Gesson J.-P. 161 Gettins P. 325 Ghio C. 27 Ghisla S. 314 317 322 Ghodoussi V. 73 Ghosez L. 136 266 Giangiordano M. A. 120 Giartosio A.307 Gibbons C. 290 Gibbons W. 9 Giesa R. 97 Giese B. 73 74 Giffard M. 95 Giguere R. J. 263 Gil G. 356 Gil P. 148 161 Gilbert A. 159 Gilbertson S. R. 124 202 Gilday J. P. 157 Gill P. M. W. 63 Gillet J. P. 227 Gillis D. J. 216 Gilman J. W. 143 Gilrnore C. 357 Gilow H. M. 179 Ginsburg J. L.,22 Giomi D. 185 Giordano C. 71 72 106 279 Girard Y. 342 348 Girdhar R. 51 Girreser V. 82 226 Givens R. S. 161 Glaser J. 106 240 Gledhill A. P. 158 Gleicher G. J. 73 Gleiter R. 86 126 151 Glickson J. D. 5 Glidewell C. 160 Clock V. 39 Gochin M. 5 Goddard J. D. 24 Goddard W. A, 24 Godfrey P. D. 93 Godfrey S. 93 Godleski S. 105 Godleski S.A. 210 Goer B. 52 Goldberg I. 187 Goldstein J. L.,356 Goldstein M. J. 29 Goldstein S. W. 128 Golebiewski W. M. 362 Gomazkova V. S. 317 Gomez-Galeno J. 161 Gommons L. H. P. 157 Gonzalez J. E. 366 GonzPlez J. M. 95 Gonzalez-Gomez J. A. 73 Good A. 299 Goode M. J. 229 Goodfellow C. L. 156 Goodman J. L. 181 Gore J. 93 95 Gore M. P. 112 273 Gorini J. A. 186 Gortfa A. M. 40 Gosmann M. 199 Gosney I. 57 Goto M. 292 Goto N. 19 Gotzmann W. 93 Gouin L. 95 Gould I. R. 35 Gould S. J. 11 364 Gould T. J. 112 Gountzos H. 282 Gouzoules F. H. 270 Grabis U. 56 Graboski G. G. 122 Graf H. 337 Granger-Veyron H. 255 Grant R. D. 194 Grant S. K. 324 Grade T.82 226 Gravier C. 340 Graziani M. 274 Greck C. 118 Green J. R. 222 Green N. J. 23 Green R. H. 331 Greenberg M. M. 181 Greenwood S. L. 367 Greerley S. C. 41 Greeves N. 119 Gref A. 78 Gregory P. S. 97 Grieco P. A, 32 191 Griesinger C. 12 Griffith D. A. 42 Griffiths P. G. 161 Grigg R. 37 307 Grimme W. 29 147 Grimshaw C. E. 360 Grindley N. D. F. 328 Grisafi P. 305 Grisebach H. 361 Grisson J. W. 35 Grobe J. 238 Grootaert W. M. 34 Gross A. W. 120 Gross R. 186 Grotjahn D. B. 146 Groziak M. P. 188 Grubbs R. H. 130 290 Grunewald G. L.,157 Gualandris R. 359 Guang-Zhi Z. 171 Guanti G. 56 Guendouz F. 292 Guest J. R. 318 Guette C. 154 Guimbal C.228 Guindon Y. 104 Guittet E. 98 Gull R. 126 Gundy A. 357 Guner 0. F. 20 Gunther M. 370 GUO,B.-S. 222 Guo G.-Z. 103 Gupta A. P. 328 Gupta B. D. 74 Gupta R. C. 31 Gupta Y. N. 38 Gustavson L. M. 42 Gut I. 59 148 Guthrie J. P. 59 Gutierrez A. 149 Gutman A. L. 370 Guyot A. 298 Ha T.-K. 25 Haber M. T. 61 Habermas K. L. 130 Habib A. 321 Hackett S. 253 Haddon R. C. 21 166 167 Hadley G. 0..18 Author Index Haeggstrom J. 343 Haffner C. D. 143 Hafner K. 167 168 Hagihara T. 207 242 Hagiwara H. 141 Hagiwara Y. 11 1 Hagmann M. 361 Hahlbrock K. 361 Hahn C. S. 271 281 Hahn G. 109 Hahn J. M. 229 Haley G. J. 126 151 217 Halim H. 18 Hall A.D. 325 Hall L. D. 3 Hall M. B. 19 236 Halle J.-C. 58 Hallensleben M. L. 300 Haller A. 128 Hallett P. 331 Halterman R. L. 101 Hamada Y. 128 333 Hamamoto I. 276 Hamann P. R. 337 Hamatani T. 257 Hamberg M. 335 342 348 Harnelin J. 192 Harnlin R. 328 Hammerschmidt F. 368 Hammond G. B. 258 Han C.-Q. 339 Hanafusa T. 22 92 Hanamoto T. 42 112 242 Handa S. 34 Handler V. 239 Handschumacher M. D. 325 Hanessian S. 104 Hannon F. J. 255 Hansen H. C. 174 Hanson A. W. 166 Hanson J. R. 347 357 358 Hanson R. M. 85 218 Hansson A. 343 Hanzlik R. P. 55 Haque K. E. 299 Haque M. S. 98 112 273 Hara O. 352 Hara S. 88 Hara Y. 292 297 Harada S. 133 Harano Y. 128 Hares O.74 Harms K. 224 225 Harpel M. R. 316 Harpp D. N. 119 Harrington K. J. 282 Harris R. K. 14 Harrison C. R. 289 298 299 300 301 Harrison D. M. 364 Hart D. J. 178 Hart G. J. 368 Hart H. 161 162 164 Harte M.R. 310 Author Index Hartley F. R. 283 Hartmanns J. 87 Hartrampf G. 312 Hartshorn M. P. 57 Harui N. 130 Haruta J. 261 Harvey R. G. 162 163 Hasan M. 363 Hasebe K. 153 Hasegawa J. 280 Hasegawa M. 106 124 Hasegawa T. 309 Haselthe J. N. 227 Hashemi M. M. 150 Hashimoto H. 243 Hashimoto J. 291 295 Hashimoto K. 111 189 Hashimoto S. 333 Haslam E. 347 Hasler H. 354 356 Hassler E. J. 366 Hassner A. 43 92 Hata N. 140 Hata S. 155 Hatanaka N.182 Hatani Y. 349 Hatano M. 81 Hattori M. 119 Hauptreif M. 126 Havens N. 301 Havlas Z. 89 HavrPnek M. 355 Hawkins C. M. 39 Hawkins J. A. 95 Hawkins L. D. 97 Hayakawa K. 32 182 Hayashi H. 282 Hayashi T. 110 206 242 273 Hayashida M. 274 Haymet A. D. J. 21 160 Hay-Motherwell R. S. 78 Haynes R. K. 333 Hazato A. 336 He R. 218 He Y.-B. 156 Headly A. D. 22 Heald S. L. 7 Heaney H. 154 Heathcock C. H. 122 143 Heaton M. M.,23 Hecht S. S. 162 Heckmann G. 177 Hedden P. 358 Hedges S. H. 362 Hegarty A. F. 25 56 Hehre W. J. 20 22 29 31 Heimgartner H. 173 Heinen H. 202 263 Heinrich N. 18 25 26 73 Heinze P. 43 Heitmann P. 107 246 Heitz M.P. 108 Heitz W. 299 300 Heller. W. 361 Helpert K. 369 Helquist P. 143 Hemling T. C. 125 Hendel W. 163 Henderson G. B. 350 Henderson M. J. 227 Hendrickson J. B. 81 Hennesey M. J. 121 Henrie N. 329 Henry W. P. 214 Herbert R. B. 347 362 Herges R. 49 168 Hermann K. 293 Hermans P. 270 Hermes J. D. 318 361 Hernandez P. E. 341 Herndon J. W. 31 205 Herscheid J. D. M. 122 Herschlang D. 61 Hertkorn N. 152 224 Hertl P. 12 HervC Y. 71 Herzog C. 39 Heslin J. C. 104 Hess B. A. Jun. 21 160 Hesse M. 231 Heumann A. 135 Hibbert D. B. 57 Hiberty P. C. 21 147 Hibi S. 187 Hielscher B. 233 236 Hietkamp S. 224 Higa K. T. 238 Higaki T. 309 Highcock R. M. 57 Higson S.182 Higuchi H. 165 Hile G. E. 21 Hill C. L. 219 Hill N. 89 Hill R. A. 350 Hillenbrand E. A. 25 Hilpert H. 175 Hilvert D. 324 Himbert G. 97 159 Hines J. B. Jun. 87 Hino T. 107 281 Hintermann M. 3 Hinz W. 180 Hirao A. 299 Hirao T. 97 107 109 128 252 255 Hiremath S. P. 189 Hiroi K. 207 242 Hirooka S. 169 Hiroya K. 34 43 Hirsch D. 314 Hirthammer M. 152 Hitchcock P. B. 177 Hite G. A. 130 Hite G. E. 160 Hiyama T. 153 278 Ho C. 321 Ho C.-K. 330 348 Ho H. T. 311 Ho M.-F. 365 Ho T.-L. 297 Hoare J. H. 360 Hoberg H. 91 218 Hodge P. 284 287 289 292 293 298 299 300 301 Hodges J. C. 143 Hodgkin E. E. 19 Hoesch L. 175 Hoffman R. 86 Hoffman R.V. 61 Hoffmann R. 29 Hofmann H.-J. 24. Hogg A. M. 353 Hohn A. 220 Holak T. A. 8 Holker J. S. E. 351 359 Hollenstein R. 175 367 Hollins R. A. 154 Holloway S. J. 348 Holmes A. B. 268 Holton D. M. 13 Homek J. F. 315 Homsen S. W. 216 Honda A. 345 Honda M. 24 Honda T. 34 363 Hong Y. H. 179 Hook D. 353 Hook J. M. 158 Hoornaert G. 194 Hopf H. 94 Hopkinson A. C. 49 168 Hoppe D. 104 115 225 Hoppilliard Y. 26 Hopwood D. A. 352 Horak R. M. 359 Hori K. 109 142 Horiguchi Y. 108 Horii H. 26 Horinouchi S. 352 Horler H. 73 Horoi K. 118 Hoshi M. 88 Hoshino M. 161 Hosokama Y. 295 Hosomi A. 250 263 274 Hosoya K. 258 Hostettler B. 173 Houghton M.287 Houk K. N. 24 25 29 34 37 38 87 Hoult J. R. S. 337 House H. O. 164 Howe R. F. 53 Hoz S. 61 Hrabie J. A. 164 Hrovat D. A. 24 181 Hruby V. J. 367 Hrudkova H. 295 Hsiao H. 322 Hsiao Y. 219 Hsu H. C. 198 Hsueh A. 326 Hu N. 299 Hu S. S. 71 Hu X. 301 Hua D. H. 118 Hua-ming Z. 21 Huang C.-K. 65 Huang D.-S. 12 63 Huang W. 296 Huber B. 166 229 237 Huber W. 152 166 167 Hudlicky T. 126 Hullmann M. 102 254 Huff B. 184 Huffman J. C. 158 220 225 Hughes D. L. 62 Hughes K. P. 214 Hughes M. G. 24 Hui R. A. H. F. 90 280 Huisgen R. 29 35 48 Hull W. E. 313 354 Hullmann M. 217 Hunig S. 34 Hunt B. J. 284 289 301 Hunt P. 331 Hupe D.J. 62 Hupfeld B. 126 Hurley L. H. 366 Hutchinson C. R. 350 Hutchinson J. 88 Hutchinson M. 358 Hutley B. G. 63 Hutton A. T. 221 Hwang J.-K. 20 Hwang S. H. 311 Hwu J. R. 41 135 Hyde A. J. 106 Hyon M. H. 178 Hyuga S. 88 Ibata T. 35 Ibe Y. B. 219 Ibuka T. 114 Ichihara A. 363 Ichikawa H. 17 Ida N. 318 Igerashi T. 109 Iguchi K. 344 345 Ihara M. 137 141 Ihle N. C. 140 Iida H. 275 Iijima H. 349 Ikeda H. 352 Ikeda M. 133 296 Ikeda N. 101 252 Ikeda Y. 83 88 95 250 Ikegami S. 143 Ikka M. 299 Illuminati G. 50 Iloughmane H. 232 Ilsemann G. V. 213 Ilsley W. H. 229 Imada Y. 220 Imai T. 100 Imamoto T. 118 255 273 Imamura A. 23 Imperiali B.323 Imwinkelried R. 104 Inaba M. 113 Inagaki K. 305 306 Inagaki S. 19 23 24 Inamoto Y. 142 Inanaga J. 98 117 213 255 258 277 Inesi A. 257 Ingel-Sundverg M. 343 Ingold K. U. 73 74 Ingolia T. D. 365 Inman K. C. 72 Inners R. R. 59 Innis C. 155 Inomata K. 84 Inoue A. 276 Inoue M. 56 137 263 Inoue S. 282 Inoue T. 111 Invergo B. J. 306 Iqbal J. 119 Irai I. 98 Iritani K. 98 210 Imgartinger H. 93 Irvine R. W. 161 Isaacs N. S. 56 Ishibashi H. 133 Ishida A. 84 Ishida Y. 182 Ishige O. 279 Ishihara K. 98 104 277 Ishii Y. 270 Ishijima S. 311 Ishikawa M. 156 Ishiyama K. 133 Ishiyama T. 156 Isobe K. 275 Ison E. R. 281 Itermodson M. 326 Itkin E.M. 95 Ito K. 299 110. s..155. Ih? Ito w. 120 Ito Y. 110 206 207 242 Itoh K. 274 Itoh M. 93 Itsuno S. 299 Iverson T. 298 Iwai K. 292 293 Iwanaga K. 31 Iwasa K. 8 Iwase K. 19 23 24 Iwashima A. 309 Iwata K. 197 Iyengar P.,326 Iyer R. 88 Iyer S. 43 Iyoda M. 143 167 216 Izawa Y. 24 Izui K. 311 Izumi Y. 107 278 Author Index Jabri N. 212 Jackson E. R. 337 Jackson P. F. 128 Jackson W. R. 95 282 Jackson Y. A. 121 Jacob L. A. 154 Jacober S. P. 55 Jacobs H. 10 Jacobson K. A, 301 Jacobson S. E. 294 Jacquesy J.-C. 155 161 Jacquier R. 292 Jadhav P. K. 94 Jagadale M. H. 298 Jain M. K. 41 Jankowski K. 78 Janout V.,295 296 302 Jansen M.P.51 Janssen E. 228 Jarman M. 160 Jarret R. M. 18 39 Jarvie T. P. 15 Jarving I. 335 Jasien P. G. 23 24 Jastrzebski J. T. B. H. 236 Jayalekshmy P. 290 Jayasuriya N. 180 Jayatilake G. S. 365 Jeffs P. W. 7 Jekel P. A. 317 Jencks W. P. 53 61 Jenkins P. R. 34 143 Jenks T. A, 37 Jenneskens L. W. 4 165 Jenni K. 91 218 Jennings W. B. 197 Jennison C. P.R. 196 Jenny C. 173 Jensen B. 174 Jenson J. M. 42 141 Jerina D. M. 163 Jerius J. J. 229 Jeropoulos S. 81 Jew S. 84 Jewel] C. F. 43 Jeyaraman R. 121 174 3,F. 296 Jia J. H. 125 Jiang W. 71 Jiang Y. 299 Jimenez J. L. 41 Jin H. 97 251 JGrgensen K. A. 86 Joh T. 98 135 Johansson R. 298 Johns A, 74 Johnson B.58 Johnson B. A. 8 Johnson B. F. G. 13 Johnson C. D. 62 Johnson C. R. 42 129 204 333 Johnson K. A. 329 Johnson R. P.. 125 Author Index Johnson S. 143 Johnston L. J. 73 Jolly P. W. 213 Jones B. A. 56 Jones C. 368 Jones D. N. 236 Jones D. W. 40 Jones J. B. 90 280 303 Jones K. 34 Jones M. D. 262 330 Jones P. G. 50 60 11 5 Jones R. 234 Jones R. A. 180 238 239 Jones R. C. F. 242 Jones R. H. 205 Jones R. J. 121 Jones T. K. 130 Jones W. D. 219 Jonsall G. 150 152 Jordan P. M. 367 Jorgensen W. L. 24 27 JosC S. M. 47 Jouannetaud M.-P. 155 Jousseaume B. 235 Jovanovic M. V. 195 Joyce C. M. 328 Jug K. 19 21 Juge S. 113 Julia S.A. 98 Jung M. E. 32 157 180 Jung S. H. 124 Jungheim L. N. 143 Jurczak J. 101 Jurezak J. 121 Jurkschat K. 232 Juska T. 149 Juszak K. D. 218 Jutand A. 257 Jutzi P. 232 233 236 237 Kabe Y. 234 Kabeta K. 206 Kachensky D. F. 137 Kachinsky J. L. C. 268 Kaczmar U. 299 Kadokura M. 107 Kadoma Y. 61 Kadonaga J. T. 360 Kadowaki T. 154 Kaesler R. W. 124 Kagan H. B. 270 273 Kagan J. 180 Kagen B. S. 121 154 Kagigaki E. 293 Kahn S. D. 20 29 31 Kai Y. 165 216 Kaim W. 186 Kaiser E. T. 324 Kaiser J. H. 78 Kaji A. 122 258 276 Kajigaeshi S. 154 192 Kakimoto S. 192 Kakiuchi H. 165 292 295 296 300 Kakizono T. 310 Kalir R. 301 Kallmerten J. 112 Kametani T.34 43 137 141 Kamimura A. 276 Kaminska J. 267 Kamlet M. J. 21 Kanagasabapathy V. M. 51 Kanavariotti A, 62 Kanda K. 23 Kanda Y. 42 141 Kanematsu K. 32 182 Kanemoto S. 85 270 Kaneta S. 345 Kaneti J. 27 Kang H. C. 166 Kang J. 275 Kanne D. 233 Kanoh S. 299 Kansal V. K. 188 Kapasas M. M. 87 Kaptein R. 5 Karatza M.-H. 180 Karelson M. M. 23 76 Karimian K. 297 Karpf M. 127 Karpfen A. 24 Karsten W. E. 320 Kasai N. 165 216 Kashima C. 187 Kashimura S. 279 Kashimura T. 156 KaSpar S. 274 Kass S. R. 148 Kataoka M. 19 160 Katchalski E. 289 301 Kato M. 299 Kato T. 169 344 Kato Y. 300 Katritzky A. R. 23 51 76 157 171 222 279 Katsuki H. 311 Katsuki T.42 112 242 Katz T. J. 164 208 Kaufmann E. 21 82 152 Kauffmann T. 252 Kaur S. 267 Kawabata A. 115 Kawabata N. 291 295 Kawaguchi A. 137 Kawai K. 103 254 Kawakami H. 192 Kawamata T. 60 Kawamoto K. 84 Kawamoto T. 273 Kawamura K. 117 Kawanisi M. 190 Kaye A. D. 340 Kay L. E. 8 Keck G. E. 137 Keefe J. R. 60 Kegley S. E. 201 Keim W. 213 Keller H. 177 Keller P. J. 11 366 Kelley W. S. 328 Kelly J. 295 Kelly J. W. 301 Kelly M. J. 34 Kelly T. R. 31 137 263 Kemmer P. 39 Kemmink J. 5 Kemmitt R. D. W. 262 Kende A. S. 143 Kennedy D. A. 197 Kennedy J. J. 302 Kennedy R. M. 100 Kenny P. W. 171 Keogh J. 92 Kerwood D. J. 16 Kesler P. 179 Kesselring U.W. 25 Kessler H. 12 Keumi T. 154 291 Kevill D. N. 51 Khailova L. S. 317 Khamsi J. 157 279 Khan 2.H. 163 Khanna R. K. 71 Khanna V. K. 161 Khoshdel E. 289 292 293 301 Khosrowshahi J. S. 270 Kibayashi C. 275 Kidd K. B. 238 239 Kieser H. M. 352 Kikuchi H. 344 Kilburn J. D. 111 244 Kim C. K. 26 Kim D. 66 Kim H. 84 Kim K. E. 275 Kim K. S. 271 281 Kim K.-W. 83 119 Kim S. C. 320 Kimmel T. 136 266 Kimura T. 2 11 294 Kimura Y. 295 Kineger C. 202 Kingston D. G. I. 367 Kinoshita H. 84 Kirby A. J. 50 60 Kirby G. W. 364 Kirk D. N. 121 Kirkpatrick R. J. 14 Kirms M. A, 168 Kirmse W. 25 52 Kirszensztejn P. 295 Kise N. 158 Kishi Y. 97 251 281 Kishimoto H.161 Kisumi M. 318 Kitajima H. 154 Kitami S. 143 Kitamura M. 103 219 254 Kitano Y. 102 103 270 Kitaoka M. 118 Kitazume T. 246 382 Kivity S. 302 Klarner F.-G. 29 39 Klassen J. B. 321 348 Kleibomer B. 93 Klein D. J. 21 160 Klein J. 291 Kleinschmit P. 234 Klenke K. 87 Klingebiel U. 231 Klingensmith K. A. 149 Klippenstein S. J. 20 Klix R. C. 161 269 Kjonaas R. A, 255 Klump G. 299 Klumpp G. W. 223 Klusener P. A. A, 221 Kmiecik-Lawrynowicz G. 174 Knaap C. T. 236 Knabe S. M. 183 Knaup G. L. 167 Knebl R. 177 Kneisley A. 115 Knight C. T. G. 14 Knight D. W. 42 140 Knight J. 66 259 Knight W. B. 54 326 Knobel J. 168 Knoch F.89 Knochel P. 84 248 Knopka J. M. 311 Knors C. 143 Knothe L. 196 Knowles J. R. 303 310 360 361 KO T. 108 Kobayashi E. 165 Kobayashi M. 119 134 Kobayashi N. 292 293 Kobayashi S. 138 247 281 Kobayashi T. 84 106 Kobayashi Y. 102 282 Kobzar G. 335 Koch W. 18 24 25 26 73 95 Kochi J. K. 58 154 Kock-van Dalen A. C. 267 KoEovskjl P. 74 216 Kodama M. 344 Kocher M. 198 Kohler F. H. 224 Koenig M. 175 Koga A. 241 Koga K. 109 114 247 Koganty R. R. 177 Kohl F. X. 237 Kohler F. H. 152 Kohnert R. 11 Kohra S. 274 Koizium T. 109 Kolbasenko S. I. 95 Kolhe J. N. 70 Kollman P. 27 Kolodziejczyk P. 363 Komatsu H. 43 Komatsu T. 120 Kondo H. 108 253 Kondo K.293 299 Kondo S. 295 Kondo Y. 251 Konig A. 313 Konishi M. 206 Konishi S. 274 Konishi Y. 333 Konno K. 189 Konoike T. 31 Koreeda M. 67 Koremoto T. 23 Kornberg A. 328 Koroniak H. 43 Kos A. J. 21 27 82 152 Kosmider B. J. 144 Kosower E. M. 187 Kost D. 23 25 Kostermans G. B. M. 165 Kosugi H. 11 8 Kotake H. 84 Kotani E. 281 Koto H. 118 255 273 Kotovych G. 8 336 Koumaglo K. 80 Kowal C. 360 Kowalski C. J. 98 Kozhushkov S. I. 171 Kozikowski A. P. 31 124 Kozima S. 181 Koz’min A. S. 87 270 Kramer T. 104 225 Kratky C. 369 Kraus G. A. 74 161 Kraus M. A. 300 Krauss M. 23 Kravetz M. 73 Kreis R. 16 Kreisz S. 90 91 Kresge A. J. 58 59 60 95 Kress J.81 252 Kreutzer E. F. 353 Krief A. 77 124 Krishnamurthy V. V. 168 Krogh-Jespersen K. 168 Krohn K. 161 Krol M. C. 23 Kroll L. C. 290 Kroneck P. M. H. 314 Kroon J. 236 Kroto H. 17 Krueger C. 213 218 Kriiger C. 91 196 233 263 Kruger C. 124 Kruithof K. J. H. 223 Krumphanzl V. 355 Kudo K. 156 Kukenhohner T. 102 253 Kuhn H. 303 Kuhn V. 168 Kukenhohner T. 207 Kulzick M. A. 15 Kumada M. 206 Author Index Kumada Y. 352 Kumagai T. 111 Kumar A. 366 Kumar G. S. 294 Kumar M. 74 Kunai A. 155 Kund K. 25 Kunisch F. 107 246 Kunze K. L. 19 Kuo L. C. 324 Kuo S. C. 67 Kupka J. 365 Kuramoto Y. 11 1 Kurita J. 197 Kuroda M. 161 Kuroda S. 169 Kurozumi S.336 Kurz J. L. 53 61 Kurz L. C. 61 Kurz W. G. W. 363 Kusakabe M. 102 Kushida T. 143 Kutney J. P. 363 Kutsuki H. 280 Kuwajima I. 108 254 259 Kuznetsova T. S. 171 Kyung S. H. 217 Laali K. 49 Laberge L. 48 Lablanche-Combier A. 349 Laboureur J. L. 124 Ladlow M. 34 Lafitte J.-A. 88 Lai S. M. F. 331 Laidig K. 74 Lakshmikantham M. V. 121 Lal G. S. 98 Lal K. 216 Lambeir A. 315 Lambed C. 98 210 Lambed D. E. 333 Lambert J. B. 49 Lambeth P. F. 331 Lammertsma K. 24 27 Lampe F. W. 283 Landgrebe K. 74 Lane M. P. 351 Langer S. H. 283 Langhals E. 35 48 Langler R. F. 22 Languin-Micas D. 340 Lansbury P. T. Jun. 344 Lantos I. 245 Laporterie A.232 Lappert M. F. 201 227 Lardicci L. 90 Lardy H. A. 311 Larock R. C. 228 Larsen S. D. 32 191 Laszlo P. 34 Latham J. A. 317 Lathbury D. 178 Lau C. K.. 71 Author Index Lau C. M. 195 Lau J. C.-Y. 59 Lau S. 322 Lau W. 154 Laue E. D. 350 351 352 Laumen K. 280 333 Lauterwein J. 10 Lawrence R. M. 112 Lawson J. A. 337 Lazzaroni R. 264 Leadlay P. L. 314 Learn K. S. 108 Leatherbarrow R. J. 330 Leblanc Y. 342 348 Lebrilla C. 95 Lecavalier P. 299 Lecker S. H.,146 152 214 Lecomte P. 330 Le Corre M. 253 Ledwith A. 285 Lee B. H. 178 281 Lee C.-S. 178 Lee H. 162 163 Lee I. 22 26 Lee J. J. 360 Lee J. L. 11 Lee J. P.,366 Lee K. 360 Lee L.C. 299 Lee L. G. 276 Lee M. S. 11 Lee N. H.,271 Lee R. E. 151 Lee T. V. 132 243 Leeper F. J. 351 368 Lee-Ruff E. 49 Leete E. 361 362 Le Fevre J. W. 367 Lefker B. A. 123 Lefour J.-M. 21 147 Le Goffic F. 292 Lehmkuhl H.,228 Lehne V. 94 Lei X.-G. 166 Leibman J. F. 151 Leibskind L. S. 43 Leidrer S. 218 Leiendecker M. 167 Leigh S. K. 363 Leimkuhler M. 228 Lelj F. 24 Le Merrer Y. 340 Lenhert P. G. 31 Lennartz H.-W. 167 Lennox R. B. 57 83 Le Noble W. J. 54 Lentenegger U. 208 Leonard N. J. 189 Leport L. 106 Lerouge P. 180 L'Esperance R. P. 91 Lessen T. A. 120 282 Lett R. 270 Lett R. M. 140 Lorey H. 116 Leumann C. 369 Lorimer G. H. 312 Leutenegger U.126 Lotz R. 228 Le Van D. 238 LOU B.-L. 103 Levenberg P. A. 274 Loupy A. 279 Levi S. 72 Lourak M. 192 Levin D. 119 Low M. R. C. 216 Lewer P. 358 Lowe D. M. 330 Lewis D. F. V. 18 Lowe G. 54 Lewis E. S. 61 Lowen G. T. 157 Lewis F. D. 82 Lown J. W. 177 Lewis J. 13 Lu S.-B. 137 Lewis K. K. 91 Ludwig E. G. Jun. 238 Lewis N. G. 363 Luning U. 76 Lex J. 168 198 Lui J. S. 299 Ley S. V. 216 Luis S. V. 148 149 161 253 Leyner U. 79 Lukehart C. M. 31 Leznoff C. C. 290 Lumm R. T. 220 Li W. 321 348 Luna H. 126 Li W.-K. 148 Lund H.,53 Liang C. D. 157 Lund T. 53 Liang T.-C. 354 354 Lunn G. 191 Licini G. 110 Luo J. 162 Liebeskind L. S. 111 205 Luskey K. L. 356 Lien M. H. 168 Lussmann L. 115 Lifson S. 18 Lustorf M.365 Likos J. J. 306 Lusztyk J. 73 Lille U. 335 Luzar M. 15 Lin H.-J. 364 Luzhkov V. B. 23 Lin I. 326 Ly C. 159 Lin L.-J. 9 Lydiate D. J. 352 Lin R. F. 147 Lin Y.-T. 24 29 Linda P. 21 Maah M. J. 177 Lindh R. 152 Maas G. 177 Lindner H. J. 167 McBain D. S. 76 Lindsay D. 284 McCague R. 160 Lindsey J. S. 198 McCann D. J. 292 Lindskog S. 315 McCarthy J. R. 185 Lippiatt J. H. 182 McCarthy K. E. 122 171 Lipscomb W. N. 324 McClelland R. A, 49 57 60 Lipshutz B. H.,171 184 83 Liras P. 330 McClure C. K. 37 192 246 Lischka H. 24 McComsey D. F. 277 Liscum L. 356 McConnell J. A. 49 Lissel M. 279 McDonald E. 367 Lister M. A. 246 Macdonald T. L. 140 Little R. D. 171 MacDonell D. L. 298 Liu B. 148 McDougal P.G. 105 180 Liu C.-Y. 38 McEwan I. 58 Liu H.-J. 281 McEwen A. B. 21 151 Liu M. T. H. 35 McFarland J. T. 314 Liu S.-H. 297 McFarlane I. J. 367 Lively C. R. 314 McFarlane W. 13 Livinghouse T. 139 155 253 McGarry D. G. 65 Lledos A. 25 McGiff J. C. 337 Lloyd D. 160 McGregor C. J. 365 Lock C. J. L. 150 McHatton R. C. 74 Lodder G. 159 Macias J. R. 38 Loh J.-P. 136 Macielag M. 158 Lohmus M. 335 Mclntyre C. R. 351 359 Lopez-Nieto M. 330 365 Mackay D. 196 Lopp A. 335 McKee M. L. 18 Loreto M. A. 157 McKenna J. M. 83 Author Index MacKenzie N. E. 324 368 McKervey M. A. 122 134 Mackie H. 357 McKinney R. J. 84 218 Maclagan R. G. A. R. 24 McLauchlin W. R. 363 McLaughlin M. L. 61 Maclean C.4 165 Mclean S. 10 McLennan D. J. 50 56 63 McManis J. 85 McManus M. J. 197 McMeekin D. S. 333 MacMillan J. 358 359 McMillan W. D. 164 McMurry J. E. 126 151 217 McNaughton D. 93 Macomber R. S. 125 McPhail A. T. 238 McPherson A. 326 McQuatties A. 315 McTigue J. J. 3 11 Madesclaire M. 122 Madhavan B. G. V. 21. Madura J. D. 27 Maeda T. 268 Markl G. 186 238 Maercker A. 82 226 Maggiora G. M. 63 Magnin D. R. 65 Magnotta V. C. 291 Magnus P. 34 Magnusson E. 24 Maguire J. A. 219 Mahdi W. 225 Mahe P. 218 Mahendran M. 150 Maier G. 231 Maillard B. 73 74 Main L. 157 Maitra U. 69 Majetich G. 132 263 Majewski M. 222 Mak T. C. W. 125 219 Makinen M.W. 324 Makino K. 118 Malacria M. 95 Malar E. J. P. 21 Maleki M. 49 Malhotra R. 291 Malik K. U. 337 Malone J. F. 37 197 Malpardita F. 352 Malthouse J. P. G. 324 Manabe D. 297 Manabe K. 336 Manabe O. 292 Mancini P. M. E. 155 Mander L. N. 158 Mane R. B. 298 Manescalchi F. 297 298 Mangeney P. 90 109 Mangini A. 24 Mankovitz P. 311 Manley P. W. 331 Mann B. E. 83 Mann J. 38 Mannitto P. 347 Mannschreck A. 93 Mansuy D. 79 Manuel G. 232 Maquin F. 89 Maraver J. J. 26 Marcelis A. T. M. 195 Marco J. A. 253 Marcos E. S. 26 Marcotullio M. C. 142 Marcus R. A. 20 Marecek J. 54 Marek I. 90 Mares F. 294 Margerum L. D. 86 Markert J. 196 Marlier J.F. 329 Marnett L. J. 188 Marriott S. 17 21 Marron B. E. 65 Marsch M. 224 225 Marshall J. A. 42 141 Marshall L. 85 Martens F. M. 63 Martin B. 309 Martin G. J. 12 Martin J. F. 330 365 Martin M. 104 Martin M. L. 12 Martin V. S. 103 Martinez A. G. 87 Martinez R. D. 155 Martinez-Gallo J. M. 279 Martinkus K. J. 364 Martyn R. J. 57 Maruoka K. 31 106 124 137 256 261 Maruyama K. 120 187 248 Maryanoff B. E. 59 277 Maryanoff C. A. 277 Marynick D. S. 21 Marzilli L. G. 5 Mas J.-M. 95 Masamune S. 100 234 Mascagni P. 9 Mascaretti O. 353 Mase T. 143 Mash E. A. 126 Maskill H. 51 Massa W. 223 225 Massey V. 315 317 Mastellari A. 185 Masters A. F. 87 Masuda T.116 Masuda Y. 88 Masumarra G. 21 Masumoto Y. 24 Mateboer A. 223 Mateham G. W. J. 367 Mathew J. 306 Mathew L. 75 Mathur N. K. 283 Math A. R. 129 Matsuda I. 107 Matsuda S. P. T. 344 Matsukura H. 276 Matsumoto M. 182 Matsumoto T. 103 189 270 Matsumoto Y. 84 Matsuoka H. 109 Matsuyama H. 134 Matsuzawa S. 108 Mattay J. 159 Mattes R. 228 Matthews A. J. 333 Matthews C. R. 310 Matthews D. P. 185 Mattingly M. A. 3 Matuszewski B. K. 161 Matz J. R. 126 151 217 Mauger J. 275 Mayo J. D. 51 Mayr H. 21 56 87 152 Mazur D. J. 192 Mazur S. 290 Mazurkiewicz W. 174 Mazzochi P. H. 81 Meador M. A. 162 Meckler H. 35 Medici A. 156 185 Mehra U. 267 Mehrsheikh-Mohammadi M.E. 39 Mehta G. 143 Mehta M. P. 69 Meidar D. 291 Meier H. 197 Meier I. K. 81 216 Meijs G. F. 156 Meiss G.-E. 128 Meldal M. 121 Melikian A. A. 162 Mellor J. M. 91 121 MenCndez J. C. 282 Menger F. M. 292 299 Meot-Ner M. 24 Mertnyi R. 76 Merrett B. K. 161 Memfield R. B. 283 Merritt A. 265 Merz K. M. Jun. 160 167 Metcalf B. W. 338 Meth-Cohn O. 115 270 Metzger A. 168 Metzger J. O. 87 Metzler D. E. 306 Meyer A. Y. 19 Meyer E. F. 322 Meyer W. L. 265 Meyers A. I. 123 191 222 Mezey P. G. 26 Michael J. P. 157 Michels R.,299 300 Michenfelder M. 313 Author Index Michl J. 126 149 Midland M. M. 93 Mignani S. M. 209 Mignard M.86 Mikami K. 42 268 Mikolajczak M. 367 Milczarek R. 177 Mildvan A. S. 330 Miles E. W. 309 Miles J. S. 318 Millar J. M. 15 Miller B. 39 40 Miller D. D. 154 Miller L. L. 161 Miller S. M. 315 Miller W. L. 331 Millirons P. L. 179 Mills N. S. 84 Mills R. J. 256 Milner D. J. 160 Mimoun H. 86 270 Minami I. 80 211 277 Minami T. 130 153 Minato T. 26 Minisci F. 71 72 Minore J. 54 Minowa N. 249 Minsker K. S. 87 Mioskowski C. 108 Miranda E. L. 109 Mirau P. A. 8 Mishra P. 121 282 Mislow K. 149 150 237 Mistry A. G. 183 Misu D. 97 107 109 252 Misumi S. 165 Mit T.-A. 107 Mitchell G. 174 Mitchell J. 126 217 Mitchell R. H. 165 Mitchell T. N.. 235 Mitoh H.192 Mitsui H. 299 Miura M. 156 Miyachi N. 140 Miyake F. 126 Miyake H. 163 Miyakoshi T. 344 345 Miyaoka H. 345 Miyaura N. 93 156 250 Miyazaki M. 113 Miyazawa M. 99 107 268 Miyazawa Y.,134 Mizrahi V. 329 330 Mizsak S. 366 Mizutani M. 208 Mloston G. 35 48 Moad G. 75 Moberg C. 135 Modena G. 110 Moffatt E. A. 54 Moghaddam M. E. 271 Mohajer D. 271 Mohamadi F. 126 127 269 Mohammed A. Y. 259 Mohan L. 121 174 Mohanazedeh F. 297 Mohri K. 275 Moise C. 255 Mokhi M. 215 Molander G. A. 79 109 132 Molla M. E. 12 Moloney M. G. 97 Mols O. 229 Molter K. 48 Mondon M. 161 Mongkolaussavaratana T. 37 Monig J. 160 Montanan F. 295 Montes J. R. 113 Moody C.J. 40 104 194 Mook R. 72 Moore C. 270 Moore H. W. 43 Moore J. A. 302 Moore P. K. 337 Moore R. N. 351 353 359 Moore T. L. 38 145 Moors R. 186 Moos R. A. 174 Mootz D. 239 Moracci F. M. 257 Moreau S. 349 Morellet G. 155 Morera E. 156 Moretti R. 113 Morgan P. J. 365 Morgan T. 81 Morgan T. M. 143 Mori A. 98 104 277 Mori K. 345 Mori S. 156 Mori Y. 23 276 345 Moriarty R. M. 270 Morimoto T. 119 158 Morini G. 71 72 Morino Y. 309 Morisaka K. 257 Moriwake T. 113 Moriyasu M. 190 Morokuma K. 23 Moroney S. E. 365 Moro-Oka Y. 263 Morris G. A. 9 10 Morris J. 342 Momson J. F. 361 Morrison R. D. 326 Mortia T. 154 Mortier W. J. 23 Morton H.E. 104 Morzycki J. 78 Moses S. R.,37 87 Moskal J. 182 Moss R. A. 168 Motherwell W. B. 78 157 Motoheshi S. 109 Motoi M. 299 Motoo Y. 282 Mottonen J. M. 323 Mountain A. E. 63 Moursounidis J. 187 Mualla M. 68 Muchmore S. 135 Muller G. 224 226 229 237 239 369 Mueller J. V. 367 Muemmler S. 363 Muetterties E. L. 15 Muir A. 361 Mukaiyama T. 138 235 246 247 249 Mukerji I. 103 Mullane M. 56 Mullen K. 152 166 167 168 Muller F. 317 Muller G. 152 166 202 Muller L. 7 Muller N. 5 Mulzer J. 101 Munch W. 101 Munger J. D. Jun. 140 Munjal R. C. 168 Munninger W. 93 Murahasi S. 220 Murai S. 84 Murakami M. 246 Murase M. 281 Murata I. 163 197 Murata M.116 Murayama A. 109 Murayama E. 109 Murch B. P. 86 Murfitt D. 314 Murphy J. A. 74 162 330 Murphy P. 187 Murphy S. P. 24 Murphy T. 57 154 Murray C. J. 61 Murray C. K. 124 Murray K. J. 77 Murray M. 13 Murray R. W. 121 174 Murthy A. N. 143 Murthy H. M. K. 325 Murthy K. S. K. 122 Mussatto M. S. 298 Mutter M. 284 Mutter M. S. 59 Muzart J. 86 Mynott R. 128 169 175 177 213 217 Nader F. W. 90 91 Naef R. 255 Nagakura N. 363 Nagao Y. 111 113 155 259 Nagaoka H. 344 345 Nagasawa H. 117 Nagase S. 22 Nagase Y. 11 1 Nagashima F. 309 Nagata S. 128 Naidorf S. 43 Najem T. S. 56 Najera C. 279 Nakagawa A. 366 Nakagawa M. 167 281 Nakahama S.299 Nakai R. 295 Nakai S. 256 Nakai T. 42 268 Nakajima T. 19 160 Nakamura E. 108 254 Nakamura K. 325 Nakamura N. 293 299 Nakanishi A. 117 259 Nakanishi K. 11 Nakano M. 257 Nakano T. 270 Nakao T. 114 Nakasato Y. 165 Nakashima T. T. 351 353 Nakatani N. 293 Nakayama J. 161 Namai T. 344 Namgoong S. K. 55 Nam-Tran H. 25 Nanbu H. 249 Naniwa Y. 117 Nanninga T. N. 209 Narang C. K. 283 Narang S. C. 291 Narasaka K. 137 249 263 270 278 Narisano E. 106 Naruse Y. 109 Naruta Y. 248 Nasr M. M. 53 Natalie K. J. Jun. 140 Natarajan R.,60 Naulet N. 12 Nazarentian K. L. 61 Ndibwami A. 60 Neckers D. C. 291 294 297 Nee G. 296 Negishi E. 91 124 142 266 Negoro T.83 95 Negrini E. 185 Neidlein R.,169 217 Neigichi E. 156 Nelson E. C. 300 Nelson K. A. 126 Nelson P. A. 359 Nemery I. 136 266 Nemoto H. 42 141 Neogi A. N. 294 Nerz-Stormes M. 111 Nesi R. 185 Netka J. 161 184 Neuman P. A. 325 Neumann B. 279 Neumann G. 168 Neumann W. P. 76 257 Neumuller B. 177 Newcomb M. 75 Newington I. M. 70 Newlands S. F. 57 Newman M. S. 161 Newton C. G. 34 Newton M. D. 21 160 Newton R. F. 331 Ngoviwatchai I. 71 Nguyen L. T. 177 Nguyen M. T. 25 Nguyen N. H. 146 152 214 264 Nguyen S. 41 Ni J. X. 58 Niccolai N. 9 Nicholas K. M. 135 Nicholson B. K. 157 Nickolson R. C. 331 Nickon A. 52 Nickson T. E. 154 Nicolaou K.C. 65 341 343 Nieduzak T. R. 31 Nieger M. 126 Nies D. E. 161 Nigam A. 296 Nihira T. 310 Niimura K. 333 Nimmesgern H. 266 Ninio J. 330 Nishida A. 154 Nishida T. 10 Nishigaichi Y. 248 Nishii S. 114 120 Nishimura J. 165 Nishizawa M. 294 Nitta Y. 176 Nixon J. F. 177 Nobes R. H. 148 Noce P. 311 Node M. 116 117 Noguchi H. 349 Noguchi M. 192 Nokami J. 248 Nolan L. D. 311 Nolte R. J. M. 86 294 Nomura M. 156 Nomura Y. 84 Nonaka T. 85 96 270 Norinder U. 166 Norman N. C. 231 Normant J. F. 84 90 94 109 212 227 248 Noms R. K. 55 Norwood T. J. 3 Noth H. 35 Nov E. 301 Nowak T. 311 Noyori R. 103 219 254 333 336 Nozaki H. 85 96 98 115 210 255 258 270 Nudelman N.S. 155 Nuiry I. I. 318 Nuiiez O. 60 Nunomoto M. 332 Author Index Nuyens L. J. 298 Oae S. 61 Oates J. A. 337 Obrecht J. P. 173 O’Brien E. 351 359 Occhiello E. 9 Ochiai M. 111 155 259 Ockawa H. 353 OConnell E. L. 311 Oda M. 143 167 168 216 Odaira Y. 165 O’Donnell T. J. 8 Oesch F. 160 163 Ogawa E. 295 Ogawa H. 248 Ogawa M. 270 Ogawa Y. 332 Ogura F. 299 Ogura K. 295 Oh Y.-I. 105 180 O’Hagan D. 356 Ohanessian G. 21 147 Ohannesian L. 154 279 O’Hara S. M. 188 Ohfune Y. 189 Ohhara H. 80 Ohkuma T. 107 268 Ohmae T. 19 Ohnishi R. 155 Ohnuma S. 344 Ohnuma T. 140 Ohsuki S. 32 Ohta A. 276 Ohta K. 23 295 Ohta M.219 Ohta T. 219 Oishi H. 278 Oishi T. 276 Ojima J. 169 Ok D. 161 Okada M. 133 Okada N. 137 263 Okada Y. 165 Okamoto S. 102 Okamoto Y. 206 Okamura N. 336 Okamura W.H. 40 Okayama H. 356 Okazaki M. E. 121 282 O’Keefe S.J. 310 Oku A. 165 Okuda Y. 96 Olah G. A. 27 35 49 53 154 168 279 291 Olah J. A. 53 291 Oldfield E. 14 O’Leary M. 75 O’Leary M. H. 361 Olejniczak E. T. 8 Oles A. M. 18 Oliva A. 26 Olivella S. 26 29 186 Oliver J. P. 188 229 Author Index Oliver R. S. 365 Olivucci M. 19 Oliw E. H. 335 Ollis D. L. 328 Olofson R. A. 59 Olson R. E. 34 O’Mallay G. J. 121 Omori K. 101 252 Omote Y. 187 Omura S. 352 366 Onaka M. 278 Ono N.122 276 Onyido I. 155 Ookawa A. 105 Oppenlaender T. 191 Oppolzer W. 113 256 Oram D. E. 237 Ordea M. S. 324 Orena M. 297 298 Oriyama T. 249 Orme-Johnson W. 315 Ortar G. 156 Osborn J. A. 81 252 Osedo H. 197 O’Shea D. M. 72,75 Oshima K. 85 96 255 258 Oshino H. 254 Ostarek R. 232 Ostercamp D. L. 171 Oswell K. D. 179 Otaka K. 263 Otani H. 216 Otera J. 115 Otsubo T. 299 Otsuka H. 353 Ottenbrite R. M. 20 Ottenheijm H. C. J. 122 183 Oturan M. A. 156 Ouchefoune M. 154 Oudejans J. C. 267 Outurquin F. 180 Overman L. E. 20 29 121 171 198 230 261 282 Overton K. H. 357 364 0-Yang C. 335 Ozawa F. 257 Ozbalik N. 78 Pacansky J. 148 Pace-Asciak C.R. 343 Pachinger W. 256 Packer K. J. 14 Paczkowski J. 297 Paddon-Row M. N. 25 Padwa A. 35 184 266 Page P. C. B. 97 Pai G. F. 314 Paik Y. H. 125 Pain G. N. 228 Paisley H. M. 285 Pak C. S. 274 Palazhn J. M. 103 Palazzi C. 11 1 246 Palke W. E. 19 Palomer A. 124 Palominos M. A. 241 Palomo C. 271 Palumbo G. 281 Palumbo P. S. 81 Pang C.-P. 365 Panster P. 234 Pantano J. E. 53 Pantoliano M. W. 322 Panunzio M. 298 Papadopoulos K. 108 Papaleo S. 185 Papanicolaou C. 330 Papasergio R. I. 227 Paquette L. A. 108 122 130 136 151 230 Paravyan S. L. 94 Parisot D. 352 Park J. 202 Park S.-U. 75 Park W. S. 100 275 Parker K. A. 72 153 Parkhouse T. 331 Parry R.J. 348 367 Parsons P. J. 66 259 Parvez M. 127 Pascal R. A. Jun. 12 63 164 314 Paschalis P. 58 Pasto D. J. 92 Pataki J. 162 Patchornik A. 289 300 301 Patel B. J. 274 Patel D. I. 182 Patel D. V. 355 Patel M. 31 Patel N. 330 Patel S. U. 180 Patel V. F. 68 Paterson I. 246 Patrick T. B. 121 154 Pattenden G. 68 340 Patterson C. W. 74 Patterson R. T. 38 Pau C. F. 20 22 29 Paulmier C. 180 Pavlatos D. 161 Pawlenko S. 230 Payard M. 175 Pazik J. C. 229 Pearson A. J. 215 Pearson W. H. 112 179 Pedersen E. B. 185 Pedoussaut M. 279 Pedrini P. 156 185 Pedrocchi-Fantoni G. 364 Pedrosa R. 113 Peel M. R. 236 Pellon P. 192 Pember S. O. 316 Penelle J.76 Penning T. D. 333 Pepper K. W. 285 Pereyre M. 235 Perez J. J. 43 130 Pericas M. A. 26 Perichon J. 106 Perlmutter P. 95 Perly B. 12 Pem S. T. 43 Pemn C. L. 60 Perry D. 365 Perry D. A. 192 Perry M. W.D. 70 Pesce M. 274 Pete J. P. 135 Peters K. 77 78 233 Peters K. S. 181 Petersen J. S. 100 Peterson D. C. 331 Peterson G. A. 124 Peterson J. R. 151 219 Petragnani N. 82 122 239 Petre J. 179 Petz W. 231 Pfaltz A. 126 208 369 Pfenninger A, 121 270 Pfirsch F. 18 Pfitzner A. 363 Haum S. 186 Ptluger F. 257 Pham D. 179 Phillips J. G. 225 Phillips J. L. 143 Phillips R. S. 309 Phinney B. O. 358 Phinney B. P. 358 Pi R. 226 Piccoli S. P. 325 Pichon C.157 279 Picken D. 357 Picken D. J. 364 Piejko K.-E. 232 Pierce J. 312 Pierini A. B. 26 Piers E. 136 Piet P. 295 PiCtrC S. 77 Pigou P. E. 73 116 Pikul S. 101 121 Pikulin S. 39 Pillai S. M. 87 Pillai V. N. R.,284 Pindur U. 183 Pines A. 5 15 Pinhas A. R. 201 220 Pinhey J. T. 97 Pinson J. 156 Pirkle W. H. 178 Pirrung M. C. 42 129 204 Pitt C. G. 238 Pizzorno M. T. 26 Plat M. 161 Plate R. 183 Platt K. L. 163 Plessi L. 298 Pock R. 87 Pohl B. 314 Pohl E. R. 62 Poli G. 79 256 Pollart D. J. 161 184 Pollok T. 90 Polt R. L. 222 Poon C.-D. 125 Popall H.,202 PopiSil S. 355 Pople J. A. 24 27 82 Portella C. 135 Porter D.J. T. 318 Porter N. A. 65 331 Porzi G. 298 Posner G. H. 31 137 171 Postma D. 182 Potenza D. 259 Potenza J. A. 168 Potier P. 71 188 Potter B. V. L. 326 Potthoff B. 189 264 Potts K. T. 187 Pouet M.-J. 58 Poulos T. 322 Powell M. F. 58 95 Powell P. 322 Power J. M. 238 Pradere J. P. 194 Pradhan J. 55 Pragnola A. 9 Prakash G. K. S. 35 154 168 Pramod K. 143 Prandi J. 270 Prasad C. V. C. 153 Prasad G. 140 Prasad J. V. N. V. 280 Prasit P. 331 Prat D. 270 Prati L. 79 Presta L. G. 322 Prestegard J. H. 8 Prewo R. 173 Price J. D. 125 Pridgen L. N. 245 Prinzbach H.,168 196 Prior M. J. 139 Pnyono W. 161 Pross A. 20 47 53 62 Prout K. 205 Prowse K.S. 122 171 Pruszyniski P. 59 Puckace J. S. 49 Puff H. 166 237 Puglis J. M. 35 Pulido F. J. 92 Purdy A. P. 238 Pumngton S. T. 121 154 Puttmann W. 168 bne S. G. 118 Pyper N. C. 13 Quanti G. 106 Quartara L. 185 Que L. Jun. 86 Queener S. W. 365 Quill S. G. 322 Quiniou H. 194 Quinn P. 364 Quintard J.-P. 255 Raabe E. 91 218 Raban M. 23 Racherla U. S. 83 Radesca L. 126 Radkowsky A. E. 187 Radner F. 58 154 Radom L. 24 148 Radpakrishnan R. 322 Radziszewski J. E. 126 Raghavachari K. 21 Rahman A. F. M. M. 188 229 Raichte T. 314 Raimondi M. 20 147 Raithby P. R. 368 Rajagopalan S. 95 250 Rajapaksa D. 183 Rajarathnam Reddy E. 344 Rajoharison H. G. 84 Ramachandran P.V. 100 Rama Rao A. V. 344 Ramaswamy S. 90 280 Ramdayal F. 10 Ramirez F. 54 Ramos F. R. 365 Rana J. 362 Rankin D. W. H. 229 Rao B. N. N. 8 Rao C. S. 274 Rapoport S. M. 303 Rappoport Z. 48 51 Rasetti V. 369 Raspel B. 213 Raston C. L. 201 227 Ratcliffe A. H. 358 Raucher S. 42 Rausch M. D. 229 Raushel F. M. 320 Ravichandran K. 121 Ravindranathan M. 87 Razenberg J. A. S. J. 86 Re A. 298 Reagan J. 104 Reams P. 14 Rebek J. 290 Rebek J. Jun. 85 Reber G. 152 166 224 Reddy A. V. 143 Reddy D. S. 143 Reddy G. S. 312 Reddy K. B. 65 Redfern P. 22 Redwine 0. D. 125 Reese C. B. 178 179 Rees C. W. 40 174 194 Reetz M. T. 102 107 207 217 232 246 253 254 Rege S.38 145 Author Index Regen S. L. 295 296 302 Regitz M. 94 128 175 176 177 Regnoli R. 298 Rei M.-H. 52 Reich H. J. 34 Reimann W. 235 Reinert T. J. 79 Reinhardt G. 29 147 Reinhardt W. 128 Reinhoudt D. N. 184 Reissig H.-A. 116 Reissig H.-U. 190 Reissig H.V. 127 Reist E. J. 193 Reitz A. B. 59 277 Reitz T. J. 157 Renaud J.-P. 79 Renaud P. 226 Renauld F. 349 Rendall W. A. 173 Rendenbach B. E. M. 108 Renfrow R. A. 62 Renneke R. F. 219 Renyard S. J. 40 Renzoni G. E. 126 Repeta D. J. 11 Retey J. 313 314 Reuter H.,166 Rey M. 32 Reye C. 232 Reynolds C. H. 18 27 Reynolds D. 331 Reynolds K. 356 Reynolds W. F. 10 Rezai S. 297 Ricci A.180 Richard J. P. 50 3 11 Richards W. G. 19 Richardson G. 289 Richardson K. A. 132 243 Richardson T. J. 160 Rickborn B. 161 183 184 Rico J. G. 105 Ridd J. H.,57 58 154 Rieker A. 12 Riera A. 26 Riera J. 76 Riffel H. 177 Rigby J. H.,38 144 145 Riley D. P. 273 Rinehart K. L. Jun. 353 Ringe D. 323 Rissler K. 166 Rissmann T. J. 51 Ritchie C. D. 50 Ritter R. H.,222 Ritterskamp P. 143 Ritzer E. 25 Riva F. 307 Rivas-Enterrios J. 255 Riveros J. M. 47 Rivitre H. 78 Rizvi S. Q. A. 194 Author Index Rizzardo E. 75 Ruckle R. E. Jun. 121 Robb M. A. 19 24 Rudd B. A. M. 352 Robert A. 275 Rudnick G. 303 Roberts B. W. 129 Ruchardt C. 77 78 Roberts D.H. 75 Riicker C. 227 Roberts K. A. 98 Ruffer M. 363 Roberts R. E. 318 Ruelle P. 25 Roberts S. M. 331 340 Ruessink B. H. 4 Robertson G. M. 68 Ruest L. 60 Robertson H. E. 229 Rufinski A. 228 Robertson L. W. 160 Ruggeri R. 192 Robins D. J. 362 364 Ruiz M. O. 87 Robinson J. A. 330 354 I 356 Rumbach T. 159 Runsink J. 159 Robinson M. J. T. 171 Ruppin C. 97 Robinson N. G. 330 Rusinko A. R. III. 84 Robinson P. L. 301 Russe R. 187 Robinson W. T. 57 Russell D. W. 356 Robl J. A. 135 Russell G. A. 71 Roche E. G. 97 Russell J. J. 68 Rodgers L. R. 12 63 Russell R. A. 161 Rodler M. 93 Russo N. 24 Rodrigo R. 183 Rutherford M. 197 Rodriguez M. A. 95 Rutter W. J. 324 Rodriguez R. 241 Ruzziconi R. 91 259 Rodwell P. W.159 Ryaboy V. M. 20 Roe D. C. 84 Ryerson C. C. 317 Roekens B. 136 266 Rzepa H. S. 18 Ronnqvist M. 58 Rosch W. 176 177 Sabatucci J. P. 128 Roesky H. W. 54 Sabek O. 57 154 Rogers D. W. 151 Sacher E. 21 Rogers W. J. 301 Sacksteder L. 31 Roise D. 305 Sadler I. H. 357 358 Rokach J. 342 348 Sadovskaya V. 335 Rollman L. D. 295 Saegusa T. 273 Rolls J. P. 366 Saengchantara S. T. 193 Romana S. 178 Safont V. S. 149 Ron E. 129 Sagawa Y. 138 Ronchi A. U. 298 Saggese C. A, 337 Roos B. O. 152 Saha M. 135 Rose E. 156 Sahlman L. 3 15 Rose 1. A. 311 SaiEiE R. 67 68 Rose-Munch F. 156 Saimoto H. 153 Rosen T. 122 143 St. Denis Y. 104 Rosenblum M. 207 St. Laurent D. R. 136 Rosenthal S. 97 Saito A. 357 Roskamp E. J. 42 129 204 Saito S.113 Rossi C. 9 Sakai S. 117 254 259 Rossi M. 110 Sakamoto M. 243 Rossi R. 94 97 251 Sakamoto T. 251 Roth H. D. 29 38 150 Sakamotom H. 318 Roth W. D. 167 Sakamura S. 353 Rothberg I. 52 Sakan K. 34 Rous A. J. 54 Sakane S. 137,261 Rousell J. 48 Sakata Y. 165 Roush W. R. 101 Sakurai H. 250 263 Roussel C. 84 Sakurai M. 31 256 Rovira C. 76 Salituro G. M. 177 321 348 Rowlands C. C. 97 365 Roy S. 74 Sall D. J. 157 Roze J. C. 194 Salomon R. G. 129 216 268 Rozen S. 83 95 339 Ruasse M.-F. 62 Salter 1. D. 13 Salunke M. M. 298 Salvadori P. 264 Samama J. 314 Samel N. 335 Samenutsu Y. 208 Sameshima K. 17 Sammakia T. 124 Sampson P. 258 Samson S. M. 365 Samuelsson B. 332 342 343 348 Sandall J.P. B. 57 Sandborn R. E. 161 183 Sande A. R. 298 Sanderson D. R. 132 Sandhu J. S. 267 Sandin S. 298 Sandri S. 297 298 Sanfilippo P. 143 Sangwan N. K. 34 Sankawa U. 349 Sano H. 275 Sansone E. B. 191 Sansoulet J. 279 Santander P. J. 369 Santer R. 137 Santucci R. 307 Sarkar A. K. 244 Sarker S. K. 5 Sasaki K. 155 Sasaoka S. 84 Sasho M. 161 Sato F. 102 103 270 Sato S. 107 207 242 Sato T. 100 109 363 Sato Y. 11 Satoh M. 250 Satomi H. 273 Sauer J. 34 Saulnier L. 12 Saunders J. 242 Saunders M.,18 39 Saunders W. H. 55 Saussine L. 86 Sauter R. 34 Sauvitre R. 94 227 Saveant J.-M. 156 Sawa I. 280 Sawada H. 124 266 Sawamura M.110 206 Sawyer J. S. 140 Sayer J. M. 163 Sayre L. M. 191 Sbrana G. 283 Schaad L. J. 21 160 Schade C. 221 222 Schaefer H. F. 24 Schafer H.J. 65 Schafer W. 126 151 Schaffner K. 143 Schakel M. 223 Schapp N. P. 59 Schauer N. L. 315 Schavarien C. J. 204 389 Author Index Scheigetz J. 77 Scheiner S. 22 25 Schenker K. V. 5 Scherer 0.J. 186 Schewe T. 303 Schick K. P. 213 Schieb T. 168 Schier A. 239 Schill G. 166 Schilling M. L. M. 29 Schinzer D. 132 Schirmer R. H. 314 Schishido K. 43 Schlesener C. J. 58 Schlesinger M.J. 325 Schleyeri P. v. R. 21 24 27 82,92 221 222 226 Schluter J. 291 Schloss J. V. 311 Schmalz T. G. 21 160 Schmickler H.168 198 Schmidbaur H. 166 229 239 Schmidbaur M. 90 Schmidt G. 223 Schmidt J. 18 Schmidt K. 168 Schmidt R. R. 34 Schmidt S. 279 Schmidt W. 163 Schmitt R. J. 96 Schmittel M. 78 Schneider E. 369 Schneider H.-J. 34 Schneider J. A. 127 Schneider M. P. 280 333 Schneider R. 56 Schneider W. P. 337 Schneiders C. 167 Schnockel H. 228 Schober P. A. 333 Schoeniger J. 3 Schoning A. 187 Schollkopf U. 126 Schollmeir M.,163 Scholz H. J. 226 Schowen R. L. 63 Schreiber J. 369 Schreiber S. L. 104 124 Schreiman I. C. 198 Schreurs A. M. M. 236 Schriefer K. 325 Schrock R. R. 204 Schroder S. 18 Schuda P. F. 143 Schuzm R.,361 Schugar H. J. 168 Schuh W. 237 Schuhn W.89 Schulman J. M. 21 Schultz A. G. 158 Schulz G. E. 314 Schulz R. C. 299 Schulz W. H. 168 Schulz W. J. 49 Schurig V. 79 Schuster F. 34 Schuster H. 233 Schuster I. I. 149 150 237 Schuttenberg H. 299 Schwab J. M. 321 348 Schwab S. T. 238 Schwager H. 169 217 Schwalb J. 186 Schwartz E. 192 Schwartz J. 81 216 Schwartzentruber K. M. 78 Schwarz H. 24 25 26 73 95 Schweizer W. B. 149 Scola P. M. 193 Scolastico C. 359 Scott A. I. 324 363 365 368 369 Scott F. E. 350 Scott L. T. 150 166 168 Scuseria G. E. 24 Sedlmeier R. 369 Sedmera P. 355 Sedrati M. 215 Seebach D. 104 226 244 265 Seehra J. S. 367 Seelen W. 187 Seelig E. 300 Seely F. L. 214 Seeman J.I. 47 114 Segal G. A. 49 Seibel W. L. 138 139 Seidel C. 220 Seikaly H. R. 38 Seitz H. 186 Seitz W. A. 21 160 Sejpka H. 238 Seki Y. 84 Sekiguchi J. 349 Sekutowski J. C. 196 Selivanov S. A. 171 Sell C. S. 297 Semerikov V. N. 270 Semmelhack M.F. 202 Semra A. 156 Senanayake C. 144 Senning A. 174 Seo H. S. 26 Seo S. 359 Serhan C. N. 342 343 Serravalle M.,71 72 Seto H. 349 Severin S. E. 317 Seyden-Penne J. 296 Sha C.-K. 187 Shackelton T. A. 216 Shade C. 92 Shahada L. A. H. 204 Shai Y.,301 Shaik S. S. 20 21 22 147 Shakhshier I. H. 284 Shankaran K. 42 Shanklin P. L. 42 Shankweiler J. M.,61 Sharma S. D. 267 Sharpless K. B. 85 218 Shaskuo J.357 Shaskus S. 357 Shawcross F. E. 49 Shea K. J. 34 41 143 193 Sheldrick G. M. 115 Shen C.-M. 299 Shen G.-Y.,40 Shen J.-Q. 365 Shen S. 168 Shepherd M. K. 39 Sheppard G. S. 146 Sheppard R. C. 121 Sher P. M.,69 332 Sherrington D. C. 283 284 285 295 Sherry B. 314 Sherwin P. F. 358 Sheu K. F. 311 Shevlin P. B. 18 Shi J. P. 330 Shibasaki M. 143 332 Shibutani M.,169 Shieh T.-L. 360 Shih C. 338 339 Shih. N.-Y. 338 Shiiki S. 295 Shillady D. D. 20 Shimada T. 154 Shimamoto T. 349 Shimazaki M. 99 124 276 Shimazaki T. 102 Shimizu I. 80 211 Shimoji K. 334 338 339 Shimura Y. 318 Shiner C. S. 148 222 Shinkai S. 292 297 Shiobara Y. 344 Shiohara T. 135 Shirahama H..189 Shirai N. 163 Shirai R. 109 241 Shirouchi Y. 261 Shishido K. 34 Shomes S. L. 315 Shono T. 158 279 Shubert D. C. 132 Shulman E. M. 137 Sibi M. P. 162 Sibille S. 106 Sicsic S. 292 Siegel C. 244 Siegel J. 149 Siegel S. 95 Sigrist R. 32 Sih C. J. 339 355 Sik V. 13 Sikorski J. A. 93 Silva G. V. J. 122 Silverman R. B. 306 Silversmith E. F. 137 Simon A. 233 Simon H.. 370 Author Index Simonnen M.-P. 58 Sonoda N. 84 Stone J. K. 181 Simpkins N. S. 109 241 Soria J. J. 132 Stoodley R. J. 31 Simpson R. E. 127 Simpson T. J. 347 349 351 354 359 Sinclair J. A. 93 Singaram B. 83 119 Singleton D. A. 32 141 Sinnott M. L. 60 350 Sorokin V. D. 270 Soucy P. 60 Southgate R.,66 259 364 Sowadski J.M. 325 Spawn C.-L. 278 Speafico F. 360 Sorrell R. M. 13 Storek C. 197 Storer A. C. 324 Stork G. 69 72 222 332 Stowell J. C. 195 Stratford P. 293 Strausz 0. P. 173 Street L. J. 180 Sinou D. 231 278 Sinozaki H. 299 Spek A. L. 236 Spencer C. M. 83 Streich E. 12 Streitwieser A. 20 58 Sivaram S. 87 Sjostrom M. 21 61 Spenser I. D. 362 Spero D. M. 72 Struck J. 166 Struss K. 291 Sjogren E. B. 111 178 Skatrud P. L. 365 Skattebprl L. 92 Spilrnan C. H. 331 Spink W. C. 229 Spogliarich R. 274 Stuart K. L. 363 Stucky G. 104 Stults J. S. 192 Skell P. S. 76 Sprecher H. 335 Stuttle K. A. 335 Skerlj R. T. 136 Sprengeler P. A. 227 Subrahmanyam D. 143 Sket B. 160 Springer D. M. 128 Subramaniam C. S. 161 Skonezny P. M. 37 Slavin A. M. Z. 104 Springer J.P. 202 Squillacote M. E. 43 Suda H. 299 Suda T. 270 Slowin A. M. Z. 31 Squires R. R. 151 Sudhakar A. 164 208 Sluma H.-D. 124 Sridar V. 66 Suenaga T. 114 Srnalley R. K. 182 Sridharan V. 37 Suga S. 103 254 Smart B. E. 19 23 24 Srinivasa R. 160 Sugimura T. 130 Smeets J. W. H. 294 Srinivasachar K. 161 Sugita K. 278 Smegal J. A. 81 216 Srivastava S. 54 Sugita W. 156 Smith A. B. 274 Staab H. A. 163 Sugiura M. 8 Smith A. B. III. 227 Stang P. J. 98 Sugiura S. 336 Smith C. M. 144 Stanton R. E. 21 160 Sugiura T. 24 277 Smith C. P. 297 Stark W. M. 364 368 Sugumaran M. 317 Smith D. A. 34 38 Starner W. E. 120 Suits J. Z. 274 Smith D. K. 106 Sta~,I. 74 Sullivan A. C. 12 Smith E. H. 81 313 Staunton J. 350 351 352 Sumi H. 20 Smith F. 48 Stavridou E. 197 Sumi K.155 259 Smits G. F. 23 Steel P. 34 137 Summers M. F. 5 11 Smith J. D. 12 230 Steele M. J. 361 Sumpter C. A. 168 Smith J.-G. 161 183 Steenken S 49 Sun F. F. 337 Smith K. 183 Steffen J. 132 Supatimusro D. 162 Smith K. I. 9 Stefianek L. 13 Surya Prakash G. K. 53 Smith L. M. 331 Smith P. J. 55 Snider B. B. 129 133 Snieckus V. 162 222 Snowden R. L. 153 Snyder G. J. 125 Stein A. R. 54 Stein R. 323 Steitz T. A. 328 Stelzer O. 224 Stenstrbm Y. 92 Stenzel D. J. 359 Suslick K. S. 79 227 Suter D. 16 Sutkowski A. C. 350 Suttie J. W. 31 1 Sutton K. H. 57 114 156 205 Snyder J. K. 86 270 Snyder R.C. 179 Snyder W. C. 353 Stevens R. W. 246 Stevens W. J. 23 24 Stevenson D. E. 308 Suya K. 207 242 Suzuki A. 79 88 93 156 250 Suzuki H. 263 Soai K. 105 Soda K. 305 306 309 Soderquist J.A. 109 Sollhuber M. M. 282 Slbrensen P. E. 60 Sogo S. G. 360 Sohn S. C. 22 Sole A. 26 186 Solladie G. 118 Solomon D. H. 75 Solyom S. 132 Sornayiji V. 52 Sorners T. C. 11 Somorjai G. A. 147 Song Y. H. 271 281 Stevenson G. I. 349 Stevenson K. J. 315 Stevenson T. 256 Stewart J. J. P. 26 29 Steyn P. S. 354 359 364 367 Still W. C. 126 127 269 Stille J. 201 Stille J. K. 156 235 257 289 Stille J. R. 130 Stirchak E. P. 115 Stirling C. J. M. 56 59 Stockigt J. 363 Stoll A. T. 124 266 Stollhoff G. 18 Stone A. J. 21 Suzuki K. 99 107 116 124 Suzuki M. 333 336 Suzuki T. 300 Suzuki T. M. 294 Suzumoto T. 158 Svoboda J. J. 34 193 Swann R.T. 166 Swanson A. G. 162 Swanson S. 357 Sweeney J. B. 69 116 236 Szarek W. A. 281 Szawelski R. J. 305 Szmalc. F. S.. 183 268 276 248 249 Szwedo M.J. Jun. 337 Tabei T. 42 Taber D. F. 121 Tabuchi T. 98 117 213 255 258 277 Taddei M. 180 Taffer I. M. 341 Taft R. W. 21 22 Taga J. 275 Taga T. 111 Tagliavini E. 101 Taguchi H. 310 Tai A. F. 86 Tajuna M. 24 Taka A. A. 366 Takacs J. M. 214 Takagi J. S. 318 Takagi T. 318 Takahashi A. 118 Takahashi H. 119 Takahashi K. 21 1 Takahashi N. 293 Takahashi O. 42 Takahashi S. 98 135 Takahashi T. 42 141 Takahashi Y. 79 Takahoshi T. 91 Takaishi N. 142 Takamuku S. 84 Takao N. 8 Takaoka Y. 155 259 Takase K. 80 Takashirna K. 47 Takaya H. 219 Takeda A. 274 Takeda K. 359 Takeda Y. 103 270 Takernoto K. 293 299 Takeshita K. 84 Takeuchi R. 108 253 Takeuchi Y. 84 109 Takeyama T.255 Takeyasu T. 92 Takinami S. 88 Taljaard H. C. 270 Tamai S. 11 1 Tarnaoka T. 248 Tamaoki T. 353 Tarnaru Y. 208 Tarnase S. 309 Tamura M. 247 Tamura T. 100 Tamura Y. 108 133 161 253 26 1 Tanabe M. 353 Tanaka H. 257 305 309 Tanaka M. 106 109 241 Tanaka T. 176 336 Tandura St. N. 232 Tang Y. 50 Tanga M. J. 193 Tanigawa Y. 220 Taniguchi M.,97 107 281 Taniguchi S. 26 Taniguchi Y. 130 220 Tanikaga R. 258 Tanizawa K. 305 Tanko J. M. 76 Tann C.-H. 364 Tanner D. 166 Tansey M. J. 183 Tantivanich A. 162 Tanzella F. L. 160 Tao W. 301 Tapia R. 40 Tata C. 42 Taylor A. 366 Taylor B. M. 337 Taylor D. A. 132 243 Taylor D. G. 318 Taylor G. W. 339 Taylor J. 285 Taylor N. J.183 196 Taylor P. B. 356 Taylor P. G. 59 Taylor R. J. K. 88 227 251 Taylor R. T. 294 Tellier F. 94 Ternme G. H. 297 Teng P. 82 Terada S. 117 Terada T. 270 Terlouw J. K. 26 95 Terpinski J. 174 Terpstra J. W. 182 Terrier F. 58 Teshima N. 154 Testaferri L. 191 Thaller V. 366 Thanupran C. 141 Thayer A. M. 15 Thayer J. L. 29 Thea S. 47 56 Thebtaranonth C. 141 Thianpatanagul S. 37 Thiebault A. 156 Thiel W. 18 Thieny J. 71 Thiruvengadam T. K. 364 Thomas A. D. 161 Thomas E. J. 34 137 Thomas M. J. 216 Thomas R. 354 Thompson A. S. 198 Thornson G. A. 365 Thornson S. A. 129 Thornton E. R. 111 244 Thornton J. M. 183 Thorpe C. 322 Thorpe F. G. 284 Threadgill M. D. 158 Tia P. R. 62 Tidwell T.T. 38 51 Tiecco M. 191 Tillman A. M. 357 Ting H. 330 365 Tingoli M. 191 Author Index Tipton P. A. 361 Tius M. A. 161 Tiwari K. N. 281 Tobe Y. 165 Tobia D. 183 Tobinaga S. 281 Tobler H. P.,308 Todesco P. E. 156 Togo H. 72 Toki S. 84 Tokles M. 86 270 Tokushige M. 318 Tomas M. 35 Tomasi J. 24 Tomasini C. 298 Tominaga Y. 274 Tomioka H. 24 270 Tornioka K. 114 247 Tomita F. 353 Tomita K. 191 Tornita Y. 359 Tomoda S. 84 Tomoi M. 292 295 296 300 Tonachini G. 19 Toppet S. 149 187 194 Topsorn R. D. 17 21,22 Toraya T. 310 Tori K. 359 Torii S. 248 249 257 Torosyan G. D. 94 Torres M. 173 Torsell K. H. G. 347 Toscano M. 24 Toth I. 106 230 Toullec T. 60 Toupet L.194 Tour J. M. 156 Towers G. H. N. 361 Town M. H. 331 Townsend C. A. 177 321 348 354 365 Townsend L. B. 188 Towson J. C. 112 273 Toyada J. 35 Toyota M. 141 Traa P. A. M.,295 Trahanovsky W. S. 38 Trainor D. A. 323 Trang N. 314 Trecarten M.,299 Trend J. E. 290 Trigo G. G. 282 Trimble L. A. 273 350 351 3 59 Trinks R. 166 Trombini C. 101 Trost B. M. 105 136 208 209 262 266 Trost J. W. 360 Trudgill P. W. 318 Tsang R. 67 Tsay Y.-H. 124 202 213 218 263 Tsipouras A. 178 Author Index Tsoi S. C. 194 TSOU C.-P. 187 Tsuchihashi G.-i. 99; 107 116 124 268 276 Tsuchiya T. 197 Tsuda K. 295 Tsuda T. 273 Tsuda Y. 275 Tsui W. C. 330 Tsuji H. 292 Tsuji J. 80 141 201 211 277 Tsuji T.42 Tsukitani Y. 344 Tu J. 296 Tubergen M. W. 269 Tuck B. 176 Tuck S. P. 54 Tuckmantel W. 96 255 Tufariello J. J. 35 Tundo P. 295 Turano C. 307 TureEek F. 74 89 Turnbull M. M. 207 Turner G. L. 14 Turner L. M. 291 Turner N. J. 365 Turner S. R. 299 Turro N. J. 17 35 166 Tutonda M. 194 Tweedy N. B. 310 Tzschach A. 232 Uchikawa M. 42 112 Uda H. 118 141 Ueda K. 248 Ueda K.-I. 165 Uenishi J. 251 Ueno Y. 34 Uggeri F. 106 279 Uggerud E. 92 Ugozzoli F. 185 Ukachukwu V. C. 51 Ukaji Y. 278 Ulatowski T. G. 112 273 Ullrich V. 337 Ultimoto K. 85 96 Um LH. 61 Umani-Ronchi A. 101 Umeda N. 299 Umemoto T. 191 Underwood D. J. 148 Uneyama K. 248 249 Uno H. 85 Unterberg H.166 Uomori A. 359 Urabe H. 259 Urano S. 353 Urbach F. L. 191 Urbi G. B. 219 Urpi F. 119 Usui Y. 180 Utaka M. 274 Utimoto K. 210 258 270 Utter M. F. 311 Uu S. Y. 281 Uyama H. 279 Uyehara T. 344 Uzar H. C. 369 Uzick W. 76 Vaccaro W. 184 Valenti G. 283 Valentine J. S. 86 Valero A. 12 Valimae T. 335 Valpey R. S. 136 van Baar B. 95 van Bekkum H. 267 van Berkel W. J. H. 317 Van Beylen M. 149 van Bladeren P.J. 163 van der Baan J. L. 220 Vanderesse R. 192 Van der Helm D. 135 van der Kerk S. M. 63 van der Made A. W. 294 van der Plas H. C. 195 van der Valk F. 26 Van Derveer D. 164 Vanderzande D. 194 Van Duyne G. 151 Van Dyk D. E. 311 Vane J. R. 332 VanEk Z. 355 Van Engen D.164 Vanermen G. 149 van Frank R. M. 365 van Gerresheim W. 63 van Heerden F. R. 354 Van Hoecke M. 76 Van Hove M. A. 147 Van Kampen P. N. 23 van Koten G. 236 van Leusen A. M. 182 van Middlesworth F. 355 van Stralen R. 182 van Vuuren G. 270 van Zijl P. C. M. 4 165 Van Zyl C. M. 96 132 Varandas A. J. C. 22 Vara Prasad J. V. N. 172 Varie D. L. 192 Varma M.,56 Vasak M. 149 Vasilopoulos P. 18 Vaughan J. 57 Vawter E. J. 255 Vecchiani S. 56 Veciana J. 76 Vedejs E. 35 37 171 192 230 Vederas J. C. 112 273 347 350 351 353 359 Vega J. C. 241 Vekemans J. 194 Venkatramanan M. K. 266 Veno H. 306 Ventura 0. N.. 25 Venturini A, 24 Verboom W. 184 Verducci J. 292 Verhoeven J. W. 63 Verkruijsse H.D. 221 Verlhac J.-B. 255 Vernon P. 178 Vetter W. 166 Vicenti M.,257 Vick B. A. 348 Victoriano L. 229 Vidal M. 87 Vidal Y. 155 Viene H. G. 76 Vigne B. 155 Vilarrasa J. 119 186 Villafranca J. J. 316 Villhauer E. B. 210 Vincent C. 292 Viola R.E. 320 Viout P. 300 Vishkautsan R. 195 Vismara E. 71 72 Visnick M. 227 Viswanatha V. 367 Vitulli G. 264 Vleggaar R. 354 359 364 367 Voegeli R.H. 166 Vogtle F. 41 166 Vogel C. 32 Vogel E. 167 168 198 Vogelbacher U.-J. 128 175 176 Vollhardt K. P. C. 146 151 152 213 214 217 264 Vollmar A. 179 Von Rague Schleyer P. 151 152 von Schnering H.-G. 77 78 233 Vorbruggen H. 331 Vorndam P. E. 148 Voronkov M. G. 232 Vottero L. R. 155 Vuister G.W. 5 Vuorinen E. 195 Vyas D. M. 37 Wada E. 53 Wada K. 169 Waddell S. T. 74 Wadischatka R. 369 Wagner C. K. 12 63 Wagner G. 5 Wahlberg I. 10 Wakabayashi S. 248 Wakabayashi Y. 309 Wakamatsu K. 96 Wakamatsu T. 140 Wakasugi T. 299 Wales D. J. 21 Walker J. C. 31 114 137 205 Walker M. E. 111. 205 394 Wall A. 88 Wallace I. H. M. 42 157 Wallace T. W. 193 Walling J. A. 161 Wallis C. J. 331 Wallis J. M. 239 Walsh C. 305 306 315 317 Walsh C. T. 305 306 314 315 Walsh K. A. 325 Walsh P. A, 59 Walters M. A. 179 Walton J. C. 74 Walts A. E. 315 Waltz W. L. 26 Waluk J. W. 149 Wan C. S. K. 89 Wang E. 306 Wang J.-X. 97 Wang K. K. 79 93 Wang L. L. 125 Wang Y.-F.339 Wanner K. T. 123 Ward D. L. 164 Warkentin J. 75 Warker P. 114 Warock J. 298 Warren S. 119 Warrener R. N. 161 Warshawsky A. 301 Warshel A. 20 Wasserman H. H. 122 171 Wasserman S. A. 305 Watanabe H. 299 Watanabe I. 282 Watanabe K. 280 Watanabe N. 182 Watanabe S. 243 Watanabe T. 300 Watanabe Y. 107 Waterhouse J. 287 292 293 301 Watson B. T. 158 220 Watson K. N. 196 Watson R. A. 255 Wayda A. 103 Webb G. A. 13 Webb M. 124 266 Webb M. B. 142 Webber S. E. 343 Weber A. E. 245 Weber J. 125 Webster N. J. G. 129 Weedon A. C. 89 Weeks G. H. 149 Wege D. 180 187 Weglein R. C. 52 Wehle D. 139 Weidenbruch M. 233 Weidmann H. 105 247 257 Weigt E. 143 Weijer W. J. 317 Weil D.A. 161 Weinig P. 102 253 Weinreb S. M. 120 193 282 Weinshenker N. M. 299 Weis A. L. 195 Weiske T. 95 Weiss E. 92 222 Weiss K. 87 Weiss P. M. 54 318 Weiss R. 128 Weissensteiner W. 149 150 237 Weissman S. A. 151 Weitz E. 82 Welch S. C. 136 Welke S. 252 Weller P. E. 188 Wells R. L. 238 Wells T. N. C. 330 Wenck H. 86 Wender P. A. 140 144 159 Wenkert E. 142 191 Wennerstrom O. 166 Wenska G. 39 Werner H. 220 226 Werner J. A. 42 204 Wernig P. 207 Wernly J. 10 West F. G. 171 230 West R. 97 149 232 Westaway K. 48 Wester R. T. 115 Westley J. W. 355 Wettlaufer D. G. 31 Whalen D. L. 51 Whangbo M.-H. 95 Wharton C. W. 305 Whelan J. 212 White A. D. 216 White A. H. 227 White D.H. 126 151 White F. H. 225 White J. D. 11 White J. M. 57 White R. L. 365 White S. 305 Whitehead J. W. F. 137 Whitesell J. K. 112 Whitesides G. M. 276 Whitham G. H. 139 Whiting A. 31 137 263 Whitlock H. W. Jun. 166 Whitney R. A. 270 Whittaker D. 48 Whitten J. P. 185 Whittle R. R. 59 Wiberg K. B. 74 125 Wiberg N. 233 Widdecke H. 291 Widdowson D. A. 156 157 213 Widlanski T. S. 360 Wiemer D. F. 258 278 Wiemers D. M. 216 Wightman R. H. 366 Wijnands R. A. 317 Author Index Wilcox C. F. Jun. 151 168 Wilcox C. S. 42 Wilde R. G. 192 Wilke G. 169 217 Wilkins C. L. 161 Wilks J. W. 331 Willard J. M. 311 Williams A. 47 56 325 Williams C. H. 307 315 Williams D. J. 31 104 234 3 54 Williams D.R. 225 Williams G. H. 156 Williams I. H. 63 Williams J. M. 337 Williams R. E. 283 Williams R. M. 178 Williamson R. L. 236 Wilson B. 204 Wilson J. Z. 144 Wilson K. D. 133 Wilson S. 18 Wilson S. R. 154 Wilson W. S. 154 Wingbermiihle D. 252 Winkler J. D. 66 Winzenberg K. 35 Win J. 59 148 Wishka D. G. 342 Wissinger J. E. 140 Wissocq F. 228 Wistuba D. 79 Witanowski M. 13 Wittenberger S. 192 Witzeman J. S. 41 Wohlman Y. 302 Wolak R. 85 Wolber G. J. 25 Wold S. 21 61 Wolfe K. 313 Wolfe S. 129 330 365 Woller P. 166 Wollmann T. A. 100 Wolmershauser G. 186 Wong D. F. 89 Wong G. S. K. 266 Wong H. N. C. 125 Wong J. Y. 299 Wong P. Y.-K. 337 Wong S. 94 Wong S. C. 194 Wong S.-T.53 Woo S. H. 161 Wood B. 13 Wood H. G. 311 Woods S. A. 318 Woodward R. B. 29 Woolrich J. 21 Worgotter E. 5 Wormald P. C. 362 Worner G. 369 Worth B. R. 363 Wright B. T. 65 Wright D. R. 53 Author Index Wright J. N. 359 Wright S. C. 216 Wright T. A. 55 Wu T.-S. 366 Wu Y.-D. 37 87 Wulff W. D. 124 202 Wurtele E. S. 358 Wust M. 153 Wuthrich K. 5 Wyckoff H. W. 325 Wynberg H. 293 Xie S. 296 Xuong N. G. 328 Yadav J. S. 24 Yagi K. 317 Yagi T. 305 Yakura Y. 261 Yamabe S. 26 Yamada R. 309 Yamada T. 137 270 Yamada Y. 344 345 349 Yamagishi A. 273 Yamaguchi M. 42 98 112 117 153 213 242 255 258 277 Yamaguchi R. 190 Yamaguchi T. 176 Yamaguchi Y. 344 Yamakawa K.109 Yamamoto A. 201 207 242 257 Yamamoto H. 31 88 98 101 104 106 109 124 137 250 252 256 261 277 Yamamoto K. 169 197 Yamamoto T. 257 Yamamoto Y. 114 120 192 202 263 349 Yamamura K. 163 Yamamuro A. 100 Yamana Y. 128 Yamanaka. H. 251 Yamano T. 293 Yamasaki M. 309 Yamasaki N. 246 Yamashita H. 133 Yamashita S. 84 Yamashita T. 293 299 Yamataka H. 22 53 Yamawaki K. 270 Yamazaki N. 275 Yamazaki S. 197 278 Yan Z.-Y. 8 Yanagihara N. 98 210 Yanagisawa A. 336 Yang B.-W. 164 Yang C.-C. 353 Yang D. C. 124 Yang J.-R. 149 Yang S. N. 92 Yang W. 23 Yang Z.-Y. 87 156 219 Yano T. 115 Yao K. 109 255 Yaroslavsky C. 289 Yasuda K. 114 247 Yasueda H. 293 Yasukouchi T. 32 182 Yates B.F. 24 Yeh H. J. C. 163 309 Yeoh B. L. 358 Yesinowski J. P. 14 Yeung Lam KO Y. Y. C. 192 Yianni P. 26 159 Yin T.-K. 126 Yokoyama T. 294 Yon G. H. 274 Yoneda N. 79 Yoon N. M. 275 Yoshida J. 295 Yoshida T. 270 Yoshida Z. I. 208 Yoshimura T. 349 Yoshimura Y. 359 Youn I. K. 274 Young B. W. 208 Young D. W. 366 Young M.A. 285 Young R. N. 119 Youngs W. J. 216 Yousaf T. I. 171 Yuan H. 168 Yuhara M. 277 Yus M. 81 279 Zagalak B. 313 Zahalka H. A. 277 Zaikov G. E. 87 Zamarlik H. 228 Zambri P. M. 294 Zamojski A. 281 Zappia G. 178 Zarate E. A. 216 Zard S. Z. 71 72 Zarkadis A. K. 76 Zax D. B. 15 Zefirov N. S. 87 95 171 270 Zellmer V. 52 Zenk M. H. 363 Zerner M. C. 23 26 76 153 Zhang B.L. 12 Zhang J. 296 Zhang. K. 294 Zhang Y. 142 Zhang Y.-Z. 103 156 213 Zhdankin. V. V. 87 270 Zheng X. 26 153 Zhou Z. 337 Ziegler F. E. 115 Ziller J. W. 229 Zilm K. W. 15 Zimmer R. 237 Zimmerman D. C. 348 Zimmermann H. 5 Zimmt M. B. 166 Zipkin R. E. 341 Zmijewski M. J. Jun. 367 Zon G. 5 Zupan M. 160 Zupancic N. 160 Zyk N. V. 95 Zylber J. 313 Zylber N. 313

ISSN:0069-3030    

DOI:10.1039/OC9868300371

出版商:RSC    

年代:1986

数据来源: RSC