摘要:

15 Synthetic Methods By R. BRETTLE Department of Chemistry The University Sheffield S3 7HF 1 Introduction Certain broad aspects of synthesis by their nature cannot be satisfactorily covered in a Report of this type but continue to receive a lot of attention. For example the latest of several recent reviews on asymmetric synthesis appeared at the end of the year.’ The concept of reactivity umpolung is now widely taught and understood and its principles lie behind many of the synthetic methods reported below. Seebach has contributed an important summarizing review article;* it is too early to say whether a new nomenclature for reagents which he introduces will be widely adopted but the concepts which they codify will remain of the greatest importance. Two other areas now rather losing their original novelty are concerned with the modification of well-known synthetic methods by the use of either phase-transfer catalysts or supported reagents; the second of these approaches has been comprehensively re~iewed.~ 2 Alkanes Further methods for the deamination of primary amines which complement other recent procedures have been developed.In particular the reduction of isocyanides which can easily be obtained by formylation-dehydration using tributylin hydride in the presence of a radical initiator has been thoroughly in~estigated.~” Tertiary secondary and primary isocyanides demand progressively higher temperature^.^ In the case of 6a -alkyl-6/3 -isocyano-penicillanates the reaction proceeds with inversion to give 6p -alkyl-peni~illanates.~ A modified work-up procedure for reductions employing tributyltin hydride has been recommended.6 Primary amines can also be deaminated by first converting them into pyridinium salts by reaction with the 2,3,4,5-tetraphenylpyryliumion; reduction with borohydride and pyrolysis of the resultant dihydropyridines then gives the hydrocarbons.’ This is one of a series (see below) of reactions developed by Katritzky’s group.’ J. W. ApSimon and R. P. Seguin Tetrahedron 1979,35 2797. D. Seebach Angew. Chem. Internat. Edn. 1979,18,239. A. McKillop and D. W. Young,Synthesis 1979,401,481. D. H. R. Barton G. Bringmann G. Lamotte R. S. Hay Motherwell and W. B. Motherwell Tetrahedron Letters 1979 2291. D. I. John E. J. Thomas and N.D. Tyrrell J.C.S. Chem. Cornrn.,1979 345. J. M. Berge and S. M. Roberts Synthesis 1979 471 ’ A. R. Katritzky K. Horvath and B. Plau J.C.S. Chem. Cornm. 1979 300. 324 R. Brettle The deoxygenation of non-hindered primary and secondary alcohols can con- veniently be accomplished by reduction of the derived thiocarbamates in 'i-butyl- amine with potassium that is solubilized by 18-crown-6.' The deoxygenation of aldehydes and ketones including aryl alkyl ketones by the reduction of the derived tosylhydrazones results in an improved yield if carried out in chloroform containing tetrabutylammonium acetate.' Selective olefin reductions are possible using borohydride in the presence of cobalt(I1) chloride a simpler procedure than the known alternatives." Limonene (1) gives (2).3 Alkenes Adamantene has been simply prepared1* by the debromination of 1,2-dibromoadamantane with bis(trimethylsilyl)mercury,an almost forgotten reagent for this type of reaction. The gas-phase pyrolysis of bridgehead acetates or chlorides can be used to make bridgehead olefins so long as the simple procedures for the removal of the accompanying acid described in a recent paper,'* are adhered to. Selenoxide eliminations continue to be uscd and it has been shown that ozone can be used to oxidize a phenylselenenyl group during the simultaneous ozonization of a double bond" (e.g. see Scheme 1). The phenylselenenic acid produced in such /CO,Et/ . .. SePh 1.11 -HO- C0,Et Reagents i 0,;ii NaBH Scheme 1 eliminations can be troublesome and it has therefore for instance been trapped by a secondary amine.However in a case where the product was an ap-olefinic ketone capable of acting as a Michael acceptor of such an amine the elimination was performed in acetic acid containing potassium acetate (giving the /3 -acetoxy-ketone) and the phenylselenenic acid was trapped by the addition of vinyl acetate or ethyl vinyl ether.14 Alternatively base-catalysed elimination of a selenonium salt can be a useful alternative to selenoxide elimination. l5 A. G. M. Barrett P. A. Prokopiou and D. H. R. Barton J.C.S. Chem. Comm. 1979,1175. G.W. Kabalka and J. H. Chandler Synrh. Cumm. 1979,9,275. lo S.-K. Chung J. Org. Chem. 1979 44 1015. J. I. G. Cadogan and R. Leardini J.C.S.Chem. Chem. 1979,783. l2 K. B. Becker and R. W. Pfluger Tetrahedron Letters 1979,3713. l3 T. A. Hase and R. Kwikari Acra Chem. Scand. (B),1979,33 589. l4 P. E. Eaton G. D. Andrews E.-P. Krebs and A. Kunai J. Org. Chem. 1979,44,2824. l5 S. Halazy and A. Krief Tetrahedron Letters 1979,4233. Synthetic Methods Many examples of the alkylation of (2)-dialk-1 -enylcuprates (3) derivable from alkynes and dialkylcuprates with a wide variety of halides (including those contain- ing compatible functionality e.g. C0,Et) have been given.16 Both alkenyl groups in the cuprate are converted into the product and the (2)configuration is retained. Enol ethers and enol thioethers are converted into alkenes by reaction with methylmagnesium bromide and other Grignard reagents lacking a p -hydrogen atom in the presence of a nickel catalyst" (e.g.see Scheme 2); the configuration at Reagents i MeMgBr [(PPh3)2NiCl,] Scheme 2 the double bond is retained. Allylic sulphides'' and ~ulphones'~ undergo a similar but faster cross-coupling with Grignard reagents catalysed by nickel or copper complexes. Usually coupling occurs at both the a-and y-positions but yy- disubstituted sulphones condense only at the a-position and the geometry of the olefin is conserved. Allylic sulphones are regioselectively desulphonylated by organotin hydrides; the reaction" involves a double migration of the double bond and should be applicable to electrophiles other than H' (Scheme3). Allylic acetates Reagents i Bu3SnH; ii E'(E = H or D) Scheme 3 and phenyl ethers are deoxygenated by catalytic reduction with formate ion [see Ann.Reports (B) 1978 75 1151; the major product is the terminal alkene (4)." l6 A. Alexakis G. Cahiez and J. F. Normant Synthesis 1979,826. l' E. Wenkert E. L. Michelotti and C. S. Swindell J. Amer. Chem. SOC.,1979 101 2246; E. Wenkert T. W. Ferreira and E. L. Michelotti J.C.S. Chem. Comm. 1979 637; H. Okamura M. Miura and H. Takei Tetrahedron Letters 1979.43. H. Okamura and H. Takei Tetrahedron Letters 1979,3425. l9 M. Julia A. Righini and J.-N. Verpeaux Tetrahedron Letters 1979 2393. 2o Y. Ueno S. Aoki and M. Okaware J. Amer. Chem. SOC.,1979 101 5416. J. Tsuji and T. Yamakawa Tetrahedron Letters 1979 613 326 R. Brettle Allylic carbamates are converted into alkenes e.g.(9,by lithium dimethylcuprate in a regio- and stereo-specific process.22 Allylsilanes can conveniently be prepared by a Wittig reaction thereby adding a two-carbon unit to a carbonyl compound. A wide Ph R' R' LiCuMe2 ,H& YSiMe 5 >CH2 NHPh Me' D R2 S02Ph R2 variety of substituted alkenes can then be obtained by the use of the appropriate electrophile (Scheme 4); protiodesilylation gives the parent alkene.23 Alkenes can also be prepared by the fluoride-induced elimination reaction of P -silyl sulphones (6),which can be obtained either by the alkylation of 2-(trimethylsily1)ethyl phenyl sulphone or by the trimethylsilylmethylation of alkyl phenyl ~ulphones.~~ R' R' R' >=O A )=CHCH2SiMe3 4 R2 R2 R2 E Reagents i Ph3PvSiMe3 ;ii BF, MeC0,H (E = H) or BF, Bu'CI (E = But) Scheme 4 Two other eliminative routes start from P-hydroxy-acids It was reported in 1975 that their decarboxylative dehydration could be brought about by treatment with the dimethyl acetal of dimethylformamide.It has now been shown that the dineopentyl acetal gives no ester by-products and better yields of the desired and this and many other aspects of the chemistry of formamide acetals have been reviewed.26 A highly stereoselective synthesis of alkenes is possible if the pure threo-isomer of the P-hydroxy-acid is used and it is known that this isomer can be obtained by the action of aldehydes on metallated carboxylate salts; the (2)-alkene is formed by reaction with triphenylphosphine and diethyl azodicarboxylate and the (E)-alkene by conversion into the P -lactone which then loses carbon dioxide on di~tillation.~~ The method is particularly recommended for the stereocontrolled synthesis of enol ethers.A new synthesis of disubstituted olefins2' uses the condensation of aldehyde tosylhydrazones with stabilized carbanions particularly those stabilized by a sul- 22 C. Gallina and P. G. Ciattini J. Amer. Chem. SOC.,1979,101 1035. 23 I. Fleming and I. Paterson Synthesis 1979,446. 24 P. J. Kocienski Tetrahedron Letters 1979 2649. 25 J. Mulzer and G. Bruntrup Tetrahedron Letters 1979 1909. 26 R. F. Abdulla and R. S. Brinkmeyer Tetrahedron 1979,35 1675. " J. Mulzer A. Pointner A. Chucholowski and G. Briintrup J.C.S. Chem. Comm. 1979,52.E. Vedejs J. M. Dolphin and W. T. Stolle J. Amer. Chem. Soc.. 1979,101,249. Synthetic Methods 327 phone group but it fails for the hydrazones of sterically hindered or ap-olefinic aldehydes (Scheme 5). NHNLi R3CH=NNHTs + 2BuLi + IR3CHCHR' -R3CH=CHR1 + R2SO2Li+ Nz R'CHzSO2R2 ISOZR2 Scheme 5 Symmetrical (E,E)-1,3-dienes (7) can be obtainedz9 under mild conditions with very high stereochemical purity by the silver(1)-ion-promoted coupling of (E)-alkenyl-pentafluorosilicates(8) which are available from alkynes and are air- stable. Unsymmetrical (E,E)-1,3-dienes can be obtained by the cross-coupling of alk-l-enylboranes with (E)-alk-l-enyl halides using tetrakis(tripheny1-phosphine)palladium as the catalyst in the presence of base; in the absence of base the coupling fails.30 Coupling with alk-1 -ynyl halides gives internal (E)-alkenyne~.~' Internal (2)-alkenynes can be prepared31 by the copper-catalysed reaction of Grignard reagents with 3-acetoxyalk-l-en-4-ynes(Scheme 6).Reagents i R3MgX. CuI; ii H30+ Scheme 6 The desire to extend the range of the Diels-Alder reaction continues to encourage new syntheses of heterosubstituted 1,3-dienes. Three recent examples are discussed here. Trost has shown that the acyloin (9),readily obtained from the Diels-Alder adduct from cyclopentadiene and maleic anhydride does have the stereochemistry 29 K. Tamao H. Matsumoto T. Kakui and M. Kumada Tetrahedron Letters 1979 1137. 30 N. Miyaura K. Yamada and A. Suzuki Tetrahedron Letters 1979,3437.31 G. Cassani P. Massardo and P. Piccardi Tetrahedron Letters 1979,633. 328 R. Brettle shown and has used it to prepare 1,4-diheterosubstituted butadienes. Scheme 7 illustrates a simple example.’* The success of the method depends on the common artifice of using a cyclohexene as a protected form of a double bond; the geometry of the diene is established stereospecifically in the thermal electrocyclic ring-opening of the cyclobutene that is released in the retro-Diels-Alder step. A method for the production of 1-alkoxy-buta- 1,3-dienes from complex alcohols that uses mild conditions would be a useful synthetic advance. Such a method has now been described,33 in the carbohydrate field but the method should be generally applicable (Scheme 8).trans-N-Acyl-N-alkyl-l-amino-1,3-dienes can be prepared from dienamines by the very mild proced~re’~ shown in Scheme 9. HO H SPh OAc Reagents i C,H,S02Cl C,H,N; ii PhS- Na’; iii NaBH,; iv (CH,CO),O C,H,N; v Flash vacuum pyrolysis Scheme 7 CHO -TsO Reagents i NaH; ii HH;iii Ph,P=CH H CHO Scheme 8 Reagents i R’COCl 25 “C; ii PhNMe, 25 “C Scheme 9 4 Alkynes Three novel methods of forming a carbon-carbon triple bond have been described during the year. Perhaps the most interesting is the one illustrated in Scheme 10 in which the key step is the surprisingly ready condensation of trichloroethene with an enolate ion.35 Non-conjugated ketones and simple esters do not react under the ’* B. M. Trost S.A. Godleski and J. Ippen J.Org. Chem. 1978,43,4559. ’’ S. David and J. Eustache J.C.S. Perkin I 1979 2521. 34 W. Oppolzer L. Bieber and E. Francotte Tetrahedron Letters 1979,981. ” A. S. Kende M. Benechie D. P. Curran and P. Fludzinski Tetrahedron Letters 1979,4513. Synthetic Methods conditions given in Scheme 10 but active-methylene compounds react under more vigorous conditions. Another new method,36 which would be more useful if the starting nitrimines were more readily available is shown in Scheme 11;ketones with both a-and a'-hydrogen atoms give some allene as well. The third method is a modification of the well-known Eschenmoser fragmentation of the tosylhydrazones of ap-epoxy-ketones which is now even used on an industrial scale. The original method suffers from the disadvantage that sterically crowded enones are not easily epoxidized but in the modification3' the tosylhydrazone of the parent enone is used.The way in which the fragmentation is brought about is shown in Scheme 12. liii iv Reagents i LDA THF at -78 "C; ii ClCH=CCl, HMPT -78 to +15 "C; iii DIBAL; iv H,O+; v HOCH2CH20H TsOH; vi BuLi Scheme 10 Reagents i NH20H; ii NaNO, H,SO,; iii (CH,C0)20 C,H,N; iv reflux Scheme 11 NHTs N/ ii -3 r Reagents i R'OH NBS; ii NaHSO Scheme 12 36 G. Buchi and H. Wuest J. Org. Chem. 1979,444116. 37 C. Fehr. G. Ohloff and G. Buchi Helv. Chim. Acra 1979,62 2655. 330 R. Brettle 5 Alcohols The need to protect hydroxy-groups during synthetic operations continues to produce new ideas and modifications to earlier methods.This year Reese has introduced the concept of the protected protecting group.38 Alcohols are converted into their 2-dibromomethylbenzoyl derivatives which are comparatively stable to both acid and alkali. The deprotection takes place in two stages. In the first treatment with silver perchlorate in a slightly wet solvent in the presence of a base such as collidine (which keeps the reaction medium virtually neutral) gives the formyl ester. It has been known for some time that the hydrolysis of a 2-formylbenzoate is one of the fastest non-enzymic hydrolyses of esters. Accordingly in the second stage treatment with morpholine leads to rapid deacylation with release of the alcohol. Several alternative methods have been proposed for the deprotection of alcohols protected as their t-butyldimethylsilyl ethers hitherto most often deblocked by the use of dilute acids or the ‘naked’ fluoride ion.It has now been that ‘naked’ fluoride ion (which also acts as catalyst for reactionsJike the Michael reaction) can be obtained by using a mixture of tetrabutylammonium chloride and potassium difluoride dihydrate; this avoids the problems caused by the hygroscopic nature of tetrabutylammonium fluoride itself. Three new reagents are boron trifluoride etherate4’ (used in a halogenated solvent) potassium s~peroxide~~ (used in con- junction with a crown ether in dimethyl sulphoxide) and acetonitrile containing some aqueous hydrogen The last of these does not cause simultaneous dehydration of p -ketols.Further significant advances have been made in controlling the diastereoselectivity of condensations of the aldol type. Two groups have demonstrated that vinyloxyboranes show a very high stereoslectivity in their condensation with aldehydes.43 In general the (2)-isomer of a vinyloxyborane reacts with an aldehyde to give a product which after oxidative hydrolysis gives a very high proportion of the erythro-isomer whereas the (E)-isomer shows a slightly lower diastereoselectivity but nevertheless gives mostly the threo -isomer as shown in Scheme 13. The nature of the alkyl groups attached to the boron atom in the boron F’ ’2R5CHO+ R4&R5 R’CHO R 4 0 R 5 R2R3B0 R’ O OH RZR3B0 H OH erythro (E) threo Scheme 13 enolates can have a profound effect on the diastereoselectivity.These methods only became feasible because stereospecific routes to the (2)-and (E)-forms of vinyl- oxyboranes were simultaneously developed.43 The Hooz synthesis from 38 J. B. Chattopadhyaya C. B. Reese and A. H. Todd J.C.S. Chem. Comm. 1979,987. 39 L. A. Carpino and A. C. Sau J.C.S. Chem. Comm.,1979 514. 40 D. R. Kelly S. M. Roberts and R. F. Newton Synth. Comm. 1979.9 295. 41 Y. Torisawa M. Shibasaki and S. Ikegami Tetrahedron Letters 1979 1865. 42 R. F. Newton D. P. Reynolds M. A. W. Finch D. R. Kelly and S. M. Roberts Tetrahedron Letters 1979,3981. 43 S. Masamune S. Mori D. Van Horn and D. W. Brooks Tetrahedron Letters 1979,1665; D. A. Evans E. Vogel and J. V. Nelson J. Amer. Chem. SOC.,1979,101 6120.Synthetic Methods 33 1 diazoketones and trialkylboranes has now been shown to lead almost exclusively to (E)-vinyloxyboranes but equilibration with lithium phenoxide or pyridine gives the (2)-isomer so that the other non-stereospecific syntheses such as the conjugate addition of trialkylboranes to a@-olefinic ketones can also be used to prepare the pure (2)-isomer. Vinyloxyboranes can also be prepared from ketones by the action of trifluoromethanesulphonyloxyboranesin the presence of base. Similar diastereoselectivity has also been in the synthesis of the thiol-esters of P-hydroxy-a -methyl-carboxylic acids again based on the use of vinyloxyboranes (Scheme 14). Very high diastereoselectivity with respect to the Reagents i. (C,H,),BOSO,CF, Pri,NEt; ii,.RCHD; iii H,02 H20 MeOH; iv 9-borabicyclo[3.3.1]non-9-yl trifluoromethanesulphonate Pri2NEt Scheme 14 positions a-and P-to the carbonyl group was also observed when a condensation of the type illustrated in Scheme 14 was carried out with an aldehyde that was so constituted that a further chiral centre was introduced at the y-position but a rather low diastereoselectivity was observed with respect to the centres at the @-and y -positions (Scheme 15). However much greater diastereoselectivity with respect 0 0 55 45 Reagents i (10);ii H20, H20 MeOH; iii CF,C02H Scheme 15 to the P-and y-positions has been observed in another synthesis of P-hydroxy-y- methyl-carboxylic acids. The reagent (11) was selected on the basis of prior considerations4’ which led to the conclusion that it would show very high erythro-selectivity with respect to the a-and P-positions and because the aldol product could 44 M.Hirama and S. Masamune Tetrahedron Letters 1979,2225; M. Hirama D. S. Gamey L. D.-L. Lu and S. Masamune ibid. p. 3937. 45 C. H. Heathcock and C. T. White J. Amer. Chem. Soc. 1979,101.7076. 332 R. Brettle be readily converted into the desired carboxylic acid. The condensation of (11)with a-phenylpropanal led to a single product with the stereochemistry (Scheme 16). p -Methylhomoallylic alcohols can be prepared47 in the erythro-form from (Z)-but-2-enylboronates (12) which can be obtained by the route shown in Scheme 17. Reagents i LDA; ii TMEDA; iii PhCHMeCHO; iv NaHCO, H20; v HJO Scheme 16 Reagents i CIB(NMe2)2; ii ; iii RCHO; iv (HOCH2CH2),N Ho OH Scheme 17 The unexpectedly sluggish reaction of 9-borabicyclo[3.3.llnonane with triple bonds permits the selective hydroboronation of primary olefins containing a non- conjugated acetylenic group and hence provides a route to acetylenic The selective monohydroboronation of the analogous non-conjugated primary and secondary dienes cannot be achieved but the development of methods for selective hydroalumination makes possible the synthesis of the olefinic primary acetate (Scheme 18).49 The photosensitized reaction of vinylsilanes with singlet oxygen leads to a-silylated ally1 alcohols and in conjunction with known reactions (Scheme 19) this gives a new 1,2-oxygen transposition leading from a ketone to an allylic Reagents i LiAlH, TiCl,; ii [Pb(OAc),] -e> ,-0 Scheme 18 SiMe SiMe i-iii iv,v ,OH -* vi DOH Reagents i PhSO,NHNH,; ii BuLi; iii Me,SiCI; iv lo2;v NaBH,; vi Bu,N’ F-Scheme 19 46 C.M. Heathcock M. C. Pirrung C. T. Buse J. P. Hagan S. D. Young and J. E. Sohn J. Amer. Chem. SOC.,1979,101,7077. 47 R. W. Hoffmann and H.-J. Zeiss Angew. Chem. Internat. Edn. 1979.18.306. ‘* C. A. Brown and R. A. Coleman 1. Org. Chem. 1979,44,2328. 49 F.Sato Y. Mori and M. Sato Tetrahedron Letters 1979,1405. Synthetic Methods 333 alcohol.sO Highly alkylated oxirans are converted into allylic alcoholss’ under very mild conditions by using the sequence shown in Scheme 20. In the case of trisubstituted oxirans the ring opens at the more highly substituted carbon atom this is the opposite of the earlier selenium-based methods of Sharpless.OSO,CF + -+ iv,v i,ii iii 0a (‘J + DOH ‘H OSiMe, H OSiMe3 Reagents i CF,SO,OSiMe,; ii 2,6-lutidine; iii DBU; iv KF; v H30+C1-Scheme 20 A few new reductive routes to alcohols have been investigated during the year and H. C. Brown (with Krishnamurthy) has surveyed ‘Forty Years of Hydride Reduc- tions’; a fitting report5* in the year in which Brown shared the Nobel Prize for Chemistry with Wittig. Both names have appeared very frequently over the years in this section of Annual Reports as a result of their outstanding contributions to organic synthesis. 1-Succinimidyl esters commonly used as activated esters in peptide synthesis are reduced to primary alcohols by sodium b~rohydride,’~ and ketones can be reduced in the presence of aldehydes by using sodium borohydride in 0 0 Reagents i NaBH, CeCl,*6H20 Scheme 21 the presence of lanthan~ids.’~ An example is shown in Scheme 21.(&)-DL isobornyloxyaluminium isopropoxide proved to be a very much better reagent than aluminium isopropoxide for the clean reduction of a prostaglandin-type enone to the corresponding allylic and sodium bis-(2-methoxyethoxy)aluminium hydride in the presence of DABCO at -20 “C,was successfully to reduce the W. E. Fristad,T. R. Bailey L. A. Paquette R. Gleiter and M. C. Bohm J. Amer. Chew. SOC.,1979,101 4420. ” S. Murata,,M. Suzuki and R. Noyori J. Amer. Chem. SOC.,1979,101 2738.’2 H. C. Brown and S. Krishnamurthy Tetrahedron 1979,35 567. ” J.-I. Nikawa and T. Shiba Chem. Letters 1979,981. 54 J. L. Luche and A. L. Gemal J. Amer. Chem. SOC.,1979,101,5848. 55 J. Hutton Synth. Comm. 1979 9,483. 56 E. J. Corey and J. G. Smith J. Amer. Chem. SOC.,1979,101 1038. 334 R. Brettle ,OEt OEt .OMEM ,OMEM 0*. HO*-.I i OH OH (13) (14) MEM = p-methoxyethoxymethyl P-ethoxy-enone (13) to the P-ethoxy-allylic alcohols (14) when many other reagents had failed to work on related model systems. There have been further reports of regio- and stereo-selective oxygenations at remote unactivated sites. la,3a -Diacetoxycholestane was prepared in 45% yield from 3a -cholestanyl xanthate via a transient iron-oxygen complex the iron itself being complexed by a sulphur atom in the xanthate groups7 (Scheme 22).6-Methylhexan-2-01 was converted into its 6-hydroxy-derivative in 88% yield on a scale of five grams by the reaction of the derived alkyl hydrogen succinate adsorbed on silica gel with a solution of ozone in a Freon.'* 'C -SMe I1 0 Reagents i AcOH Fe(ClO,), 0,,trace Fe3" Scheme 22 6 Ethers Methods for the epoxidation of alkenes continue to be discovered. A development of the Corey sulphur ylide method which can be applied on a large scale involves the use of solid trimethylsulphonium chloride (where the use of the hard counter-ion is crucial) and solid sodium hydroxide in dimethyl sulphide containing a phase-transfer catalyst. This system permitted a virtually quantitative conversion of the rather unreactive ketone p-ionone (15) into the epoxide (16) and hence by rearrangement '' H.Patin and G. Mignani J.C.S. Chem. Comm. 1979,685. A. L. J. Beckwith and T. Duong J.C.S. Chem. Comm. 1979,690. Synthetic Methods 335 into the homologous aldehyde." Another successful method used a polymeric sulphonium salt and a phase-transfer catalyst in a water-dichloromethane system.60 New epoxidizing agents include triphenylsilyl hydroperoxide61 and 2-hydro- peroxyhexafluoropropan-2-01;62the latter gives excellent yields even with acid- senstive products owing to the very low acidity of the hexafluoropropane-2,2-diol which is the other product and it is exceptionally stereoselective; for example in the epoxidation of 3-hydroxycyclohex-1-ene.Enol thioethers have hitherto found only limited use in organic synthesis but suggestions in a recent paper63 by Trost could alter this. Oxidation with lead tetra-acetate leads to bis-acetoxylation at the double bond and the product can then be converted into the substituted allylic acetate. Amongst the synthetic operations possible with these are conversion into the thioenol ether of the 1,2-diketone (Scheme 23) which might form the basis for a 1,2-carbonyl transposition and coupling with cuprates to give the enol thioethers of substituted ketones. Reagents i [Pb(OAc),]; ii BF,.Et,O; iii K,CO, MeOH H20 iv MnO Scheme 23 7 Halides Diphosphorus tetraiodide is an excellent reagent for the synthesis of alkyl iodides from alcohols.Primary secondary and tertiary alcohols including neopentyl-type alcohols are transformed with inversion but without rearrangement into the iodides in a slow reaction in carbon disulphide solution at room tempe~ature.~~ The reagent also converts aldoximes and primary nitroalkanes into nitriles and deoxy- genates epoxides sulphoxides and ~elenoxides.~~ Primary aliphatic amines can be converted into alkyl chlorides by reaction with 2,4,6-triphenylpyrylium chloride with azeotropic removal of water and subsequent thermolysis of the resulting N-alkyl-pyridinium chlorides66 (cf.Section 2). Alipha-tic aromatic and heteroaromatic iodides can similarly be prepared generally in high yields from 2,4,6-triphenylpyrylium i~dide.~' Analogous procedures permit the conversion of primary amines into alkyl thiocyanates thiocarbonates acetates and benzoates.@ 59 M.Rosenberger P. McDougal G. Saucy and J. Bahr Pure Appl. Chem. 1979,51,871. 6o M. J. Farrall. T. Durst and J. M. J. Frechet. Tetrahedron Letters 1979 203. " J. Rebek and R. McCready Tetrahedron Letters 1979,4337. " R. P. Heggs and B. Ganem J. Amer. Chem. SOC.,1979,101,2484. 63 B. M. Trost and Y.Tanigawa J. Amer. Chem. SOC., 1979,101,4413. 64 M. Lauwers B. Regnier M. van Eenoo J. N. Denis and A. Krief Tetrahedron Letters 1979 1801. 65 H. Suzuki T. Fuchita A. Iwasa and T. Mishina Synthesis. 1978 905; J. N. Denis and A. Krief Tetrahedron Letters 1979 3995. 66 A. R. Katritzhy K. Horvath and B. Plau Synthesis 1979,437. '' A. R. Katritzky N.F. Eweiss and P.-L.Nie J.C.S. Perkin I 1979,433. 68 A. R. Katritzky U. Gruntz N. Mongelli and M. C. Rezende J.C.S. Perkin Z 1979 1953; A. R. Katritzky U. Gruntz D. H. Kenny M. C. Rezende and H. Sheikh ibid. p. 430. 336 R. Brettle Some new methods for the ionic chlorination of alkenes to give allylic chlorides have been de~eloped.~~ The reaction of the alkene (17)with N-chlorosuccinimide in the presence of diphenyl diselenide is very selective and gives a good yield of the rearranged chloride (18);the addition of some pyridine suppresses the formation of isomeric allylic chlorides. P-Pinene (19)is exceptional in that the product is almost exclusively the thermodynamically less stable unrearranged allylic chloride; the different regioselectivity in this case has been attributed to the formation of a different active selenium-containing catalyst.Usefully the regioselectivity which is observed with p -pinene is the opposite to that observed in the allylic chlorination by t-butyl hypochlorite radical. The selenium-catalysed chlorination with N-chloro- succinimide fails with terminal alkenes but another briefly reported new system which largely gives the unrearranged allylic chloride works in such cases; the catalyst in this system is N-sulphinyltoluene-p-sulphonamide. 8 Nitriles The cycloaddition of a-nitroso-acrylic esters or of a-nitrosoacrolein prepared in situ to alkenes gives access to 5,6-dihydro-4H-l,2-oxazine-3-carboxylicacids which on thermal decomposition give y-hydroxy-nitriles corresponding to the syn-addition of HOCHzCNto the alkene7' (Scheme 24).The trimethylsilyl ethers of NOH NOH II II Reagents i BrCH2CC02Et Na,CO,; ii NaOH; iii CICH,CCHO; iv Ag,O; v heat to 150 "C Scheme 24 y-hydroxy-nitriles can be prepared by the reaction of an epoxide with the anion from 2-trimethylsilylacetonitrile at low temperatures followed by quenching with water; a more convenient route to trimethylsilylacetonitrile was also rep~rted.~~ The anti-cyanohydroxylation of alkenes can of course be achieved by opening of the derived epoxide with cyanide ion.A new procedure for syn -cyanohydroxylation 69 T. Hari and K. B. Sharpless J. Org. Chem. 1979,44,4204,4208. 'O T. L. Gilchrist and T. G. Roberts J.C.S. Chem. Comm. 1979 1090. I. Matsuda S.Murata and Y. Ishii J.C.S. Perkin I 1979 26. Synthetic Methods 337 which is more acceptable than earlier methods using cyanogen N-oxide or fulminic acid involves the 1,3 -dipolar addition of benzenesulphonylnitrile oxide prepared in situ to the alkene followed by reductive cleavage of the benzenesulphonyl- isoxa~oline~~ (Scheme 25). . .. a R3 R4 R'XRz CN R4 Reagents i PhSO,C=NOH; ii K2C03; iii 2%Na-Hg alloy I Br Scheme 25 The reductive hydrocyanation of alkynes to give alkyl cyanides [see Ann. Reports (B) 1978 75 3181 can in fact be carried out without using either hydrogen or hydrogen cyanide by means of the tetracyanonickelate ion in conjunction with sodium b~rohydride.~~ An old reaction originally applied to camphor by Lapworth has been revived to prepare an a-cyano-ketone from a hydroxymethylene ketone.74 The cyano-ketone undergoes a sort of Michael reaction with 1,l-diethoxyprop-2- ene (Scheme 26).This reaction has further synthetic potential. Me CHOH 0"- Me Me Me Reagents i NH,OH (5 equiv.) NaOMe MeOH reflux; ii CH,=CHCH(OEt), benzene 80 "C Scheme 26 9 Nitro-compounds The uses of nitroacetic acid and its esters in organic synthesis have been re~iewed.~' Two general methods for the C-alkylation of pre-formed nitronate anions have at last been di~covered.'~ In one the alkylating agent is an N-alkyl-pyridinium salt (see Sections2 and 7) and in the other which is a photochemical radical chain reaction an alkyl-mercury halide. 72 P.A. Wade and H. R. Hinney J. Amer. Chem. SOC.,1979,101,1319. 73 T. Funabiki and Y. Yamazaki J.C.S. Chem. Comm. 1979 1110. " R. M.Coates S.K. Shah and R. W. Mason J. Amer. Chem. SOC.,1979,101,6765. 75 M. T. Shipchandler Synthesis 1979,666. 76 A. R. Katritzky G. de Ville and R. C. Patel J.C.S. Chem. Comm. 1979 602; G. A. Russell J. Hershberger and K. Owens J. Amer. Chem. SOC.,1979,101 1312. 338 R. Brettle 10 Amines The use of bis(trifluoroacetoxy)iodobenzene at room temperature in aqueous acetonitrile to convert simple amides into the corresponding primary amines represents a mild alternative to the classical Hofmann degradati01-i.~~ It cannot be used with aromatic amides owing to the further oxidation of the product by the reagent but is eminently suitable for use with hippuramide.A new synthesis of lysine (Scheme 27) uses the reaction of a bromide with an alkali-metal cyanate in an alcohol to form a urethane followed by hydrolysis to produce a primary amine and thereby avoids the formation of a piperidine derivative which occurs if the 1,5-dibromide is treated with ammonia.78 Primary amines can now be a-alkylated by the procedure79 shown in Scheme 28. In the a-alkylation of secondary amines through the nitrosamines Seebach the originator of the method has shown that a two-stage reduction of the alkylated nitrosamine by lithium aluminium hydride (which gives the hydrazine) and then Raney nickel is a safe method insofar as it avoids any contamination of the product by carcinogenic nitrosamines.80 A transition-metal-catalysed transformation of tertiary amines into secondary amines and sulphides with thiolate anions has synthetic potential; the order of preference in the cleavage of the C-N bonds is tertiary > secondary >primary.8' An application of this reaction in the alkaloid field is illustrated in Scheme 29.The rearrangement sequence shown in Scheme 30 provides an efficient route to N-allyl-toluene-p-sulphonamides.82Allylamines can be prepared through the transition-metal-catalysed process83 shown in Scheme 31. In a cyclic chiral system both configurations are formed at the site of the new C-N bond. NHC0,Me BrdC02Me HNdCO,Me I C0,Me Reagents i KOCN MeOH DMF 100OC; ii HCO,H HCl H20 Scheme 27 R'CH2NH2 % R'CH2N=hR2 %R'CHR3-N=NR2 R'CHR3NH2 I 0- Reagents i Bu'OCI I,; ii R2NO; iii excess R3Li; iv Zn AcOH EtOH Scheme 28 " A.S. Radhakrishna M. E. Parham R. M. Riggs and G. M. London J. Org. Chem. 1979,44,1746. " F. Effenberger and K. Drauz Angew. Chem. Internat. Edn. 1979,18,474. 79 D. H. R. Barton G. Lamotte W. B. Motherwell and S. C. Narang J.C.S. Perkin I 1979,2030. D. Seebach and W. Wykypiel Synthesis 1979,423. S.-I. Murashi and T. Yano J.C.S. Chem. Comm. 1979,270. M. Kakimoto T. Yamamoto and M. Okawa Tetrahedron Letters 1979,623. 83 B. M. Trost and E. Keman J. Org. Chem. 1979,44,3451. Synthetic Methods 339 0 LI PhS Reagents i PhS- Na+ RuCI Scheme 29 Reagents i ArSH TsOH C,H,; ii NaClNTs; iii NaOEt EtOH 50 "C Scheme 30 RVOAC or & R-NHCH /Ar & RANH, 'Ar R Ar = p-MeOC6Hd Reagents i Ar,CHNH, [(PPh,),Pd]; ii >88% HCO,H 80 "C Scheme 31 Ph 0 Reagents i LDA; ii EtCHO at -78 "C; iii warm to 0 "C;iv NaBH,; v MeOH Scheme 32 Diethyl phosphorocyanidate can be used with an amine in a non-aqueous solvent for the preparation of a-amino-nitriles from aldehydes and ketones -the Strecker The use of a-amino-nitriles as acyl equivalents has been reported before [see Ann.Reports (B),1978,75,318],as has their reduction by borohydride to give the corresponding amines.A variety of electrophiles can be used in the reaction with a-amino-nitrile anions and two useful synthetic sequences based on this methodology have appeared. The first8' (Scheme 32) provides a highly 84 S.Harusawa Y.Hamada and T. Shioiri Tetrahedron Letters 1979,4663. G. Stork R. M.Jacobson and R. Levitz Tetrahedron Letters 1979 771. 340 R. Brettle stereoselective route to erythro-1,2-amino-a1cohols and the second86 (Scheme 33) leads via a new Michael acceptor 2-(N-methylanilino)acrylonitrile (20) to a versatile ketone synthesis. a-Amino-nitriles can also be used as precursors of enamines as dehydrocyanation occurs on heating with excess powdered potassium t-butoxide in an aromatic ~olvent.~' Enamines can also be prepared by using the diphenylphosphine oxide methodology of Warren. Suitable choice of the amine component allows the reaction to be applied to aliphatic aromatic and alp-0lefinic aliphatic aldehydes and to ketones88 (Scheme 34).CN CN CN / i ii i iii b H2C=C / I CH2 ivlv b R'CH2CR2 & R'CH2COR2 I \NMePh 'NMePh NMePh (20) Reagents i LDA; ii Me,SiCl; iii CH,O; iv R'Li; v R2X;vi H30+C1-Scheme 33 0 R' ,NR3R4 R2' €10-C-R' H I\ (R2=H R3R4= 0; R' R2#H R3=Me R4=Ph) 0 U I1 Reagents i PhzPCHLi-NR3R4; ii NH,CI; iii KH Scheme 34 11 Aldehydes and Ketones Triphenylbismuth carbonate shows remarkable selectivity for functional groups and alcohols can be oxidized to the corresponding aldehyde or ketone even in the presence of benzenethiol indole or pyrr01e;~~ cis-cyclohexane-1,2-diolis cleaved to hexane- 1,6-dial. Pyridinium dichromate (PDC) introduced by Corey at the start of the year,9o has quickly become established as a very useful oxidizing agent for alcohols.It is an alternative to Collin's reagent which has to be used in large excess and can be used in more nearly neutral conditions than pyridinium chlorochromate (PCC). PDC can easily be prepared and stored and is used either as a solution in DMF when it oxidizes primary (but not allylic) alcohols to the carboxylic acids or more generally as a suspension in dichloromethane when all types of primary alcohols are oxidized to the corresponding aldehydes and secondary alcohols give ketones. A complex secondary alcohol containing a thioacetal group was selectively oxidized at the alcohol group by PDC." A similarly functionalized molecule was 86 H. Albrecht and K. Pfaff Synthesis 1978,897. H. Albrecht W.Raab and C. Vonderheid Synthesis 1979 127.88 N. L. J. M. Broekhof F. L. Jonkers and A. van der Gen Tetrahedron Letters 1979 2433. 89 D. H. R. Barton D. J. Lester W. B. Motherwell andM. T. B. Papoula J.C.S. Chem. Comm. 1979,705. 9o E. J. Corey and G. Schmidt Tetrahedron Letters 1979,399. Synthetic Methods selectively oxidized to the ketone retaining the thioacetal group by DMSO in the presence of DCC and a minimal amount of phosphoric acid (the original Pfitzner- Moff att reagent).” Minor but significant modifications to the two-phase dichromate method for the oxidation of primary alcohols to aldehydes reported last year [see Ann. Reports (B) 1978 75 3111 have appeared.92 A suspension of potassium permanganate and hydrated copper sulphate in benzene smoothly oxidizes secondary alcohols in benzene.93 Despite the warning given last year [see Ann.Reports (B),1978,75,311] about the instability of tetrabutylammonium permanganate the use of quaternary ammonium permanganates continues to be explored. The benzyltriethylammonium salt has been put forward as a reagent for the selective oxidation of olefins to dialdehydes under homogeneous non-aqueous condition^,^^ and yet the solid reagent originally introduced9’ for the oxidation of hydrocarbons and ethers has since been shown (following an explosion) to be thermally unstable and shock- sensitive.96 Surely such reagents would be better avoided. Alcohols can be efficiently oxidized to carbonyl compounds by t-butyl hydro- peroxide or chloramine T when the reaction is catalysed by diary1 diselenides.Olefinic bonds and selenides are not oxidized and the cyclization that accompanies the oxidation of an alcohol such as citronellol can be suppressed by the addition of a little of a secondary amir~e.~’ Trialkylborates can be oxidized to carbonyl compounds by pyridinium chloro- chromate (PCC). This is of no advantage if the borate has been prepared from the alcohol but there can be advantages if the borate has been generated directly as a reaction intermediate. Scheme 35 shows a good synthesis of aldehydes from acids based on this.98 CH2R OSb 3RC02H I IRCHZB HBCHZR 0 3RCHO Reagents i BH,.Me,S; ii PCC Scheme 35 The synthesis of aldehydes and ketones (and also of carboxylic acids) from lower carbonyl compounds by carbon-carbon coupling reactions has been reviewed.The syntheses are classified in terms of the number of carbon atoms separating the new carbonyl group from the original carbonyl carbon atom.99 The enamine synthesis 91 I. Dyong R. Hermann and G. von Kiedrowski Synthesis 1979,527. 92 D. Pletcher and S. J. D. Tait J.C.S. Perkin I 1979 788; D. Landini F. Montanari and F. Rolla Synthesis 1979 134. 93 F. M. Menger and C. Lee J. Org. Chem. 1979,44,3446. 94 T. Ogino and K. Mochizuba Chem. Letters 1979,443. 95 H.-J. Schmidt and H. J. Schafer Angew. Chem. Internat. Edn. 1979 18 68 69. 96 H. Jager J. Lutolf and M. W. Meyer Angew. Chem. Internat. Edn. 1979,18,786; H.-J. Schmidt and H. J. Schiifer ibid. p. 787. 97 M. Shimizu and I. Kuwajima Tetrahedron Letters 1979 2801.98 H. C. Brown S. U. Kulkarni and C. Gundu Rao Synthesis 1979,702; H. C. Brown C. Gundu Rao and S. U. Kulkarni ibid. p. 704. 99 S. F. Martin Synthesis 1979 633. 342 R. Brettle shown in Scheme 34 provides a recent example of the synthesis of an aldehyde (generated in this case by hydrolysis of the enamine) with one more carbon atom than the starting aldehyde or ketone and a second recent example is provided by the route illustrated in Scheme 36.l" Reagents i Me,SiCH,OMe; ii Bu'Li; iii KH; iv H20,HC0,H Scheme 36 It is in fact possible to prepare ketones in excellent yield by the action of a Grignard reagent on an acid chloride,"' although to avoid the formation of the tertiary alcohol the reaction must be carried out in THF at -78°C.Similarly ketones can be prepared from esters by the action of a Grignard reagent and triethylamine at -35 OC.lo2 The reaction was successfully performed on the non-conjugated ester group of compound (21),despite the fact that the molecule also contains conjugated COMe MeMgI Et3N at -35 "C 0 CO,CHPh CO2CHPh2 (21) ester amide and lactam functions. Preparation of saturated ketones by the Birch reduction of ap-olefinic ketones goes in considerably improved yield in the presence of catalytic amounts of ferric ~hloride,"~ and in the preparation of ketones by the hydrolysis of vinyl chlorides in the Wichterle annelation sequence the hydrolysis can be brought about in neutral conditions at room temperature by the use of mercuric trifluoroacetate in nitromethane dichloromethane or benzene followed by the addition of dilute hydrochloric acid.lo4 An as yet unexplained transposition of the oxygen occurs if methanol is used as the solvent.An efficient method for carrying out the transformation (22)-P (23) has been worked out and used to construct a key intermediate in the Woodward reserpine synthesis. The method,'05 which uses a loo P. Magnus and G. Roy,J.C.S. Chem. Comm. 1979,822. lo' F.Sato M. Inoue K. Oguro and M. Sato Tetrahedron Letters 1979,4303. M. Yoshioka I. Kikkawa T. Tsuji Y. Nishitani S. Mori K. Okada M. Murakami F. Matsubara M. Yamaguchi and W. Nagata Tetrahedron Letters 1979,4287. lo3 G. S.R. Subba Rao and N. S. Sundar J. Chem. Res. (S) 1979,282. H.Yoshioka T.Takasabi M. Kobayashi and T.Matsumoto Tetrahedron Letters 1979 3489. lo5 B.A.Pearlman J. Amer. Chem. SOC.,1979,101 6398 6404. Synthetic Methods de Mayo photochemical cyclization to develop a @ -hydroxycarbonyl system which then undergoes retro-aldol fission is outlined in Scheme 37. Me 1iv v OCOMe & fJ Me02C ; ii Ag20 CaSO,; iii hv;iv H2S04 MeOH; v CF,CO,H Reagents &j Scheme 37 0 Synthetic methods based on the Shapiro approach often call for the regeneration of ketones from their arylsulphonylhydrazones. Many reagents have been suggested for this purpose in recent years. The latest ones include hydrogen peroxide- potassium carbonate,lo6 aqueous bromine,'" and aqueous trifluoroacetic acid- sodium nitrite."* The last of these is an additional reagent for the regeneration of aldehydes and ketones from their thioa~etals.'~~ 0-Keto-esters.-Three useful syntheses of @ -keto-esters have been published.The most significant of these from Masamune's group which clearly closely parallels the acylation mechanism operating in the biosynthesis of fatty acids allows @ -keto-esters to be formed under virtually neutral conditions. The acylating agent is an acyl-imidazole which is condensed with the neutral magnesium salt of a malonic half-ester,'" as shown in Scheme 38. A closely related process employs the condensation of an acyl chloride with the dianion from a malonic half-ester and like the first method gives nearly 00 + Mgz+ 0yoR3] __* R'COCHR2C02R3 Scheme 38 lo6 J. Jirieny D.M. Orere and C. B. Reese Synthesis 1978 9L9. lo' G. A. Olah Y. D. Vankov and G. K. S. Prakash Synthesis 1979,113. lo* L.Caglioti F. Gasparrini D. Misiti and G. Palmieri Synthesis 1979 207. G. A. Olah S. C. Narang G. F. Salem and B. G. B. Gupta Synthesis 1979,273. 'lo D. W.Brooks L. D.-L. Lu and S. Masarnune Angew. Chem. Internar. Edn. 1979,18 72. 344 R. Brettle quantitative yields.'" In the third method (a modification of earlier ones) a-diazo- P-hydroxy-esters are converted into P-keto-esters by treatment with a new reagent rhodium(r1) acetate used in catalytic amounts at room temperature; this reagent unlike the earlier ones permits the preparation by this route of y8-olefinic-P-keto- esters.' l2 Olefinic Aldehydes and Ketones.-Corey's triumphant total synthesis of gibberellic acid finally achieved after so many years of work in twenty-five or so laboratories leading to some 150 papers deserves to be intensively studied through the original paper^."^ Here just one step (24)-+(25) i.e.an intramolecular aldol condensation CHO OHC/' leading to an a@-olefink aldehyde will be considered. The reagent used in benzene at 50 "C,was dibenzylammonium trifluoroacetate a crystalline solid which proved to be an outstanding selective reagent for this transformation. It was arrived at by systematic variation of the amine and acid components in the belief that to activate the methylene group adjacent to the less hindered of the two aldehyde groups as an enamine would require a not-too-basic sterically discriminating secondary amine under almost neutral aprotic conditions.Several syntheses of ap-olefinic ketones have appeared. Two of them (see Scheme 39) build the acyl group onto the original carbon skeleton by means of an 2' R isY RY R2 YYi Reagents i R3CHClC02R4 NaH; ii NaOH; iii [Pb(OAc),]; iv heat; v R'CHCISOPh LDA; vi H30+ C1- Scheme 39 111 W. Werenga and H. I. Skulnick J. Org. Chem. 1979,44,310. 112 R. Pellicciari R. Fringuelli P. Ceccherelli and E. Sisani J.C.S. Chem. Comm. 1979 959. 113 E.J. Corey R. L. Danheiser S. Chandrasekaran P. Siret G. E. Keek and J.-L. Gras J. Amer. Chem. Soc. 1978,100,8031;E.J. Corey R. L. Danheiser S. Chandrasekaran G. E. Keck B. Gopalan S. D. Larsen P. Siret and J.-L. Gras ibid. p.8034. Synthetic Methods epo~ide.'~~Another~*~ uses a connective method (Scheme 40) rather than the existing methods based on interchanges of functional groups to prepare phenyl- selenomethyl ketones which can be converted into ap-olefinic ketones by known methods that involve alkylation followed by selenoxide elimination. 0 OH 0 . .. LSePh & LSePh L R&SePh -0-R -H Reagents i PhSeBr EtOH; ii H,O+; iii RMgX H,O+; iv Scheme40 A new approach to ketone synthesis"' is based on the enolonium equivalents (26) and (27),and it can be put into practice through the palladium-catalysed reactions of (26) (27) allylic acetates although special conditions are required because of the presence of the electron-donating alkoxy-substituent.A rather simple application leading to an a@-olefinic y-keto-ester is shown in Scheme 41. OEt RCHO & __* iii Me,CHO,C OAc 9, V k Me,C HO,C Reagents i <OEt ;ii Ac,O C,H,N; iii PhS02CH2C02CHMe2 [Pd(Ph,P),] DBU; iv O.02M-HCI Li THF; v Et,N Scheme 41 Reduction of Mannich base methiodides followed by exchange of the anion gives y -hydroxy-quaternary ammonium hydroxides which on thermolysis fragment to give an olefin and a carbonyl group.'" The procedure can be used to prepare olefinic aldehydes where the better-known base-catalysed fragmentation of 1,3-diol mono- tosylates cannot be used. 'I4 V. Reutrakul S. Nimgirawath S. Panichanum and Y. Srikirin Tetrahedron Letters 1979 1321; D. F. Taber and B. P. Gunn J. Org. Chem.1979,44450. R. Baudat and M. Petrzilka Helv. Chim. Acta 1979,62 1406. B. M. Trost and F. W. Gowland J. Org. Chem.. 1979,44,3448. L. H. F. Tietze G. Kinast and H. C. Uzar Angew. Chem. Znternat. Edn. 1979 18,541. 346 R. Brettle 12 Carboxylic Acids and Derivatives Benzyltrialkylammonium permanganates have been suggested as reagents for the oxidation of aldehydes to carboxylic acids"* or of ethers to ester~,'~ but in view of the extremely hazardous nature of the solid oxidantsg5 (see Section ll) such reagents cannot be recommended here. Two groups have developed related syntheses"' of saturated p -alkyl-substituted carboxylic esters from cup-olefinic aldehydes (Scheme 42). The use of carbonyl OSiR OSiR: I I RICH=CHCHO & R'CH=CH-CHPOX2 ii' jii PR'R3CH-CH= CPOX2 Reagents i RiSiOPX (R2=Me X =OEt or R2 = Et X = NMe,); \tv (ii) LDA; iii R3X; iv H' R40H (for R2=Me X = OEt) or R40-,R40H (for R2 = Et X = NMe,) R'R3CHCH2C02R4 Scheme 42 compounds in the alkylation step gives a route to y-lactones.Another way of achieving the same end is to use a 'sterically protected' ap-olefinic carbonyl compound e.g. (28) or (29) so that 1,4-addition of organometallic reagents occurs. In these cases the addition product can be converted into the p-alkyl-substituted acid by the Haller-Bauer cleavage of the ketone or by hydrolysis coupled with a retro-Mannich cleavage of the amide.12' Dh . ,o In some synthetic sequences protection of a carboxylic acid group is necessary. The success of a synthesis of penem-carboxylic acids by R.B. Woodward depended on the protection of a carboxylic acid as its acetonyl ester. The ester withstood procedures involving trifluoroacetic acid and sodium bicarbonate but it was efficiently cleaved by hydrolysis with a stoicheiometric amount of aqueous sodium hydroxide at 0 OC.121 Methylthiomethyl (MTM) esters can be prepared quan- titatively under very mild Pummerer-like conditions by treating the sodium car- boxylate with the adduct from DMSO and t-butyl bromide,!22 and can be cleaved under basic conditions if required by molybdate-catalysed oxidation to the sul- phone followed by alkaline hydr01ysis.l~~ Activation of acids continues to attract attention. Acyl chlorides can be made at room or lower temperatures without the formation of hydrogen chloride by the D.Scholz Monatsh. 1979,110 1471. D. A. Evans J. M. Takacs and K. M. Hurst,J. Amer. Chem. SOC.,1979,101,371;T. Hata M. Nakajima and M. Sekine Tetrahedron Letters 1979 2047. ''O D. Seebach and R. Locher Angew. Chem. Internat. Edn. 1979,18 957. lZ1 H. R. Pfaendler J. Gosteli and R. B. Woodward J. Amer. Chem. SOC.,1979,101,6306. lZ2 A. Dossena R. Marchelli and G. Casnati J.C.S. Chem. Comm. 1979,370. J. M. Gerdes and L. G. Wade jr. Tetrahedron Letters 1979,689. Synthetic Methods 347 treatment of acidswith the enamine (30).124 Much of the work is directed towards the synthesis of macrolides and a very full account by Mukaiyama of the activation of carboxy-and hydroxy-groups based on the onium salts of aza-arenes has appeared.125 A better method for preparing pyridine-2-thiol carboxylic esters has appeared,'26 but if the 3-cyano-4,6-dimethylpyridinethiolesters now are used they react more rapidly with alcohols and a silver ion catalyst is no longer required.12' t-Butylthiol esters128 and benzeneselenol which are all very powerful acyl-transfer agents have also been investigated. Esterification reactions employing isoureas some of which [e.g. (31),which is an alternative to the use of diazomethane] are commercially available have been reviewed. 130 They avoid the N-acyl-ureas that are persistently formed with carbodi-imides; this drawback can also be overcome whilst still using carbodi-imides if the esterification is carried out in pyridine containing a little toluene-p -sulphonic acid.13' New syntheses of ap-olefinic esters include the use of the Claisen orthoester rearrangement with trimethyl 3-phenylseleno-orthopropionate followed by selenoxide eliminati~n'~~ (Scheme 43)and the reaction of primary cuprates with the enol-phosphates of P-keto-e~ters,'~~ an example of which is given in Scheme 44.A PhSesR. C02Me 4 JRl C0,Me HOd R 2 \ \ R2 R2 Reagents i PhSeCH,CH,C(OMe),; ii Me3CC02H 170 "C; iii H202 Scheme 43 0 I Reagents i NaH; ii CIPO(OEt),; iii LiMe,Cu Scheme 44 A. Devos J. Remion A.-M. Frisque-Hesbian A. Colens and L. Ghosez J.C.S. Chem. Comm. 1979 1180. T. Mukaiyama Angew. Chem. Znternat. Edn. 1979 18,707. E. J. Corey and D. A. Clark Tetrahedron Letters 1979 2875.lZ7 U. Schmidt and D. Heermann Angew. Chem. Internat. Edn. 1979,18 308. D. N. Harpp T. Aida and T. H. Chan Tetrahedron Letters 1979 2853. 129 T. G. Back and S. Collins Tetruhedrm Letters 1979,2661. I3O L. J. Mathias Synthesis 1979 561. K. Holmberg and B. Hansen Acta Chem. Scand. (B), 1979,33,410. 132 S.Raucher K.-J. Hwang and J. E. Macdonald Tetrahedron Letters 1979 3057. F. W. Sum and L. Weiler Canad. J. Chem. 1979,57 1431; F. W. Sum and L. Weiler J. Amer. Chem. SOC.,1979,101,4401. 348 R. Brettle new connective synthesis of ap-olefinic acids is illustrated in Scheme 45.'34 It is notable for amongst other things the use of a t-butyl ketone as a masked carboxylic acid the acid finally being generated from the cyanide which results from the Beckmann type-I1 cleavage of the ketoxime.yoTo i-iii HO H A Mew H O 1v-vii H Reagents i KH 25 "C; ii Bu'Li at -78 "C; iii H. ,0 "C; iv MeONa 4 days; v NH,OH; vi PCl,; P vii KOH H,O (HOCH,), 150"C; viii 2 equiv. LDA quench Scheme 45 0 Me Si RKH rLSiMe Rd N\ M e 2 liii 0 0 R d o E t R d N M e 2 Reagents i Me,Si H ; ii (MeO),CMeNMe, 80°C; iii HF -75 to -20°C; iv Et,O' BF,-; H Li V KzC03 HZO Scheme 46 SMe MeS Me C0,Et Reagents i LDA; ii RCHO; iii Raney nickel W-2; iv 2.1 equiv. K' Bu'O-; v NH,,CI H,O Scheme 47 The Claisen amide acetal rearrangement as applied to 3-(trimethylsily1)allyl alcohols which can be prepared from aldehydes and trimethylsilylvinyl-lithium provides a route to the @)-forms of py-olefinic amides and esters (Scheme 46).13' A method for the stereospecific synthesis of the type of a-methyl-substituted dienoic acid fragment present in rifamycin has been des~ribed,"~ and is illustrated in Scheme 47.134 D. Seebach and M. Pohmakotr Helv. Chim. Acta 1979,62,843. 13' P. R. Jenkins R. Gut H. Wetter and A. Eschenmoser Helv. Chim. Acta 1979,62 1922. 13' E. J. Corey and G. Schmidt Tetrahedron Letters 1979,2317. Synthetic Methods Lactones.-The synthesis and the synthetic uses of halogeno-lactones particularly their reduction to the halogen-free lactones and their dehydrohalogenation to olefinic lactones have been re~iewed.'~' N-Bromosuccinimide in completely dry dimethyl sulphoxide oxidizes cyclic enol ethers e.g. (32),to a-brorno-la~tones.~~~ Benzeneseleninic anhydride is an efficient reagent for the cup-dehydrogenation of lactones but is inefficient with acyclic A new butenolide ~ynthesis'~~ uses the condensation of an aldehyde or ketone with a metallated p -bromo-acrylamide and is of some generality since p -bromo-acraldehydes are readily available from ketones through the Vilsmeier reaction.The overall sequence is shown in Scheme 48. Another route to butenol- ides,14' based on known reactions not hitherto linked together to achieve this result starts from y-iodoallyl alcohols; the carbonyl group is introduced by a palladium- catalysed carbonylation under mild conditions. 0"O-v,vi & 0 Reagents i Me,k=CHBr Br-; ii Ag,O; iii SOCI,; iv Me,NH; v 2.1 equiv.Bu'Li; vi R'R'CO Scheme 48 Remarkable though not unexpected stereospecificity is displayed in the ferric- chloride-induced cyclization of the ethylenetricarboxylate (33) which gives the single stereoisomer (34). Compound (33) decomposed at temperatures where acyclic allylic dimethyl ethylenetricarboxylates undergo the thermal ene reaction to give p -alkenyl-la~tones.'~~ .H H Me02C -0 I c1S h H Me02C 13' M. D. Dowle and D. I. Davies Chem. Soc. Rev. 1979,8 171. 13' W. F. Berkowitz I. Sasson P. S. Sampathkumar J. Hrabe S. Choudhry and D. Pierce Terrahedron Lerrers 1979 1641. 13' D. H. R. Barton R. A. H. F. Hui D. J. Lester and S. V. Ley Tetrahedron Lerrers 1979,3331. W. R. Baker and R. M. Coates J. Org. Chem. 1979,44 1022. 14' A.Cowell and J. K. Stille Tetrahedron Letters 1979 133. 14' B. B. Snider and D. M. Roush 3. Org. Chem. 1979,44,4229. 350 R. Brettle A new a -methylenelactone synthesis related to Eschenmoser's chloro-nitrone route [see Ann. Reports (B) 1973 70,6881 has appeared.'43 The new method is illustrated in Scheme 49. Earlier work on phenylselenolactonization has been published in full,144 and it has been shown that the procedure can be extended to the formation of phenylselenyl-substituted macrolides (Scheme 50) if the phenyl- selenation is carried out with N-phenylseleno-phthalimide or -succinimide; the preparation of these reagents is de~cribed.'~~ -O*&/CY 0,2+ /CY . ( iii iv :v N i ii H. 0 /CY 0 H' CN OSiMe CH,OSiMe 1".vi cY= H ~ Ht vii viii 0 ,CY :vcN R H' H' CH2 CH,OMs RR Reagents i CF,SO,SiMe, at -78 "C; ii warm to -30°C; iii )=( ;iv KCN; v 2M-HCI MeOH HH CH,CI,; vi MeSO,Cl C,H,N; vii K' Bu'O-; viii H,SO Scheme 49 f=OH + diolides 0 Yields (n = 11 or 13) 50% 15'/o 10% Scheme 50 Several other routes to macrolides have been investigated.The intramolecular cyclization of an o-hydroxy-acid can be brought about by activating the acid group as its mixed anhydride with 2,4,6-trichlorobenzoic acid and then adding the hydroxy-anhydride very slowly to refluxing benzene containing 4-dimethylamino- M. Riediker and W. Graf Helv. Chim. Acta 1979,62 205 1586. K. C. Nicolaou S. P. Seitz W. J. Sipic and J. F. Bount J. Amer. Chem. SOC.,1979,101 3884. K.C. Nicolaou D. A. Claremon W. E. Barnette and S. P. Seitz. J.Amer. Chem. SOC.,1979,101,3704. Synthetic Methods 351 0 (35) (36) ~yridine.'~~ The cyclization of (35) to (36) was achieved by this method in 46% yield. In macrolide syntheses based on ring closure at the site of the ester function it has normally been the acyl-oxygen bond which has been formed as in this case. A new procedure14' is based on the formation of the alkyl-oxygen bond. Caesium salts of w-iodo-acids cyclize at 40°C in DMF,without the use of high-dilution or slow-addition techniques the reaction was successful with a secondary iodo-acid. Two groups have looked at the use of intramolecular keto-phosphonate cyclizations in macrolide The method is particularly useful for the construction of trans-ap-olefinic macrolides using phosphonate esters (Scheme 5 l),although in 0 60-7 0Yo Reagents i Li' Pr'O- 1% HMPT THF high-dilution conditions Scheme 51 some cases both geometries at the double bond are formed.Eschenmoser has used a decarboxylative double fragmentation to generate a doubly unsaturated macrolide (37) in very high ~ie1d.l~' (37) 146 J. Inanaga K. Hirata H. Saeki T. Katsuki and M. Yamaguchi Bull. Chem. SOC.Japan 1979,52,1989; J. Inanaga T. Katsuki S. Takimoto S. Ouchida K. Inoue A. Nakano N. Okukado and M. Yamaguchi Chem. Letters 1979 1021. 14' W.H. Kruitzinga and R. M. Kellogg J.C.S. Chem. Comm. 1979,285. 14' G.Stork and E. Nakamura J. Org. Chem. 1979,44,4010; K. C. Nicolaou S. P. Switz M. R. Pavia and N.A. Petasis J. Org. Chem. 1979 44,4011. 149 D. Sternbach M. Shibuya F. Jaisli M. Bonett and A. Eschenmoser Angew. Chem. Internat. Edn. 1979 18 634. E. J. Corey and H. L. Pearce J. Amer. Chem. SOC.,1979,101,5841. 352 R. Brettle Corey’s total synthesis of picrotoxin used lead tetra-acetate to bring about the unusual bis-lactonization (38) +(39) in almost quantitative yield the scope and mechanism of this reaction are under investigation. 150 “OCOPh C02H oTo (38) (39) 13 Alkylation There has been a lot of interest in the reactions of trimethylsilyl enol ethers and in methods for their preparation. Several useful modifications to the standard methods for the preparation of kinetically controlled enol ethers have been published.15’ Surprisingly it has been found that treatment of an aldehyde ketone or enone with trimethylsilyl iodide (for which a convenient new synthesis has appeared15*) and hexamethyldisilazane at room temperature or below in tetrachloromethane leads to the thermodynamic equilibrium mixture of silyl enol ethers within a few Other good routes to silyl enol ethers include the rearrangement of ally1 and silyl ethers with dihydrotetrakis(tripheny1phosphine)rutheni~m~~~ several routes from acyl-trimethylsilanes which are regiospecific and in one case stereoselective as well’55 (Scheme 52). The conversion of alkenes into enol silyl OH I R’COSiMe -&R’-CJ 3 I SiMe Reagents i PhS0,CHLiMe; ii LDA; iii PhS0,SPh; iv EtLi; v H,C=CHMgBr; vi. BuLi; vii R2X Scheme 52 ethers e.g.(40) by means of hydrosilanes and carbon monoxide is covered by a review.lS6 0-MeEt2SiH CO TSiEt’.”’ I. Fleming and I. Paterson Synthesis 1979 736; H. Vorbriiggen and K. Krolikiewicz ibid. p. 34. lS2 H. Sakurai A. Shirahata K. Sasaki and A. Hosomi Synthesis 1979,740. R. D. Miller and D. R. McKean Synthesis 1979 730. Is* H. Suzuki Y. Koyama Y. Moro-oka and T. Ikawa Tetrahedron Letters 1979 1415. Is’ H. J. Reich J. J. Rusek and R. E. Olson J. Amer. Chem. SOC.,1979 101 2225; I. Kuwajima and M. Kato J.C.S. Chem. Comm. 1979,708. S. Murai and N. Sonoda Angew. Chem. Internat. Edn. 1979,18,837. Synthetic Methods 353 Silyl enol ethers do not react with alkyl halides in the absence of a catalyst but they do react with a variety of halides in the presence of Lewis-acid catalysts e.g.titanium and tin tetrachlorides and zinc bromide. The reactions succeed with the enol ethers of ketones aldehydes and esters provided that the appropriate Lewis-acid catalyst is selected. Phenylthioalkylation followed by desulphurization with Raney nickel or sulphoxide elimination then leads to the alkylated and alkylidenated products respectively,lS7 The use of 1-chloro-l-phenylthio-2,2-dimethylpropaneallows a neopentyl group to be introduced. The choice of kinetic or thermodynamic enol ethers permits regiospecific substitution and the dienol ethers usually lead to a high proportion of the y-alkylated products. In a similar way the use of phenylsulphenyl chloride converts an crp -olefink ketone into the y-phenylthio-derivative and elimination of sulphoxide then leads to the conjugated dienone.lS8 Alkylation with certain alkyl halides has been reported; cation rearrangement does not occur. 15' With 2-halogeno-propanes elimination takes place but isopropylation is still possible using a ferric-chloride-catalysed reaction with 2,2-bis(ethylthio)propane followed by desulpfiurization. Both enol silyl ethers and enol acetates react with methoxymethyl chloride in the presence of active zinc catalysts!60 The bis-silyl ether (41) a protected form of methyl acetoacetate similarly reacts with the cyclic bis-acetal (42)to give the bicyclic product (43).161One enol derivative that does OMe Me,SiO + foMe TiCI, &:2Me OSiMe OMe (41) (43) undergo an uncatalysed reaction with alkyl halides is the potassium enoxytriethyl- borate (see Scheme 53).16* I Reagents i KH; ii Et,B; iii RX s25 "C Scheme 53 There has been further interest in the synthetic applications of keten thioacetals.There are advantages in the use of open-chain thioacetals and these can be prepared 157 I. Paterson and I. Fleming Tetrahedron Letters 1979 993 995 and 2179; I. Fleming J. Goldhill and I. Paterson ibid. p. 3209. lS8 I. Fleming J. Goldhill and I. Paterson Tetrahedron Letters 1979 3205. 159 M. T. Reetz S. Hiittenhain P. Walz and U. Liiwe Tetrahedron Letters 1979 4971; M. T. Reetz I. Chatziiosifidis U. Lijwe and W. K. Maier ibid. p. 1427; I. Paterson ibid. 1979 1519. 160 T. Shono I. Nishiguchi T.Komamura and M. Sasaki J. Amer. Chem. SOC.,1979,101,984. P. Brownbridge and T.-H. Chan Tetrahedron Letters 1979 4437; T.-H. Chan and P. Brownbridge J.C.S. Chem. Comm. 1979,578. E.-I. Negishi M. J. Idacavage F. DiPasquale and A. Silveira jr. Tetrahedron Letters 1979 845. 354 R. Brettle by heating carboxylic acids or esters with aluminium thi~phenoxide,'~~ from alde- hydes and ketones by reaction with the lithium derivatives of cyclic esters of bis(pheny1thio)methaneboronic and by the reaction of dimethyl disulphide with lithio-NN-dimethyl-3-(phenylthio)-prop-2-enylamine, which gives a keten thioacetal containing a basic In the last reaction metallation (and hence electrophilic attack) occurs at the sp2 carbon atom next to sulphur (Scheme 54) whereas the related phenylthio-substituted allylic ethers and thioethers undergo metallation at the sp3 carbon atom to give allylic carbanions.PhSANMe2 PhS =phs* Li--*NMe -E)7,NMe2 Scheme 54 New methods for the preparation of cyclic keten thioacetals derived from 1,3-dithian include a route from thioamides'66 and a dehydrogenation of 2-alkyl- 1,3-dithian~.'~~Keten thioacetals on reductive lithiation with lithium naphthalenide at -70 "C,give metallated vinyl sulphides (44) known to be useful acyl-anion equivalents which now become readily available from acids and esters. 16* Keten thioacetals (45) can be deprotonated and the anions will then add to SPh / R 'R2C=C Li (44) 0 0 Product ratio 71 parts 20 parts in presence of CuI and (Me0)3P 2 Parts 98 parts cup-olefinic ketones.16' Most of the addition occurs in a conjugate manner and the regiospecificity with respect to the ally1 anion can be largely controlled by the reaction conditions.T. Cohen R. E. Gapinski and R. R. Hutchins J. Org. Chem. 1979,44,3598. A. Mendoza and D. S. Matten J. Org Chem. 1979,44 1352. 165 J. J. Fitt and H. W. Gschwend J. Org. Chem. 1979,44 303. 166 T. Harada Y. Tamaru and Z. Yoshida Tetrahedron Letters. 1979,3525. 167 Y. Nagao K. Seno and E. Fujita Tetrahedron Letters 1979,4403. T. Cohen and R. B. Weisenfeld J. Org. Chem. 1979,44 3601. 169 F. E. Ziegler and C. C. Tam Tetrahedron Letters 1979,4717. Synthetic Methods Conjugate addition of the anions from saturated thioacetals to a@ -olefink ketones takes place provided that hexamethylphosphoric triamide is pre~ent.’~’ The con- jugated thioacetal(46) can be prepared as shown in Scheme 55.Alkylation of the derived anion gives a thioacetal which on hydrolysis gives a conjugated dienone.”l OH TsOH P s,hwSMe 5phw SR ’ SR ’ R2 Reagents i KH; ii Bu’Li; iii Ph2CO; iv MeI; v LDA HMPT; vi R2X; vii MeI H20 THF MeCN CaCO Scheme 55 Many other anion equivalents have been prepared and their reactions with electrophiles studied; several have already been described in earlier sections of this Report. Two further representative examples will be discussed here. The acyl-anion equivalent lithi0-4~4-dimethyl- 173-oxathiolan S,S-dioxide (47) reacts with many electrophiles. Pyrolysis of the alkylated material gives an aldehyde and the only other products are ga~eous.”~ A homoenolate ion equivalent is produced by the deprotonation of the phosphonamide derivative (48) which is readily prepared from the cup-olefinic aldehyde.A simple example’73 of the use of this reagent is shown in Scheme 56. (48) Reagents i Et,SiOP(NMe2)2; ii BuLi; iii R2X; iv MeOH MeO- Na’ Scheme 56 Shono has developed his reaction involving the conjugate addition of an organo- metallic reagent to an active olefin with trapping of the intermediate by a carbonyl C. A. Brown and A. Yamamaichi J.C.S. Chem. Comm. 1979 100; J. Lucchetti W. Dumont and A. Krief Tetrahedron Letters 1979 2695. M. Pohmakotr and D. Seebach Tetrahedron Letters 1979,2271. G. W.Gokel H.M. Gerdes D. E. Miles J. M. Hufnal and G. A. Zerby Tetrahedron Letters 1979,3375. 173 D. A. Evans J. M. Takacs and K. M. Hunt J. Amer. Chern. Soc. 1979 101,371. 356 R. Brettle compound by substituting (pheny1thio)magnesium iodide for the organometallic reagent as in the example shown in Scheme 57.174 The presence of a phenylthio- group in the products adds to their utility as synthetic intermediates. The generation of alkenyl-lithiums from alkyl methyl ketone aryl-sulphonylhydrazones described previously [cf. Ann. Reports (B) 1978 75 1851 normally gave predominantly an alk-l-enyl-lithium. A variation has now made it possible to generate the (Z)-alk-2-enyl-lithium which reacts with electrophiles in the normal way with retention of the geometry of the 01efin.l~’ 14 Ring Synthesis Considerable ingenuity has been displayed in devising routes to cycloalkenyl vinyl ketones (49) which can be cyclized by the Nazarov cyclization thus providing three-carbon annelation procedures.Two groups have developed complementary routes based on the reaction between a vinylsilane and an cup -olefink acyl chloride making use of the stabilization of a cation by an adjacent trimethylsilyl (This chemistry and much more besides is covered in a review of the applications of the electrophilic substitution of organic silicon compounds in synthesis. 177) Another route uses a protected cyanhydrin as an cup-olefinic acyl-anion equivalent which reacts with a ketone to give a product that can be converted by dehydration into the requisite cross-conjugated dienone,l7* and a further route (Scheme 58) is based on a ?* Scheme 58 174 T.Shono Y.Matsumura S.Kashimura and K. Hatanaka J. Amer. Chem. SOC.,1979,101,4752. 17’ A. R.Chamberlin and F. T. Bond Synthesis 1979,44. 176 F. Cooke J. Schwindeman and P. Magnus Tetrahedron Letters 1979,1995; W.E. Fristad D. S.Dime T. R. Bailey and L. A. Paquette ibid. p. 1999. 177 T. H. Chan and I. Fleming Synthesis 1979 761. ‘78 R. M. Jacobson and G. P. Lahm J. Org. Chem. 1979,44,462. Synthetic Methods 357 little-known reaction of a,a'-dihydro~y-acetylenes.'~~ Another route (Scheme 59) that is based on the acylation of a silane,lSo in this case a trimethylsilyl-alkyne also leads to cyclopentenones though not by a Nazarov cyclization.&cl + ii 0 0 / Reagents i Me,SiC=CMe; ii 650 OC Scheme 59 Other noteworthy syntheses of cyclopentenones have appeared during the year; attention has already been drawn to an example of a regiospecific intramolecular aldol condensation [(24) -B (25)]. Pentannelations based on intramolecular Horner- EmmonslS1 and Wittig"* reactions used respectively the phosphonate (50) and the OEt 0 0 Ph II BrCH ,C I =CHP(OMe) Br& PLPh '\ Ph (50) (51) ylide (51) as three-carbon units to alkylate ketone enolates. Two other cyclo- pentenone ~yntheses'~~*~~~ are illustrated in Schemes 60 and 61;the formerlS3 occurs under very mild conditions. eLo OSiMe Reagent i Pd(OAc), 20 OC Scheme 60 S< i-iii ;ii @CO,Me; iii NH,Cl H,O; iv HCl HzO,THF; v Me,SiI Scheme 61 179 T.Hiyama M. Shinoda and H. Nozaki J. Amer. Chem. SOC.,1979,101 1599. M. Karpf and A. S. Dreiding Helu. Chim. Acta 1979,62 852. lS1 E. Piers B. Abeysekera and J. R. Scheffer Tetrahedron Letters 1979 3279. J.-J. Altenbach Angew. Chem. Intemat. Edn. 1979,18,940. Y. Ito H. Aoyama T. Hirao A. Mochizuki and T. Saegusa J. Amer. Chem. SOC. 1979,101,494. J. P. Marino and L. C. Katterman J.C.S. Chem. Comm. 1979,946. 358 R. Brettle An interesting cyclopentanone employed Stetter's thiazolium reagent to bring about the intramolecular Michael condensation of an aldehyde converted in situ into an acyl-anion equivalent with an ap-olefinic ester (Scheme 62) and a Me Reagents i "'Xi' I- Et,N (excess) refluxing Me,CHOH HOCH2CH2 Scheme 62 synthesis'86of methylenecyclopentanes used the palladium-catalysed condensation of (2-acetoxymethylally1)trimethylsilane(52) with alkenes carrying one or two electron-withdrawing groups.The (E)-alkenes gave the trans-products but with the (2)-alkenes there was substantial crossover. Pd" -Me Si &OAc + i Yn Cyclopentenes can be prepared by the palladium-catalysed cyclization of 1,6-dienes that are substituted by electron-withdrawing substituents at the 4-p0sition,'~' and the reaction of cyanide ion with ap-olefinic esters gives alkyl cyano- cyclopentanonecarboxylates e.g. (53).188A double condensation is shown. Cyano-cycloalkanones also result from the cyclization of w-cyano-amides a reaction which has advantages over the Thorpe-Ziegler am-dicyanide cyclization because the regiospecificity is controlled in unsymmetrically substituted systems.lg9 Two aspects of the stereochemistry of formation of five-membered rings have been investigated. Cyclization of $3-olefinic aldehydes (54) to cyclopentanones is lS5 B. M. Trost C. D. Shiney F. DiNinno jr. and S. M. McElvain J. Amer. Chem. SOC.,1979,101,1284. lS6 B. M. Trost and D. M. T. Chan J. Amer. Chem. SOC.,1979,101,6429. R. Grigg T. R. B. Mitchell and A. Ramasubba J.C.S. Chem. Comm. 1979,669. 188 H. Stetter and H. Kuhlmann Annalen 1979 303 944 and 1122. M. Larcheveque and P. Mulot Canad. J. Chem. 1979,57 17. Synthetic Methods stereo~pecific,’~~ and ring-closure of (55) by an ScN’ process leads to transfer of chirality in the sense shown with an anti relationship between the incoming and departing group^.'^' (55) EtO A new ring-closure reaction (Scheme 63) depends on participation by a phenyl- selenyl group and at the same time gains by the synthetic potential offered by a phenylselenyl group in the a aoAc CF3C02H PhSe PhSe OAc OH Scheme 63 The synthesis of five- and seven-membered rings by the reaction of polybromo- ketones with iron carbonyl has been reviewed193 and also used intramolecularly in a terpene synthesis which converts geraniol into camphor dihydrocarvone and other minor The use of disodium tetracarbonylferrate to cyclize a pent-4-enyl tosylate to a cyclohexanone (e.g.Scheme 64) has now been used intramolec- ularly in a total synthesis of aphidic01in.l~~ {y& (6 H H ,Na,[Fe(CO),] 50 “C Scbeme 64 R.C. Cookson and S. A. Smith J.C.S. Chem. Comm. 1979,145. 19’ G. Stork and A. R. Schoofs J. Amer. Chem. SOC.,1979 101 5081. 19* T. Kametani K. Suzuki H. Kurobe and H. Nemoto J.C.S. Chem. Cumm. 1979 1128. 19’ R. Noyari Acc. Chem. Res. 1979,12,61. 194 R. Noyari M. Nishizawa F. Shimizu Y. Hayakawa K. Maruoka S. Hashimoto H. Yamamoto and H. Hozaki J. Amer. Chem. Soc. 1979,101 220. 19’ J. E. McMurry A. Andrus G. M. Ksander J. H. Musser and M. A. Johnson J. Amer. Chem. SOC.,1979 101,1330. 360 R.Brettle Some of the finest examples of the use of the classical intermolecular Diels-Alder reaction are from the work of Danishefsky using methoxy- and trimethylsilyloxy- substituted dienes.The work which culminated in elegant syntheses of griseofulvin disodium prephenate and pentolenolactone has now been published in full. 196 New examples of the intramolecular Diels-Alder reaction in which two rings are formed simultaneously continue to appear. One was used in Corey's total synthesis of gibberellic acid113 and another provides an efficient entry into the galanthan alkaloid series.lg7 cis-Decalones can also be obtained from acyclic precursors through this type of reaction,19* as shown in Scheme 65. H A" Reagents i MeSO,CI Et,N Scheme 65 Pattenden and Oppolzer have continued to explore the synthetic uses of the intramolecular De Mayo reaction using 2-(alk-4-enyl)-1,3-dione enol acetates.'99 Some very short syntheses of otherwise hardly accessible polycyclic ring systems have been achieved but the outcome of any one reaction cannot yet be predicted; some are not regioselective or take unexpected courses and in some cases the photo-Fries rearrangement intrudes.Another related [2 +21 intramolecular photocyclization (Scheme 66)is notable for giving a single stereoisomer and that in a Scbeme 66 molecule with three contiguous quaternary centres.200 A further reaction which is more effective in the intramolecular mode is diyl trapping.201 The very high 196 S. Danishefsky T. Kitahara C. F. Yan and J. Morris J. Amer. Chem. SOC. 1979 101 6996; S. Danishefsky C. F. Yan R. K. Singh R. B. Gammill P. McCurry N. Fritsch and C. J. Clardy ibid.p. 7001;S. Danishefsky T.Harayama and R. K.Singh ibid. p. 7008;S. Danishefsky M.Hirama N. Fritsch and C. J. Clardy ibid.,p. 7013;S. Danishefsky and F. J. Walker ibid. p. 7018;S. Danishefsky, M. Hirama K. Gombatz T. Harayama E. Berman and P. F. Schuda ibid. p. 7020. D. J. Morgans jr. and G. Stork Tetrahedron Letters 1979 1959. J.-L.Gras and M. Bertrand Tetrahedron Letters 1979 4549. 199 M. J. Begley M. Mellor and G. Pattenden J.C.S. Chem. Comm. 1979,235;W.Oppolzer and T. G. C. Bird Helv. Chim. Acta 1979,62 1199. ,O0 M. C. Pirrung J. Amer. Chem. SOC., 1979,101,7130. R.D. Little and G. W. Muller J. Amer. Chem. SOC.,1979,101 7129. 19' 19' Synthetic Methods stereoselectivityobserved (Scheme 67)was rationalized in terms of bonding inter-actions of secondary orbitals.MeCN - reflux N Scbeme 67 Finally Robinson's famoustropinone synthesis 62 years on has been applied in a spectacularsynthesisof the ladybird defence alkaloids (Scheme 68) in a reaction that creates three rings and five chiral centres at one time in an aqueous buffer and from which a single stereoisomer crystallized out.202 CO,Me MeOiC Scbeme 68 '"R. V. Stevens and A. W. M. Lee J. Amer. Chem. SOC., 1979,101,7032.

ISSN:0069-3030    

DOI:10.1039/OC9797600323

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

16 Biological Chemistry Part (i) Terpenoids and Steroids By J. R.HANSON School of Molecular Sciences University of Sussex Brighton BN1 9QJ 1 Introduction The terpenoids and steroids were last reviewed in these Reports in 1973l“ and 197S1’ respectively. However rather than attempt to cover the intervening years in the limited space available attention has been concentrated on the past two years with the omission of biosynthesis which was covered last year.“ For detailed reviews the reader is referred to the Specialist Periodical Reports on ‘Terpenoids and Steroids’2 and to the relevant chapters in the companion volume on ‘Bio~ynthesis’.~ The advent of high-field ‘H n.m.r. spectroscopy and the widespread use of 13C n.m.r. in structural elucidation have made a significant impact on the number and variety of known terpenoids.Some useful reviews of the I3Cdata have a~peared.~ An increasing number of structures without a heavy atom have been elucidated by X-ray analysis. 2 Monoterpenoids Amongst the many novel terpenoids which have been isolated from marine organisms are a number of halogenated monoterpenoids exemplified by chondrocolactone (l).5The number of known highly oxygenated iridoids has continued to grow and these now include the S-methylthiocarbonate paedorside (2)6and xylomollin (3).’ The latter has a relatively unusual trans-fused ring junction. Amongst the new irregular monoterpenoids are the epimeric santolinyl lactones the santolinolides (4) which were isolated’ from Artemisiu tridentutu.Many monoterpenoids play an important role as insect pheromones.’ Con-sequently attention has been directed not only at their identification but also at their (a)B. A. Marples Ann. Reports (B),1973,70,549; (b)D. N. Kirk ibid. 1975,72,366;(c)J. R. Hanson ibid. 1978 75 329. ’ ‘Terpenoids and Steroids,’ ed. J. R. Hanson (Specialist Periodical Reports) The Chemical Society London 1979 Vol. 9 and preceding volumes. ‘Biosynthesis,’ ed. J. D. Bu’Lock (Specialist Periodical Reports) The Chemical Society London 1977 Vol. 5 and preceding volumes. F. W. Wehrli and T. Nishida Fortschr. Chem. org. Naturstoffe,1978 36 1; W. B. Smith Ann. Rep. N.M.R. Spectroscopy 1978,8 199. F. X. Woolard R. E. Moore D. van Engen and J. Clardy Tetrahedron Letters 1978,2367.‘G. J. Kapadia Y. N. Shukla A. K. Bose H. Fujiwara and H. A. Lloyd Tetrahedron Letters 1979,1937. ’M. Nakane C. R. Hutchinson D. van Engen and J. Clardy J. Amer. Chem. SOC. 1978,100,7079. W. W. Epstein and L. A. Gaudioso J. Org. Chem. 1979 44,3113. For a recent review see J. M. Brand J. C. Young and R. M. Silverstein Fortschr. Chem. org. Naturstofe 1979,37. 1; see also R. Baker and D. A. Evans Ann. Reports (B),1977,74 367. 364 J. R. Hanson synthesis. Ipsenol(5) and ipsdienol(6) aggregation pheromones of the bark beetle Ips confusus have been the subject of several syntheses." The use of methyl- cyclobutene (7) as an isoprene equivalent figured" in one such synthesis. The unusual ether lineatin (8) a pheromone of the beetle Trypodendron lineaturn which attacks the Douglas fir has also been synthesized.'* The success of the pyrethroids as insecticide^'^ has stimulated a number of syntheses of chrysanthemic acid (9).14 C0,Me og)ooMe ' OH (3) d v C0,H Monoterpenoids have provided the basis for a number of reagents employed for asymmetric induction in synthesis.Thus improvements have been described" in the preparation of mono- and di-isopinocamphenylborane which are useful reagents for hydroboronation-oxidation whilst some terpene alkanolamines e.g. (lo) have been recomrnendedl6 for the asymmetric synthesis of 2-substituted aldehydes by alkylation of the corresponding metallo-enamines. The enantiomeric purity of C-2 chiral aldehydes has been determined," using the position of the 'H n.m.r.signal of the aldimine proton in their condensation products with 2-amino- 1-methoxymenth-M.Bertrand and J. Viala Tetrahedron Letters 1978 2575; A. Hosomi M. Saito and A. Sakurai ibid. 1979,429; K. Mori,T. Takigawa and T. Matsuo Tetrahedron 1979,35,933. l1 S. R.Wilson L. R. Phillips and K. J. Natalie J. Amer. Chem. SOC.,1979,101 3340. K. Mori and M.Sasaki Tetrahedron Letters 1979 1329. I3 For a recent review see M.Elliott and N. F. James Chem. SOC.Rev. 1978,7,473. l4 See for example M. J. De Vos,J. N. Denis and A. Krief Tetrahedron Letters 1978,1847; M. J. De Vos and A. Krief ibid. 1979 1511 1515 and 1891. Is H. C. Brown J:R. Schwier andB. Singaram,J. Org. Chem. 1978,43,4395; A. Pelter D. J. Ryder J. H. Sheppard C. Subrahmanyam H.C. Brown and A. K. Mandal Tetrahedron Letters 1979,4777. l6 A. I. Meyers Z. Brich G. W. Erickson and S. G. Traynor J.C.S. Chem. Comm. 1979 566. A. I. Meyers and Z. Brich J.C.S. Chem. Comm. 1979 567. Biological Chemistry -Part (i) Terpenoids and Steroids 8-enes. Monoterpenoid ketones have been used'* in the synthesis of optically active a-deuterio-ketones in which the optical activity of the final product arises solely from the centre bearing deuterium. A useful review of X-ray structure analyses of monoterpenoids has appeared. l9 Monoterpenoids often provide suitable model substrates for examining the scope of novel reactions. Thus a 1,2-carbonyl transposition based on the epoxidation of enol silyl ethers reduction with lithium aluminium hydride and oxidation with chromic acid has been examined2' with menthone.The formation of allylic alcohols by the reduction2' of a/3-unsaturated ketones with sodium borohydride-cerium(I11) chloride and the cis-hydroxylation of alkenes using tetraethylammonium acetate and t-butyl peroxide in acetone catalysed by osmium tetroxide,22 are useful pro- cedures which have been examined in the monoterpene series. Further studies have been on the hydrolysis of geranyl chloride phosphate and pyrophosphate which give acyclic primary and tertiary substitution products whilst neryl derivatives give with participation cyclization products. Biomimetic cyclizations of geraniol and nerol in aqueous citric acid24 and under more vigorous acidic conditions (85'/o phosphoric acid)2' have also been described.The syn -addition of DC1 to the less-hindered face of a-and /3-pinenes (11) has been demonstrated,26 using a combination of 13C and 2Hn.m.r. spectroscopy. The initial tertiary chloride that is formed rapidly isomerizes to bornyl chloride (12). The mechanism of the acid-catalysed opening of the cyclopropane ring of the thujols (13) to form a methylcyclopentenium ion (14) in FS03H-SbF5-S02 at -80 "Chas been studied by deuterium labelling.27 +A c1 boH ** S. G. Levine and B. Gopalakrishnan Tetrahedron Letters 1979,699. l9 R. B. Yeats in ref. 2p. 5. 2o W. A. Fristad T. R. Bailey and L. A. Paquette J. Org. Chem. 1978,43 1620. 21 J.-L. Luche L. Rodriguez-Hahn and P. CrabbC J.C.S. Chem. Comm. 1978,601. 22 K. Akashi R.E. Palermo and K. B. Sharpless J. Org. Chem. 1978,43 2063. " C. A.Bunton 0.Cori D. Hachey and J.-P. Leresche J. Org. Chem. 1979,44,3238. 24 D.L.Baxter W. A. Laurie and D. McHale Tetrahedron 1978,34,2195. 25 J. P. McCormick and D. L. Barton Tetrahedron 1978,34,325. 26 E.F.Weigand and H. J. Schneider Chem. Ber. 1979,112 3031. 27 J. C. Rees and D. Whittaker J.C.S. Chem. Comm. 1978 1096. 366 J. R. Hanson 3 Sesquiterpenoids The number of known sesquiterpenoids has continued to increase rapidly partly as a result of an extensive phytochemical survey of the Compositae as a whole” and of species of Eupatorium Helenium and related genera in particular in the search for tumour-inhibitory substances. The sesquiterpenoid lactones isolated from the genus Artemisia have been re~iewed,’~ whilst a lengthy survey of the sesquiterpenoid lactones isolated from both plants and fungi has a~peared.~’ Typical of the lactones are esters of the germacranolide (15)31 and the guaianolide mikanocryptin (16),the X-ray analysis of which has been rep~rted.~’ Novel microbial metabolites include pentalenolactone G (17) isolated from a Strept~mycete,~~ and a carotane aspterric acid (18) from an Aspergillus species.Marine organisms have yielded a number of unusual sesquiterpenoids such as spirodysin (19)35 and the iodinated compounds (20) and (21).36 The X-ray analysis of the sulphide (22),obtained from mint has been de~cribed.~’ The liverwort Plagiochila semidecurrens contains3’ some 2,3-seco-alloaromadendranes such as (23) (ovalifoliene) whilst (-)-bicyclo-humulenone (24) has been isolated3’ from another Plagiochila species.QH HO 0 HO 0 (19) 28 ‘Biology and Chemistry of the Compositae’ ed. V. V. Heywood J. B. Harborne and B. L. Turner Academic Press London 1977;for Part 231of an extensive survey of the Compositae see F. Bohlmann C. Zdero H. Robinson and R. M. King Phytochemistry 1979,18 1993 and refs therein. 29 R. G. Kelsey and F. Shafizadeh Phytochemistry 1979,18 1591. ’O M. H. Fischer E. J. Olivier and H. D. Fischer Fortschr. Chem. org. Naturstofe 1979,38,47. W. Herz R. de Groote R. Murari N. Kumar and J. F. Blount J. Org. Chem. 1979,44,2784. ’* M. J. Bovill M. H. P. Guy G. A. Sim D. N. J. White and W. Herz J.C.S. Perkin ZZ,1979 53. 33 H.Seto T. Sasaki J. Uzawa S Takeuchi and H. Yonehara Tetrahedron Letters 1978,923,4411. 34 Y.Tsuda M. Kaneda A. Tada K. Nitta Y. Yamamoto and Y.Iitaka J.C.S. Chem. Comm.. 1978,160. ’’ R. Kazlauskas P. T. Murphy and R. J. Wells Tetrahedron Letters 1978,4949;for a review see R. J. Wells Pure Appl. Chem. 1979 51 1829. ’‘ R. R. Izac and J. J. Sims J. Amer. Chem. Soc. 1979,101,6136 ’’ T. Yoshida S. Muraki K. Takahashi T. Kato C. Kabuto T. Suzuki T. Uyehara and T. Ohnuma J.C.S. Chem. Comm. 1979,512. ’* A. Matsuo K. Atsumi M. Nakayama S. Hayashi andK. Kuriyama J.C.S. Chem. Comm. 1979,1010 see also Y. Asakawa M. Toyota T. Takemoto and C. Suire Phytochemistry 1979,18 1355. 39 A. Matsuo H. Nozaki M. Nakayama Y. Kushi S. Hayashi T. Komori and N. Kamijo J.C.S. Chem. Comm..1979,174. Biological Chemistry -Part (i) Terpenoids and Steroids The biological activity of various sesquiterpenoids has provided the stimulus for many syntheses. A number of new strategies have been developed4' for the construction of the a-methylene lactone moiety found in many of the cytotoxic substances. Further syntheses of the tumour-inhibitory bis-methylene lactone vernolepin (25) have been rep~rted.~~ The unsaturated ketone (26)has formed a key -PhCH,O I HO AcO intermediate in the synthesis of both the potent cytotoxic substance helenalin (27)42 and of the pseudoguaianolide bigelovin (28).43 The sex-attractant pheromone of the American cockroach (Periplaneta americana) i.e. periplanone B (29) hitherto available in microgram quantities has been synthesized" and its absolute stereo- chemistry determined45 by the exciton chirality method.The variety of ring systems found amongst the sesquiterpenoids have also provided a number of synthetic 40 R. M. Adlington and A. G. M. Barrett J.C.S. Chem. Comm. 1978 1071. 41 M. Iio M. Isobe and T. Goto J. Amer. Chem. SOC.,1979 101,6076; F.Zutterman H.de Wilde R. Mijnheer P. de Clerq and M. Vandewalle Tetrahedron 1979,35,2389; cf. P. A. Grieco M. Nishizawa T. Oguri S. D.Burke and N. Marinovic J. Amer. Chern. SOC.,1977,99,5773;S.Danishefsky P. F. Schuda T. Kitahara and S. J. Etheredge ibid. p. 6066. 42 Y. Ohfune P.A. Grieco C.-L. J. Wang and G. Majetich J. Amer. Chem. SOC.,1978 100 5946. 43 P. A. Grieco Y. Ohfune and G. Majetich J.Org. Chem. 1979 44,3092. W. C. Still J. Amer. Chem. SOC.,1979,101,2493. 45 M.A. Adams K. Nakanishi W. C. Still E. V. Arnold J. Clardy and C. J. Persoons J. Amer. Chern. SOC. 1979,101,2495. 368 J. R. Hanson H challenges. Thus the tumour-inhibitory antibiotic pentalenolactone (30),46which possesses an unusual pentalene ring system and a spiro-epoxymethylene lactone and another antibiotic hirsutic acid (31),47 have both been the subject of stereo-controlled syntheses. The parent hydrocarbon hirsutene has also been synthe~ized.~~ Amongst the bridged structures which have attracted interest are the tricyclic compound gymnomitrol (32)49and the isocyanopupukeananes e.g. (33).50 A (32) (33) Monoterpenoids have provided the basis for a number of sesquiterpenoid syntheses.The synthesis of the highly oxygenated compound picrotoxinin (34) startsS1 from carvone. The photochemical adduct (35) of methylcyclobutene and L-piperitone is a key intermediate52 in the synthesis of (-)-shyobunone (36)and its elemene isomers. A similar approach using cyclobutenecarboxylic acid and piperitone has been in the synthesis of the germacrene and cadinane skeleta. (34) (35) (36) 46 S. Danishefsky M. Hirama K. Gombatz T. Harayama E. Berman and P. F. Schuda J. Amer. Chem. SOC., 1978 100,6536; 101,7020. 47 B. M. Trost C. D. Shuey F. DiNinno jr. and S. S. McElvain J. Amer. Chem. SOC.,1979 101 1284. 48 K. Hayano Y.Ohfune H. Shirahama and T. Matsumoto Tetrahedron Letters 1978,1991; K. Tatsuta K. Akimoto and M.Kinoshita J. Amer. Chem. SOC.,1979,101 6116. 49 R. M. Coates S. K. Shah and R. W. Mason J.Amer. Chem. SOC.,1979,101,6765; G.Buchi and P.-S. Chu ibid. p. 6767; S. C. Welch and S. Chayabunjonglerd ibid. p. 6768. E. J. Corey and M. Ishiguro Tetrahedron Letters 1979 2745; E. J. Corey M. Behforouz and M. Ishiguro J. Amer. Chem. SOC.,1979 101 1608; H. Yamamoto and H. L. Shan ibid. p. 1609. 51 E. J. Corey and H. L. Pearce J. Amer. Chem. SOC.,1979,101 5841. 52 J. R. Williams and J. F. Callahan J.C.S. Chem. Comm. 1979,404. 53 G. L. Lange and F. C. McCarthy Tetrahedron Letters 1978,4749. Biological Chemistry -Part (i) Terpenoids and Steroids A number of biomimetic studies have focused on humulene (37) as a possible precursor of polycyclic sesquiterpenoids.The relationship between the confor- mation of humulene and its cyclization products has been e~amined.’~ The con- version of humulene into the proto-illudane skeleton has been reported.’’ Epoxides have been considered as possible initiators of cyclization. The biomimetic acid- catalysed cyclization of humulene 4,5-epoxide to compounds of the africanol type (38) and of epoxygermacrene-D (39) to compounds of the selinane (40) and oppositol (41) skeleta has been examineds6 in this context. 4 Diterpenoids The diversity of diterpenoid skeleta now parallels that of the sesquiterpenoids. An interesting cyclic ether zoapatanol(42) has been from a Mexican plant Montanoa tomentosa which is used as an abortifacient. Phytochemical surveys of both the Compositae and the Labiatae have also yielded many new diterpenoids.Thus a series of compounds e.g. (43),58related to marrubiin have been obtained s4 H. Shirahama E. Osawa and T. Matsumoto Tetrahedron Letters 1978 1987. ” S. Misumi T. Ohtsuka Y. Ohfune K. Sugita H. Shirahama and T. Matsumoto Tetrahedron Letters 1979,31;S. Misumi T.Ohtsuka H. Hashimoto Y. Ohfune H. Shirahama and T. Matsumoto ibid. p. 35;also see W. Renold G. Ohloff and T. Norin Helo. Chim. Acta 1979,62 985. 56 M. Niwa M. Iguchi and S. Yamamura Tetrahedron Letters 1978 4043; ibid. 1979 4291; J. A. Mlotkiewicz J. Murray-Rust P. Murray-Rust W. Parker F. G. Riddell J. S.Roberts and A. Sattar ibid. 1979 3887. ’’ S.D.Levine R. E. Adams R. Chen. M. L. Cotter A. F. Hirsch V. V. Kane R. M. Kanojia C.Shaw M. P. Wachter E. Chin R. Huettemann P.Ostrowski J. L. Mateos L. Noriega A. Guzman A. Mijarez and L. Tovar J.Amer. Chem. Soc. 1979,101,3404. ’* G. Savona F. Piozzi J. R. Hanson and M. Siverns J.C.S. Perkin I 1978 1271 and refs therein. 370 J. R. Hanson p (44) 0 from Ballota species (Labiatae) together with a number of pre-furan 9,13-ethers (44)59 for some Marrubium species. The structure of clerodin was determined by an X-ray analysis in 1961 and the absolute stereochemistries of a number of diterpenoids have subsequently been related to it through the sign of the Cotton effect of their 6-ketones. However the absolute stereochemistries of 3-epi-caryopterin and clerodin have been reversed to (45a)"' and (45b)."l This has ramifications throughout the clerodanes which like many diterpenoids have members in both the 'ent' and 'normal' series.The original source of clerodin CZerodendron infortunatum was indeed aptly named. A range of clerodanes have been isolated from Salvia [e.g. (46)] and Teucrium species [e.g. (47)]."'~"' Q ' "H HO OAc 0 (45) a; R=OAc b; R=H An extensive investigation of Puducarpus species particularly P. nagi has led to the isolation of a series of cytotoxic lactones e.g. (43).64 The leaf-gland colouring materials of various Coleus and Plectranthus species (Labiatae) contain a number of highly oxygenated diterpenoids known as the coleons. Recent examples include 59 G. Savona F. Piozzi L. M. Aranguez and B. Rodriguez Phytochemistry 1979,18,859.6o N. Harada and H. Uda J. Amer. Chem. SOC.,1978,100,8022. D. Rogers G. G. Unal D. J. Williams S. V. Ley G. A. Sim B. S. Joshi and K.R. Ravindranath J.C.S. Chem. Comm. 1979,97. 62 G. Savona M. P. Paternostro F. Piozzi,J. R. Hanson P. B. Hitchcock and S. A. Thomas J.C.S. Perkin I 1978,643;ibid. 1979,1915; G. Savona M. P. Paternostro F. Piozzi and J. R. Hanson ibid. 1979,533. 63 E. Gacs-Baitz L. Radics G. B. Oganessian and V. A. Mnatsakanian Phytochemistry 1978,17,1967. 64 Y. Hayashi T. Matsumoto and T. Sakan Heterocycles 1978 10 123 (and refs. therein); see also Y. Hayashi T. Matsumoto T. Hyono N. Nishikawa M. Uemura M. Nishizawa,M. Togami and T. Sakan Tetrahedron Letters 1979 33 11. Biological Chemistry -Part (i) Terpenoids and Steroids 37 1 coleon U and 3p -acetoxyfuerstion (49).65 Solenostemon species (Labiatae) are the source66 of some unusual rearranged diterpenoids in which one of the substituents at C-4 has migrated to C-3.The compounds e.g. (50),also contain a spirocyclopropane ring as found in barbatusin. 0 After some controversy the stereochemistry of the y-lactone (5l),obtained by treatment of dihydroisopimaric acid with acid has been established6' by an X-ray analysis. A variety of synthetic strategies have been developed directed at the tricyclic diterpenoids. One route68 involves the Wittig reaction between cy -cyclo-citral (ring A) and various benzylphosphonium salts (ring C) followed by partial reduction and cyclization. This has afforded ferruginol totarol and some more highly oxidized relatives such as the royleanones.A large number of polyhydroxylated ent-kaur-15- and -16-enes bearing various oxygen functions at C-3,-7 -15 -18 and -19 have been isolated from Sideritis and Isodon species (Labiatae). Some of the latter e.g. (52),69show tumour-inhibitory properties. Enmein obtained from Isodon species has formed the starting material for a number of diterpenoid partial The unusual skeleton (53) reminiscent of aphidicolin has been assigned to helifulvanolic acid.71 65 P. Ruedi and C. H. Eugster Helu. Chim. Acta 1978 61 709; G.Buchbauer P. .Ruedi and C. H. Eugster ibid. p. 1969. 66 T. Miyase P. Ruedi and C. H. Eugster J.C.S. Chem. Comm. 1977 859. " W. Herz and J. F. Blount J. Org. Chem. 1979,44 1172. "T. Matsumoto and S.Usui Bull. Chem. SOC.Japan 1979,52,213;T. Matsumoto and A. Suetsugu ibid. p. 1450; T. Matsumoto and S. Ilarada ibid.,p. 1459;T.Matsumoto and S.Takeda Chem. Letters 1979 409. 69 I. Kubo M. J. Pettei K. Hirotsu H. Tsuji and T. Kubota J. Amer. Chem. SOC., 1978,100,628 70 T. Fujita I. Masuda S. Takao and E. Fujita J.C.S. Perkin I 1979 915. 71 F. Bohlmann C. Zdero R. Zeisberg and W. S. Sheldrick Phytochemistry 1979 18 1359. 372 J. R. Hanson OH (52) CO,H (53) Fifty-six gibberellin plant hormones are known.72 Their chemistry has been examined in connection with synthesis73 and structure-activity whilst an X-ray comparison has been made75 between the C1,and Cz0series revealing some interesting differences. Undoubtedly the major synthetic achievement in this area has been the total synthesis of gibberellic The tricyclic compound (54) formed a key intermediate and this was converted into the homoannular diene (55) and thence into gibberellic acid (56).Another successful strategy77 for gibberellin synthesis makes use of the reactions of diazo-ketones in both the construction of ring D and the contraction of ring B. (54) R =CH20CHzCHz0Me An increasing number of diterpenoids have been isolated with structures based on the macrocyclic cembrane These include many marine products isolated from various corals.79 The X-ray analysis has been reported” of the tetra-acetate of ingol(57) a member of the lathyrane series plausible cyclizations of which may lead to the tigliane daphnane and ingenane series of tumour-promoting esters of the Euphorbiaceae.*l 72 For recent reviews see J.E. Graebe and H. J. Ropers in ‘Phytohormones and Related Compounds’ ed. D. S. Lethan P. B. Goodwin and J. J. V. Higgins Elsevier Amsterdam 1978 Vol. 1 p. 107; J. MacMillan,Pure Appl. Chem.,1978’50,995;for gibberellins A,,-, see N. Murofushi M. Sugimoto K. Itoh and N. Takahashi Agric. Biof. Chem. (Japan) 1979,43 2179. 73 G. Stork and J. Singh J. Amer. Chem. Soc. 1979,101,7109. . 74 B. E. Cross and A. Erasmuson J.C.S. Chem. Comm. 1978 1013; K. Boulton and B. E. Cross J.C.S. Perkin I 1979 1354. ” G. Ellames J. R. Hanson P. B. Hitchcock and S. A. Thomas J.C.S. Perkin I 1979 1922. 76 E. J. Corey R. L. Danheiser S. Chandrasekaran C. E. Keck B. Gopalan S.D. Larsen P. Siret and J. L. Gras J. Amer. Chem. SOC.,1978,100,8034;E. J. Corey and J. Gorzynski-Smith,ibid. 1979,101,1038. ’’L. N. Mander and S. G. Pyne J. Amer. Chem. SOC. 1979,101,3373. 78 For a review see A. J. Weinheimer C. W. J. Chang and J. A. Matson Fortschr. Chem. org. Naturstoffe 1979,36,285. 79 See,for example B. N. Ravi and D. J. Faulkner J. Org. Chem.,1978,43,2127;B. F. Bowden J. C. Coll S. J. Mitchell and G. J. Stokie Austral. J. Chem. 1979 32 653. H. Lotter H. J. Opferkuch and E. Hecker Tetrahedron Letters 1979,77. For a review see F. J. Evans and C. J. Soper Lloydia 1978,41 193; E. Hecker Pure. Appl. Chem. 1977,49,1423. Biological Chemistry -Part (i) Terpenoids and Steroids A number of diterpenoids have been obtained with structures which resemble prenylated sesquiterpenes.These include dictyodial(58) which has been isolateds2 from various marine Dictyota (algae) and Aplysia (sea hare) species. Amongst unusual diterpenoids are the trinervitene alcohols e.g. (59),83obtained from termites the fungal cyathins e.g. (60),84and the verrucosanes e.g. (61),” obtained from the liverwort Myliu verrucosa. H OH (59) (60) 5 Sesterterpenoids The number of known sesterterpenoids has continued to increase particularly in isolates from marine organisms,86 from fungi,” and from insects.88 However not all CZ5fungal metabolites are sesterterpenes. Thus the andibenins’’ appear to be of 82 J. Finar J. Clardy W. Fenical L. Minale R. Riccio M. Kirkup and R. E. Moore J. Org. Chern.1979 44,2044. 83 J. Vroc M. Budesinsky and P.Sedmera Coll. Czech. Chem. Comm. 1978,43,1125,2478. 84 W. A. Ayer T. Yoshida and D. M. J. van Schie Canad. 1. Chern. 1978,56,2113. 85 S. Hayashi A. Matsuo H. Nozaki M. Nakayama D. Takaoka and M. Hiroi Chern. Letters 1978,953. 86 See for example G. Cimino S. de Stefano L. Minale R. Riccio K. Hirtosu and J. Clardy Tetrahedron Letters 1979 3619. C. Rossi and L. Tuttobello Tetrahedron Letters 1978,307. F. Miyamoto H. Naoki T. Takemoto and Y. Naya Tetrahedron 1979,35 1913. 89 A. W. Dunn R. A. W. Johnstone T. J. King L. Lessinger and B. Sklarz J.C.S. Perkin I 1979,2113;T. J. Simpson ibid. p. 2118. 374 J. R. Hanson mixed polyketide-terpenoid origin. A total synthesis and the X-ray analysis of gascardic acid (62) have been de~cribed.~' 6 Triterpenoids The identification and occurrence of triterpenoids and particularly of the friedelin group have been reviewed." An interesting review of the palaeochemistry of the hopanoids has also appeared.92 A number of modified squalene 2,3-epoxides have been prepared,93 for use in experiments to define the substrate specificity of 2,3-oxidosqualene cyclase.Studies on the biomimetic polyene cyclizations of squalene relatives have continued with the examination of molecules containing an internal nucleophilic centre that is suitably oriented to trap carbo-cationic intermediate^.^^ A number of new fungal metabolites e.g. (63) related to fusidic acid have been obtainedg5 from Fusidium coccineum. The lanostane derivative abietospiran (64) is presentg6 in quite large quantities in the bark of Abies alba.I HO 90 R. K. Boeckman D. M. Blum and E. V. Arthur J. Amer. Chem. SOC.,1979,101 5060; for X-ray analysis see R. K. Boeckman D. M. Blum,E. V. Arthur and J. Clardy Tetruhedron Letters 1979,4609. 91 P. Pant and R. P. Rastogi Phytochemistry 1979,18,1095; R. F. Chandler and S. N. Hooper ibid.,p. 711. 92 G. Ourisson P. Albrecht and M. Rohmer Pure Appl. Chem. 1979,51,709. 93 E. E. van Tamelen A. D. Pedlar E. Li and D. R. James J. Amer. Chem. SOC.,1977,99,6678;M. Herin P. Sandra and A. Krief Tetrahedron Letters 1979 3103. 94 M. E. Garst Y.-F. Cheung and W. S. Johnson J. Amer. Chem. SOC.,1979,101,1279,4404. 95 W. 0.Godtfredsen N. Rastrup-Andersen S. Vangedal and W.D. Ollis Tetruhedron 1979 35,2419. 96 W. Steglich M. Klaar L. Zechlin and H. J. Hecht Angew. Chem. Internut. Edn. 1979 18 698. Biological Chemistry -Part (i) Terpenoids and Steroids A short synthesis of cycloartenol from 1lp-oxygenated lanostanes by photolysis of nitrite esters has been de~cribed.'~ The rearrangements of lanostane 9,ll-epoxides have been examined with a view to inducing the rearrangement of the methyl group at C-10 to C-9 and the formation of the cucurbitane skeleton.'* The tumour-inhibitory properties of the cucurbitacins have attracted some atten- tion. Isocucurbitacin D (65)and its 3-epimer are new tumour-inhibitory compounds which have been isolated from the leaves of Phormium tenax." A number of the limonoids also show tumour-inhibitory properties.Aphnastatin (66) from Aphnamixis grandifolia was isolated"' in this context. Some highly oxygenated limonoids e.g. polystachin (67) have been obtained"' from A. polystacha. The insect antifeedant activity of the tetranortriterpenoids has also attracted attention."* The quassinoids are another group of biologically active nortriterpenoids. The compound (68) isolatedlo3 from Simarouba amara has antineoplastic properties. An interesting variant amongst the nortriterpenoids is the compound clausenolide (69) whose structure was determined by an X-ray analysis.'04 OH HO.. "OH I \\ H Me 0 (66) 97 R. B. Boar and D. P. Copsey J.C.S. Perkin I 1979 563. 98 G. V. Baddeley H. J. Samaan J. J. H. Simes and T. H. Ai J.C.S.Perkin I 1979,7; Z. Paryzek ibid. p. 1222. 99 S. M. Kupchan H. Meshulam and A. T. Sneden Phytochemistry 1978,17,767. 100 J. Polonsky Z. Varon B. Arnoux C. Pascard G. R. Pettit J. H. Schmidt and L. M. Lange J. Amer. Chem. Suc. 1978,100 2575. 101 D. A. Mulholland and D. A. H. Taylor J. Chem. Res. 1979 (S)294 (M)3101; J. D. Connolly C. Labbe D. S. Rycroft D. A. Okorie and D. A. H. Taylor J. Chem. Res. 1979 (S)256 (M)2858. 102 See for example W. Kraus W. Grimminger and G. Sawitski Angew. Chem. Internat. Edn. 1978,17 476. 103 J. Polonsky Z. Varon H. Jacquemin and G. R. Pettit Experientia 1978,34,1122; cf.M. E. Wall and M. C. Wani J. Medicin. Chem. 1978 21 1186. 104 D. P. Chakraborty P. Bhattacharyya S. P. Bhattacharyya J. Bordner G.L. A. Hennessee and B. Weinstein J.C.S. Chem. Comm. 1979 246. 376 J. R. Hanson A simple stereoselective route for the preparation of pentacyclic intermediates used in triterpene synthesis has been described."' It is based as are a number of steroid syntheses on the cycloaddition reaction of o-quinodimethanes derived by the thermolysis of benzocyclobutanes. An unusual oleanane is the p -1actone papyriogenin G (70) which was obtainedlo6 from the leaves of Tetrapanax papyriferum. Its structure is based on an X-ray analysis. HO-' (70) (71) Officinalic acid (71) is a novel triterpene with a rearranged carbon skeleton which has been obtainedlo7 from the fungus Fumes officinalis. Its carbon skeleton has the appearance of a 'bis-drimane' rather than a degraded triterpenoid.The hopanes have attractedlo8 some attention through their occurrence in shales. 7 Steroids Benzeneseleninic anhydride has been rec~rnmended~~' as a reagent for the pre- paration of the biologically active steroidal 1,4-dien-3-ones. The corresponding thiones have also been prepared. lo The scope of diethylaminosulphurtriflnorideas a reagent for introducing fluorine into the steroid skeleton has been examined T. Kametani Y. Hirai Y. Shiratori K. Fukumoto and F. Satoh J. Amer. Chem. SOC.,1978,100,554. Y. Ogihara M. Asada and Y. Iitaka J.C.S. Chem. Comm. 1978,364; cf. S. Amagaya T. Takeda Y. Ogihara and Y. Yamisaki J.C.S. Perkin Z. 1979 2044. lo' W. W. Epstein F. W. Sweat G.Vanhear F. M. Lovell and E. J. Gabe J. Amer.Chem. SOC.,1979,101 2748. lo' W. K. Siefert J. M. Moldowan G. W. Smith and E. V. Whitehead Nature 1978 271,436. D. H. R. Barton A. G. Brewster R. A. H. F. Hui D. J. Lester S. V. Ley and T. G. Back J.C.S. Chem. Comm. 1978,952. 'lo D. H. R. Barton L. L. Choi R. M. Hesse M. M. Pechet and C. Wilshire J.C.S. Perkin Z 1979 1166. 377 Biological Chemistry -Part (i) Terpenoids and Steroids further.' '' Neighbouring-group participation has been noted' l2 in the formation and hydrolysis of steroidal 3-hydroxy- 1,2-epoxides. The stereochemistry of various addition reactions of steroidal A2-enes has continued to attract attention.' l3 The participation of a 19-oxygen function in the addition of hypobromous acid to a A2-ene is manife~t"~ in the formation of 19-2 ether and lactone rings.Some curious results have been noted' l5 in the unimolecular solvolysis of 3-trifluoroacetoxy- cholest-4-enes which imply conformational differences between the carbo-cations arising from the 3-epimers. The stereochemistry of the formation of A-homo- steroids in the acid-catalysed cleavage of 2,3-dihalogenocyclopropyl-3-acetoxy-steroids has been examined,'16 as has the contraction of the ring during the cleavage of cyclo-steroids with hydrogen chloride gas.' 17a Another ring-contraction of ring A which possibly involves the formation of cyclo-steroid intermediates is the base- catalysed rearrangement of 5p,6p-epoxy-4-ketones (72). ''7b The stereochemistry of some reactions of ring A in the 9-methyl-5a/5P,9P,lOa -0estran-3-one series (73) has been examined."8 The equilibration of 6a-and 6p-nitrocholest-4-enes re~eals''~ the influence of the homoallylic participation of the olefin.The product of solvolysis of 3p- tosyloxy-5P- hydroxycholestan-6-one (74) has been shown to be the A-homo-B-nor-keto-oxide (75) which is formed by participation of the carbonyl oxygen in the displacement reaction.'*' The 4-phenyl-1,2,4-triazoline-3,5-dioneadducts of steroidal 5,7-dienes have been used to protect this system in the partial synthesis of derivatives of vitamin D. (74) I (75) OTs "' S. Rozen Y. Faust and H. Ben-Yakov Tetrahedron Letters 1979 1823. '" E. Glotter and P. Krinsky J.C.S. Perkin I 1978,408,413; D. Baldwin J. R. Hanson and D. Raines ibid. 1979 344. '13 R.C. Cambie H. H. Lee P. S. Rutledge and P. D. Woodgate J.C.S. Perkin I 1979 757. 'I4 P. Kocovsky and V. Czerny Coll. Czech. Chem. Comm. 1978,43 327,1924. '" G. Ortar M. P. Paradisi E. Morera and A. Romeo J.C.S. Perkin I 1978,5. '" P. CrabbC J.-L. Luche J.-C. Damiano M.-J. Luche and A. CNZ J. Org. Chem. 1979 44 2929. 'I7 E. J. Brunke Chem. Ber. 1979,112,1606; J. R. Hanson D. Raines and H. Wadsworth,J.C.S. Perkin I 1978,743. '" J. C. A. Boeyens J. R. Bull J. Floor and A. Tuinnan J.C.S. Perkin I 1978 808. J. T. Pinhey and G. C. Smith Austral. J. Chem. 1978 31,2563. V. Dave and E. W. Warnhoff J. Org. Chem. 1978 43 4622; R. W. G. Foster and B. A. Marples Tetrahedron Letters 1979 2071. 378 J. R. Hanson A simplified method of deprotection has been described."' The oxidation of the 5,7-dienes with potassium permanganate has been the subject of some contro-versy."' Further studies have been made on the mechanism of the Barton reaction in efforts'23 to identify the origin and hence suppress the formation of various by-products.The formation of As-7-ones in the reaction of 5&6p-epoxy-7-hydroxy-androstanes with thionyl chloride containing sulphur dioxide has been observed.124 The formation of D-homo-c-nor-steroids has been reviewed.'25 Further studies of the acid-catalysed D-homoannulation of 17a-hydroxy-pregnan-20-oneshave been published.'26 The reaction of thallium(1)acetate and iodine with enol-acetates has been examinedlZ7in the context of the formation of 16-iodo-17-ketones. The majority of sterols including the moulting hormones and metabolites of vitamin D possess the R configuration at C-20.A number of synthetic efforts have been made'28*'29to generate this system.Marine organisms have yielded several sterols with unusual ~ide-chains,'~' exemplified by xestosterol (76)131and various 23-methyl-22-dehydro-compounds.'32Their detection by mass spectrometry has been reviewed.'33 A stereospecific synthesis of the side-chain of the Achlya sex-hormone oogoniol (77) has defined the stereochemistry of this The molecular rearrangements of the steroid framework have continued to attract attention. The products of reductive rearrangement of androst-4-ene-3,17-dione in HF-SbF in the presence of a hydrogen donor are 6a-and 6P-methyl-14P-OH I HO HO (76) (77) M.Tada and K. Oikawa J.C.S. Chem. Comm. 1978,727. 12' M. Anastasia A. Fiecchi and A. Scala TetrahedronLetters 1979 3323. lZ3 D. H. R. Barton R. M. Hesse M. M Pechet and L. C. Smith J.C.S. Perkin I 1979 1159. lZ4 J. R. Hanson A. W. Johnson and M. A. C. Kaplan J.C.S. Perkin I 1978 263. lz5 E. Brown and M. Ragault Tetrahedron 1979,35,911. lZ6 D. N. Kirk and C. R. McHugh J.C.S. Perkin I 1978. 173. "'R. C. Cambie R. C. Hayward J. L. Jurlina P. S. Rutledge and P. D. Woodgate J.C.S. Perkin I 1978 126. For a review see D. M. Piatak and J. Wicha Chem. Rev. 1978,78 199. lZ9 B. M. Trost P. R. Bernstein and P. C. Funfschilling J.Amer. Chem. SOC.,1979,101,4378; P. A. Grieco T. Takigawa and D. R. Moore ibid. p. 4380. W. Hofheinzand G. Oesterhelt Hefv.Chim.Acra 1979,62,1307;W.C. Kokke M. C. Pak W. Fenical and C. Djerassi ibid. p. 1310. 131 W. C. Kokke C. Tarchini D. B. Stierle and C. Djerassi J. Org. Chem. 1979,44 3385. 13' W. C. Kokke I. J. Massey N. W. Withers W. Fenical and C. Djerassi TetrahedronLetters 1979,3601. 133 C. Djerassi Pure Appl. Chem. 1978,50 171. 134 J. R. Wiersig,N. Waespe-Sarcevic,and C. Djerassi J. Org. Chem.,1979,44,3374; M. W. Preus and T. C. McMorris J. Amer. Chem. SOC.,1979 101 3066. 379 Biological Chemistry -Part (i) Terpenoids and Steroids oestranediones.13' The aromatization of steroid rings has continued to be of interest. The aromatization of ring cby rearrangement of some A9"')-17-hydro~y-steroids'~~ and of 9,ll -epoxy- 17-hydroxy-steroid~'~~ has been described.The mechanism of the rearrangement 2a-hydroxycholest-4-en-3-one to 2-methoxy-4-methyl-19-norcholesta-l,3,5( 10)-triene has been examined.138 The chromogenic reactions used in the assay of testosterone have been examined'39 and C- 14 carbo-cationsproposed as the chromophores. A series of papers have appeared that give details of the synthesis of various derivatives of vitamin D. These include syntheses of various intermediates la -hydroxy-vitamins D3and D4 22,23-epoxy-vitamin D2 and 24-fluoro-25- hydroxy-vitamin D3.140*141 A growing number of pregnanes have been isolated from marine organisms including the unusual 18-acetoxypregna- 1,4,2O-trien-3-one. 14' A number of esters of lucibufagenin (78) form the defensive steroids of the firefly Photinus p~ra1is.I~~ 0 OH HO OH Further steroidal alkaloids of the Solanaceae and of the c-nor-D-homocevanine series have been is01afed.l~~ A number of novel syntheses of steroids have been described particularly those based on o -quinodimethane cycl~additions.'~~ Thus thermolysis of the benzocyclobutene (79) affords an enantioselective route to 3-methoxy-1,3,5( 10)- 135 R.Jacquesy and C. Narbonne Bull. SOC. chim. France Part ZI 1978 163. 136 A. B. Turner J.C.S. Perkin I 1979 1333. 137 H. T. A. Cheung R. G. McQueen A. Vadasz and T. R. Watson J.C.S. Perkin I 1979 1048. 138 B. R.Davis G. W. Rewcastle and P. D. Woodgate J.C.S. Perkin I 1978,735. 139 T. Miura H. Takagi K. Harita and M. Kimura Chem. and Pharm. Bull. (Japan) 1979,27 452; T.Miura H. Takagi and M. Kimura ibid. p. 783. 140 B. Lythgoe R. Manwaring J. R. Milner T. A. Moran M. E. N. Nambudiry and J. Tideswell J.C.S. Perkin Z 1978,387; B. Lythgoe T. A. Moran M. E. N. Nambudiry J. Tideswell and P. W. Wright ibid. p. 590; P. J. Kocienski B. Lythgoe and D. A. Roberts ibid. p. 834; P. J. Kocienski B. Lythgoe and S. Ruston ibid. 1979 1290; P. J. Kocienski B. Lythgoe and I. Waterhouse Tetrahedron Letters 1979 4419; D. W. Guest and D. H. Williams J.C.S. Perkin Z,1979 1695. 141 Y. Kobayashi T. Taguchi T. Terada J.-I. Oshida M. Morisaki and N. Ikekawa Tetrahedron Letters 1979,2023;K. Ochi I. Matsunaga M. Shindom and C. Kaneko J.C.S. PerkinI,1979,161;M. Tada and A. Kawa ibid. p. 1858. 142 R. A. Ross and P. J.Scheur Tetrahedron Letters 1979,4701. 143 J. Meinwald D. F. Wiemer and T. Eisner J. Amer. Chem. SOC. 1979 101 3055. 144 K. Kaneko M. Tanaka K. Haruki M. Naruse and H. Mitsuhashi Tetrahedron Letters 1979 3737. 145 W. Oppolzer Synthesis 1978 793. 380 J. R. Hanson oestratriene-ll,l’ir-dione (80).146Similar routes have been developed in other laboratorie~,~~~ and the generation of the u-quinodimethane by the chelotropic elimination of sulphur dioxide has recently been de~cribed.’~’ 8 Carotenoids Lectures from the 5th International Symposium on Carotenoids have been pub- li~hed’~~ and provide a valuable group of reviews of progress in this area. Natural prephytoene alcohol has been identified15’ as the (+)-(lR,2R,3R)-isomer (81).The structure 7,9,7’,9’-tetra-~is-$,$-carotenehas been assignedl’l to the poly(cis)caro- tenoid prolycopene. The cis-pentaene chromophore of phytofluene has been synthe~ized.”~ Amongst novel more highly oxidized carotenoids are a number of marine products whilst flavoxanthin (82)and its epimer chrysanthemaxanthin have been ~btained”~ from flowers of Taruxacum oficinale. A number of degraded 146 W. Oppolzer K. Battig and M. Petrzilka Helv. Chim. Actu 1978,61 1945. 14’ R. L. Funk and K. P. C. Vollhardt,J. Amer. Chem. SOC. 1979,101,215; T. Kametani H. Matsumoto H. Nemoto and K. Fukumoto ibid. 1978,100,6218. 148 K.-C. Nicolaou and W. E. Barnette J.C.S. Chem. Comm. 1979 1119. 149 Pure Appl. Chem. 1979,51,435-675. lS0 L. J. Altman R. C. Kowerski H. C. Rilling and D.R. Laungani J.Amer. Chem. SOC. 1978,100,6174. lS1 G. Englert B. 0.Brown G. P. Moss B. C. L. Weedon G. Britton T. W. Goodwin K. L. Simpson and R. J. H. Williams J.C.S. Chem. Comm. 1979 545; J. M. Clough and G. Pattenden ibid. p. 616. lS2 J. M. Clough and G. Pattenden Tetrahedron Letters 1979 5043. lS3 H. Cadosch U. Vogeli P. Ruedi and C. H. Eugster Helv. Chim. Acta 1978,61 1511. Biological Chemistry -Part (i) Terpenoids and Steroids carotenoids have been isolated particularly from tobacco.’54 The chemistry and biology of abscisic acid has been re~iewed.”~ There has been considerable synthetic activity in the carotenoid area particularly in the preparation of compounds with unusual end-groups and partially degraded str~ctures.’~~ A novel synthesis of crocetin (84) used the cleavage of the dienone (83) that was obtained by alkylation of 2,6-dimethylphen01.’~’ Novel syntheses of abscisic acid and its relatives have also been rep~rted.’~’ Electrochemical reduction has been usedls9 to prepare astaxanthin from astecene.0 (83) (84) The chromophoric unit of the visual pigments is known to consist of 11-cis-retinal covalently bound as a protonated Schiff’s base to the E-amino-group of lysine in opsin. An external point-charge model based on an electrostatic interaction with a charged group on the rhodopsin has been to account for the shift in absorption maximum between protonated Schiff’s bases of retinal and the visual pigment bovine rhodopsin. Some simple compounds have been synthesized which show this effect.154 See for example E. Demole and P. Enngist Helu. Chim. Acta 1978,61,2318; R. Uegaki T. Fujimori, H. Kaneko K. Kato and M. Noguchi Agric. Biol.Chem. (Japan),1979,43 1149. Is’ B. V. Milborow in ‘Phytohormones and Related Compounds’ ed. D. S. Letham P. B. Goodwin and J. J. V. Higgins Elsevier Amsterdam 1978 Vol. 1 p. 295. 156 See for example M. Akhtar A. E. Faruk C. J. Harris G. P. Moss S. W. Russell and B. C. L. Weedon J.C.S. Perkin I 1978 1511. Is’ G. Quinkert K. R. Schmieder G. Durner K. Hache A. Stegk and D. H. R. Barton Chem. Ber. 1977 110,3582. F. Kienzle H. Mayer R. E. Minder and H. Thommen Helu. Chim. Actu 1978,61 2616. E. A. H. Hall G. P. Moss,J. H. P. Utley and B. C. L. Weedon J.C.S. Chem. Comm. 1978 387.160 B. Honig U. Dinur K. Nakanishi V. Balogh-Nair M. A. Gawinowicz M. Arnaboldi and M. G. Motto J. Amer. Chem. SOC.,1979,101,7084;M. Sheves K. Nakanishi and B. Honig ibid.,p. 7086.

ISSN:0069-3030    

DOI:10.1039/OC9797600363

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

16 BioIogicaI Chemistry Part (ii) Alkaloids By D. G. BUCKLEY Departrnent of Chemistry Queen Mary College (Universiv of London) Mile End Road London El 4NS 1 Introduction In the three years since alkaloids were last reviewed in Annual Reports’ a large amount of new work has been published and for a comprehensive survey the reader is referred to Volumes 8 and 9 of the Specialist Periodical Reports on the which cover the period July 1976 to June 1978. Biosynthetic aspects are also treated in the companion volumes475 on biosynthesis and these include a tabular survey of all tracer incorporations into alkaloids reported in the years 1975-78. The period covered by this short review is 1977-79 inclusive. 2 Pyridine and Piperidine Alkaloids Crombie and Whiting have reported6-’ the isolation and characterization of eleven new celastraceous alkaloids of mainly Ethiopian and Kenyan origin having molecu- lar weights of ca.600-c~.1200 and a sesquiterpene core. They have been classified in three groupd (a) cathedulins E2 and E8 which are esters of a new penta- hydroxysesquiterpene ether (1)(reported previously” as cathedulins 2 and 8); (b) cathedulins K1 K2 K6 and K15 which are esters of the known nonahy- droxysesquiterpene ether euonyminol (2) to which is attached a single dilactone bridge; and (c) cathedulins E3 E4 E5 E6 and K12 which are more complex esters of euonyminol containing two dilactone bridges. In each case the basic functionality is provided by one or more esterified nicotinic acid derivatives.The structure of D. G. Buckley Ann. Reports (B),1976,73 397. * ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Chemical Society London 1978 Vol. 8. ‘The Alkaloids’ ed. M. F. Grundon (Specialist Periodical Reports) The Chemical Society London 1979 Vol. 9. ‘Biosynthesis’ ed. J. D. Bu’Lock (Specialist Periodical Reports) The Chemical Society London 1977 VOl. 5. ’ ‘Biosynthesis’ ed. J. D. Bu’Lock (Specialist Periodical Reports) The Chemical Society London 1980 Vol. 6. R. L. Baxter L. Crombie D. J. Simmonds D. A. Whiting 0.J. Braenden and K. Szendrei J.C.S. Perkin I 1979,2965. R. L. Baxter L. Crombie D. J. Simmonds and D. A. Whiting J.C.S. Perkin I 1979 2972. L. Crombie W. M. L. Crombie D. A. Whiting and K. Szendrei J.C.S. Perkin I 1979 2976.R. L. Baxter W. M. L. Crombie L. Crombie D. J. Simmonds D. A. Whiting and K. Szendrei J.C.S. Perkin I 1979 2982. lo R. L. Baxter L. Crombie D. J. Simmonds and D. A. Whiting J.C.S. Chem. Comm. 1976 465. Biological Chemistry -Part (ii) Alkaloids O("' Me.-+ Me cathedulin K2 (3),the most abundant alkaloid isolated from Kenyan-grown plants is illustrative of the complex structures of the cathedulins. The biosynthesis of anatabine (4) is unusual'*11*12 in that its dehydropiperidine ring derives from nicotinic acid (5) rather than lysine which is the source of the similar fragment in anabasine (6).13 Most interestingly it has been shown14 that the piperidine fragment of dioscorine (7) also derives from nicotinic acid (5) [2-14C]-and [5,6-'3C,,'4C2]-nicotinicacids were tested as precursors and in the latter case the 13C-labelling of the dioscorine was shown by 13C n.m.r.spectroscopy to be at C-1 and C-7. Thus 3,6-dihydronicotinic acid (S) which is probably an important intermediate in the biosynthesis of the pyridine ring of nicotine and anaba~ine'~ and of both rings in anatabine,'." also seems to be involved in the biosynthesis of dioscorine (7) (Scheme 1). Details of the introduction of the remaining fragments (acetate-deri~ed'~)are not yet available but clearly such details are well worth pursuing. The alkaloids represented by tylophlorine (9) and cryptopleurine (10) exhibit various interesting biological properties including anti-cancer action.16 Exploita- tion of these properties in the synthesis of analogues requires efficient elaboration of these and related ring systems and based on biogenetic considerations Herbert has de~eloped'~ an economical synthesis of septicine (11); this on treatment with thallium(II1) trifluoroacetate gives tylophlorine (9) in high yield (Scheme 2).18 Extension of this route to the synthesis of cryptopleurine (10) did not prove E.Leete and S. A. Slattery J. Amer. Chem. SOC.,1976,98,6326. l2 E. Leete J.C.S. Chem. Comm. 1978,610. I3 E.Leete and Y.-Y. Lin Phytochemistry 1973,12,593;R. B.Herbert in 'The Alkaloids' ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 1973,Vol. 3 p. 7. l4 E. Leete and S. A. Slattery J. Amer. Chem. Soc. 1977,99 648; Phytochemistry 1977,16 1705.Is R.B.Herbert in ref. 2 p. 1. I6 J. L. Hartwell and B. J. Abbott Adu. Pharmacol. Chemother. 1969,7,117;N.R.Farnsworth,N. K. Hart S. R. Johns J. A. Lamberton and W. Messmer Austral. J. Chem. 1969,22,1805. l7 R.B.Herbert F. B. Jackson and I. T. Nicholson J.C.S. Chem. Comm. 1976,450. R.B.Herbert J.C.S. Chem. Comm. 1978,794. 384 D. G. Buckley 5pJc02H+ N Nicotinic acid (5) Anatabine (4) :%Me- 0 Dioscorine (7) Anabasine (6) Scheme 1 straightforward but has now been completed in fair overall yield." The key intermediate (12) itself an alkaloid was easily synthesized by condensation of 3,4-dimethoxybenzoylaceticacid (13) with A'-piperidine generated in situ from cadaverine by pea-seedling diamine oxidase. The required enamine-ketone condensation occurred readily in the case of (14)," but a Lewis acid such as titanium(1v) chloride was required to effect the ring-closure of (15) to give the known alkaloid julandine (16).18 Transformation of (16) into cryptopleurine (10) was achieved in 69% yield by using thallium(II1) trifluoroacetate even though the linkage to one aryl ring of (16)is metu to the methoxy-substituent; as in the synthesis of tylophlorine (9),only one of the possible coupling products was detected.3 Pyrrolizidine Alkaloids Significant advances are now being made in the synthesis of various pyrrolizidine alkaloids." Danishefsky and co-workers have developed a novel route to the saturated pyrrolizidine alcohols,*' outlined in Scheme 3. The lithium salt of propargyl alcohol tetrahydropyranyi ether (17) was converted into the (2)-diazomaionate (18) in a number of steps.Intramolecular syn-addition of the carbenoid from (18)to give (19) was carried out by boiling with copper bronze in toluene for 22 h. Treatment of the activated cyclopropane (19) with an excess of hydrazine released the free amine which underwent intramolecular homoconjugate addition with complete inversion of stereochemistry and subsequent lactam formation to give the pyrrolizidine hydrazide (20). Hydrolysis with decarboxylation produced a salt containing a l9 D. J. Robins in ref. 2 Ch. 3; in ref. 3 Ch. 4. *' S. Danishefsky R. McKee and R. K. Singh J. Arner. Chem. Soc. 1977,99,4783. Biological Chemistry -Part (ii) Alkaloids 385 OMe MeOk ~ Meoh / CO,H (CH,), HNJ 0 OMe OMe R R (11) R=OMe n = 1 (14) R=OMe n = 1 (16) R=Hyn=2 (15) R=Hyn=2 (9) R=OMe,n=l (10) R=Hyn=2 Reagents [for (13)+(lo)] i H,N(CH,),NH, pea-seedling diamine oxidase pH 7; ii p-MeOC,H,CH,CHO C,H,; iii TiCl,; ivy NaBH, Pr'OH; v Tl(OCOCF,), CF,CO,H room temperature Scheme2 y-lactone function which was assigned the structure (21).The pyrrolizidine system (22) was regenerated using sodium methoxide and a final reduction step yielded (*)-trachelanthamidine (23). Careful analysis of the pyrrolizidine derivative (22) by 'H n.m.r. spectroscopy at 250 MHzshowed that there was no contamination with the C-1 epimer. Analogous treatment of the (E)-isomer of (18) afforded this C-1 epimer (*)-isoretronecanol(24).Danishefsky et al.'l have extended this strategy to synthesize necine bases with hydroxyl functions at C-7 namely (*)-hastanecine (25) and its epimer (*)-dihy- droxyheliotridane (26). '' S. Danishefsky R. McKee and R. K. Singh J. Amer. Chem. SOC.,1977,99 7711. 386 D. G. Buckley . ... Li+ CrCCH20THP 2R=N(CH&C_CCH20H (17) \-vi z R=N(CH2)3CH=CHCH20COCC02Me It N2 (18) 0 t- [p] c1-ix '0 (22) ( f)-(23) THP=tetrahydropyranyl; R =o-phthaloyl Reagents i Br(CH,),Br; ii K+R=N; iii H+; iv MeO,CCH,COCl; v H,-S%Pd/BaSO, quinoline; vi Et,N TsN,; vii Cu bronze toluene boil 22 h; viii NH,NH,; ix HCl; x NaOMe; xi LiAIH Scheme 3 ( f1424) ( f1425) (f)-(26) Robins' group has developed useful syntheses of both the fully saturated necine bases and the physiologically active 1,2-unsaturated pyrrolizidine derivatives e.g.supinidine (27). 22*23 Their strategy involves the conversion of saturated 1-substi-tuted pyrrolizidines into the required 1,2-didehydro-compounds by thermal eli- mination of a phenylseleno-group. This approach is exemplified by the synthesis of (*)-suphidine (27) (Scheme 4).22 The thermodynamically less stable racemate of ethyl pyrrolizidine- 1-endo-carboxylate (28) was prepared in 80% overall yield using the method of Pizzorno and Alb~nico.~~ This involves regiospecific 1,3-dipolar cycloaddition of ethyl pro- piolate to the postulated azomethine ~lide~~ that is formed by heating N-formyl-L- 22 D.J. Robins and S. Sakdarat J.C.S. Perkin 2 1979 1734. 23 D. J. Robins and S. Sakdarat J.C.S. Chem. Comm. 1979 1181. 24 M. T. Pizzorno and S. M. Albonico J. Org. Chem. 1974,39,731. Biological Chemistry -Part (ii) Alkaloids (f)-(27) (31) Reagents i H,-10% PcIIC; ii Pri2NLi+ PhSeC1; iii LiAlH,; iv H202 Scheme 4 proline in acetic anhydride to give the dihydropyrrolizine ester (29) followed by catalytic hydrogenation. Selenylation of the lithium enolate derived from the ester (28) was readily accomplished with phenylselenium chloride to give the ester (30). Reduction with lithium aluminium hydride gave the derived primary alcohol (31); on treatment with hydrogen peroxide this gave (*)-supinidine (27). The stereo- chemistry of the intermediate phenylselenides (Scheme 4) is uncertain but the authors were able to show that elimination of the phenylselenyl group from (3 1)gave only the required 1,2-double bond and that no 1,8-didehydropyrrolizidine was produced.In an elegant extension of this procedure (Scheme 5) Robins et dZ3 have used the NO-diformyl derivative (32) to produce the chiral alcohol (33). Catalytic hydrogenation of (33) gave the crystalline pyrrolizidine alcohol (34) formed by stereospecific cis-addition of hydrogen to the less hindered @-face of (33). Replacement of the 6a-hydroxy-group of (34) by chlorine followed by catalytic hydrogenolysis gave the key optically active pyrrolizidine ester (35). Reduction of this ester with lithium aluminium hydride gave (+)-isoretronecanol(24) the overall yield of optically active product being 45% from the readily available (-)-4- hydroxy-L-proline.Epimerization at C-1of the thermodynamically less stable ester (35) was achieved with sodium ethoxide in ethanol and reduction of the product gave (+)-laburnine (36)* in 64% yield from (35). The ester (35) was also converted (in 21% overall yield) into (+)-supinidine (27) using the method outlined in Scheme 4; a higher overall yield was obtained when purification of intermediates was omitted. Although a natural (-)-4-hydroxy-~-proline can be converted into its enantiomer by epimerization of both chiral centre^,^' thus allowing the synthesis of the enan- tiomers of (+)-(24) (+)-(36) and (+)-(27) the authors devisedz3 a simpler pro- cedure which involved efficient isomerization of the chiral intermediate (33).The hydroxy-ester (+)-(33) was first converted into its tosylate derivative in high yield. 25 D. S. Robinson and J. P. Greenstein J. Biol. Chem. 1952 195 383. 388 D. G.Buckiey Reagents i SOCI,; ii H,-Raney nickel; iii LiAlH4; iv NaOEt EtOH; v steps ii-iv of Scheme 4 Scheme 5 Inversion of stereochemistry was then achieved by SN2 displacement with formate anion to give after hydrolysis the enantiomer of (33) required for conversion as outlined above into the 8a-pyrrolizidine bases ( -)-isoretronecanol [as (24)] (-)-trachelanthamidine [as (23)]* and (-)-supinidine [as (27)]. Ornithine putrescine and arginine have been shown26 to be specific precursors of retronecine (37) the most common necine-base portion of pyrrolizidine alkaloids e.g.retrorsine (38). Degradations of retronecine (37) derived biosynthetically from [S-14C]ornithine (39) [2-14C]ornithine [as (39)] or [1,4-'4C2]putrescine (40) demonstrated that in each case one quarter of the total radioactivity of the necine base was located at C-9 suggesting that C-2 and C-5 of the molecule of ornithine used to form ring B of retronecine (37) become equivalent (see Scheme 6). Further degradationsof the retronecine have been necessary to establish whether the second molecule of ornithine involved in the biosynthesis also passes through a symmetrical intermediate. Robins's group has now reported2' the first degradation designed to examine ring A. Their use of improved feeding techniques in these studies has led to much higher incorporations and to the identification of two new polyamine pre- cursors.* (+)-Laburnine (36)23 is the enantiomer of (-)-trachelanthamidine [as (23)];20*23 the racemate is named (f )-trachelanthamidine (23)." 26 E. Nowacki and R. U. Byerrum Life Sciences 1962 1 157; W. Bottomley and T. A. Geissman Phyrochemistry 1964,3,357; C. A. Hughes R. Letcher and F. L. Warren J. Chem.Soc. 1964,4974; N. M. Bale and D. H. G. Crout Phyrochemisrry 1975,14,2617. 27 D. J. Robins and J. R. Sweeney J.C.S. Chem. Comm. 1979,120. Biological Chemistry -Part (ii) Alkaloids Scheme 6 Good incorporations of precursors into retrorsine (38) were achieved27 by direct absorption through stem punctures in Senecio isatideus.These studies indicate that the best precursors for retronecine biosynthesis examined so far are putrescine (40) and the previously untested polyamines spermidine (41) and spermine (42). Putres- cine was found to be a much more efficient precursor than ornithine (39) thus supporting the theory28 that putrescine follows ornithine on the biosynthetic pathway. The necine base retronecine (37) obtained by basic hydrolysis of retrorsine (38) was degraded in two ways for experiments involving each of the precursors (39) (40) (41) and (42). One set of degradations showed that 25,24,23 and 22% of the total 14C activity was located at C-9 of retronecine (37) after incorporations of (39) (40) (4 l) and (42) respectively in agreement with previous results.26 Modified Kuhn- Roth of (37) gave p-alanine (43) isolated as its 2,4-dinitrophenyl derivative.This fragment corresponds to (C-5 +C-6 +C-7) of retronecine (37) (Scheme 6). In experiments involving the same precursors viz. (39) (40) (41) and (42) it was found that 22,22,23 and 24% respectively of the total 14Cactivity of retronecine (37) was located in this fragment. Robins et al. that these results taken together with earlier point to the involvement of a later symmetrical intermediate in the biosynthesis of retronecine (37) such as (44) derived from two molecules of putrescine (40). T. A. Geissman and D. H. G. Crout ‘Organic Chemistry of Secondary Plant Metabolism’ Freeman Cooperand Co. San Francisco 1969 p. 448. 29 Y.K.Ho R.N. Gupta D. B. MacLean and I. D. Spencer Canad.J. Chem. 1971,49,3352. 390 D. G.Buckley 4 fl -Phenethylamines and Isoquinoline Alkaloids During the 1960's the biosynthetic pathway to the Ipecac alkaloids e.g. cephaeline (45) and emetine (46) was found to be as outlined in Scheme 7.30*3' The non- dopamine portion was found to be derived from secologanin (47) formed by a fascinating cleavage of the monoterpenoid loganin (48). Condensation of seco- loganin (47) with dopamine then occurs to give one or both of the two possible basic glucosides desacetylipecoside (49a) and desacetylisoipecoside (50) epimeric at C-5 (terpenoid numbering). The correct isomer is then transformed in a number of steps into the various Ipecac alkaloids e.g. (45) and (46).It had been thought3' that the 5&isomer desacetylipecoside (49a) was the natural precursor of the Ipecac alkaloids even though this would require subsequent Desacetylisoipecoside(50) Desacetylipecoside (49a) R = H Ipecoside (49b) R = COMe J I/ dopamine Cephaeline (45) R=H Emetine (46) R=Me Scheme 7 30 A. R. Battersby and R. J. Parry Chem. Comm. 1971,901. 31 J. Staunton in 'The Alkaloids' ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London,1972 Vol. 2 p. 6. Biological Chemistry -Part (ii) Alkaloids 391 inversion of configuration at C-5. [The (5s)stereochemistry of desacetylipecoside (49a) follows unambiguously from an X-ray analysis of its 00-dimethyl deriva- Recent has now shown that the 5a-isomer desacetylisoipecoside (50) is the correct precursor of cephaeline (45) and emetine (46) in Cephaelis ipecacuanha not the 5P-isomer (49a); the 5P-isomer (49a) is the precursor of the 5P-basic glucoside ipecoside (49b).Since the 5a configuration of desacetylisoipe- coside (50)matches that of the corresponding centre in cephaeline (45) and emetine (46) it is now clear that this part of the biosynthetic pathway is stereochemically unexceptional. As part of his Manchester group’s biomimetic alkaloid syntheses R. T. Brown has developed34 a useful route to various Ipecac alkaloids e.g. cephaeline (45) and emetine (46). The Ipecac alkaloids are formed in vioo (in the main) by condensation of a dopamine or tryptamine residue with protoemetine (51) which itself is comprised of a dopamine residue and secologanin (47) (see Schemes 7 and 8); identical absolute configurations at C-2 and C-7 in (51) and (47) reflect this biosynthetic relationship.Brown’s synthetic strategy (Scheme 8) involves the conservation of stereochemistry at C-2 and C-7 of the natural precursor (47) an approach which avoids the problems of stereochemical control encountered in earlier syntheses3’ of the clinically important compound emetine (46). Methyl 3,4-dihydrosecoxyloganintetra-acetate (52) was prepared from seco- loganin (47) in 63% isolated yield.36 Zemplen deacetylation and enzymic removal of the sugar afforded the aglycone (53) which was treated with 2-(3,4-dimethoxy- pheny1)ethylamine and sodium cyanoborohydride to give the tetrahydropyridine (54a) in 42% overall isolated yield.34 The tetrahydropyridine (54a) had been obtained previously using a ‘one-pot’ procedure,37 albeit in lower yield.Careful analysis and chemical investigation established that the above procedure did not result in any significant inversion at C-2 to give the more stable trans-isomer (54b) itself available by prior equilibration of the aglycone (53) under basic conditions. Selective hydrolysis and decarboxylation of (54a) gave (59 which was converted into the protected pyridone aldehyde (56) in 85% yield with an excess of NN- dimethylhydrazine. Although this key intermediate (56) was used in two different ways to produce various types of related alkaloids,34 only the route to cephaeline (45) and emetine (46) is given in Scheme 8 Bischler-Napieralski cyclization subsequent reduction and hydrolysis of the NN-dimethylhydrazone afforded the unstable proto-emetine (5l) which has the illustrated natural (S) configuration at C-5 (terpenoid numbering).Pictet-Spengler condensation of (51)gave cephaeline (45) together with a smaller amount of isocephaeline (57). Subsequent treatment of (45) with diazomethane completed the synthesis of emetine (46). 32 0.Kennard P. J. Roberts N. W. Isaacs F. H. Allen W. D. S. Motherwell K. H. Gibson and A. R. Battersby Chem. Comm. 1971,899. 33 A. R. Battersby N. G. Lewis and J. M. Tippett Tetrahedron Letters 1978,4849. 34 R.T. Brown A. G. Lashford and S. B. Pratt J.C.S. Chem. Comm. 1979,367. ” Reviewed by A. Brossi S. Teitel and G.V. Parry in ‘The Alkaloids’ ed. R. H. F. Manske Academic Press New York 1971,Vol. XIII Ch. 3. 36 R. T. Brown C. L. Chapple D. M. Duckworth and R. Platt J.C.S. Perkin Z 1976 160. ” R. T. Brown and J. Leonard J.C.S. Chem. Comm. 1978,726. 392 D. G.Buckley OMe .OGlc ..OR ~ (47) (52) R=GIC(O-AC)~ 2-H (53) R=H (54a) a (54b) P lii,iii Me0 e/ ompH M 4-iv Meo2feNqMe 2=./ H-$H=NNMe OH (56) (55) 1v-vii viii,ix - Cephaeline (45) R = H; 9p-H (57) R=H; 9a-H Emetine (46) R = Me; 9B-H Reagents i 3,4-(OMe),C,H,CH,CH2NH,, NaCNBH, MeOH 15 min; ii 1% HCl-MeOH boil 1 h; iii Et3N; iv H,NNMe,; v POCI, C,H,Me; vi NaBH,; vii Cu(OAc), H,O; viii 3-OH,4-OMe- C6H3CH2CH2NH2, HOAc-H,O; ix [for (45) -b (46)] CHzNz Scheme 8 The unravelling of the biosynthesis of protostephanine (58)and of hasubanonine (59) has proved to be a long and difficult Previous investigations led to the conclusion that these alkaloids of Stephuniu juponicu are both constructed from two tyrosine-derived C6-Czunits.The unit which is the source of ring c and the attached ethanamine side-chain in (58) and (59) combines as (60)with the other Sixteen possible benzylisoquinolines synthesized formally from (60)and the acids (64) have been examined4' as precursors for (58) and (59). Of these the bases with 38 D. G.Buckley in ref. 1 p. 402; R. B. Herbert in ref. 3 pp. 8-10. 39 A. R. Battersby R. C. F. Jones R. Kazlauskas C. Poupat C. W. Thornber S. Ruchirawat and J. Staunton J.C.S. Chem. Comm. 1974,773.40 A. R. Battersby A. Minta A. P. Ottridge and J. Staunton Tetrahedron Letters 1977 1321. Biological Chemistry -Part (ii)Alkaloids O-methyl groups at C-8 and/or C-3’ [see (63)] were not incorporated but (63) as well as (61) and (62) were and specifically so where examined; the results also show that the timing of N-methylation is not critical. The biosynthesis indicated by these results is illustrated in Scheme 9. It is noteworthy that phenol oxidative coupling must occur on (63) itself and not an 0-methylated derivative of it and thus this pathway is unique in that two hydroxy-groups must be present on one ring for coupling to occur. The important conclusion is that protostephanine (58) and hasubanonine (59) are members of the large family of modified benzylisoquinoline alkaloids.OH Tyrosine OH OH OH (60) (61) (62) Me0 para-para -coupling Me0 Me0 O L L OH (63) d 0 OMe Protostephanine (5 8) Hasubanonine (59) = 14C; R = H or Me Scheme 9 New methods for the demethylation of codeine (65) to morphine (66),previously a capricious reaction have been reported the product being obtained in good yield in each case. Demethylation by boron tribromide in chloroform gives 90°/041 and by potassium t-butoxide in propanethiol gives 80% of Various methods have been developed to convert thebaine into codeinone and thence into codeine in K.C. Rice J. Medicin. Chem. 1977,20 164. 42 J. A. Lawson and J. I. DeGraw J. Medicin. Chem.. 1977 20 165. 394 D.G. Buckley Ro / C02H 9SNMe (64) R'=H R*=OH HO-' R'=R 1=OH Codeine (65) R=Me R1 =OMe R2 = OH Morphine (66) R=H R' = OH R2 =OMe high overall yield.43 Detailed investigations of the biotransformation of thebaine into codeine and morphine have continued and have shed new light on the mechanisms of the demethylation of codeine in ui~u.~~ 5 Erythrina and Homoerythrina Alkaloids The biosynthesis of the Erythrina alkaloids has been investigated in detail. Barton and Widdowson have that they are built up from two molecules of tyrosine (67) uia the 1-benzylisoquinoline norprotosinomenine (68) as outlined in Scheme 10. The key precursor erysodienone (71) is later modified in a variety of ways to generate the wide range of Erythrina alkaloids e.g. erythraline (72).'H OH OH M::% tt Me0 0 Me0 (71) OH Scheme 10 43 Reviewed by K. W. Bentley in ref. 2 pp. 112-114. 44 Reviewed by R. B. Herbert in ref. 3 pp. 8-10. 45 D. H. R. Barton R. B. Boar and D. A. Widdowson J. Chem. SOC.(C) 1970,1213; see also D. H. R. Barton R. D. Bracho C. J. Potter and D. A. Widdowson J.C.S. Perkin I 1974 2278 and refs. cited therein. Biological Chemistry -Part (ii)Alkaloids Synthetic studies have shown that erysodienone (71) can be prepared by phenol oxidative coupling of the amine (73).46 In a detailed investigation on model compounds Barton et al. later that this oxidation in vitro proceeded via an initial C-C coupling to give the biologically significant dibenzazonine (70). Subsequent oxidation to the diphenoquinone (74)and cyclization gave erysodienone (71) in 30% overall yield (Scheme 11).Thus unexpectedly formation of the nine-membered ring (70) must occur readily. Further model studies to investigate the structural requirements for formation of the intermediate dibenzazonine (70) have now been reported48 by Barton's group and their results support the mechanism outlined above. Their approach involved synthesis of the amide (79 ketone (76),and pentamethylene derivative (77) to investigate their reactions under various conditions designed to promote phenol oxidative coupling. 0 Y Me0 OH OH (73) X = CH2 Y = NH (75) X=CO,Y=NH (76) X = COYY = CH2 (77) X=Y=CHz (78) X=CO,Y=NH (81) X=Y=CHz (70) X = CHI Y = NH (80) X = COY Y = CHz (82) X=CO Y=NH (74) X = CH2 Y = NH (83) X = COY Y = CH2 Scheme 11 The amide (75) was prepared4* by mostly standard methods Oxidation with alkaline potassium hexacyanoferrate(II1) in chloroform and water gave the azoninone derivative (78) in 10-12% yield (allowing for recovered starting material); various modifications of the reaction conditions did not alter the yield significantly.Oxidation of (75)with vanadium oxychloride gave the product (78) in 16% yield. Oxidations with manganese dioxide (with or without silica as diluent) or the iron(II1) chloride-DMF complex [Fe(DMF),CI,]' [FeCl,]-gave no dibenz- azonine (78). In each case the structure of the product was shown to be that due to para-para phenol oxidative coupling and no product arising from ortho-coupling could be detected.However a dimeric product was also formed but in much lower yield and its structure was not determined. Having established that the dibenzazonine (78) was readily obtained from the bisphenol (73 phenol oxidative coupling of the nitrogen-free analogues (76) and (77) was then examined. The required ketone (76) was prepared via alkylation of the isocyanide (79a) with the iodide (79b) and subsequent oxidative hydrolysis and 46 J. E. Gervay F. McCapra T. Money G. M. Sharma and A. I. Scott J.C.S. Chem. Comm. 1966,142; A. Mondon and M. Ehrhardt Tetrahedron Letters 1966,2557. *'I D. H. R. Barton R. B. Boar and D. A. Widdowson J. Chem. Sac. (C),1970 1208. 48 A. G. M. Barrett D. H. R. Barton G. Franckowiak,D. Papioannou.and D. A.Widdowson J.C.S.Perkin I 1979,662. 396 D. G. Buckley PhcH20m2R1 Me0 \ (79a) R' = NC R2 = 4-MeC6HdS02 (79b)R' = H R2 = CH2I hydrogen~lysis.~' Huang-Minlon reduction of the intermediate protected ketone followed by deprotection gave the corresponding alkane (77). Phenol oxidative coupling of the keto-bisphenol (76) using alkaline potassium hexacyanoferrate(II1) under various conditions gave mostly polar material and a minor dimeric product. The use of 18-crown-6 as a phase-transfer catalyst increased the rate of reaction and traces of an additional compound were formed. However addition of cetyltriethylammonium bromide gave consistently good results both the dimeric product (10-14%) and the keto'dibenzazonine (80) (7-1 1%) were formed.Again no monomeric product arising from ortho-coupling was detected. In contrast the pentamethylene-bisphenol (77) gave mostly an intractable polar mix- ture on oxidation. Possibly unfavourable steric congestion prevented formation of the cyclononane (81),since McDonald49750 has shown that the presence of sp2 centres may greatly improve intramolecular phenol oxidative coupling reactions (see below). Clearly cyclizations in vitro of bisphenols to analogues of the erysodienone precursor (70) do not require a basic nitrogen function with a possible chelating or electron-transfer role. Unlike precursor (73) oxidation of (75) and (76) produced the cyclononane derivatives (78) and (go) respectively. These gave polar tars on further oxidation presumably because neither amide nor ketone functions could trap the corresponding diphenoquinones (82) and (83)intramolecularly and thereby prevent competing intermolecular reactions (see Scheme 1 1).Thus these results provide further strong evidence in favour of the intermediacy of the dibenzazonine (70) in the formation of erysodienone (71) in uitro. Recently a series of B-homoerythrina alkaloids e.g. schelhammeridine (84) has been found in plants of the genera Schelhammera and Cephalotaxus. It seems likely that these alkaloids are biosynthesized by a pathway analogous to that operating for the Erythrina alkaloids (Scheme lo) and in particular it is probable that the intermediates (85) and (86) are invol~ed.~' Furthermore the dibenzazecine (85) might also serve as a precursor of the more unusual Cephalotaxus alkaloids e.g.cephalotaxine (87)52(Scheme 12). No c-homoerythrina alkaloids have yet been reported though as McDonald has pointed these might reasonably be expected from the dibenzazecine (85) via the 6;6-fused dienone (88)* (see Scheme 12). * Closure of the ten-membered ring of (85) by oxidation and subsequent nucleophilic attack by nitrogen could lead to the formation of either two new six-membered rings as in the 6;6-fused dienone (88),or new five- and seven-membered rings as in the 5;7-fused dienone (86). 49 E. McDonald and A. Suksamrarn. J.C.S. Perkin I 1978,434. E. McDonald and A. Suksamrarn J.C.S. Perkin I 1978,440; preliminary communications E. McDonald and A. Suksamrarn Tetrahedron Letters 1975,4421,4425.See A. R. Battersby E. McDonald J. A. Milner S. R. Johns J. A. Lamberton and A. A. Sioumis Tetrahedron Letters 1975 3419. '' See J. N. Schwab M. N. T. Chang and R. J. Parry J. Amer. Chem. SOC.,1977,99,2368. Biological Chemistry -Part (ii) Alkaloids Me0 \ 0 Hoe$ 9 9 -i .L Meo8+H Me0 \OH MeO- in uitro) (89) Scheme 12 Kametani had found that oxidation of the amino-bisphenol (89) with alkaline potassium hexacyanoferrate(II1) gave in 4% yield a dienone presumably formed via (85),to which he initially assigneds3 the 6;6-fused structure (88). After further investigation he changed the assignment in favour of the 5;7-fused dienone McDonald et al. have now rep~rted~~'~' $he synthesis of the unknown c-homo- erysodienone (88).This synthesis,49 outlined in Scheme 13 is of major significance since it has led to a better understanding of some of the factors involved in oxidative coupling reactions of phen01s.'~ The authors had originally envisaged that the best route to the required dienone (88)would be the reduction of (go) deprotection and phenol oxidative coupling of the resulting bisphenol(91). However inspection of molecular models revealed a set of three 1,3-diaxial interactions between the substituents at the marked atoms in the intermediate (92). Thus they concluded that the desired intramolecular phenol oxidative couplings would be unlikely and that oxidation would favour inter-molecular coupling leading eventually to polymeric products.It was also evident that if one of the sp3-hybridized carbon atoms C-9 and C-11 were replaced by an sp2-hybridized atom two of the three troublesome interactions would be removed." The authors have now shown that these considerations are essentially correct. The N-acetyltetrahydroquinoline(93) was prepared in the protected form (90) using standard procedure^.'^ Reduction of (90) with lithium aluminium hydride gave the corresponding amine which gave the amino-bisphenol (91) on hy-drogenolysis. Oxidation of (9 1)under various conditions gave only complex mix- tures and none of the required dienone (88)could be detected. However phenol ''T. Kametani and K. Fukumoto Chem. Comm. 1968,26 T. Kametani and K. Fukumoto J. Chem. SOC.(C) 1968,2156. 398 D.G. Buckley oxidative coupling of the corresponding amide (93) gave the desired dienone (94) in high yield (up to 67%). Thus no matter what the mechanism of the overall phenol oxidative coupling reaction removal of steric interactions by the introduction of an sp2 centre can dramatically improve the yield of the desired intramolecular reaction. This finding may well prove to be highly significant for the synthesis of many natural prod~cts.~" The synthesis of the 6;6-fused dienone (88) was completed49 as shown in Scheme 13. Removal of the amide function was accomplished by a two-stage reduction of the protected dienone (95) to give the epimeric mixture of dienols (97) uia the lactam dienol mixture (96); direct reduction with lithium aluminium hydride gave the same epimeric mixture (97) but in lower yield.Oxidation of the dienol mixture (97) was troublesome and in all cases some of the 0x0-dienone (98) was produced often as the major product. The required dienone (99) was eventually prepared by careful oxidation of the mixed dienols (97) with Jones reagent albeit in low yield. The benzyl protecting group of (99) was removed cleanly using wet trifluoroacetic acid to give the phenolic 6;6-fused dienone (88) in essentially quantitative yield. The 5;7-fused dienone (86) was prepared readily4' from the 6;6-fused dienone derivative (94) as outlined in Scheme 14. Reductive cleavage of the dienone lactam (94)with chromium(I1) chloride in acidic aqueous acetone" gave the fragmentation MeO\@ O ROWo &HMeO\@PN M O q MeO' \ Me0 / \ ROW HO.Me0 (90) RzCHZPh (93) R=H 1iii RO mophcH20Fx Me0 \ 1% M il n 0 &H 0 (94) R=H (96) X=O (98) X=O (95) R=CHzPh (97) X=H2 (99) X=H2 1vi (88) Reagents i LIAIH,; ii H,-10% Pd/C; iii 1 1 CHCl,-5% NaHCO, K,[Fe(CN),]; iv NaBH,; v Jones oxidation 0 "C 45 s; vi 3 :1 CF,CO,H-H,O Scheme 13 '' D. H. R. Barton R. James G. W. Kirby D. W. Turner and D. A. Widdowson J. Chern.Soc. (C) 1968 1529. Biological Chemistry -Part (ii) Alkaloids OR OR - iv.v 1 ii,iii -* __* (94) Meo%H Me0 \OR OR (100) R=H (102) R = CHzPh (101) R = CHtPh (85) R=H Reagents i CrCI in 1 :2 Me,CO-3% HC1 N, 2 h; ii K,CO,-MeOH PhCH,Cl; iii; LiAlH,; iv H,-10% Pd/C HCI-MeOH; v 1 1CHCI,-S%NaHCO, K,[Fe(CN),] Scheme 14 product (100)” in 87% yield.Benzylation gave the lactam (101) which was reduced to the corresponding amine (102) with lithium aluminium hydride. Hydrogenolysis of (102) gave the diphenolic dibenzazecine (85),(a likely biosynthetic precursor of the Schelhamrneru alkaloids) in 44% overall yield from the 6;6-fused dienone (94). Two-phase oxidation of the bisphenol (85) with potassium hexacyanoferrate(II1) gave the 5;7-fused dienone (86) in 61% yield together with a trace of an unidentified product. Marino and Samanen have a different synthesis of the dibenzazecine (85). They obtained a 3 1 mixture of B-homoerysodienone (86) and c-homo- erysodienone (88) on oxidation of the bisphenol (85) using a slightly different two-phase system.Both of these studies in together with Kametani’s conversion of the open-chain bisphenol (89) intr P-homoerysodienone (86)54 (see above) provide firm supporting evidence for the possible biosynthetic origin of the Schelhummera and Cephalotuxus alkaloids suggested in Scheme 12. Furthermore oxidative cyclization of diphenolic dibenzazecines e.g. (85) appears to provide a regioselec- the4’ and efficient synthetic entry to alkaloids of the Schelhummeru type. 6 Terpenoid Indole Alkaloids Recent publications concerned with the role of vincoside (103) and strictosidine (isovincoside) (104)t in the biosynthesis of terpenoid indole alkaloids are clearly most significant. However this aspect is only a small part of the biosynthesis of these alkaloids and must be seen in this perspective.Extensive research on the elaboration of terpenoid indole alkaloids in whole plants by several research groups allowed a fairly clear picture of their biosynthesis to * The correct structure of this fragmentation product is as formulated in (100) (Scheme 14),in agreement with the spectral data given in ref. 49 for this product and its dibenzyl ether (101). The lactam carbonyl group has been misplaced in the structures given for these two compounds in ref. 49 (and the names used reflect these incorrect structures); E. McDonald personal communication. tTo simplify the literature it is best that (104) should be known as strictosidine6’ and (103) as vincoside. s6 J. P. Marino and J. H. Samanen J.Org. Chem. 1976 41 179. 400 D. G. Buckley be drawn. 57-59 Early results obtained using tissue cultures have provided useful supplementary evidence.60*61 The important building blocks had been shown to be secologanin (47) and tryptamine (105). 57*58 Chemical condensation of these two compounds affords vincoside (103) and strictosidine (104),62 which are epimeric at C-3 (Scheme 15). It had been thought that vincoside (103) with the 3p (R) stereochemistry was the natural precursor of indole alkaloids.63 This was puzzling because the first terpenoid indole bases to be formed have the 3a (S)configuration. A number of recent publications have been concerned with the solution of this a-pNH2 N H Tryptamine (105) + (In vlrro) -Vincoside (103) + MeO,C-u .OGlc Secologanin (47) Me0,Cn&o Strictosidine (104) Scheme 15 When [2-'4C]tryptamine and secologanin (47)were incubated with an enzyme preparation from a Catharanthus roseus (syn.Vinca rosea) cell culture in the presence of a P-glucosidase inhibitor or at low pH strictosidine (104) and not vincoside (103) was formed; the reaction was clearly en~yme-dependent.~~,~~ This crude enzyme preparation also converted labelled strictosidine (104) into ajmalicine (106) 19-epi-ajmalicine (107) and tetrahydroalstonine (108) in the presence of '' A. R. Battersby Pure Appl. Chem. 1967,14 117; A. R. Battersby in 'The Alkaloids' ed. J. E. Saxton (Specialist Periodical Reports) The Chemical Society London 1971 Vol. 1 p. 31. 58 For reviews see (a) G.A..Cordell Lloydiu 1974 37 219; (6)R. J. Parry in 'The Carhurunrhw Alkaloids' ed. W. I. Taylor and N.R. Farnsworth Dekker New York 1975 p. 141;(c)R. B. Herbert in 'Comprehensive Organic Chemistry' ed. D. H. R. Barton and W. D. Ollis Pergamon Oxford 1978 Vol. 5 p. 1045. See also 'The Alkaloids' (Specialist Periodical Reports) The Chemical Society London 1972-77 Vols. 2-7; R. B. Herbert in ref. 2 p. 27. 59 R. B. Herbert in ref. 3 p. 18. 'O A. I. Scott and S.-L. Lee J. Amer. Chem. Soc. 1975 97 6906; A. I. Scott S.-L. Lee and W. Wan Biochem. Biophys. Res. Comm. 1977,75 1004. J. Stockigt J. Treimer and M. H. Zenk F.E.B.S. Letters 1976 70 267; J. Stockigt H. P. Husson C. Kan-Fan and M. H. Zenk J.C.S. Chem. Comm. 1977,164. 62 G.N. Smith Chem.Comm. 1968,912; K.T.D. DeSilva G. N. Smith and K. E. Warren ibid.,1971,905. " A. R. Battersby A. R. Burnett and P. G. Parsons J. Chem. SOC.(C),1969 1193. " J. Stockigt and M. H. Zenk F.E.B.S.Letters 1977,79,233. J. Stockigt and M. H. Zenk J.C.S. Chem. Comm. 1977,646. Biological Chemistry -Part (ii) Alkaloids 401 NADPH. In the absence of NADPH cathenamine (109)was produced as noted previously6’ (see Scheme 16). Cell-free preparations from cell-suspension cultures of various plants known to produce terpenoid indole alkaloids were also found to convert secologanin (47)and tryptamine (105)into strictosidine (104);the formation of vincoside (103)was never Thus it became clear that it must be strictosidine (104) and not vincoside (103) which is the natural precursor of the terpenoid indole alkaloids.This finding was also confirmed for whole-plant bio~ynthesis.~’ Doubly-labelled strictosidine (104)was incorporated in C. roseus into representatives of the three main groups of alkaloids i.e. ajmalicine (106),serpentine (1 lo),vindoline (11l),and catharanthine (112) without significant changes of isotope ratio indicating that there was intact incorporation. In parallel experiments vincoside (103) was not utilized for alkaloid bio~ynthesis.~’~’ Vindoline (1 11) Serpentine (1 10) \I I HO N C0,Me io Catharanthine (112) Camptothecin (1 13) Many recent ~t~die~~~~~~*~~~~ have put the above finding beyond doubt. Furthermore camptothecin (113) which had previously been deduced to arise from strictosidine la~tam,~’ is now known to be derived initially from strictosidine (104).7’ Thus it is now clear that terpenoid indole alkaloids belonging to the Corynanthe (3a and 3p series) Aspidosperma and Iboga types from various plant families and related alkaloids are all derived from strictosidine (104),the first terpenoid indole base on the biosynthetic pathway to all such alkaloid^.^^ Further advances in our understanding of the biosynthesis of the heteroyohimbine and related alkaloids have now been made as a result of detailed studies with enzyme preparations from Catharunthusroseus cell Early work with such systems 66 A.I. Scott S. L. Lee P. de Capite M. G. Culver and C. R. Hutchinson Heterocycles 1977,7,979. 67 M. Rueffer N. Nagakura and M.H. Zenk Tetrahedron Letters 1978,1593. R. T. Brown J. Leonard and S. K. Sleigh Phytochemistry 1978,17 899. 69 N.Nagakura M. Ruffer and M. H. Zenk J.C.S. Perkin I 1979,2308. 70 C. R. Hutchinson A. H. Heckendorf P. E. Daddona E. Hagaman and E. Wenkert J. Amer. Chem. Soc. 1974,96,5609. A.H. Heckendorf and C. R. Hutchinson Tetrahedron Letters 1977,4253. 72 M. Rueffer C. Kan-Fan H.-P. Husson J. Stockigt and M. H. Zenk J.C.S. Chem. Comm. 1979,1016. 402 D. G. Buckley Tryptamine (105) + + --* QT%o Secologanin .OGlc (47) Me0,C \ Strictosidine (104) HO 4,21-Didehydrocorynantheinealdehyde (1 16) 1 N. H H* NADPH Cathenamine (109) HO 4,21-Didehydrogeissoschizine (1 14) NADPH 19-H20-H HO Ajmalicine (106) j3 P Geissoschizine (1 15) (107) a P (108) B a Scheme 16 had revealed61 the intermediacy of cathenamine (109) in ajmalicine biosynthesis.The clue to another important intermediate came from a study of the plant Guettardu eximiu (Rubiaceae) known73 to be a rich source of strictosidine (104),from which 4,21-didehydrogeissoschizine(114) was isolated.74 Chemical tran~formations~~ of (114) lead to either cathenamine (109) or geissoschizine (115). These biomimetic reactions reflect closely the postulated biosynthetic expectations of an intermediate located between 4,21-didehydrocorynantheine aldehyde (116) and cathenamine (109). 'I3 H.-P. Husson C. Kan-Fan T. Sevenet and J. P. Vidal Tetrahedron Letters 1977 1889. 'I4 C. Kan-Fan and H.-P. Husson J.C.S.Chem. Comrn. 1979,1015. Biological Chemistry -Part (ii) Alkaloids Rigorous studies7* with enzyme preparations from C. roseus cell cultures established 4,21-didehydrogeissoschizine(114) as an obligatory intermediate in the biosynthetic pathway to the heteroyohimbine alkaloids (Scheme 16). Furthermore it was shown that as well as being the immediate precursor of (log) 4,21- didehydrogeissoschizine is transformed under NADPH-regenerating conditions into geissoschizine (115) which is known not to be a direct precursor of ajmalicine (106) and its isomers (107) and (108).7’ The authors con~luded’~ that 4,21- didehydrogeissoschizine(114) occupies a crucial position at the branch point in the biosynthesis of the Iboga Aspidosperma and Corynanthe alkaloids.’* J.Stockigt J.C.S. Chern. Cornrn. 1978 1097

ISSN:0069-3030    

DOI:10.1039/OC9797600382

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

16 Biological Chemistry Part (iii) Insect Chemistry By R. BAKER and J. W. S. BRADSHAW Department of Chemistry The University Southampton SO9 5NH 1 Introduction Since the last Annual Report on this subject,’ the volume of literature on chemicals which mediate the behaviour and ecology of insects has increased particularly during 1979 and while the scope of this review remains similar to that of the 1977 Report it has proved necessary to limit coverage to the more detailed or important papers. A number of books and review articles have been published.2 2 Sex Attractants and Related Compounds The discovery of attractants for male moths from a number of well-studied families has now become a routine procedure and will not be reviewed here. The principle that the females of the majority of species produce more than one bioactive compound is well established and the Table (see pages 406 and 407)lists structures from a number of detailed examinations.The abdominal scent glands of female Bornbyx mori from which the first Lepi- dopteran sex pheromone i.e. (E,Z)-hexadeca-lO,l2-dien-l-ol(bombykol) was isolated in 1959 have been found to contain the analogous aldehyde (b~mbykal)~ and the (E,E)-isomer of the alcoh01.~ The first Lepidopteran potentially chiral female sex pheromone (1)has been reported from Adoxophyes orana fasciafa.’ No less than seven compounds all but one of them aldehydes have been isolated from I R. Baker and D. A. Evans Ann.Reports (B) 1977,74,367. ‘BiochemistryofInsects’ ed. M. Rockstein Academic Press London 1978;‘Arthropod Venoms’ ed.S. Bettini Springer Berlin 1978;E. Kramer Recept. Recognition Ser. B. 1978,5,231; J. Meinwald G.D. Prestwich K. Nakanishi and I. Kubo Science 1978,199,1167;R. Baker and D. A. Evans in ‘Aliphatic and Related Natural Product Chemistry’ ed. F. D. Gunstone (Specialist Periodical Reports). The Chemical Society London 1979,Vol. 1 p. 102;‘Chemical Ecology Odour Communications in Animals’ ed. F. J. Ritter Elsevier Amsterdam 1979;J. A. Pickett Educ. Chem. 1979,16,44. G.Kasang K. E. Kaissling 0.Vostrowsky and H. J. Bestmann Angew.Chem. Internut.Edn. 1978,17 60. G. Kasang D. Schneider and W. Schaefer Nutunviss. 1978,65,337. ’Y.Tamaki H. Noguchi H. Sugie R. Sato and A. Kariya Appl. Entomol. Zool. 1979,14 101. Biological Chemistry -Part (iii) Insect Chemistry the ovipositors of Heliothis uirescens and four from Heliothis zea6 A four-component pheromone has been demonstrated for a New World population of Grapholitha molest^,^ and the role of each component in mediating behaviour of males has been investigated in detail.' One of these four components dodecan-1-01 could not be detected in a French population of the same specie^;^ the role of ratios of (E)-and (Z)-dodec-8-en-l-y1 acetates in maintaining sexual isolation in four species of the genus has been demonstrated." Two forms of the European corn borer Ostrinia nubilalis which produce (and respond to) opposite (97 :3 and 4 :96)ratios of (2)-and (E)-tetradec- 11-en-1-yl acetates have been investigated biochemically" and genetically," to determine whether the differences in pheromones have led to reproductive isolation of the strains and hence to the formation of two species.Geographical variations in compositions of sex pheromones within a species are probably more widespread than the current literature indicates. Scent-scales on the wings of Pieris butterflies produce a mixture of terpenes (a-pinene P-pinene myrcene p-cymene limonene neral geranial and linalool) and n-undecane ;these compounds may be useful chemotaxonomic criteria.13 In the Coleoptera four compounds (2)-(5) isolated from the frass of female boll weevils (Anthonomus grandis) attract males in the lab~ratory.'~ Females of the pecan weevil Curculio caryae also produce (3)." The sex pheromone of the drugstore beetle Stegobium paniceum is reported as (6),16while that of the cigarette beetle Lasioderma serricorne is (7).17Further investigations of the sex pheromones of the dermestid Trogoderma granarium have shown that the (-)-(R)-isomers of (8a) J.A. Klun J. R. Plimmer B. A. Bierl-Leonhardt A. N. Sparks and 0.L. Chapman Science 1979,204 1328. A.M. Carde T. C. Baker and R. T. Carde J. Chem. Ecol. 1979,5,423. T. C. Baker and R. T. Carde Environ. Entomol. 1979,8,956. G. Biwer C. Descoins and M. Gallois Compt. rend. 1979,288,0,413. lo G. Biwer and C. Descoins Compt. rend. 1978,286,0,875. l1 R.T.Carde W. L. Roelofs R. G. Harrison A. T. Vawter P. F. Brussard A. Mutuura and E. Munroe Science 1978,199,555. l2 J. A. Klun and S.Maini Environ. Entomol. 1979 8,423. l3 N. Hayashi Y. Kuwahara and H. Komae Experientiu 1978,34,684. l4 P.A.Hedin G. H. McKibben E. B. Mitchell and W. L. Johnson J. Chem. Ecol. 1979 5,617. Is P.A.Hedin J. A. Payne T. L. Carpenter and W. Neal Environ. Entomol. 1979,8 521. l6 Y.Kuwahara H. Fukami R. Howard S. Ishii F. Matsumura and W. E. Burkholder Tetrahedron 1978 34 1769. l7 T. Chuman M. Kohno K. Kato and M. Noguchi Tetrahedron Letters 1979,2361. R. Baker and J. W. S. Bradshaw and (8b) are much less effective in inducing attraction of unmated males than are the (+)-(S)-isomers.18 A female-produced sex pheromone has been demonstrated in the Colorado beetle Leptinotarsa decemlineata. l9 The majority of the so-called sex pheromones of Diptera (true flies) operate as close-range or contact sex-recognition stimuli rather than as long-range attractants.The alkenes from the cuticle of the stable fly Stomoxys calcitrans have been described; that most active in inducing male copulatory behaviour is 13-methyl-Table Some female sex pheromones of Lepidoptera Parent Terminal chain functional length group ClO Acetate c12 Alcohol Acetate Acetate c14 (10-methyl) Alcohol Aldehyde (21-9(2)-11 (2,E)-9,12 - c16 Acetate Alcohol Aldehyde (21-7 (2)-9 (21-9 (2)-11 (2)-11 (E,E)-10,12 (E)-11 - c18 Acetate Alcohol Acetate (21-7 (21-9(2)-11 (E,Z)-10 12 (2)-11 (2,Z)-3,13 (2,Z)-3,13 R. Rossi P. A. Salvadori A. Carpita and A. Niccoli Naturwiss. 1979,66,211. l9 H. Z. Levinson A. R. Levinson andT.L. Jen Nuturwiss. 1979,66,472. Biological Chemistry -Part (iii) Insect Chemistry 407 Species A Agrotis segetum; B A. fucosa; C Grapholitha molesta; D Homona cofearia; E,Rhyacionia subtropica; F,Hedya nubiferana ; G Cnephasia pumicana; H Spodoptera frugiperda; I Homona magnanima ; J Agrotis ipsilon ; K,Adoxophyes orana ; L Homoeosoma electellum ; M. Choristoneura rosaceana ; N Pandemis heperana ; 0,Heliothis (Helicouerpa) oirescens; P Prays oleae; Q Tortrix viridana; R,Chilo partellus; S Chrysoteuchia topiaria; T Bombyx mori; U,Heliothis (Helicoverpa) zea ; V Plutella xylostella ; W Manduca sexta ; X Mamestra brassicae; Y,Aegeria tibialis. (a) H. J. Bestmann 0. Vostrowsky K. H. Koschatzky H. Platz T. Brosche I. Kantardjiew M. Rheinwald & W.Knauf Angew. Chem. Znternar. Edn. 1978 17 768;(6) S. Wakamura Appl. Enromol. Zool. 1978 13 290;(c) A. M. Carde. T. C. Baker & R. T. Carde I.Chern. Ecol. 1979 5 423;(d) J. P.Kochansky W. L. Rwlofs & P. Sivapalen ibid. 1978 4 623; (e) G. Biwer C. Descoins & M. Gallois Camp?. rend. 1979 288 D 413;(f) W.L.Roelofs A. S.Hill C. W. Berisford & J. F. Godbee Enuiron. Entomol. 19798 894;(g) B. Frerot E. Priesner & M. Gallois Z. Narurforsch. 1979 34c 1248; (h) G. Biwer C. Descoins M. Gallois. E. Priesner. J. P. Chambon G. Genestier & M. Martinez Ann. Zoo1.-Ecol. Anim. 1978 10 129;(i) R. L.Jones & A. N. Sparks J. Chem. Ecol. 1979 5 721;(i)H.Noguchi Y. Tamaki & T.Yushima Appl. Enromol. Zool. 1979 14 225;(k)A. S.Hill R. W.Rings S.R. Swier & W. L. Roelofs J. Chem. Ecol. 1979 5 439;(I) Y.Tamaki H. Noguchi H. Sugie R. Sato & A. Kariya Appl. Entomol. 2001.1979 14 101;(m) E.W. Underhill A. P. Arthur M. D. Chisholm & W. F.Steck Enuimn. Entornol. 19798740;(n) A. S. Hill & W. L. Roelofs J. Chem. Ecol. 1979 5 3;(0) B. Frerot M. Gallois & J. Einhorn Compr. rend. 1979 288 D 1611;(p) J. A. Klun J. R. Plimmer. B. A. Bierl-Leonhardr A. N. Sparks & 0.L. Chapman Science 1979 204 1328;(4)D.G. Campion L. J. McVeigh J. Polyrakis. S.Michaelakis G. N. Stravrakis P. S.Beevor D. R. Hall & B. F. Nesbitt Experientia 1979 35 1146;M. Renon C. Descoins E. Priesner M. Gallois & M. Lettere Compt. rend. 1979 288 D 1559;(r) H. Am E. Priesner H. Bogenschutz H. R. Buser D. L. Struble S.Rauscher & S.Voerman 2.Naturforsch.1979 34c 1281; (s) B. F. Nesbitt. P. S. Beevor D. R. Hall R. Lester J. C. Davies & K. V. S. Reddy I. Chem. Ecol. 1979 5 153; (I) L. M. McDonough & J. A. Kamm ibid. 1979 5 211;(u) G. Kasang D.Schneider & W. Schaefer Narunviss. 1978 65 337;(u) Y.S. Chow Y. M. Lin & C. L. Hsu Bull. Ins?. Zool. Acad. Sin. 1977 16 99;(w) G.Kasang K. E. Kaissling 0. Vostrowsky & H. J. Bestmann Angew. Chem. Inrernar. Edn. 1978 17 60;(x) A. N. Starratt K. H. Dahm N. Allen J. G. Hildebrand T. L. Payne & H. Roeller Z. Naturforsch. 1979 34c 9;(y) H. J. Bestmann 0. Vostrowsky K. H. Koschatzky H. Platz & A. Szymanska Tetrahedron Letters 1978 605; Y.Hirai H. Kimura. K. Kawasaki & Y. Tamaki Appl. EntomoI.Zool. 1978 13 136;(z)E.W.Underhill W. Steck M. D. Chisholm H. A. Worden & J. A. G. Howe Canad. Entomol. 1978 110 495. tritriacont- 1-ene and the activity is enhanced by adding (Z)-hentriacont-g-ene and the previously reported 11-methylhentriacontane.20The appearance with increas- ing age of sex-specific hydrocarbons in females of Fannia species and their effects in stimulating male copulatory behaviour have been reported.21 The three most active compounds in the sex pheromone of the tsetse fly Glossina morsitans i.e. (9a) (9b) and may derive from a mixed isoprenoid and polyketide biosynthesis. Chemoreception of these compounds in this species probably occurs uia the feet (tarsi) rather than the antennae.22 A contact mating pheromone has also been reported in the biting midge Culicoides melleus; the most active hydrocarbons from the cuticle are monomethyl-docosanes and -trico~anes.~~ Hexanal isolated from whole extracts of Sarcophugu bullara attracts females but not males of this species and is thus a possible long-range sex pheromone.24 The structure of the major sex pheromone of the cockroach Peripluneta americana has been confirmed as (lR 2R 7S,10R)-(5E)-1,2:10,14-diepoxygermacra-4(15),-2o P.E. Sonnet E. C. Uebel W. R. Lusby M. Schwarz and R. W. Miller J. Chem. Ecol. 1979,5,353. 21 E. C. Uebel M. Schwarz R. E. Menzer and R. W. Miller J. Chem. Ecol. 1978,4 73; E. C. Uebei M. Sctwarz R. W. Miller and R. E. Menzer ibid. p. 83. 22 D. A. Carlson P. A. Langley and P. Huyton Science 1978 201 750 23 J.R. Linley and D. A. Carlson J. Insect Physiol. 1978,24 423. 24 J. E. Girard. F.J. Germino J. P. Budris R. A. Vita and M. P. Garrity J. Chem. Ecol. 1979 5 125. R. Baker and J. W. S. Bradshaw 5-dien-9-one (11),25 and the absolute configuration has been assigned by a c.d. study of the corresponding A second compound (12) isolated from the excreta of the same species may be a natural degradation produ~t.~' One component of the sex pheromone of BZateZZa germanica has been shown to be the (S,S)-isomer of 3,l 1-dimethylnonacosan-2-one,but a mixture of epimers is reported to have the same behavioural effect as the single isomer produced by this coakroach.28 The female-produced sex pheromones of two species of scale insect have been shown to be related structures.Those of AonidielZa aurantii the California red scale are (13) and (14),2g and (15) has been isolated from A. citrina the yellow scale.3o Compounds specific to males have been isolated from the abdominal glands of certain true bugs (Heteroptera). The dorsal abdominal glands of Posidus maculi- uentris contain representative compounds from aliphatic terpenoid and aromatic pathways.31 A wide range of aromatics is found in the ventral abdominal gland of some Leptoglossus species together with octan-1-01.~~ 25 C. J. Persoons P. E. J. Venviel E. Talman and F. J. Ritter J. Chem. Ecol. 1979 5 221. 26 M. A. Adams K.Nakanishi W. C. Still E. V. Arnold J. Clardy and C. J. Persoons J.Amer. Chem. SOC. 1979,101,2495. '' E. Talman P.E. J. Verwiel F .J. Ritter and C. J. Persoons Israel J. Chem. 1978 17 227. 28 R. Nishida Y.Kuwahara H. Fumaki and S. Ishii J. Chem. Ecol. 1979 5 289. 29 W. L. Roelofs M. J. Gieselmann A. Carde H. Tashiro D. S. Moreno C. A. Henrick and R.J. Anderson J. Chem. Ecol. 1978,4 211; H. Tashiro M. J. Gieselmann and W. L. Roelofs Environ. Entomol. 1979,8 931. 30 M. J. Gieselmann D. S.Moreno J. Fargerlund H. Tashiro and W. L. Roelofs J Chem.Ecol. 1979,5 27. 31 J. R. Aldrich M. S.Blum H. A. Lloyd and H. M.Fales J. Chem. Ecol. 1978,4 161. 32 J. R. Aldrich M. S.Blum and H. M. Fales J. Chem. Ecol. 1979,5 53. Biological Chemistry -Part (iii) Insect Chemistry 409 3 Aggregation Pheromones and Population Attractants Most of the studies in this area are concerned as in previous years with bark beetles (S~olytidae).~~ As in the Lepidoptera population differences in pheromone chem- istry have been established for a few species; in Dendructunus pseudutsugue popu-lations from W.Oregon and Idaho produced different spectra of volatiles including two compounds new to this group on insects i.e. pent-3-en-1-01 and 6-(or 4-) methylhept-5-en-2-one. Cross-feeding tests indicated that the population differences were host-determined rather than No neurophysiological differences were found between chemically distinct populations of Ips ~ini.~~ cis-Verbenol has been added to the aggregation pheromone blend of I.ucuminatus. The (S)-isomers of cis-verbenol and ipsdienol attract this species whereas the enan- tiomers suppress this response.36 Females of Dendructunus jeffreyi produce heptan- 1-01 and heptan-2-01 and these together with heptane from the host constitute the aggregation pheromone of this species3’ Volatiles trapped from logs of Ulmus prucera that were infested with Sculytus sculytus include ( -)-threu-and ( -)-erythru-4-methylheptan-3-01 the former being produced only by the Males of the dermestid beetle Demzestes maculatus produce a unique blend of isopropyl esters in a subepidermal abdominal gland.The secretion of this gland attracts both males and female^.^' An aggregation pheromone and possibly an alarm pheromone are produced by certain stages of the subsocial bug Oncupeltus fasciat~s.~’ 4 Chemistry of the Hymenoptera The Hymenoptera exhibit the full range of sociality from completely solitary species to the advanced social forms such as certain bees wasps and the ants.From the sawflies (Symphyta) a relatively primitive group adults of both sexes of Neudipriun sertifer contain (16);41this is produced separately from the sex pheromone. Macro- cyclic lactones such as 18-octadecanolide and the Czo,CZ2,and c24 homologues together with the corresponding o-hydroxy-acids have been reported from Dufour’s gland in several genera of halictine4’ and C01letes~~ bees. In the latter genus at least the brood cells are lined with a polyester derived from these hydroxy-acid~.~~ The mandibular glands of several species from the same genus contain linalool neral and geranial which serve as aggregation pheromone~.~~ A 33 M.C. Birch Amer. Sci. 1978,66,409; K. Beck J. Chem. Educ. 1978,55 567. 34 L. C. Ryker L. M. Libbey and J. A. Rudinsky Environ. Entomob 1979,8 789. 35 M. E. Angst and G. N. Lanier J. Chem. Ecol. 1979,s. 131. 36 A. Bakke Oikos 1978 31 184. 37 J. A. A. Renwick and G. B. Pitman Environ. Entomol. 1979,8 40. M. M. Blight L. J. Wadhams and M. J. Wenham Insect Biochem. 1978,8 135; ibid. 1979 9 525. 39 H. Z. Levinson A. R. Levinson T. L. Jen J. L. D. Williams G. Kahn and W. Francke Nuturwiss.,1978 65,543; W. Francke A. R.Levinson T. L. Jen and H. Z. Levinson Angew. Chem. Internat. Edn.. 1979 18,796. 40 T. Aller and R. L. Caldwell Physiol. Entomol.. 1979 4 287. 41 G.Ahlgren G. Bergstrom J. Lofqvist A. Jansson and T. Norin J. Chem. Ecol. 1979 5 309. 42 A. Hefetz M.S. Blum G. C. Eickwort and J. W. Wheeler Comp. Biochem. Physiol. 1978,61B 129; G. Bergstrom and J. Tengo Acta Chem. Scand. (B),1979,33,390. 43 A. Hefetz H. M. Fales and S. W. T. Batra Science 1979 204 415. 44 G. Bergstrom and J. Tengo J. Chem. Ecol. 1978,4,437;A. Hefetz S. W. T. Batra and M. S.Blum Experientia 1979. 35 319. R. Baker and J. W. S. Bradshaw cephalic secretion from the non-social sphecid wasp Sceliphron caemenfarium contains geranyl acetate and dec-2-en-1-01 the latter a novel compound in arthro- pod~.~~ Straight-chain alkanes and esters and two sesquiterpene acetates have been identified from various species of anthophorid bees? the Dufour’s gland of Xylocarpa virginica is used to mark flowers and is a short-term repellent for con~pecifics.~~ The complex secretions of the mandibular gland of bumble bees in this case several species of Alpinobombus have received further attention.48 Additional compounds have been reporfed from the stings of honeybees Apis mellifer~,~~ and the alarm pheromone from this source in A.dorsata and A. florea is dec-2-en-1-yl a~etate.~’ Abdomens of the social wasp Paravespula uulgaris contin both (E)-and (2)-isomers of the spiro-ketals (17)and (18) which may serve to protect individuals from attacks by their sister A brood-warming pheromone (2)-pentacos- g-ene has been identified from pupae and brood cells of the hornet Vespa ~rabro.~~ R’ (16) (17) R’=H,R2=Me (18) R’=Me,R2=H (19) a; R’=R2=R3=R4=Me b; R’+R2=Me+Et,R3=R4=Me c; R’ = R2 = Et R3+R4 = Me+Et The ants (Formicidae) continue to be studied in detail.Reviews of chemistry chemical communication and chemosystematics have been p~blished.’~ The species Myrmica scabrinodis has been investigated and its pheromones have been compared to those of M. r~bra.~~ The Dufour’s gland of the former contains the terpenoids (19a) (19b) and (19c) which may be used in the marking of territories. Alkyl- pyrazines have been reported from a number of species. The leaf-cutting ant Atta sexdens rubropilosa produces (20) as a trail pheromone,” and related structures have been reported from ponerine antss6 and an un-named species of CaZomyrme~.~~ The latter produces a highly complex secretion from the mandibular glands including ” A.Hefetz and S. W. T. Batra Experientiu 1979,35 1138. 46 S. W. T. Batra and A. Hefetz Ann. Entomol. SOC. Amer. 1979 72 514. 47 S. B. Vinson G. W. Frankie M. S. Blum and J. W. Wheeler J. Chem. Ecol. 1978,4 315. 48 B. G. Svensson and G. Bergstrom J. Chem. Ecol. 1979,5603. 49 M. S. Blum H. M. Fales K. W. Tucker and A. M. Collins J. Apicultural Res. 1978 17,218. H. J. Veith J. Weiss and N. Koeniger Experientia 1978 34,423. ” W. Francke G. Hindorf and W. Reith Angew. Chem. Internat. Edn. 1978 17,862. ’* H. J. Veith and N. Koeniger Nuturwiss. 1978,65 263. ’’ K. Parry and E. D. Morgan Physiol. Entomol. 1979,4,161; B. Holldobler Ado. Study Behao. 1978,8 75; J. M. Brand Biochem. Syst. Ecol. 1978,6 337. ” E. D. Morgan M. R. Inwood and M. C. Cammaerts Physiol. Entomol, 1978,3,107; E.D. Morgan K. Parry and R. C. Tyler Insect Biochem. 1979,9,117; M. C. Cammaerts,M. R. Inwood E. D. Morgan K. Parry and R. C. Tyler J. Insect Physiol. 1978,24,207. ’’ J. H. Cross R. C. Byler U. Ravid R. M. Silverstein S. W. Robinson P. M. Baker J. Sabino de Oliveira. A. R. Jutsum and J. M. Cherrett J. Chem. Ecol. 1979.5 187. ” C. Longhurst R. Baker P. E. Howse and W. Speed J. Insect. Physiol. 1978,24 833. ” W. V. Brown and B. P. Moore Insect Biochem. 1979,9,451. Biological Chemistry -Part (iii) Insect Chemistry 411 pyrazines monoterpenes and three compounds novel to insects i.e. the aldehydes (21) and (22) and the lactone (23). The lactone is found in males only and is probably a sex pheromone. A compound more typical of Lepidoptera (2)-hexadec- 9-enal is reported to be an aggregation pheromone of the Argentine ant Irido-myrmex humili~.~' The chemical alarm communication systems of the African weaver ant Oeco-phylla longinoda have been studied in Major workers produce hexanal hexan-1 -01 undecan-3-one and (24) in their mandibular glands and after emis- sion from the gland these components form a complex sequential message in both space and time.59 Variations in the composition of the contents of the manibular gland are apparent between major workers collected in different areas between major and minor worker castes and between the workers and the males; the latter produce acids including (25a) and (25b).60 The mandibular gland chemistry of a number of other species of West African ants has been investigated and correlated with the ease of their detection by prey species of termite.This phenomenon has been termed chemical crypsis.62 A specialized termite predator Megaponera foetens produces sulphides including benzyl methyl sulphide in its mandibular glands and uses these with the poison-gland secretion to co-ordinate raids on termite CHO RmCo2H)q+ (24) (25) a; R=Me b; R=Et 5 Defence Secretions A large number of complex and diverse structures have been reported from the defence secretions of insects. Some of the most complex structures come from termites; chemical defence in this Order has been reviewed.64 Three macrocyclic diterpenes inluding cubitene (26)65 and (32)-cembrene A (27),66have been isolated from the secretion of the frontal gland of soldiers of Cubitermes umbratus.Novel " G. W. K. Cavill P. L. Robertson and N. W. Davies Experientiu 1979,35,989. s9 J. W. S. Bradshaw R. Baker and P. E. Howse Physiol. Entomol. 1979,4 15. 6o J. W. S. Bradshaw R. Baker P. E. Howse and M. D. Higgs Physiol. Entomol. 1979,4,27 61 J. W. S. Bradshaw R. Baker and P. E. Howse Physiol. Entomol. 1979,439. 62 C. Longhurst R. Baker and P. E. Howse Experientiu 1979,35870. 63 C. Longhurst R. Baker and P. E. Howse J. Chem. Ecol. 1979,5,703. 6o G. D. Prestwich J. Chem. Ecol. 1979,5,459. " G. D. Prestwich D. F. Wiener J. Meinwald and J. Clardy J. Amer. Chem. SOC. 1978,100 2560. 66 D. F. Wiemer J. Meinwald G. D. Prestwich and I. Miura J. Org. Chem. 1979 44 3950. 412 R.Baker and J. W.S. Bradshaw diterpenes of the trinervitene type have been found in Trinerviterrnes grati~sus~~ and Nasutitermes rippertii.68 The frontal gland of soldiers of the latter species also contains monoterpenes that function as alarm pheromone~.~’ Nasutitermes uctupilis produces the novel tetracyclic diterpenes (28a) and (28b).” Compounds previously found in both Trinervitermesand Nasutitermes occur in Grullatutermes africanus and confirm the taxonomic relationship between these three gene~a.~’ Novel sesquiter- penes have been elucidated in Ancistrotermes cavithorax ;(29) is characteristic of the minor soldiers while (30) is produced by major Four additional terpenes have been found in Amitermes ezluncifer including (31) (32a) and (32b).73 a..Rl R2 (28) a; R=H b; R=OAc The defence secretions of beetles (Coleoptera) have also received considerable attention.The range of species in which any particular compound occurs has been found both to complement74 and disagree with7’ the conventional classification of those species. Several novel steroid pyrones have been isolated from the fireflies Phutinus ignitus P. marginellus and P. pyralis including (33). These compounds are responsible for the unpalatibility of these beetles to birds.76 A chrysomelid beetle Chrysolina coerulans produces the cardenolides (34a) and (34b) which it does not derive directly from cardenolides in its food plants7’ Chrysomelidial and its enol lactone have been reported from a second species of leaf beetle Gastruphysa 67 G.D. Prestwich Experientia 1978.34.682. “J. Vrkoc M. Budesinsky and P. Sedmera Coil. Czech. Chem. Comm. 1978,43,1125. 69 J. Vrkoc J. Krecek and I. Hrdy Acta Entomol. Bohemoslou. 1978.75 1. 70 G. D. Prestwich J. W. Lauher and M. S. Collins Tetrahedron Letters 1979,3827. 71 G. D. Prestwich Insect Biochem. 1979,9,563. 72 R. Baker P. H. Briner and D. A Evans J.C.S. Chem. Comm. 1978,410. 73 R. Baker D. A. Evans and P. G. McDowell Tetrahedron Letters 1978,4073. 74 K. Dettner Biochem. Syst. Ecol. 1979,7 129. 7s B. P. Moore and W. V. Brown Insect Biochem. 1978,8,393. 76 T.Eisner D. F. Wiemer L. R. W. Haynes and J. Meinwald Proc. Nut. Acad. Sci. U.S.A. 1978,75905; M. Goetz D. F. Wiemer L. R. W. Haynes J. Meinwald and T. Eisner. Helu. Chim. Acta 1979,62 1396; J.Meinwald D. F. Wiemer and T. Eisner J. Amer. Chem. SOC. 1979,101,3055. 77 D. Daloze and J. M. Pasteels J. Chem. Ecol. 1979,5,63. Biological Chemistry -Part (iii) Insect Chemistry 413 0 HO RZ (33) (34) a; R~=OH,R*=H b; R'=H,R2=OH c~anea.~'A tenebrionid beetle Apsena pubescens uses inter alia 8-hydroxy-isocoumarin and 3,4-dihydro-8-hydroxycoumarinin a defensive p-Cresol and phenol constitute the defensive secretion of the Malayan cock- roach.80 Larvae of the moth Schizuru concinna produce formic acid decyl acetate dodecyl acetate and tridecan-2-one in their thoracic defensive glands;81 such a blend of compounds is normally considered typical of the defensive secretion of formicine ants. 6 MiscellaneousCompounds A number of compounds have been isolated from insects which are not readily categorized under the headings above.The unusual P-triketones (35a) and (35b) are found in the larval mandibular glands of the moth Anagasta kuehniella;82 the secretion of these glands is a repellant to other larvae. The wax of coccids has proved 00 R (35) a; R=OH b; R=H (36) (37) " M. S. Blum J. B. Wallace R. M. Duffield J. M. Brand H. M. Fales and E. A. Sokoloski J. Chem. Ecol. 1978,4,47. 79 H. A. Lloyd S. L. Evans A. H. Kahn W. R. Tschinkel. and M. S. Blum Insect Biochem. 1978,8,333. U. Maschwitz and Y. P. Tho J. Chem. Ecol. 1978,4 375. J. Weatherston J. E. Percy L. M. MacDonald and J. A. MacDonald J. Chem. Ecol. 1979,5 165. 82 A.Mudd J.C.S. Chem. Comm. 1978 1075.R. Baker and J. W.S. Bradshaw to be a fruitful source of novel sesterterpenes including (36)and (37).83Two species of coccids collected from the same tree were found to produce different enan- tiomers of the same terpene~.~~ Oviposition of female house longhorn beetles Hylutrupes bajulus is stimulated by ( -)-verbenone synergized by p-cymen-8-01 which were extracted from the larval boring Previously infested timber is therefore a preferred site for egg-laying. The opposite is true of certain fruit flies which deposit an oviposition-deterring pheromone from their ovipositors;86 in one case the same secretion acts as an oviposition stimulant for a para~itoid.~~ The alerting pheromone of a mite Tyruphagus putrescientiae has been identified as (38).88 CO,Me O+=OMe Oyy ' OH 0 (38) (39) AcO (42) R=H (43) R=OAc 83 J.S. Calderon L. Quijano and T. Rios,Experientia 1978,34,421; T. Kusimi T. Kinoshita K. Fujita and H. Kakisawa Chem. Letters 1979 1129; F. Miyamoto H. Naoki T. Takemoto and Y. Naya Tetrahedron 1979,35,1913. Y. Naya F. Miyamoto and T. Takemoto Experientia 1978,34,984. M. D. Higgs and D. A. Evans Experientia 1978,34,46. R. J. Prokopy J. R. Ziegler andT. T. Y. Wong J. Chem. Ecol. 1978,4 55. R. J. Prokopy and R. P. Webster J. Chem. Ecol. 1978,4,481. Y. Kuwahara Shokubutsu Boeki 1978,32,62. Biological Chemistry -Part (iii) Insect Chemistry 415 7 Antifeedants Antifeedant insecticidal and hormonal effects have been reported from a number of plant constituents.The following are representative structures for which antifeedant properties have been demonstrated. Compounds active against Spodoptera exempta include xylomollin (39)89and schkuhrin (40).9" Feeding of the flour beetle Tri-bolium confusum is reduced in a concentration-dependent way by alantolactone (41) found in many members of the Compo~itae.~' Two novel 7,8-seco-tetra- nortriterpenoids (42) and (43) are antifeedants for the Mexican dried bean beetle Epilachna vari~estis.~~ The resistant pasture legume Lotus pedunculatus produces (-)-(3R)-vestitol (44) which is a feeding deterrent for the beetle Costelytra ~ealandica.~~ 8 Biosynthesis and Biotransformation Elucidation of the pathways of synthesis for the terpenoid pheromones of bark beetle has continued.In a particularly elegant study deuterium labelling was used to study the interconversions of ipsdienol ipsenol and ipsdienone in Ips paraconfus~s.~~ The first two of the compounds mentioned have also been investigated in other species where their production from myrcene is stimulated by analogues of juvenile horm~ne.~'The oxidation of a-pinene in Dendroctonus terebrans is achieved by inducible microsomal enzymes.96 The sex pheromone of Bombyx mori is apparently present in the haemolymph of the female pupa and adult in an inactive form probably bound to a Similar phenomena may account for the low titre of free pheromone found in some other species. Incorporation of ['4C]acetate into all parts of (Z)-dodec-7-en-l-y1 acetate in the moth Trichoplusia ni has been in contrast labelled acetate is incorporated preferentially into the acetate moiety of decyl acetate in the ant Formica ~chaufussi.~~ Biosynthesis of formic acid in Camponotus pennsylvanicus occurs via tetrahydrofolate derivatives from serine glycine or histidine.'" 9 Chemoreception Perception of pheromones and related compounds by insects is studied from several aspects;lo' only those directly concerned with insect chemistry will be considered here.Pheromone mimics have been shown to be sensitive probes of specialized 89 M. Nakane C. R. Hutchinson D. VanEngen and J. Clardy J. Amer. Chem. Soc. 1978,100,7079. 90 M. J. Pettei I. Miura I. Kubo and K. Nakanishi Heterocycles 1978 11,471.91 A. K. Picman R. H. Elliott and G. H. N. Towers Biochem. Sysr. Ecol. 1978,6 333. 92 W. Kraus W. Grimminger and G. Sawitzki Angew. Chem. Internat. Edn. 1978,17,452. 93 G. B. Russell 0.R. W. Sutherland R. F. N. Hutchins and P. E. Christmas J. Chem. Ecol. 1978,4,571. 94 R. H. Fish L. E. Browne D. L. Wood and L. B. Hendry Tetruhedron Letters 1979 1465. 95 C. M. Harring 2. Angew. Entomol. 1978 85 281; J. A. A. Renwick and J. C. Dickens Physiol. Entomol. 1979 4 377. 96 R. A. White R. T. Franklin and M. Agosin Pestic. Biochem. Physiol. 1979,10 233. 97 K. Hayashiya M. Kitao A. Yamazaki M. Kumazawa Y. Okeda and J. Nishida Appl. Entomol. Zool. 1979,23,28. 98 I. F. Jones and R. S. Berger Environ. Entomol. 1978,7,666. 99 R. A. Graham J. M. Brand and A.J. Markovetz Insect Biochem. 1979,9,331. loo A. Hefetz and M. S. Blum Science 1978 201,454; Biochim. Biophys. Acta 1978,543,484. lo' 'Neurotoxicology of Insecticides and Pheromones' ed. T. Narahashi Plenum New York 1978; W. D. Seabrook Ann. Rev. Entomol. 1978 23,471; W. Roelofs Chemtech. 1979,9 222. R. Baker and J. W.S. Bradshaw chemoreceptors. A chiral analogue of the pheromone of the red-banded leaf -roller Argyrotaenia velutinana has been used to differentiate between stereochemically distinct receptor sites for the same (achiral) pherornone.lo2 A photoaffinity-labelled pheromone mimicTo3 and crown polyethers'm have also been used to study percep- tion mechanisms. The behavioural and neurophysiological effects of enantiomers of natural pheromones have been found to vary considerably between species.'os A threshold hypothesis for pheromone perception has been advanced to account for some hitherto anomalous results from trapping Lepidopteralo6 when sex pheromones were used as the lure.10 Techniques of Micro-scale Structure Elucidation The trapping of insect-derived compounds from the vapour phase has been improved by two new methods the one utilizing Tenax as the collecting medium"' and the other a molecular sieve followed by bromination of unsaturated compounds and analysis on a gas chromatograph fitted with an electron-capture detector.'o* By contrast simple washings from the walls of flasks which had contained calling females gave good recovery of the sex pheromones of Grapholitha molesta.' Iso-meric olefins such as the sex pheromones of Lepidoptera can be readily separated on a smectic liquid-crystal stationary phase by gas chromat~graphy,'~~ and I3C n.m.r.spectroscopy has been used to distinguish (E)-and (Z)-isomers."o For less volatile and less stable molecules a high-performance liquid chromatography technique has been developed,"' particularly suited to the sesquiterpenoids found in water beetles. 11 Behaviour-modifying Chemicals in Pest Control As part of a continuing expansion in the use of pheromones and related compounds in the field of pest control investigations have been carried out into improved formulation methods,"* both for population monitoring and for the disruption of mating. While the former application is now becoming routine for a variety of pest species the latter which relies on continuous release of relatively high levels of pheromone has not always been entirely SUCC~SS~U~.'~~ '02 0.L.Chapman J. A. Klun K. C. Mattes R. S. Sheridan and S. Maini Science 1978,201,926;0.L. Chapman K. C.Mattes R. S. Sheridan and J. A. Klun J. Amer. Chem. SOC., 1978,100,4878. Io3 I. Ganjian M. J. Pettei K. Nakanishi and K. E. Kaissling Nature 1978,271 157. '04 J. G. Kostelc B. J. Garcia G. W. Gokel and L. B. Hendry J. Chem. Ecol. 1979,5 179. R. Rossi and A. Niccoli Nurunviss. 1978,65,259;K.Mori S.Tamada and P. A. Hedin ibid. p. 653; R. Rossi P. A. Salvadori A. Carpita and A. Niccoli ibid. 1979,66,211;J. R. Miller and W. L. Roelofs Environ. Entomol. 1978,7,42;M. Kraemer H. C.Coppel F. Matsurnura T. Kikukawa and K. Mori ibid. 1979,8 519. W. L.Roelofs J. Chem. Ecol. 1978,4,685. lo' M. Vanhaelen R. Vanhaelen-Fastre J. Geeraerts and T. Wirthlin Microbios 1978,23 199. J. Caro B. A. Bierl H.P.Freeman and P.E. Sonnet J. Agric. Food Chem. 1978,26,461. '09 R. Lester J. Chromatogr.,1978 156 55. 'lo A.Barabas A. A. Botar A. Gocan N. Popovici and F. Hodosan Tetrahedron 1978,34,2191. '11 A.T.Newhart and R. 0.Murnma J. Chem. Ecol. 1978,4,503. '12 D.G. Campion R. Lester and B. F. Nesbitt Pestic. Sci. 1978,9,434;L.F.Wiener and J. L. Capinera Ann. Entomol. SOC.Amer. 1979 72 369; W.F.Steck B. K. Bailey M. D. Chisholm and E. W. Underhill Environ. Entomol. 1979,8,732. H. Kanno S.Tatsuki and K. Uchiurni Appl. Entomol. 2001.. 1978,13,321;E.F.Taschenberg and W. L. Roelofs Enuiron. Entomol. 1978,7,103;R. J. Marks B. F. Nesbitt D. R. Hall and R. Lester Buff. Entomol. Res. 1978.68.11. Biological Chemistry -Part (iii) Insect Chemistry 12 Synthetic Studies Reviews on the synthesis of chiral components of insect pheromone^"^ and appli- cations of insoluble polymer supports in pheromone ~ynthesis"~ have appeared. An extremely valuable appraisal of recent advances in the chemistry biology and application of insect phereomones has been published."6 Acyclic Derivatives.-A stereoselective synthesis of &substituted a@-unsaturated esters using the reaction of dialkylcuprates with the enol phosphate of p-keto-esters has been deve10ped.l'~ This method was employed in the preparation of (E,E)-10-hydroxy-3,7-dimethyldeca-2,6-dienoicacid (49),produced by the male Monarch butterfly (Scheme 1).'18 The dianion of methyl acetoacetate reacted with the THPO HO (49) Reagents i NaH Bu"Li; ii THPOCH,CH,Br; iii NaH PO,(OEt),Cl; iv LiMe,Cu; v LiAlH,; vi Bu"Li MeS0,Cl; vii LiBr; viii ~H,C&HCO,Et; ix NaOH; x dil.HCl Scheme 1 tetrahydropyranyl (THP) ether of 2-bromoethanol to yield the y-alkylated product (45).Conversion into the enol diethyl phosphate (46)then followed by treatment with sodium hydride and diethyl phosphorochloridate in ether. The key step is then reaction with lithium dimethylcuprate to produce the trisubstituted olefin (47). Invariably in this reaction the major product is formed with retention of the geometry of substitution of the phosphate.After formation of (48),repetition of this sequence leads to (49).A general method is therefore available to introduce isoprene units in a stereoselective fashion in a synthetic sequence. 1*4 R. Rossi Synthesis 1978,6 413. '15 C. C. Leznoff Accounts Chem. Res. 1979,11,327. J. M. Brant J. C. Young and R. M. Silverstein Fortschr. Chem. org. Naturstofe 1979 37 1. 11' F.W.Sum and L. Weiler Canad. J. Chem. 1979,57 1431. '18 F.W.Sum and L. Weiler J.C.S. Chem. Comm. 1978 985. R. Baker and J. W.S. Bradshaw (2)-Trisubstituted olefins have been formed via a [2,3]-sigmatropic rearrange- ment having a transition state with a preferential pseudo-axial substit~tion."~ The allylic alcohol (50) was deprotonated and alkylated with iodomethyltributyltin.Direct treatment of this with butyl-lithium gave (51) (Scheme 2). It is clear that the transition state (52) having a pseudo-axial butyl substituent is strongly preferred over (53). This rearrangement was used in the synthesis of (54) an active component in the sex attractant of the citrus pest the California red scale Aonidiella aurantii. A second component (55) of the pheromone of this insect has been prepared an aluminium-catalysed ene reaction of methyl propiolate with citronellyl acetate being a key step.120 Reagents i KH Bu,SnCH,I; ii BuLi Scheme 2 POAc roAc (54) [3,3]-Sigmatropic rearrangements of 0-allylic thionocarbamates have been used for stereospecific synthesis of ap-unsaturated carboxylic esters and ketones and applied to the formation of the alarm pheromones (E)-2,4-dimethylhex-2-enoic acid (57) and (E)-4,6-dimethyloct -4-en-3 -one (5 8).121 Treatment of the common precursor (56)with either one or two moles of dimethyl disulphide eventually leads to the formation of (57) and (58) (Scheme 3).In these cases the (E)stereochemistry was obtained exclusively but in others small amounts of (2)-isomers were found. The selective transformation of organoboranes into alkyl-magnesium compounds has been achieved by use of pentane-l,5-di(magnesiumbromide).'** The resulting Grignard reagents have been coupled with alkenyl halides in syntheses of a range of alkenes. Considerable further effort has been expended on investigations of the value of Wittig reagents in pheromone synthesis.Reactions of Wittig reagents with undec- 'I9 W. C. Still and A. Mitra J. Amer Chem. SOC.,1978,100,1927. B.B.Snider and D. Rodini Tetrahedon Letters 1978 1399. T.Nakai T.Mimura and T. Kurokawa Tetrahedron Letters 1978,2895. 122 K. Kondo and S. Murahashi Tetrahedron Letters 1979,1237. Biological Chemistry -Part (iii) Insect Chemistry Reagents i Me,NCSCI; ii LiNPri; iii 2xMeSSMe; iv HgCI, H20 v MeSSMe (1 equiv.); vi EtI; vii HgO BF Scheme 3 10-enal and an ozonolysis product from vaccenyl acetate* have been used to form 1-substituted-(2)-alk-1 l-ene~.'~~ The value of the base sodium bis(tri-methylsily1)amide in the controlled specific formation of (Z)-olefins in Wittig reactions has been further demonstrated in preparations of (Z)-dec-Senyl acetate (the sex attractant of the turnip moth Agrutis segetun~),~~~ (Z)-octadec-l3-enal (a component of the pheromone of the rice stem borer Chilu suppres~alis),~~~ (2)-alk-6-enyl acetates,126 and (2)-tetradec-7-enyl acetate and (Z)-dodec-7-enyl acetate.12' Cycloheptanone has been converted into its methyl vinyl ether derivative and the ozonolysis product used in a synthesis of (E,Z)-dodeca-7,9-dienyl acetate.'28 A series of alkyl-branched analogues of lepidopteran pheromones have been prepared from alkyl(tripheny1)phosphonium salts.'*' Reduction of the appro- priate diethylphosphonate with lithium aluminium hydride has led to formation of (E,E)-alka-n,(n +3)-dienes.13' Selective ozonolysis of 1-methylocta-1,S-diene gave a keto-aldehyde which has provided the starting point for stereospecific synthesis of (2)-alkenyl acetates.131 * Octadec-11-en-1-yl acetate.Senior Reporter. H. J. Bestmann I. Kantardjiew P. Rosel W. Stransky and 0.Vostrowsky Chem. Ber. 1978,111,248. lZ4 H. J. Bestmann 0.Vostrowsky K. H. Koshatzky H. Platz T. Brosche I. Kantardjiew M. Rheinwald and W. Knauf Angew. Chem. Internat. Edn. 1978,17 769. H. J. Bestmann R. Wax and 0. Vostrowsky Chem. Ber. 1979 112 3740. H. Horicke M. Tanouchi and C. Hirano Agric. Biol. Chem. 1978.42 1963. H. J. Bestmann 0.Vostrowsky H. Platz Th. Brosche and K. H. Koschatzky Tetruhedron Letters 1979 497; H. J. Bestmann K. H. Koschatzky and 0.Vostrowsky Chem. Ber. 1979,112,1923. H. J. Bestmann J. Sub and 0.Vostrowsky Tetrahedron Letters 1979 2467.H. J. Bestmann P. Rosel and 0.Vostrowsky Annalen 1979 1189. H. J. Bestmann J. Sub and 0.Vostrowsky Tetrahedron Letters 1979 245. G. A. Tolstikov V. N. Odinokov R. I. Galeeva R. S. Bakeeva and V. R. Akhunova Tetrahedron Letters 1979,485 1. R. Baker and J. W.S. Bradshaw Copper reagents have received attention and precursor (60) of methyl (E)-tetradeca-2,4,5-trienoate the sex attractant of the male dried bean beetle Acanthoscelides obtectus has been prepared by the reaction of an organocuprate with an acetylenic methanesulphonate (59); no allylic substitution occurred. 13* The enantiomer with (-)-(R)-configuration has also been prepared by the reaction of lithium dioctylcuprate with a single diastereomer of the carbamate derived from a racemic secondary propargyl alcohol and (R)-1-(1-naphthy1)ethyl i~ocyanate.”~ Trisubstituted olefins have been prepared by the addition of alkyl-copper reagents to terminal acetylenes with subsequent reaction with organic halides ap-unsaturated carbonyl compounds and ep0~ides.l~~ This method was applied in the preparation of (2,2)-7-methy1-3-propyldeca-2,6-dien-1-01 a component of the pheromone of the codling moth Laspeyresia p~monella.’~~ General syntheses of conjugated dienes continue to generate interest.Hydro- zirconation of acetylenes leads to (E)-alk-1-enylzirconium intermediates and addi- tion to vinylic halides yields (E,E)-dienes in high yield.’36 In another approach dienaminium salts (6l),obtained from 2-alkyl-pyridines are coupled with suitable Grignard reagents to yield (2,E)-dienes (62)(Scheme 4).13’ A third approach Reagents i MeI; ii NaBH,; iii 9M-KOH; iv Li,CuCl, R2MgBr Scheme 4 involves the reaction of lithium dialkylcuprates with 3-acetoxypent-1-en-4-yneto give conjugated (2)-en~nes.~~~ These derivatives are readily converted into the corresponding (2,Z)-or (E,Z)-dienes.A similar scheme has been used for the synthesis of (2,E)-hexa-7,ll-dienyl acetate.139 A 1,3-isomerization of dicarbonyl(methylcyclopentadienyl)manganese com-plexesof electrophilic acetylenes (63)in the presence of basic aluminium oxide yields the corresponding allene complexes (64). Reaction with a phosphonate and removal of the metal complex with ferric chloride yields (65) (Scheme 5).l4’ 132 H.Kleijn H. Westmijze K. Kruithof and P. Vermeer Rec. Trao. chim. 1979,98 27. 133 W. H. Pirkle and C. W. Boeder J. Org. Chem. 1978 43 2091. 134 A. Marfat P. R. McGuirk and P. Helquist J. Org. Chem. 1979 44 3888. 13’ A. Marfat P. R. McGuirk and P. Helquist I. Org. Chem. 1979,44 1345. N. Okukado D. E. Van Horn and W. L. Klima Tetrahedron Letters 1978,1027. 13’ G. Decodts G. Dressaire and Y. Langlois Synthesis 1979 510. 13* G. Cassani P. Massardo and P. Piccardi Tetrahedron Letters 1979 633. 139 A. Hammoud and C. Descoins Bull. SOC. chim. France Part II 1978,299. M. Francke-Neumann and F. Brion Angew. Chem. Internat. Edn. 1979,18 688. Biological Chemistry -Part (iii) Insect Chemistry 421 --CHO 1 = CHO 4 /=C-CHO I R MnL R PLlnL (R=n-C8H17) Me Reagents i [MnL,]; ii A1203;iii (MeO),POCHCO,Me; iv FeCI Scheme 5 Sorbyl acetate has been coupled with the appropriate Grignard reagent in the presence of lithium chlorocuprate to yield (E,E)-dodeca-8,10-dien-l-ol and other analogues.141 Although not stereospecific (E)-dodeca-9,11 -dienyl acetate has been prepared from a butadiene tel~mer.'~' Acetylenic routes have been employed for preparations of (Z,Z)-and (Z,E)-octadeca-3,13-dienylacetate the attractants for the cherrytree borer Synanthedon hector.'43 Greater than 98% selectivity has been found in the Claisen rearrangement of the t-butyldimethylsilyloxy vinyl ether of the acetates of secondary enynols due presumably to the 1,3-interactions in the transition This reaction has been used in the synthesis of (E,Z)-hexadeca- 10,12-dienyl-l-ol.A 1,4-dehydration of an allyk alcohol has been used in a synthesis of (E)-dodeca- 9,ll -dienyl acetate. Treatment of (66)with 2,4-dinitrobenzenesulphenylchloride in the presence of triethylamine yields a sulphonate ester which rapidly rearranges to the corresponding allylic sulphoxide followed by elimination (Scheme 6).145 (66) Reagents i 2,4-(N0,),C6H,SC1 Et,N CH,CI2 A Scheme 6 Ipsenol and ipsdienol components of the aggregation pheromone of Ips paracon -fusus,have again been prime targets. The reaction of 2-(trimethylsilylmethy1)buta-1,3-diene with isovaleraldehyde in the presence of titanium tetrachloride gave a good yield of ipsenol; this method clearly provides an isoprenylation A similar approach is found in the use of the Grignard reagent derived from 3- D.Samain and C. Descoins Synthesis 1978 388; H. J. Bestmann J. Sub and 0. Vostrowsky Tetrahedron Letters 1978,3329. I** T. Mandai H. Yasuda M. Kaito J. Tsuji R. Yamaoka and H. Fukami Tetrahedron 1979,35 309. 143 M. Uchida K. Mori and M. Matsui Agric. Biol. Chem. 1978,42 1067. 144 D. Samain and C. Descoins Bull. SOC. chim. France Part II 1979,71. 14' J. H. Babler and B. J. Invergo J. Org. Chem. 1979,44,3723. A. Hosomi M. Saito and H. Sakurai Tetrahedron Letters 1979,429. 14'esters of allenic alcohols has provided a new approach to myrcene derivatives. 422 R. Baker and J. W. S. Bradshaw methylene-4-chlorobutyl phenyl ~ulphide.'~' Thermal transposition of the ortho- Site-specific addition of benzenesulphenyl chloride to the isopropylidene terminus of terpenoids such as myrcene can be achieved? and this has been employed in a synthesis of ipsdienol and other derivative~.'~~ Formation of (67)is followed by acetoxylation oxidation thermally induced formation of a double bond and allylic rearrangement (Scheme 7).Q Q SPh iii iv v vi + + HO OAc OAc SPh (67) Reagents i PhSCI; ii NaOAc AcOH; iii H202 AcOH; iv 120"C,toluene; v p-TsOH AcOH; vi LiAlH4 Scheme 7 Both antipodes of ipsdienol have been synthesized from (+)-(R)-glyceraldehyde acetonide and (+)-(R)-malic acid and naturally occurring (+)-ipsdienol was established as having the (S) config~ration.'~~ The (R)-enantiomers of (2)-and (E)-14-methylhexadec-8-en-1-01and of (2)-and (E)-14-methylhexadec-8-enal components of the sex pheromone of the female dermestid beetles have been prepared from (+)-(R)-citronellol as the starting point.'51 Conversion of the initially formed epoxide into the aldehyde was a key step.Two components of the sex pheromone of Phthorimaea operculla the potato tubeworm moth have been prepared.'52 In both cases (68)was used and its reaction with (69)and (70)gave after reduction? (E,Z)-trideca-4,7-dien-l-01and THPO-/ '*BrMg = "'""17,k (68) (69) (E,Z,Z)-trideca-4,7,10-trien-l-01. The former compound has also been prepared by a conjugate opening of an allylic epoxide by a vinylic organocopper reagent."3 Another triene (Z,Z)-pentacosa-1,7,13-triene(a major component of the cuticular lipid of the male stable fly Stomoxys calcitrans) together with the three other isomers has been prepared.ls4 Hydrogenation of acetylenic linkages and metal reductions with metal and amine were used to prepare (2,Z)-and (2,E)-isomers followed by inversion of the olefins to obtain the other two isomers.The (E,E)-isomer (72)was prepared from the (2,Z)-isomer by the reaction of (71)with 14' B. Cazes E. Guittet S. Julia and 0.Ruel J. Organometallic Chem. 1979,177,67. 148 M. Bertrand and J. Viala Tetrahedron Letters 1978 2575. 149 Y.Masaki K. Hashimoto K. Sakuma and K. Kaji J.C.S. Chem. Comm. 1979,855. K. Mori T. Takigawa and T. Matsuo; Tetrahedron 1979 35,933. Is' K.Mori,T. Suguro and M. Uchida Tetrahedron 1978,34,1; R.Rossi P. A. Salvadori and A. Carpita ibid. 1979 35,2039; T.Suguro and K. Mori Agric. Biol. Chem. 1979 43,409. S. Voerman and G. H. L. Rothschild J. Chem. Ed. 1978,4,531. A. Alexakis G.Cahiez and J. F. Normant Tetrahedron Letters 1978,2027. P. E.Sonnett J. Chem. Ecol. 1979,5,415. Biological Chemistry -Part (iii) Insect Chemistry 423 rn-chloroperbenzoic acid followed by treatment of the tris-epoxide with tri- phenylphosphine dibromide and then reductive dehalogenation with zinc. The (2,E)-isomer was also converted into the tris-epoxide and its reaction with excess trifluoroacetyl chloride followed by heating with sodium iodide gave the (E,Z)- isomer. C11H23' 1\ (72) Syntheses of all the possible stereoisomers of erythro- 3,7-dimethylpentadec-2-~1 acetate and propionate have been re~0rted.l~~ The crucial steps were the attack of chiral organocopper reagents to yield (+)-(2R,3R)-2,3-epoxybutane(73) and the (-)-(2S,3S)-epoxide respectively.The second part of the molecule (-)-(R)-1-bromo-4-methyldodecane and its enantiomer were derived from (+)-(R)-citron-ellol. A coupling of (73) and (74) gave (2R,3R,7R)-erythro- 3,7 -dimethylpenta-decan-2-01 and the other three enantiomers were obtained similarly. H CuLi H=c. +!3 H Enan tiof ace-diff erentiating hydrogenation of methyl 2 -me thyl-3 -0xobutyrate over tartaric-acid-modified nickel catalyst gave methyl 3-hydroxy-2-methylbutyratein high diastereomer and enantiomer excess enabling the (+)-(2S,3S)- and (-)-(2R,3R)-enantiomers of the same compound to be prepared.'56 The erythro- and threo-isomers of 3,7-dimethylpentadecan-2-01have also been prepared from cis- and trans-dimethylcyclohexanol,157 and a diastereomeric mixture has been obtained from an oxy-Cope transposition of 4-ethynylhexa-l,S-dien-3-01,obtained from reactions of a vinylallenic Grignard with acr01ein.'~~ Field studies on the effective- ness of racemic 3,7-dimethylpentadec-2-y1 propionate with four species of pine sawflies have been made.ls9 The four stereoisomers of 3,ll-dimethylnonacosan-2-one,the female sex pheromone of the German cockroach Blatella gennanica have also been prepared and the natural pheromone has been shown to have the absolute configuration 15s K.Mori,S.Tamada and M. Matsui Tetrahedron Letters 1978,901;K.Mori and S.Tamada Tetrahedron 1979,35 1279. A. Tai M. Imaida T. Oda and H. Watanabe Chem. Letters 1978,61. G. Magnusson Tetrahedron 1978.34 1385. P. Place M. L. Roumestant and G. Gore J. Org. Chem. 1978 43 1001. D. M. Jewett F. Matsumura and H. C. Coppel J. Chem. Ecol. 1978 4 277. R. Baker and J. W.S. Bradshaw (3S,llS).'60 The key step in the synthesis was the coupling of a chiral tosylate (75) with a chiral Grignard reagent (76); both of these were obtained from (+)-(R)- citronellol. A non-stereospecific synthesis of this pheromone has been reported involving an oxy-Cope reaction of 4-ethynylhexa-1,5-dien-3-01.'~' Both enantiomers of epoxy-2-methyloctadecanehave been prepared from routes beginning with L-(+)-tartaric acid; the (+)-(7R,8S)-enantiomer was found to be biologically active.'62 A resolution technique involving liquid-chromatographic separation of diastereomeric (RJ-1-( 1-naphthy1)ethyl isocyanates has also been used for the same preparation^.'^^ Racemic disparlure was also synthesized by selective ozonolysis of cyclo-octa- 1,S-diene followed by Grignard coupling'64 or Kolbe electr~lysis.'~~ An ene reaction between methyl acrylate and oct-1 -ene in a eutectic mixture of the chlorides of sodium aluminium and potassium has been reported to give good yields of hendec-5-enoic acid methyl ester and this has been converted into (2)-heneicos- 6-en-ll-one the pheromone of the Douglas fir tussock moth Orgyia pseudo-tsugata.166An alternative synthesis based on a Wittig reaction on a lact01,'~~ and the identification and synthesis of heneicosa-1,6-dien-l1 -one (a second component of the pheromone) have appeared.16' Other enantiomer-specific syntheses include those of (+)-(3R,4R)-4-methyl- heptan-3-01 involving reduction of a chiral ketone with actively fermenting of (-)-(R )-6-methyloctan-3 -one from (-) -(S)-3,7-dimethyloct-6-en-1-01,'~'and of (+)-(S)-4-methylheptan-3-one,via asymmetric alkylation of a ketone.17' Further solid-phase syntheses on polymer supports,'72 the monoacetylation of symmetrical di~ls,"~ and the preparation and separation of geometrical isomers by formation of urea c~mplexes"~ have been reported.160 K. Mori T. Suguro and S. Masuda Tetrahedron Letters 1978. 3447. 16' P. Place M.L.Rownestant. and J. Gore Tetrahedron 1978,34 1931. 16' K.Mori T. Takigawa and M.Matsui Tetrahedron 1979,35,933. 163 W. H.Pirkle and P. L. Rinaldi J. Org. Chem. 1979,44 1025. lWG. A.Tolstikov V. N. Odinokov R. I. Galeeva and R. S. Bakeeva Tetrahedron Letters 1978 1857. 16' H.Kluneberg and H. J. Schafer Angew. Chem. Infernat. Edn. 1978,17,47. B. Akermark and A. Ljungqvist J. Org. Chem. 1978,43,4387. 16' M. F6tizon and C. Lazare J.C.S. Perkin I 1978,842. L. M.Smith R. G. Smith T. M. Loehr and G. D. Daves jun. G. E. Daterman and R. H. Wohleb J. Org. Chem. 1978,43,2361. G. Frater Helv. Chim. Acta 1979,62,2829. 170 R. Rossi and P. A. Salvadon Synthesis 1979,209. "' D. Enders and H. Eichenauer Angew. Chem. Internat. Edn. 1979,18,397. 172 C.C.Leznoff,J.C.S.Chem. Comm. 1978,327;T. M. Fyles C. C.Leznoff and J. Weatherston Canad. J. Chem. 1978,56 1031; T. M. Fyles C. C. Leznoff and J. Weatherston,J. Chem. Ecol. 1978,4,109. 173 J. H.Babler and M. J. Coghlan Tetrahedron Letters 1979 1971. '" G. Leadbetter and J. R. Plimmer J. Chem. Ecol. 1979.5 101. Biological Chemistry -Part (iii) Insect Chemistry Alicyclic Derivatives.-Both enantiomers of grandisol one of the four pheromones of the male boll weevil Anthonomus grandis have been prepared. 175 Photocyclo-addition of ethylene to (77) gave (78) which was then converted into the acid (79); this was resolved by treatment with optically active bases. Separation into the two enantiomers was followed by conversion into the two enantiomers of grandisol (Scheme 8) exemplified by the formation of (+)-( lR,2S)-grandisol (80).C0,Et Etozco 4? 0 HO ""'Q (77) An acid-catalysed rearrangement of an oxycyclopropanecarbinol into a cyclo- butanone has also been used in a synthesis of (+)-grandi~ol.'~~ Conversion of (81) into (82) with a Simmons-Smith reaction followed by acid-induced hydrolytic rearrangement gave (83) which was converted into (+)-(80). Treatment of racemic 6,7-epoxygeranyl t-butyl sulphide with butyl-lithium and 1,2-bis(dimethyl-amino)ethane has been shown to yield substantial amounts of a cyclobutyl deriva- although other products were also formed. A further synthesis of grandisol involved the addition of an organocuprate to a cyclobutenyl ester. 17' MeoQo-MeQo -+ 'Q0 .-\OH -++d-H H =-t Syntheses of the three other components of the sex pheromone of the boll weevil have been reported.The addition of ethyl vinyl ether to (84) in the presence of ZnC12 gave (85) which on treatment with sodium acetate in acetic acid yielded (86) and (87).179 Reduction with sodium borohydride gave (88) and (89) as shown in Scheme 9. The compounds required for the pheromone mixture are (86) (87) and K. Mori Tetrahedron 1978.34. 915. 176 E. Wenkert D. A. Bergers and N. F. Golob J. Amer. Chem. SOC.,1978,100,1263. "'V.Rautenstrauch,J.C.S. Chem. Comm. 1978 519. 17* R.D.Clark Synth. Comm. 1979,9,325. J. P. de Souza and A. M. R. Goncalves J. Org. Chem.. 1978,43,2068. R. Baker and J. W.S. Bradshaw Reagents i FOEt ZnCI,; ii AcOH; iii NaBH Scheme 9 (89) and some difficulties might be found in separating them.These compounds have also been prepared by the reaction of the ketone corresponding to (84) with (2)-2-ethoxyvinyl-lithium and subsequent silica-gel-catalysed rearangement which yields (86) and (87).180 Both enantiomers of seudenol 3-methylcyclohex-2-en-l-ol,an aggregation pheromone of the Douglas fir beetle Dendroctonus pseudotsugae have been pre- pared by the reaction of 3-iodocyclohex-2-en-1-ol with lithium dimethylcuprate and their absolute configurations determined.'" The structure of lineatin an attractant compound isolated from frass produced by female beetles of Trypodendron lineaturn has been confirmed as (93) although the synthesis would not be appropriate on any scale (Scheme The two ketones (91) and (92) were prepared beginning with AcO AcO 0 (90) + Qo (93) o*o (92) Reagents i,& pTsOH; ii KCN EtOH; iii CrO, py HCl; iv LiBu',BH; v Ac,O PY; vi LiNPr', Me,SiCI; vii 03,PPh,; viii CH,N,; ix CH,(OH)CH,OH pTsOH; x MeMgI; xi dil.HCI Scheme 10 R. H. Wollenberg and R. Peries Tetrahedron Letters 1979,297. la K. Mori S. Tamada M. Uchida N. Mizumachi T. Tachibana and M. Matsui Tetrahedron 1978,34 1901. lS2 K.Mori and M. Sasaki Tetrahedron Letters 1979 1329. Biological Chemistry -Part (iii) Insect Chemistry 427 photocycloaddition of vinyl acetate and (90). Chromatography on silicic acid gave the two ketones of which (91)was the major product. A systematic study has been made on the synthesis of eleven 1,6-dioxa- spiro[4.4]nonanes and their mass spectra have been The use of (+)-(R)-y-caprolactone (94) has allowed the preparation of a mixture of the two diastereomers (97) and (98) which serve as the principal component of the aggre- gation pheromone of the beetle Pityogenes chacograph~s.*~~ The reaction of (94) with the lithium salt of the propargyl alcohol derivative (95) gave (96) which on hydrogenation and treatment with hydrochloric acid led to a mixture of (97) and (98).The preparation of the other two enantiomers is possible from (-)-(S)-y-caprolac- tone. These two pairs of optically active diastereomers have also been prepared by a route in which the key step was the alkylation of the dianion of an a-acetyl-y- butyrolactone (100) with (R)-1,2-epoxybutane (99).'*' OTHP a0 + Lid (94) (95) y+1 + 00 & v? + BuLi NaH (+)-(R)-Frontalin (105) the aggregation pheromone of the southern pine beetle Dendroctonus frontalis has been prepared in a demonstration of the use of a-methyl- a-chlorotrimethylsilyl carbanion ( 102).'86 Beginning from (-)-(3R)-linalool the a@-epoxysilane (103) was prepared by the action of (102) on the aldehyde (101) (Scheme 11).The action of boron trifluoride etherate on (104) gave (105). The overall reaction represents the highest overall yield for a chiral synthesis of this derivative. Frontalin has also been prepared in a route involving the reaction of the dianion of methyl acefoa~etate'~' and by an impressive titanium-chloride-catalysed photo-reaction of he~tane-2,6-dione.l~~ Multistriatin one of the three components of the 183 W.Francke and W. Reith Annalen 1979 1. L. R. Smith J. J. Williams and R. M. Silverstein Tetrahedron Letters 1978 3231. K. Mori M. Sasaki S. Tamada T. Suguro and S. Masuda Tetrahedron 1979 35 1601; Heterocycles 1978 10 111. P. Magnus and G. Roy J.C.S. Chem. Comm. 1978,297. P. E. Sum and L. Weiler Canad. J. Chem. 1979 57 1475. 188 T. Sato S. Yamaguchi and H. Kaneko Tetrahedron Letters 1979 1863. 428 R.Baker and J. W. S.Bradshaw I Me SiMe H? -bfi] "2 +BF,.Et,O OH Me SiMe Scheme 11 (104) European elm beetle Scolytus multistriatus has also been a popular target.'" Four diastereomeric glycopyranosides obtained from carbohydrate a-enones provide chiral synthons for the four multistriatin~.'~~ Two similar syntheses have been used for the sex pheromone of the drugstore beetle Stegobiurn paniceurn.Sequential reaction of diethyl ketone with ethyl propionate and acetaldehyde gave (106) which on treatment with acid gave a mixture of two diastereomeric racemates (107) and (108) (Scheme l2).lg1 In a separate approach erythro-3-methylpent-1-en-4-01(110) of predominantly (3R,4R) configuration has been prepared by employing 3-endo-phenyl-2-em- 0 OH iii / (107) Reagents i LiNPr', EtC0,Et; ii LiNPr', MeCHO; iii HCl Scheme 12 P. A. Bartlett and J. Myerson J. Org. Chem. 1979.44 1625; W. J. Elliott G. Hromnak J. Fried and G. N. Lancer J. Chem. Ecol. 1979 5,279.B. J. Fitzsimmons D. E. Plaumann and B. Fraser-Reid Tetrahedron Letters 1979 3925. "I M.Sakakibara and K. Mori Tetrahedron Letters 1979,2401; J. M. Ansell and A. Hassner ibid.,p. 2497. Biological Chemistry -Part (iii) Insect Chemistry 429 dihydroxybornane(109).19' This was then converted into (11l) which on conden- sation with the dianion of 4-methylheptane-3,Sdione (112) gave (113)(Scheme 13). After cyclization c.d. studies showed that the final product had (2R,3S) configura- tion and that the natural pheromone had (2S,3R) configuration. Scheme 13 Enantiomeric specific syntheses of a number of 4-alkyl(or alkeny1)-y -1actones of known absolute configuration have been made from glutamic acid enantiomer~.'~~ The alkyl side-chain was introduced by conversion of the acid into a toluene-p- sulphonate followed by displacement with lithium dialkylcuprates.These enan- tiomerically pure lactones have also been prepared by the separation of diastereomeric carbamates although large-scale syntheses by this method cannot be envisaged.lg4 The synthesis of pederamide a key intermediate for a route to pederin a vesicant compound of the beetle Paederus fuscipes was accomplished from trans-2,3-epoxy-butane.'95 Two syntheses of (+)-phoracantholid J (116) a compound found in the metasternal secretion of the eucalypt longicorn beetle Phoracantha synonyma have appeared. In the first the lactonization was achieved by silver-catalysed reaction of the 5-(2-pyridyl)thioe~ter.'~~ A second method involved the formation of the acetal (114) with the aid of benzeneselenyl bromide followed by oxidation and ther- molysis which affords (116) after a Claisen rearrangement of (115) (Scheme 14).197 Scheme 14 19' R.W. Hoffman and W. Ladner Tetrahedron Letters 1979,4653. 193 U.Ravid R. M. Silverstein and L. R. Smith Tetrahedron 1978,34,1449. 194 W.H.Pirkle and P. E. Adams J. Org. Chem. 1979,44,2169. 19' M.A. Adams A. J. Duggan J. Smolanoff,and J. Meinwald J. Amer. Chem. SOC.,1979 101 5364. H.Gerlach and K. Oertle Helo. Chim. Acra 1978,61 1226. 19' 19' M.Petrzilka Helv. Chim. Ada 1978,61 3075. 430 R. Baker and J. W. S.Bradshaw This reaction is not completely stereospecific since some of the trans-isomer is also produced (cis:trans = 7 :2) but could provide a new method for syntheses of other lactones.Probably the most outstanding synthetic contribution to this field in the past two years has been provided by in the synthesis of three of the possible four diastereomers of periplanone-B the sex pheromone of the American cockroach Periplaneta americana. The cyclodecadienone (118) was the key intermediate which was obtained by the oxy-Cope reaction of (117) (Scheme 15). The important strategy which led to formation of the active isomer (119)was the introduction of the diene moiety in 0"-(119)before epoxidation. i-iv I OAc ' OAc EEO) EEO' EEO' v vi 1 (EE= 1-ethoxyethyl) I EEOi viil OSiMe,Bu' EEO' (118) EEo' (117) xiiil Reagents i LiNPr', MeCH=CHCHO; ii Ac,O; iii Me,SnLi; iv Me,SiCl; v LiMe,Cu; vi m-ClC,H,CO,H; vii CH,=CHLi; viii KH THF 18-crown-6; ix Me,Bu'SiCl; x H,O-AcOH; xi o-NO,C,H,SeCN Bu,P; xii H,O, THF; xiii Bu'OOH KH THF; xiv Me,&=CH X-; xv.Bu,N' F-; mi CrO, py Scheme 15 19' W. C. Still J. Amer. Chem. SOC.,1979 101 2493. Biological Chemistry -Part (iii) Insect Chemistry 431 The chemistry of antifeedants has gained considerable attention. A total synthesis of warburganal (120) involved sequential protection and oxidation of (121)199 and in a separate approach has also been obtained from isodrimenine (122).200 Ring B of this compound has also been prepared by using 2,2-dimethylcyclohexanone as a A cis-decalin derivative (123) having similar functionalities to ajugarin was obtained by a route in which a key step was Lewis-acid-catalysed cyclization of (124) to (125).202 This cis-decalin part of ajugarin has also been constructed by a Diels-Alder approach.203 Precoccinellin (126) and coccinellin (127) defensive alkaloids of the ladybug Coccinella septempunctata have been prepared from perhydroboraphenalene (128) involving conversion into the enamine (129) and isomerization of the methylated derivative (130) to (13l).204 Alternatively in another scheme a Robinson-Schopf- Q H HQH H H H (3J HQ FSOj -H / (129) (130) (131) 199 S.P. Tanis and K. Nakanishi J. Arner. Chem. SOC.,1979,101,4398. T. Nakata H. Akita T. Naito and T. Oishi J. Amer. Chem. SOC.,1979 101,4400. 201 A.J. G. M. Peters J. M. Roskam and A. de Groot Rec.Trau. Chim. 1978,97 277. *02 W.P.Jackson and S. V. Ley J.C.S. Chem. Comm. 1979 732. 203 D.J. Goldsmith G. Srouji and C. Kwong J. Org. Chem. 1978,43,3182. R. H. Mueller and M. E. Thompson Tetrahedron Leners 1979,1991. R. Baker and J. W.S. Bradshaw type condensation of (132) and acetonedicarboxylate ester (133) to yield (134) was employed.205 The major component of the poison gland of the thief ant Solenopsis molesta and of S. texanas has been identified as 2-hexyl-5-pentylpyrrolidineand synthesized from the appropriate diketone.206 Other insect defensive compounds have been attractive targets. Chrysomedial (135) and plagiolactone (136) are two defensive compounds from chrysomelid (135) (136) beetles; both were prepared from limonene by initial functionalization of the terminal double bond ozonolysis and Knoevenagel condensation of (137).207 Ancistrodial(138) from the termite Ancistrotermes cauithorax has been prepared by a sequence involving Stobbe condensation of y-cyclohomocitral and diethyl SUC-cinate."* A more difficult target was provided by ancistrofuran (139) found in the major soldiers of the same termite and this was obtained by cyclization of (140).209 -0 ++ H3 Hk-0 H 0 i 'OS R.V. Stevens and A. W. M. Lee J. Amer. Chem. SOC.,1979,101,7032. T. H. Jones M. S. Blum and H. M. Fales Terruhedron Letters 1979,1031. 'O' J. Meinwald and T. M. Jones J. Amer. Chem. SOC.,1978,100 1883. *08 R.Baker P. H. Briner and D. A. Evans J.C.S. Chem. Comm. 1978,410. '09 R.Baker P.H. Briner and D. A. Evans J.C.S. Chem. Comm. 1978,981.

ISSN:0069-3030    

DOI:10.1039/OC9797600404

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

16 Biological Chemistry Part (iv) Marine Natural Products By C. CHRISTOPHERSEN H. C. Orsted Institute University of Copenhagen DK-2100 Copenhagen Denmark and N. JACOBSEN Cheminova Ltd. P.O. Box 9 Lemvig DK-7620 Lemvig Denmark 1 Introduction This is the first report on marine natural products to appear in Annual Reports. Although basically marine natural products could be accommodated in reviews on the various well-established classes of natural products the last decades have seen such an increasing interest in the chemistry of marine organisms that a temporary segregation seems justified. For quite a long time the main emphasis in marine natural products chemistry has been laid on the differences between marine and terrestrial organisms spurred on by the discovery of a number of unique features in the marine metabolites.Apparently novel structural features now cause less stupefaction than earlier. Hence there has been an increased desire to discover the biological significance of marine natural products. In order to comply with this tendency we have chosen to arrange the material phylogenetically except for a section on sterols and carotenoids devoting a rela- tively higher proportion of the space to the (alas) few papers dealing with biological aspects of marine natural products chemistry. In 1979 comparatively few reviews have appeared the most prominent and extensive being volume I1 of a series of reviews;' it includes chapters on marine carotenoids,la sterols of marine invertebrates,lb diterpenoids," terpenoids from Coelenterates,ld and applications of 13C n.m.r.spectroscopy to marine natural products." The translation of Hashimoto's book on biologically active marine compounds2 is a most welcome and stimulating event. Reviews have appeared on compounds from microalgae; in particular their influence on the field of marine natural products3" and molecular aspects of the halogen-based biosynthesis of 'Marine Natural Products. Chemical and Biological Perspectives' ed. P. J. Scheuer Academic Press New York San Francisco and London 1978 Vol. 11. (a)S. Liaaen-Jensen;(6)L. J. Goad; (c) W. Fenical; (d) B. Tursch J. C. Braekman D. Daloze and M. Kaisin; (e) J. J. Sims A. F. Rose and R. R. Izac. * Y. Hashimoto 'Marine Toxins and Other Bioactive Marine Metabolites' Japan Scientific Societies Press 1979.(a) Y. Shimizu Recent Adv. Phytochem. 1979 13,199; (b)W. Fenical ibid. p. 219. C. Christophersen and N. Jacobsen marine natural products,3b Pigments of marine invertebrates4 and marine aliphatic natural products' have also been reviewed. 2 Marine Sterols and Carotenoids Although there is much research on marine sterols it will only be briefly mentioned because of the lack of criteria on which to base a selection of the most relevant investigations. The origin and fate of the diversity of sterol structures and their role in symbiotic relationships are mainly unaccounted for.6 A comprehensive review on the origin distribution and transformation of sterols in invertebrates has appeared.lb Sterols having unusual side-chains are frequently encountered in marine organisms particularly sponges where they are sometimes major sterols indicating that they serve an as yet unknown f~nction.~-~ Much evidence suggests the unicellular algae to be the prime producers of marine sterols leaving most inverte- brates in the role of accumulators or structural modifiers.The dinoflagellate Cryptecodinium cohnii introduces the 23- and 24-methyl groups of dinosterol from methionine." This may have relevance to the biosynthesis of gorgosterol a 23- methyl sterol originally isolated from gorgonians which was recently found in the dinoflagellate Peridinium foliaceum ;I1 gorgonians have zooxanthellae (symbiotic dinoflagellates).' Furthermore 23-methyl-22-dehydrocholesterol has been characterized from zooxanthellae.'2 Modification of the sterol ring system is exemplified by sterols and A4v7-3,6- dioxo-sterols isolated from the sponges Biemna fortis l3 and Rhaphidostila incisa l4 respectively.The field of marine carotenoids shares several features with that of sterols making it equally difficult to select the most relevant carotenoid papers for the present report. Most aspects of marine carotenoid research are dealt with in a review.'O By analogy with the situation within the sterol field it is suspected that only the algae are capable of carotenoid synthesis de nooo. Many observations support this hypothesis; e.g. the identification of the typical dinoflagellate carotenoid peridinin as the main carotenoid in several species of the Alcyonacea (soft corals) that have symbiotic dinoflagellate^'^ and as the pigment (earlier known as sulcatoxanthin) in the sea anemone Anernonia sulcata.16 G.Y. Kennedy Adv. Marine Biol. 1979,16,309. ' R. E. Moore in 'Aliphatic and Related Natural Products Chemistry' ed. F. D. Gunstone (Specialist Periodical Reports) The Chemical Society London 1979,Vol. 1 p. 20. J. L. Boutry A. Saliot and M. Barbier Experientia 1979,35 1541. 'W. Hofheintz and G. Oesterhelt Helv. Chim. Acta 1979 62 1307. W. C. M. C. Kokke. C. Tarchini D. B. Stierle and C. Djerassi J. Org. Chem. 1979,44 3385. C. Delseth L. Tolela P.J. Scheuer R. J. Wells and C. Djerassi Helv. Chim. Actu 1979,62 101. lo N. W. Withers R. C. Tuttle L. J. Goad andT. W. Goodwin Phytochemistry 1979,18,71.l1 N. W. Withers W. C. M. C. Kokke M. Rohmer W. H. Fenical and C. Djerassi Tetrahedron Letters 1979,3605. l2 W. C. M. C. Kokke N. W. Withers I. J. Massey W. Fenical and C. Djerassi Tetrahedron Letters 1979 3601. l3 C. Delseth Y. Kashman and C. Djerassi Helv. Chim. Actu 1979,62 2037. l4 A. Malorni L. Minale and R. Riccio Nouveau J. Chim. 1979 2,351. Is M. Hallenstvet and S. Liaaen-Jensen Biochem. Syst. Ecol. 1979,7 171. l6 A. Fiksdahl M. Hallenstvet L. Beress and S. Liaaen-Jensen Biochem. Syst. Ecol. 1979,7 173. Biological Chemistry -Part (iv) Marine Natural Products Many recent studies have been concerned with the determination of absolute stereochemistry (e.g. tunaxanthin”) and of the structures of complexes between carotenoids and proteins (e.g.alloporin from the coral Allopora californica 18).3 Marine Plants Like their terrestrial counterparts marine plants (particularly algae) play a major role as producers of secondary metabolites. It is however characteristic of the marine environment that species from several phyla of invertebrates are known to contain copious amounts of substances strongly resembling plant metabolites. This has led several natural products chemists to believe that these compounds have their origin in the algae (or bacteria) which are symbionts epiphytes or simply the diet of these invertebrates. A few chemical relationships between algae and invertebrates have been demonstrated or indicated such as the relationship between the saco- glossan mollusc Placobranchus ocellatus and its symbiotic algal chl~roplasts.’~ Although many of the substances reported from marine invertebrates are undoubtedly of algal origin they will be mentioned in the appropriate section on invertebrates but where an algal origin has been indicated this will be mentioned.Cyanophyceae (Blue-green Algae).-The structures of a series of chlorine-containing amines for example malyngamide A (l),from shallow-water strains of Lyngbya majuscula were reported.20’21 The authors point out the interesting structural similarity between the central amino-acid part of the malyngamides and dysidin a metabolite from a sponge Dysidia herbacea which is known to contain large amounts of symbiotic blue-green algae; A series of amides that are structurally related to the malyngamides for example pukelimide A (2) were also isolated from L.m~juscula.~~*~~ This alga is known to cause a dermatitis called ‘swimmer’s itch’ in Hawaii. One of the substances respon- sible for this effect i.e. lyngbyatoxin A has been characterized as an indole alkaloid (3) that is closely related to a fungal metabolite teleocidin B which causes similar physiological eff ect~.’~ ” A. Bingharn Jr. D. W. Wilkie and H. S. Mosher Comp. Biochem. Physiol. (B),1979,62 489. H. Rflnneberg G. Borch D. L. Fox and S. Liaaen-Jensen Comp. Biochem. Physiol. (B),1979,62,309. l9 C. Ireland and P. J. Scheuer Science 1979 205,922. 2o J. H. Cardellina II. F.-J. Marner and R. E. Moore J. Amer. Chem. SOC.,1979,101,240. *’ J.H. Cardellina II. D. Dalietos,F.-J. Marner J. S. Mynderse and R. E. Moore Phytochemistry 1978,17 2091. 22 C.J. Sirnrn0ns.F.-J. Marner J. H. Cardellina II. R. E.Moore and K. Seff Tetrahedron Letters 1979,2003. 23 J. H. Cardellina 11. and R. E. Moore Tetrahedron Lerters 1979,2007. 24 J. H. Cardellina II. F.-J. Marner and R. E. Moore Science 1979,204 193. C. Christophersen and N. Jacobsen m HoMe *yMe 'OH Ra;n:e H Ph (4) R=H (5) R=C1 Alkaloids were also present in Hyella caespitosa from which the two unusual carbazole alkaloids hyellazole (4) and chlorohyellazole (5) were isolated.25 Rhodophyceae (Red Algae).-A large portion of the pioneering work on metabolites of red algae has been done on members of the genus Laurencia ; since then a vast number of compounds belonging mainly to two classes (i.e.halogenated terpenoids and halogenated compounds containing a CISstraight-chain skeleton) have been described from this genus.Most of the recent papers on Laurencia metabolites report only minor variations within already known structural types or are concerned with details of known structures. In the non-terpenoid class a polycyclic acetylenic ketal obtusin (6),26and an acetylenic chlorine- and bromine-containing nine-membered cyclic ether obtusenyne (7),27have both been isolated from Mediterranean L. obtusa whereas a bromo-allene laurallene (8),28was found in L. nipponica. " J. H. Cardellina II. M. P. Kirkup R. E. Moore J. S. Mynderse K. Seff and C. J. Simmons Tetrahedron Letters 1979,4915.26 B. M. Howard W. Fenical E. V. Arnold and J. Clardy Tetrahedron Letters 1979 2841. '' T. J. King S. Imre A. Oztunc and R. H. Thomson Tetrahedron Letters 1979 1453. ** A. Fukuzawa and E. Kurosawa Tetrahedron Letters 1979,2797. Biological Chemistry -Part (iu) Marine Natural Products 437 The genus Laurencia has presented certain taxonomic problems because there is considerable morphological variation within the species. Preliminary attempts to employ gas chromatography-mass spectrometry of crude extracts as a chemotax- onomic aid have been A number of Laurencia sesquiterpenoids especially of the chamigrene types [e.g. obtusol (9)] contain a chloro- and a bromo-substituent in a vicinal arrangement. Determination of the exact positions of these substituents has so far been done with a high degree of uncertainty.Thus after X-ray analysis of members of this group some earlier assignments had to be revised,30 and using this information combined with a detailed 13C n.m.r. analysis of a number of related structures the structures of two new compounds isofurocaespitan (10) and obtusan (1l),from L. caespitosa and L. obtusa respectively could be determined with greater confiden~e.~~ While bromo- and chloro-substituents have been found to be commonplace features of marine natural products the two compounds (12) and (13) isolated from L. nana represent the first examples of iodinated se~quiterpenes.~~ From a Californian L. spectabilis an unusual collection of a@ -unsaturated a-branched aldehydes exemplified by the major constituent 2-dodecylhexadec-2- enal (14) was identified.33 \/H CHO CH3(CH2)12CH=C/ ’a \ OH (CH2)llCb Prostaglandins PGE (15) and PGF2 (16) isolated from Gracilaria lichenoides are the first examples of prostaglandins from a plant.34 This finding suggests that the prostaglandins found in gorgonians may have their origin in symbiotic algae since both (15) and (16) have been isolated from gorgonian~.~’ Fenica13’ has suggested that several of the simple halogenated compounds (acrylic acids halogenomethanes lactones etc.) from members of the family Bonne- maisoniaceae arise by simple transformations of halogenated ketones.Recent 29 S. Caccamese L. P. Hager K. L. Rinehart Jr. and R. B. Setzer Butanica Marina 1979,22,41.30 A. G. Gonzales J. D. Martin V. S. Martin M. Martinez-Ripoll and J. Fayos Tetrahedron Letters 1979 2717. ” A. G. Gonzales J. D. Martin V. S. Martin and M. Norte Tetrahedron Letters 1979,2719. 32 R. R. Izac and J. J. Sims J. Amer. Chem. SOC.,1979 101 6136. 33 R. P. Maiden and J. A. Pettus Abstract 575 ACS/CSJ Chemical Congress Honolulu Hawaii April 1-6 1979. 34 R. P. Gregson J. F. Marwood and R. J. Quinn Tetrahedron Letters 1979,4505 and references therein. 35 Y. Komoda T. Kanayasu and M. Ishikawa Chem. Pharm. Bull. 1979,27,2491. C. Christophersen and N. Jacobsen -**WCO H OH OH (15) R=O (16) R=a-OH P-H on the whole supports this hypothesis but further work is needed in order to determine which of these transformations occur in vivo and which during the isolation procedure.Phaeophyceae (BrownAlgae).-The work on metabolites of brown algae reported in 1979 has been concentrated within two families i.e. the Dictyotaceae (in particular the genera Dictyota Dictyopteris Dilophus and Stypopodium) and the Sargassaceae (genera Sargassum and Cystophoru). It has been suggested that some of the CI1 hydrocarbons e.g. dictyopterene A (17),from Dictyopteris species might arise from suitable alkenols derived from fatty acids. Both (17) and its assumed precursor dictyoprolene (18) have been isolated from Dictyopteris prolifera and it was shown that the absolute stereochemistry of (18) is consistent with this hypothe~is.~~ Within the Dictyotaceae a group of genera (including Dictyota and Dilophus) appear more closely related than the others.Further support for this relationship has been gained by the isolation of hydroxydilophol (19)39from Dictyota rnasonii. This diterpenol is closely related to dilophol from Dilophus ligulutus. A related (but structurally novel) diterpenoid dictyodial(20) was found in Dictyotu crenulata and D. flabellata.4a Several compounds containing a sesquiterpenoid (drimane) substituent on a benzenoid moiety are known from Dictyopteris undulata the latest being yahazunol "F. X. Woolard R. E. Moore and P. P. Roller Phytochemistry 1979,18,617. 37 N.Jacobsen and J. 0.Madsen Tetrahedron Letters 1978 3065. K. Yamada H. Tan and H. Tatematsu J.C.S. Chem. Comm. 1979 572. 39 H.H.Sun and W. Fenical J.Org. Chem. 1979,44 1354. 40 J. Finer J. Clardy W. Fenical L. Minale R. Riccio J. Battaile M. Kirkup and R. E. Moore J. Org. Chem. 1979,44,2044. 439 Biological Chemistry -Part (iv) Marine Natural Products (21) (2l).41A likely precursor for these compounds the polyprenylquinone (22) was found in the same alga.42 Stypopodium zonale is toxic to herbivorous fish. Compounds responsible for the toxicity have been isolated and shown to be a diterpenoid-substituted o-benzo- quinone stypoldione (23) and its corresponding hydroquinone stypotriol(24). The latter is the most powerful toxin but is rapidly aerially oxidized to (23) outside the alga.43 In the genus Sargassum plastoquinones such as sargaquinoic acid (25) and sargaquinal(26) frequently occur.44 It has been suggested that a series of derivatives of farnesylacetone (27) isolated from S.micracanthum are derived from plasto- quinones by oxidative cleavage as indicated in (25).45 Chlorophyceae (Green Algae).-The structures (28) were originally tentatively assigned to caulerpicin a bioactive mixture of homologous compounds from a Philippine Caulerpa rucemosa. Two of these (28; n = 24) and (28; n = 25) have now been synthesized and shown to be different from the original ca~lerpicins.~~ A mixture of similar compounds N-acyl-sphingosines (29) has been isolated from a Sri Lankan C.racemosa and is claimed to be the same as ~aulerpicin.~~ A comparison of the physiological and physical properties of this mixture with those of caulerpicin has not however been reported.Green algae from the families Codiaceae and Caulerpaceae are often avoided by herbivores. From Rhipocephalus phoenix (Codiaceae) two toxic feeding deterrents against fish were isolated and identified as the sesquiterpenoids rhipocephalin (30) and rhipocephenal(3 l).48 41 M. Ochi H. Kotsuki K.Muraoka and T. Tokoroyama Bull. Chem. SOC.Japan 1979,52,629. 42 M. Ochi H. Kotsuki S. Inoue M. Taniguchi and T. Tokoroyama Chem. Letters 1979,831. 43 W. H. Gerwick W. Fenical N. Fritsch and J. Clardy Tetrahedron Letters 1979 145. 44 T. Kusumi Y. Shibata M. Ishitsuka T. Kinoshita and H. Kakisawa Chem. Letters 1979 277. 45 T. Kusumi M. Ishitsuka Y. Nomura T. Konno and H. Kakisawa Chem. Letters 1979 1181. 46 U. Smensen and C. Christophersen unpublished results.47 M. Mahendran S. Somasundaram and R. H. Thomson Phytochemistry,1979,18,1885. 48 H. H. Sun and W. Fenical Tetrahedron Letters 1979 685. C. Christophersen and N. Jacobsen CH3(CH2)13CHCH*OH CH3(CH2) 12CH&HCH( OH)CHCH20H I I NHCO( CHz) CH3 NHCO(CH*),CH3 (28) (29) CHO OH OAc (30) (31) 4 Marine Invertebrates Poiifera.-Marine sponges still remain popular sources of intriguing compounds. In spite of the wealth of structural information gathered from these species study of biochemical biosynthetic and ecological information is virtually lacking. This sad state of affairs is mainly due to three inherited problems in sponge research. Sponge systematics is based on relatively few characters and since these animals display considerable natural variation classification is often extremely difficult.Sponges are filter-feeders and it is not known to what extent they may retain food-derived metabolites. Finally many sponges are known to harbour a wealth of parasitic or symbiotic micro-organisms especially microalgae and bacteria. Nothing is known of the role of this microflora; however several compounds described from sponges have a striking resemblance to known algal and bacterial metabolites. These points may be demonstrated by the recent isolation of alkylated scalarins from Dysidea herbacea collected in the Gulf of Suez;49 specimens of D. herbacea from other geographical regions however lack these Furthermore a 49 Y. Kashman and M. Zviely Tetrahedron Letters 1979 3879.C. Charles J. C. Braekman D. Daloze B. Tursch and R. Karlsson Tetrahedron Letters 1978 1519; R. Kazlauskas P. T. Murphy and R. J. Wells ibid. 1978,4945,4949; R. J. Wells Pure Appl. Chem.,1979 51,1829. 441 Biological Chemistry -Part (iv) Marine Natural Products survey of the genus Spongia from Australian waters has revealed that species collected from tropical environments have never yielded Czlfurano-terpenes while diterpenoids have never been detected in non-tropical Spongia in spite of the fact that the two classes of compounds are abundantly represented within this genus.’l The sesterterpenoid hydroxyquinols toxistylide A and B were only present in some collections of Microciona toxistyla while all of them contained sesquiterpenoid~.~~ These few examples also deliver the coup de grace to the hypothesis that sponge taxonomy may be based on simple analyses of secondary metabolites.Several reports on peroxides isolated from sponge material have appeared. From Chondrosia collectrix a mixture of (32) and its C-3 epimer has been characterized. The corresponding methyl esters were also Apparently these peroxides are derived from fatty acids with methyl or ethyl side-chains while muqubilin (33) is a CZ4isoprenoid from an unidentified Prianos sp.54 An ichthyotoxic peroxide sigmosceptrellin-A (34),from Sigmosceptrefla laeuis is a nor-~esterterpenoid~~ which curiously enough possesses the same sesquiter- penoid skeleton as the orange compound (39 poetically named ilimaquinone from Hippiospongia metachromia (tentative cla~sification).~~ 0 Quinones are well-known structural elements in marine natural products; however renierone (36),” from an unidentified Reniera sp.is the first example of an isoquinoline quinone. Renierone displays strong antimicrobial activity. Other ” R. Kazlauskas P. T. Murphy R. J. Wells K. Noack W. E. Oberhansli and P. Schonholzer Austral. J. Chem. 1979,32,867. ’’ G. Cimino S. De Stefano L. Minale R. Riccio K. Hirtosu and J. Clardy Tetrahedron Letters 1979 3619. 53 D. B. Stierle and D. J. Faulkner J. Org. Chem. 1979,44 964. 54 Y. Kashman and M. Rotem Tetrahedron Letters 1979 1707. 5s M. Albericci M. Collart-Lempereur J. C. Braekman D. Daloze B. Tursch J. P. Declercq G. Germain and M. Van Meerssche Tetrahedron Letters 1979,2687.” R. T. Luibrand T. R. Erdman J. J. Vollmer P. J. Scheuer J. Finer and J. Clardy Tetrahedron 1979.35 609. 51 D. E. McIntyre D. J. Faulkner D. V. Engen and J. Clardy Tetrahedron Letters 1979 4163. C. Christophersen and N. Jacobsen alkaloids such as fistularine 1(37),from Aplysina fistularis forma fulua exhibit very interesting growth-inhibiting effects on cells in uitro.’* Coe1enterata.-The two phyla Cnidaria and Ctenophora constitute the Coelen- terata. Class Anthozoa in phylum Cnidaria is divided into the subclass Alcyonaria (Octocorallia) and Zoantharia (Hexacorallia). Four orders of Alcyonaria have been investigated. For one of them Telestacea only one report has appeared describing the isolation and structural elucidation of the pregnanes (38)and (39),from Telesto riisei.” & 0.’AcO .cl Aq 0’ 0 (38) R=Ac (40) (39) R=H Diterpenoids exemplified by stylatulide (40),isolated from a Stylatula sp.belonging to the order Pennatulacea (sea pens) are examples of more complex marine products. Since (40) was reported to be toxic to copepodid larvae (Crus- taceae) the authors speculate that these diterpenoids may protect the coelenterate from larval settling.60 Members of the order Alcyonacea (soft corals) have given rise to the isolation of an amazing variety of terpenoids. The rich harvest of fourteen-membered-ring cembranolide diterpenes has continued plus an occasional thirteen-membered ring e.g. (41).61 Diterpenoids from soft corals include nine-membered-ring represen- tatives e.g.isoxeniolide A (42)from Xenia nouae-britanniae.62 Among the many sesquiterpenoids isolated from members of the Alcyonacea those derived from the capnellane skeleton have been the subject of further investigations. The soft coral Capnella imbricata showed considerable geographical Y. Gopichand and F. J. Schmitz Tetrahedron Letters 1979 3921. 59 R. A. Ross and P. J. Scheuer Tetrahedron Letters 1979,4701. 6o S. J. Wratten and D. J. Faulkner Tetrahedron 1979 35 1907. 61 Y. Yamada S. Suzuki K. Iguchi K. Hosaka H. Kikuchi Y. Tsukitani H. Horiai and F. Shibayama Chem. Pharm. Bull. 1919,21,2394. J. C. Braekman D. raloze B. Tursch J. P. Declercq G. Germain and M. Van Meerssche Bull. SOC. chim. belges.1979,88 71. Biological Chemistry -Part (iv)Marine Natural Products and individual variation in ratios of capnellane-derived metabolite^.^^ Species from the northern coast of New Guinea for example were found to contain A9(12)-capnellene-2.5,8,10-tetraol(43). Interestingly enough A9('2)-~apnellene (44) was found to co-occur with precapnelladiene (45) in a hydrocarbon fraction. This observation has given rise to the suggestion that (45) is a biogenetic precursor of the capnellane ~keleton.~~ The first marine spermidine derivatives (46) and dihydro-(46) have been repor- ted from the soft coral Sinularia bronger~mai.~~ These derivatives exhibit interesting levels of cytotoxicity an effect which in other coelenterates has often been traced to the cembranolides.The fourth order the Gorgonacea has received ample attention earlier; however work published during 1979 has been extremely sparse. A representative of the Hexacorallia the gold coral a Pacific zoanthid species of the genus Gerardia has added two more variations e.g. (47),66 to the tetra- azacyclopentazulene theme. (47) Mol1usca.-Significant progress has been achieved in unravelling important ques- tions in the chemical ecology of subclass Opisthobranchia (sea slugs). Members of this subclass lack external shells and are often conspicuously coloured delicate 63 M. Kaisin,B. Tursch J. P. Declercq G. Germain and M. Van Meerssche Bull. Soc. chim. belges. 1979 88,253. 64 E. Ayanoglu T. Gebreyesus C. M. Beechan and C. Djerassi Tetrahedron 1979 35 1035.65 F. J. Schmitz K. H. Hollenbeak and R. S. Prasad Tetrahedron Letters 1979 3387. 66 R. E. Schwartz M. B. Yunker P. J. Scheuer and T. Ottersen Canad. J. Chem. 1979 57 1707. C. Christophersen and N. Jacobsen slow-moving animals. These characteristics are only compatible with survival of the species in a highly competitive environment provided that other defensive strategies are adopted. Ophisthobranchia seem mainly to have relied on chemical defence tactics; e.g. the concentration of food-chain-derived noxious or toxic secondary metabolites is well documented for many sea hares of the order Ana~pidea.~~ These herbivorous animals often graze preferentially on a single or a few species of algae whether red brown or blue-green.The advantages of this speciation are dual since the noxious character of the seaweed presumably discourages other potential grazers and the accumulation of the chemicals in the digestive glands of the sea slug deters would-be predators. A beautiful illustration of the perfection evolved in this type of relationship is offered in the investigation of the nudibranch Phyllidia varicosa.68 When provoked this organism will secrete a mucous slime containing a mixture of 2-iso-cyanopupukeanane (48) and 9-isocyanopupukeanane (49) lethal to fish and crus- taceans. The sesquiterpenoid isocyanides (48) and (49) originate from a sponge (Hymeniacidon sp.) the prey of P. varicosa. Undoubtedly the mixture of (48) and (49) functions also as an allomone in this predator-prey relationship.Total syntheses have been published for (48)69 as well as for (49).70 However the biosynthesis of isocyanides in sponges is far from clear. Isocyanides are often accompanied by the corresponding isothiocyanates and formamides. Recent evi- dence seems to indicate that isocyanides are not formed via formamides leaving the immediate precursor ~nknown.~' Future research in this area may very well benefit from a closer examination of the role of symbiotic micro-organisms in the sponge tissue. Opisthobranchia may not only benefit from the accumulation of chemical substances from prey organisms but may in certain cases secure the complete intact organelle responsible for synthesis as exemplified by the sacoglossan mollusc Placo branc h us ocella tus which assimilates photosynthetically viable chloroplasts from the siphonous algae upon which they graze.The mollusc-chloroplast symbiotic pair will incorporate 14C from radioactive hydrogen carbonate into 9,lO-deoxy- tridachione (50). The activity appears slowly in photodeoxytridachione (5l),as a result of an unprecedented photochemical isomerization in vivo. The authors speculate that this reaction may serve as a chemical s~nscreen.'~ 67 W. Fenical H. L. Sleeper V. J. Paul M. 0.Stallard and H. H. Sun Pure Appl. Chem. 1979,51,1865. 68 M.R.Hagadone B. J. Burreson P. J. Scheuer J. S. Finer and J. Clardy Helv. Chim. Acta 1979,62 2484. 69 E.J. Corey and M. Ishiguro Tetrahedron Letters 1979,2745. 70 (a)E.J. Corey M. Behforouz and M.Ishiguro J. Amer. Chem. SOC.,1979,101,1608;(6) H. Yamamoto and H. L. Sham ibid.,p. 1609. 71 A. Iengo C. Santacrose and G. Sodano Experientia 1979,35,10. Biological Chemistry -Part (iv) Marine Natural Products Me0 That some Opisthobranchia possess synthetic ability of their own is exemplified by an investigation of Nuvanax inemis (Cephalaspidea). The members of this species locate each other by following the slime trail laid down by a crawling animal. If heavily molested the sea slug will deposit a bright yellow secretion containing three main components; navenones A (52) B (53) and C (54). The presence of this 0 RII R= 0 (53) (52) R=Ph (54) R=aOH mixture elicits a specific avoidance behaviour in any Navanax,namely termination of trail-following and migration in a new direction that forms an angle of greater than 90”with that of the original direction.Labelled acetate (‘“C) given with the food was incorporated into the navenones the highest activity being found in (54) followed by (53). Partly based on evidence from the labelling experiment the authors have suggested a biogenetic relationship (54) +(53) +(52);67this hy- pothesis warrants further study. Mycosporin analogues are known from fungi algae and coelenterates. Two such compounds mytillins A (55) and B (56),have recently been isolated from the bivalve Mytillus galloprovincialis a Mediterranean variant of Mytillus edulis (mussel) which is perhaps the most commonly eaten bivalve in Europe.’* Compound (56) was also present in the red alga Porphyra tenera which is a part of the common Japanese diet.73 OMe w CYOH R HO CH,OH (55) R=H (56) R=Me The branchial heart of Octopus vulgaris the common octopus contains an iron-containing pigment adenochrome.As a result of a considerable amount of work desferriadenochrome has been shown to be a peptide composed of glycine and 72 F. Chioccara,G. Misuraca E. Novellino and G. Prota Tetrahedron Letters 1979,3181. ” S. Takano A. Nakanishi D. Uemura and Y. Hirata Chem. Letters 1979,419. C. Christophersen and N. Jacobsen (57) 3,6-X2 (58) 5,6-X2 (59) 3,5-x2 three iron-binding amino-acids (57) (58),and (59) named adenochromines A B and C re~pectively.~~ The adenochromines were suggested to arise from addition of 5-mercapto-~-histidine(60) to L-dopaquinone formed by enzymatic oxidation of L-dopa and the suggestion was supported by the realization of the reaction in 0itr0.~’ Other Phyla.-Work on echinoderms has included the elucidation of the structures of the carbohydrate moieties of steroidal saponins of a starfish (Asterias am~rensis)~~ and a sea cucumber (Holothuria leucospil~ta).~~ The starfish saponin was suspected to play a regulatory role in the follicle cells.Of the many aromatic polyketides isolated from crinoids most if not all are present in the animal as sulphate esters. Some of these sulphated derivatives have been shown to be food deterrents for several species of fish.’* The phylum Bryozoa (moss animals) has not until now attracted the attention of natural products chemists.Recently the brominated alkaloids flustramines A and B [(61) and (62) respectively] were isolated from Flustra f01iacea.’~ 0 t MezSCH2CH20H (63) (62) R= A Another bryozoan Alcyonidium gelatinosum responsible for a severe eczematous dermatitis among fishermen has been investigated and the allergen has been 74 S. Ito G. Nardi A. Palumbo and G. Prota J.C.S. Perkin I 1979 2617. 75 S.Ito G. Nardi A. Palumbo and G. Prota Experientia 1979 35 14. 76 S.Ikegami K. Okano and H. Muragaki Tetrahedron Letters 1979,1769. 77 I. Kitagawa T. Nishino and Y. Kyogoku Tetrahedron Letters 1979 1419. 78 J. A.Rideout N. B. Smith and M. D. Sutherland Experientia 1979,35,1273. 79 J.S.Carl6 and C. Christophersen J. Amer. Chem. SOC.,1979,101,4012; J. Org. Chem. 1979,45,1586. Biological Chemistry -Part (iv) Marine Natural Products 447 identified as a sulphoxonium compound (63).80 Urochordates reportedly display a high incidence of compounds that have anti-cancer activity. In the case of the tunicate Aplidium californicum this activity was accounted for by prenyl- hydroquinone while two other metabolites i.e. 6-hydroxy-2,2-dimethylchromene and prenylquinone have anti-mutagenic activity.81 J. S. Carl6 and C. Christophersen J. Amer. Chem. SOC.,1980,102,5107. B. M. Howard K. Clarkson and R. L. Bernstein Tetrahedron Letters 1979,4449.

ISSN:0069-3030    

DOI:10.1039/OC9797600433

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

16 Biological Chemistry Part (v) Nucleic Acids (a) Nucleosides and Nucleotides By G.SHAW School of Chemistry University of Bradford Bradford BD7 IDP 1 Introduction The previous report on nucleoside and nucleotide chemistry appeared in 1976 and in the intervening years there has been no abatement to the flood of publications in this field stimulated not least by the continued isolation of new nucleosides from micro-organisms or as constituents of tRNAs. Several of these are C-nucleosides and this has no doubt added to the enhanced interest in the chemistry of this type of substance over the period. Indeed the close structural similarity of most of these compounds to components of nucleic acids or to intermediates in nucleotide biosynthesis de nuvo is remarkable and adds weight to the search for synthetic chemotherapeutically active compounds in this area.The first successors’ to the invaluable series ‘Synthetic Procedures in Nucleic Acid Chemistry’ and the first volumes’ in what promises to be a major review of the field have appeared. Several other reviews3-” covering a wide range of nucleic acid chemistry include specialist accounts’ of modified nucleosides of tRNAs nucleoside antibiotics,’ cyclic nucle~tides,~*’~ and the formation of purine nucleosides from imidazole precursors. ” Nucleic Acid Chemistry’ ed. L. Townsend and R. S. Tipson Wiley-Interscience New York 1978 Vols. 1 and 2. ’‘The Chemistry of Nucleosides and Nucleotides’ ed. R. K. Robins and L. B. Townsend Plenum Press New York 1979.‘Chemistry and Biology of Nucleosides and Nucleotides’ ed. R. E. Harmon R. K. Robins and L. B. Townsend Academic Press New York 1978. Nucleic Acids Res. 1978 Special Publication No. 4. ‘Nucleoside Analogues’ ed. R. T. WaIker E. De Clercq and F. Eckstein NATO Advanced Study Institute Series Plenum Press New York and London 1979. K. Galankiewicz Khim. geterotsikl. Soedinenii 1978 723. ’J. A. McCloskey and S. Nishimura Accounts Chem. Res. 1977,10,403. ‘Nucleoside Antibiotics’ A. Bloch in Kirk-Othmer Encyclopaedia of Chemical Technology ed. M. Grayson and D. Eckroth Wiley New York 1978 Vol. 2 p. 962. Advances in Cyclic Nucleotide Research’ Vol. 9 ed. W. J. George and L. J. Ignarro Raven Press New York 1978. ‘Advances in Cyclic Nucleotide Research Vol.10 ed. G. Brooker P. Greengard and G. A. Robison Raven Press New York 1979. A. Yamazaki and M. Okutsu J. Heterocyclic Chem. 1978 15 353. Biological Chemistry -Part (u)a Nucleosides & Nucleotides 449 2 Nucleoside Antibiotics and tRNA Constituents Oxazinomycin (1) (which yields pseudouridine with ammonia) and its a-anomer have been synthesized12 (Scheme 1)from the 2’,3’-0-isopropylidene-5’-0-trityl-D-ribofuranosylacetonitriles (2). HO HO OH (1) (Tr =Ph3C; Im = 1-imidazolyl) Reagents i (Me,N),CHOBu‘; ii NH,OH; iii H,-Pt; iv H,O’; v Im,CO; vi CF,CO,H-H,O (9:1) Scheme 1 Formycin (3) and formycin B (4) have been synthesi~ed’~ by cyclization of appropriate ribofuranosyl-pyrazoles (9, which were prepared by addition of N2CHR2 to NCCR3=CHC02R’ (R3= 2,3,5-tri-O-benzoyl-fl-D-ribofuranosyl).The total synthesis of wyosine (Nucleoside Yt) (6) which occurs in the next position to the 3’-end of the anticodon of yeast tRNAPhe has been rep~rted,’~ by cyclization of 5-methylamino-4-cyano-1-(2,3,5-tri-0-acetyl-fl-~-ribofuranosyl)-imidazole. Wyosine is strongly fluorescent and its unusual extreme lability to hydrolysis is characteristic of 3-alkyl-guanosines. (4) X=OH (Rf =P-D-ribofuranosyl) ’’ S. DeBernardo and M. Weigele J. Org. Chem. 1977.42 109. l3 L. Kalvoda Coll. Czech. Chem. Comm. 1978 43 1431. l4 S. Nakatsuka T. Ohgi and T. Goto Tetrahedron Letters 1978,2579. 450 G. Shaw A total synthesis of optically pure Nucleoside Q (7) the first position of the anticodon of the tRNA of Escherichia cofi (Tyr His Asp and Asn) has been recorded.Two diastereoisomers were obtained one of which [with a (3S,4R,5S) configuration in the cyclopentenyl side-chain] was identical to the natural nucleoside. New syntheses of showdomycin (8) have been recorded including one from 2,3,5-tri-O- benzylribofuranosylethyne (9) involving six stages,16 and an interesting stereocontrolled ~ynthesis'~ from the intermediate (lo) which was obtained from the adduct of sym -tetrabromoacetone and furan (Scheme 2). lviii Reagents i [Fe,(CO),]; ii Zn-Cu couple; iii OsO, H,O,; iv HClO, Me,CO; v CF,CO,H; vi furfural; vii Bu'COCl; viii NaOMe; ix 0,;x Ph,P=CHCONH,; xi H,O+ Scheme 2 0 (9) (11) dRf = 2-deoxy-Rf The triazine nucleoside (11)from Streptomyces platensis has been synthesized" by a conventional reaction of the silylated aglycone and a protected deoxyribofuranosyl halide.1-Methylpseudouridine which is also produced by this organism has been synthesized in 57% yield by methylation of an acetylated pseudouridine with methyl iodide over 4 days." Is T. Ohgi T. Kondo and T. Goto J. Amer. Chem. SOC. 1979,101,3629. l6 J. G.Buchanan A. R. Edgar M. J. Power and C. T. Shanks J.C.S. Perkin I,1979,225. " T.Sato R. Ito Y. Hayakawa and R. Noyori Tetrahedron Letters 1978 1829. *' H. Skulnick J. Org. Chem. 1978,43 3188. l9 R. A Earl and L. B. Townsend J. Heterocyclic Chem. 1977,14,699. Biological Chemistry -Part (v)a :Nucleosides & Nucleotides 45 1 New naturally occurring nucleosides continue to be discovered both from micro- organisms and from tRNAs.They include the pyridine nucleoside clitidine (12) from Clitocybe acromelalga,2Q mildiomycin (13) from Streptoverticillium rimo -facierq21 the somewhat analogous Nucleoside N (14) from the first letter position of the anticodon of tRNAGIYof Bacillus subtilis,22 polyoxin N (15) (a N-nucleoside analogous to pyrazomycin) from Streptom yces fiomogene~,~~ anthelmycin (16) A4eN~CH2NHCH2C02H H2NfOH A ON R,B HO HO OH (14) CH,OCONH (15) HOfoH HO 07CH2CONH2 Me02C (17) 2o K. Konno K. Hayano H. Shivahama;H. Saito and T. Mastoumoto Tetrahedron Letters 1977,481. *' S. Harada E. Mizuta andT. Kistii J. Amer. Chem. Soc. 1978,100,4895. 22 K. Murao and H.Ishikura Nucleic Acids Res. 1978 Special Publication No. 5 S333. 23 M. Uramoto J. Uzawa S. Suzuki K.Isono J. G. Liehr and J. A. McCloskey Nucleic Acids Res. 1978 Special Publication No. 5 S327. 452 G. Shaw (identical with hikizimycin) from S. Zongissimus," and the novel indole acetamide nucleoside neosidomycin (17) from S. hygroscopicus." The cytokinin-active ribonucleoside cis-zeatin-D-riboside (18) has also been isolated from the tips of plants of Nicotiana tabacum.26 An interesting synthesis of pentostatin (2'-deoxycoformycin) (19) has been described2' from imidazole precursors (Scheme 3). The compound is an inhibitor of adenosine deaminase and is used to increase the efficacy of arabinofuranosyladenine as an anti-tumour drug by prolonging its action in viva 0 0 OZN CH,Ph vi-ix/ (19) Reagents i Im,CO; ii MeNO Bu'OK; iii SnCl, HCl; iv H,-Pd; v (ETO),CH; vi (Me,Si),NCOCF,; vii 3,5-di-O-p-toluoyl-2-deoxy-~-r~bose; viii NaOMe ix NaBH Scheme 3 A related inhibitor of adenosine deaminase isocoformycin (20) has also been synthesized,*' the structure of the highly modified nucleoside (21) from mammalian tRNA has been elucidated by high-resolution mass ~pectrometry,~' and 7-methyl- xanthosine has been identified as an intermediate in caffeine bio~ynthesis.~' 24 M.Vuilhorgne S.Ennifar B. C. Das J. W. Paschal R. Nagarajan E. W. Hagaman and E. Wenkert J. Org. Chem. 1977,42 3289. 25 R. Furuta S.Naruto A. Tamura and K. Yokogawa Tetrahedron Letters 1979 1701. 26 K. Kimura T. Sugiyama and T.Hashizume Nucleic Acids Res. 1978,Special Publication No. 5 S339. " D. C.Baker and S.R. Putt I. Amer. Chem. SOC. 1979,101,6127. M. Shirnazaki,S.Kondo K. Maeda M. Ohno and H. Umezawa J. Antibiotics 1979,32 537. 29 Z. Yamaizumi S.Nishimura K. Limburg M. Raba H. J. Gross,P. F.Crain and J. A. McCloskey J. Amer. Chem. SOC. 1979,101 2224. 30 T. W. Baumann E. Dupontlooser and H. Wanner Phytochemistry 1978,17,2075. Biological Chemistry -Part (v)a Nucleosides & Nucleotides 3 Nucleosides Organopalladium continue to be used for the preparation of 5-substituted uracil nucleosides and an unusual alkylation of uridine at C-6 has been described33 in which 2’,3’-0-isopropylideneuridineis lithiated in THF and treated with an alkyl halide at -78 “Cto produce the 6-alkyl derivative in 4640% yield with no evidence for alkylation at the N-3 or 5’-0 positions.Alkylation of purine and pyrimidine nucleosides or nucleotides with alkyl halides has been found to proceed in high yields in the presence of tetrabutylammonium fluoride in THF at room temperat~re.~~ A mass spectral study of eleven mono-benzylated nucleosides has enabled the site and extent of benzylation to be determined.35 A mild nitrating agent nitronium tetrafluoroborate has been to produce 5-nitro-2‘-deoxy- uridine from 2’-deoxyuridine. New routes to pseudouridine and pseudocytidine continue to be reported. Pseudocytidine has been prepared in 60% yield by the reaction of 1,3-dimethylpseudouridinewith guanidine3’ or from the ribofuranosylacetonitrile (2).A general stereocontrolled synthesis of C-nucleosides including pseudouridine 2-thiopseudouridine and pseudocytidine from the non-carbohydrate intermediate (10)has been described39 (Scheme 4). The acid derived from (10)has been Reagents i Me,NCHO; ii NH2CONH, ETONa; iii H30S Scheme 4 Analogous reactions of pseudouridine that has been modified at C-5‘ have been similarly a~hieved,~’ commencing with substituted derivatives of (10). 2’-Deoxy-pseudouridine and its CY -anomer have also been prepared from 2,4-di-t-butoxy-5- lithiopyrimidine and 3,s-di-0- benzyl-2-deoxy-~-ribose, in yields of 22 and 25 o/o re~pectively.~~ 31 D. E. Bergstrom and M. K. Ogawa J. Amer. Chem. SOC. 1978,100,8106. 32 A. S. Jones G. Verhelst and R.T. Walker Tetrahedron Letters 1979,4415. 33 H. Tanaka I Nasu and T. Miyasaka Tetrahedron Letters 1979,4755. 34 K. K. Ogilvie S. L. Beaucage M. F. Gillen D. Entwistle and M. Quillam Nucleic Acids Res. 1979,6 1695,2261. 3s H. T. Cory K. Yamaizumi D. L. Smith D. R. Knowles A. D. Broom and J. A. McCloskey J. Heterocyclic Chem. 1979,16,585. 36 G.-F. Huang and P. F. Torrence J. Org. Chem. 1977,42,3821. ” K. Hirota K. A. Watanabe and J. J. Fox J. Ore. Chem. 1978,43 1193. C. K.Chu U. Reichman K. A. Watanabe and J. J. Fox J. Org. Chem. 1977 42 711. 39 R. Noyori T. Sato and Y. Hayakawa J. Amer. Chem. Soc.,1978,100,2561. 40 T. Sato M. Watanabe and R. Noyori Tetrahedron Letters 1978,4403. 41 S. D. Bridges D. M. Brown and R. C. Ogden J.C.S. Chem Comm. 1977,460.454 G. Shaw 5 -@-D-Arabinofuranosylisocytosine(22) prepared from pseudoisocytidine by inversion at the 2'-position with acetoxyisobutyryl chloride isomerizes at room temperature to the ~u-anomer.~* Photochemical reactions of nucleosides still continue to excite considerable interest. Irradiation of 5'-0-tritylthymidine in the presence of pyruvoyl chloride produced the 3'-oxo-derivative (23)43 in 61?Ao yield. 2',3'-0-Isopropylideneuridine when irradiated in methanol gave the 6-hydroxymethyl-dihydrouridine(24),44 and a S-C photorearrangement of a pyrimidine S-ribofuranoside has resulted in a novel route to pse~douridine.~' HoY2N'"NH Irradiation of diazotized 2',3',5'-tri-0- acetyladenosine in the presence of a hydrogen abstractor has given an interesting synthesis of nebularine (25).46 Electrochemical reduction of the di-iododideoxythymidine derivative (26) gave the unusual cyclopropane derivative (27) in 36% yield.47 A similar compound was obtained from the analogous uracil nucleoside.Electrolysis of the 3'-deoxy-3'- bromo-D-xylosyladenine (28)gave the 2',3'-unsaturated nucleoside (29).48 OAC (Thy = thymine) (28) (Ade = adenine) " C. K. Chu U. Reichman K. A. Watanabe and J. J. Fox J. Medicin. Chem. 1978,21,96. 43 R. W.Binkley D. G. Hehemann and W. W. Binkley J. Org. Chem. 1978,43,2573. '' J.-L. Fourrey G. Henry and P. Jouin Tetrahedron Letters 1979 951. '' J.-L. Fourrey G. Henry and P. Jouin J. Amer. Chem. SOC.,1977,99,6753. 46 V.Nawi and S. G. Richardson Tetrahedron Letters 1979,1181.'' T.Adachi T. Iwasaki M. Miyoshi and I. Inoue J.C.S. Chem. Comm. 1977,248. " T.Adachi T. Iwasaki I. Inoue and M. Miyoshi J. Org. Chem. 1979,441404. Biological Chemistry -Part (v)a Nucleosides & Nucleotides OH (30) A novel synthesis of a nicotinamide D-xylofuranoside involves the reaction of 3’,5’-O-isopropylidene-D-xylosylaminewith 1-(2,4-dinitropheny1)-3-carbamoyl-pyridinium chloride in methanol at room temperature when a good yield of a mixture of the anomers (30) was Stereospecific syntheses of xylofuranosyl- and of ribofuranosyl-uracil have also been reported from 2,3-0-isopropylidene-~-ribofuranosylamineand 3,5-0-isopropylidene-D-xylofuranosylamine,which with ethyl N-(a-ace tyl- p-ethoxyacry1oyl)carbamate gave after deblocking 5-acetyluridine and 5-acetyl-~-a-D-xylofuranosy~uraci~ respectively; these were the sole anomers formed.’’ The stereospecificity is explained by the formation of a cyclic inter- mediate (31).COMe qOMe HOAO OxO (31) Other routes to 5-acetyluridine” and related compounds including 5-ethynyl- ~ridine,~’ have also been recorded N-Methyluridine may be converted into the diazepine nucleosides (32)in 28% yield by reaction with a carbene (Scheme 5).53 no-y=bo H.. :CXY R,BNKNMe 0 0 Rrs KNMe (32) X Y =C1 or Br Scheme 5 49 N. I. Oppenheimer J. Carbohydr. Nucleosides Nucleotides 1978,5 251. 50 R. Lofthouse G. Shaw P. S. Thomas G. Mackenzie D. H. Robinson and P. W. Rugg,J.C.S. Perkin Z. 1977,997. 51 A.S. Jones G. P. Stephenson and R. T. Walker Tetrahedron 1979,35 1125. 52 P. J. Barr A. S. Jones P. Serafinowski and R. T. Walker J.C.S. Perkin I 1978 1263. 53 H. P. M. Thiellier G. J. Koomen and U. K. Pandit Tetrahedron 1977,33 2609. 456 G. Shaw The reaction of adenosine “-oxide with cyanogen bromide has given a 90% yield of (33) which rearranges in basic conditions to give good yields of 2,6-diamino- purine nucleosides and 6-thiog~anosine.~~ The reaction also proceeds at the nucleotide level (see Scheme 6). X =NH2or SH Reagents i MeOH NH,; ii MeI; iii HO-; iv H,-Ni or H2S Scheme 6 A further application of the useful transglycosylation procedure involves conden- sation of 2‘-amino-2‘-deoxyuridinewith N6-octanoyladenine or N2-palmitoyl- guanine in the presence of trimethylsilyl trifluoromethanesulphonate to give 2’- amino-2’-deoxyadenosine or -guanosine.” 2‘-Amino-2’-deoxy-/3-D-arabinofuranosyladen~ne and related compounds have also been prepared by reduction of the corresponding 2‘-deoxy-2’-azido- nucleo~ide.’~ The corresponding amino-nucleoside has provided an improved route by to 9-~-~-arabinofuranosyl-2’-deoxy-2’-fluoroaden~neits diazotization in tetrafluoroboric a~id.~’ The fluoro-nucleoside is a hydrolysable precursor of the anti-tumour compound 9-P-D-arabinofuranosyladenine.Further modifications at the 5’-position in nucleosides include the formation of 5‘-chloro-2’,5‘-dideoxyadenosine (34)from 2’-deoxyadenosine and thionyl chloride in hexamethylph~sphoramide.~~ reacts with sodium 5’-Chloro-5’-deoxyadenosine phenylselenide and hydrogen peroxide to give 54% of the seleno-derivative (35) which is converted into the useful unsaturated derivative (36) in 94% yield by dimethyl ~ulphoxide.~~ c,yo” PhSellyoyde H2C<aye 0 HO HO OH HO OH (34) (35) (36) Similar 4’(5‘)-unsaturated nucleosides have been produced by iodinating purine nucleosides with methyltriphenoxyphosphonium iodide followed by dehydro- halogenation of the 5’-iodo-5‘-deoxy-nucleosides that are formed.60 The 5’(6’)- 54 T.Ueda K. Miura and T. Kasai Chem. Pharm. Bull. 1978,26,2122. 55 M. Imazawa and F. Eckstein J. Org. Chem. 1979,44,2039. 56 A. Sato R. Imai N. Nakamizo andT. Hirata Chem. Pharm. Bull. 1979,27,821. 57 J. A. Montgomery S.D. Clayton and A. T. Shortnacy J. Heterocyclic Chem. 1979.16 157. L. M. Beacham. 111 J. Org. Chem. 1979 44 3100. 59 N. Zylber and J. Zylber J.C.S. Chem. Comm. 1978 1084. S. D. Dimitrijevich J. P. Verheyden and J. G.Moffatt J. Org. Chem. 1979 44,400. 457 Biological Chemistry -Part (v)a Nucleosides & Nucleotides acetylenic nucleosides (37) have also been obtained via a Wittig reaction on the aldehydes (38).61 Crossed aldol reactions have been employed6' to give 4'mbstituted nucleosides including the adenosine derivative (39) from the 5-aldehyde and formaldehyde. Reduction of the deuteriated compound (40) with the adduct from (-)-pinene and 9-borabicyclo[3.3.1]nonane has given a sample of (5'R)-[5-*Hl]adenosine with 60% optical purity at C-5.63 (Ura = uracil) The 9-phenylxanthen-9-yl group which is removable by acids has been used to protect the 5'-OH of deoxyribon~cleosides,~~ and a regioselective 2'-0- deacylation of fully acylated purine and pyrimidine nucleosides by hydrazine gives 39-70% of the intended products although the 5'-0-acyl derivatives may be produced quan- titative~~.~~ The tetraisopropyldisiloxane-1,3-diylgroup has been used66 to functionalize the 2'-hydroxy-group in nucleosides by simultaneous protection of the 3'- and 5'- hydroxy-groups and 4-dimethylaminopyridine has been proposed as a selective catalyst for the silylation of secondary alcohols6' and in a simplified procedure for the preparation of triphenylmethyl ethers.68 Imidazole and related nucleosides continue to attract attention.5-Amino- 1-a-and -p-D-mannofuranosylimidazole esters (41) have been prepared from di-iso- propylidene-D-mannofuranosylamine(42) and converted into mannosyl-adenines and into lyxose nucleosides (Scheme 7). The 'H n.m.r. spectra of comparable pairs of anomeric mannofuranosyl-imidaoles and 2',3'-O-isopropylidene-D-mannofuranosyl-adenines showed that they did not accord with the widely used empirical rule relating anomer configuration with the field positions of H-l'.69 '' R. A. Sharrna and M. Bobek J. Org. Chem. 1978,43,367. 62 G. H.Jones M. Taniguchi D. Tegg and J. G. Moffatt J. Org. Chem. 1979.44 1309. '' R. J. Parry J.C.S. Chem. Comm. 1978,294. 64 J. B. Chattopadhyaya and C. B. Reese J.C.S. Chem. Comm. 1978,639.'' Y.Ishido N. Nakazaki and N. Sakain J.C.S. Perkin I 1979 2088. " W.T.Markiewicz J. Chem. Res. 1979,(S)24 (M)181. 67 S.K.Chaudhary and 0.Hernandez Tetrahedron Letters 1979 99. S. K.Chaudhary and 0.Hernandez Tetrahedron Letters 1979,95. '' G. Mackenzie and G. Shaw J.C.S. Chem. Comm. 1977,753. 458 G. Shaw ii-iv 1 Reagents i EtOCH=NCH(CN)CO,Et; ii NH,; iii POCl,; iv HN=CHNH,'; v H,O+; vi KIO,; vii NaBH,; viii H,O' Scheme 7 Ethyl 5-amino- l-~-~-arabinofuranosylimidazole-4-carboxylate (43) and the -4-carboxamide (44) have been prepared7' by condensation of 2,3,5-tri-0-benzyl-a -D-arabinofuranosyl chloride with ethyl 5-aminoimidazole-4-carboxylate or 5 -aminoimidazole-4-carboxamide, respectively. The glycosyl bromide or iodide failed to react.The imidazole nucleosides are useful precursors of 9-P-D-arabino- furanosyl-purines including 94- D-arabinofuranosyladenine. An acyclic D-arabinityl-aminoimidazole(45) has been isolated71 from the reaction of N-D-arabinopyranosyl-N'N'-dimethylformamidinewith a-amino-a-cyano-acetamide and methanolic acetic acid. The acyclic imidazole nucleoside was converted into the acyclic D-arabinityl-hypoxanthine(46) and the adenine (47). Hog;OH HO (43) X=OEt (44) X=NH2 (46) X=Hyp (47) X=Ade (Hyp = hypoxanthine) Methylation of ethyl 5 -amino-1-(2,3-0-isopropylidene-P- D-ribofuranosy1)- imidazole-4-carboxylate has been found to produce the 3-methylquaternary salt (48).'* An attempt to prepare compounds analogous to the antibiotic bredinin (49) by diazotization of the corresponding 5-amino-imidazole nucleoside gave an 18% yield of the 2-imidazolone nucleoside (50) the structure of which was confirmed by synthesis from the silylated aglycone and a ribose derivati~e.'~ 70 G.Mackenzie and G. Shaw. J.C.S. Chem. Comm. 1978,882. 71 G. Mackenzie G. Shaw and D. H. Robinson J.C.S. Perkin I,1977 1094. 72 T.Brown K. Kadir G. Mackenzie and G. Shaw J.C.S.Perkin I 1979,3107. 73 P.C. Srivastava R. J. Rousseau and R. K. Robins J.C.S. Chem. Comm. 1977,151. Biological Chemistry -Part (v)a; Nucleosides & Nucleotides Me 5-Amino-1-~-~-ribofuranosylimidazole-4-carboxylic acid (51) forms peptides including the naturally occurring aspartate derivative (52) in aqueous solution with 1-cyclohexyl-3-(4-ethylmorpholin-2-yl)carbodi-imidein yields of up to 10%.The isopropylidene derivative of (51)reacts with acetic anhydride in pyridine to produce the oxazin-7-one nucleoside (53).74 0 R,B (51) X=OH (52) X=L-ASP OX0 (53) 4 Nucleotides The absolute configuration at the phosphorus atom in diastereoisomers of adenosine 5'-(a-thiotriphosphate) (54)has been and stereospecific syntheses of (Sp) and (Rp)adenosine 3',5'-(cyclic)phosphorothioates (55) and (56)respectively have been Compounds of these types including compounds labelled with oxygen isotopes have been used to obtain information on binding mechanisms and stereochemical interactions with various enzymes. 78779 In addition to the normal 5'-phosphorylation reaction 3-P-D-ribofuranosyl- adenine was found" to react with phosphoryl chloride to produce the 9,S-cyclic I HO I OH I OH HO OH (54) 74 G.Shaw P. S. Thomas C. A. H. Patey and S. E. Thomas,J.C.S.Perkin I 1979 1415. 75 R. L. Jarvest and G. Lowe. J.C.S. Chem. Comm. 1979,364. 76 J. P. Richard H. T. Ho and P. A. Frey J. Amer.' Chem. Soc. 1978 100 7756. 77 J. Baranak R. W. Kinas K. Lesiak and W. J. Stec J.C.S. Chem. Comm. 1979,940. W. A. Blattler and J. R. Knowles J. Amer. Chem. SOC.,1979,101 510. 79 J. P. Richard and P. A. Frey J. Amer. Chem. Soc. 1978,100,7757. J. T. Uchic Tetrahedron Letters 1977 3775. 460 G. Shaw phosphonate (57) and 3',5'-cyclic phosphoramidates and phosphites have been obtained from t h ymidine and hexamet hylp hosp horamidite.81 The 3',5'-cyclic phosphate of 6-mercaptopurine has been prepared in 65% yield by the reaction of CAMP with liquid hydrogen sulphide in aqueous pyridine over 7 days." New phosphorylating agents continue to appear. Of special interest is the use of 8-quinolyl dihydrogen phosphate (58) which converts adenosine into AMP in 75% yield in pyridine solution in the presence of CuC12 (Scheme 8) UMP CMP and GMP may also be prepared in this way.83 'J. O\ /O+-CU"/, o=p-o-o=P-o/ I I OH OH (58) Reagents i CuCI,; ii ROH Scheme 8 5-Chloro-8-quinolyl phosphate has also been usedg4 for similar purposes. p -Chlorophenyl-N-phenylchlorophosphoramidatehas been usedg5 togood effect for the phosphorylation of nucleosides. P'P2-Bis(5'-nucleosidyl)diphosphates have been produced" under hypothetical prebiological conditions; thus when a solution of uridine ADP Mg" and imidazole was allowed to dry out UppA was formed.NAD has also been produced under similar conditions with appropriate precursors. From the same laboratories it has been reported that nucleosides have been phosphorylated in aqueous alkaline solutions using trimetaphosphates to give good "G. S. Bajwa and W. G. Bentrude Tetrahedron Letters 1978,421. R. B. Meyer T. E. Stone and F. P. Heinzel J. Heterocyclic Chem. 1978,15 1511. 83 H. Takaku Chem. Phann. Bull. 1977,25,2121. 84 H.Takaku R. Yamaguchi and T. Nomoto,Tetrahedron Letters 1979,3857. 13' E.Ohtsuka,T. Tanaka and M. Ikehara J. Amer. Chern. SOC.,1979,101,6409. 86 R.Lohrmann and L.E. Orgel J. Mol. Eool. 1978,11 17. Biological Chemistry -Part (u)a Nucleosides & Nucleotides 461 yields of nucle~tides.~’Deoxynucleosides gave mixtures of the 3’-and 5‘-tri-phosphates in ~44%yield, whereas adenosinein the presence of borate gave ATP in 9.9% yield and 3’-deoxythymidinegave the 5’-triphosphatein 15% yield. In a similar series of experiments,when solutionsof adenosine 5’-pyrophosphates (n 3) or P’P2-bis(5‘-adenosyl)diphosphate were allowedto dry out in the presence of arnines,appropriatelysubstituted adenosine 5‘-phosphoramidateswere formed in yields of 10-50% .BB Dinucleoside phosphoramidates have been preparedB9from silylated nucleoside phosphites and 5’-deoxy-5’-azido-nucleosides(Scheme 9). HOYoY + .-(”‘y”’ 0 HO o=p-o-‘OSiMe, I yNSiMe3 H 0 I o=p-o-HO Scheme 9 X-Ray crystal structures that have been determined include 3’-UMP9’ and thy-midine 3’,5’-cyclicNN-dimethylph~sphoramidate,~’ and details of the binding of copper ions to IMP92and UMP have appeared.93 E.Etaix and L. E. Orgel J. Carbohydr. Nucleosides Nucleotides 1978,5,91. R. Lohrmann J. Mol. Evol. 1977 10 137. 89 D. E. Gibbs Tetrahedron Letters 1977,679. 90 T. Srikrishnan S. M. Fridey and R. Parthasarathy J. Amer. Chem. SOC.,1978,100,3739. 91 M. G.Newton N. S. Pantales G. S. Bajwa and W. G. Bentrude Tetrahedron Letters 1977,4457. 92 K. Aoki J.C.S. Chem. Comm. 1977,600. 93 B. E. Fischer and R. Bon. J.C.S. Chem. Comm. 1977 272.

ISSN:0069-3030    

DOI:10.1039/OC9797600448

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

16 Biologi ca I Chemist ry Part (v) Nucleic Acids (b) Oligonucleotides and Polynucleotides By M. J. GAIT Medical Research Council Laboratory of Molecular Biology Hills Road Cambridge CB2 2QH 1 Introduction It has been customary in previous Reports to cover biological and chemical aspects of oligo- and poly-nucleotides. With the rapid growth in molecular biology and the need to cover three years’ literature (1977-79) in limited space this Report concentrates unashamedly on nucleic acid chemistry. Reviews of a more biological nature may be found in recent issues of Annual Reviews ofBiochernistry and Progress in Nucleic Acids Research and Molecular Biology. 2 Determination of Base Sequences of Nucleic Acids Two recent reviews highlight the remarkable advances that have been made in DNA sequence analysis.’ Continuous sequences of several thousand bases are now published for example complete sequences of bacteriophages 4X1742 and G4,3 mammalian viruses SV404 and hepatitis B,’ sections of DNA corresponding to mammalian genes (insulin,6 globin,’ and ovalbumin’) and human mitochondria1 DNA.9 Such feats have been possible due to the emergence of two new sequencing methodologies.The first” relies on partial and base-selective chemical cleavage of 32P-end-labelled DNA followed by separation of the resultant fragments by gel S. M. Weissman Analyt. Biochem. 1979,98 243; R. Wu Ann. Rev. Biochem. f978,47 607. * F. Sanger A. R. Coulson T. Friedmann G. M. Air B. G. Barrell N. L. Brown J. C. Fiddes C. A. Hutchinson 111 P.M. Slocombe and M. Smith J. Mol. Biol. 1978 125 225. G. N.Godson B. G. Barrell R. Staden and J. C. Fiddes Nature 1978,276 236. W. Fiers R. Contreras G. Haegeman R. Rogiers A. Van de Voorde H. Van Heuverswyn J. Van Herreweghe G. Volckaert and M. Ysebaert Nature 1978,273,113;V. B. Reddy B. Thimmappaya R. Dhar K. N. Subramanian B. S.Zain J. Pan P. K. Ghosh M. L. Celma and S. M. Weissman Science 1978,200,494. F. Galibert E.Mandart F. Fitoussi P. Tiollais and P. Charnay Nature 1979 281,646. B. Cordell G. Bell E. Tischer F. M. De Noto A. Ullrich. R. Pictet W. J. Rutter and H. Goodman Cell 1979,18,533;P. Lomedico N. Rosenthal A. Efstratiadis W. Gilbert R. Kolodner and R. Tizard ibid. p. 545. ’A. Van Ooyen J. Van den Berg N. Mantel and C. Weissmann Science 1979,206,337.J. F. Catterall B. W. O’Malley M. A. Robertson R. Staden Y. Tanaka and G. G. Brownlee Nature 1978,275,510; K. O’Hare R.Breathnach C. Benoist and P. Chambon Nucleic Acids Res. 1979,7 321. B. G. Barrell A. T. Bankier and J. Drouin Nature 1979,282 189. lo A. M. Maxam and W. Gilbert Proc. Nut. Acad. Sci. U.S.A.,1977,74 560. Biological Chemistry -Part (v)b:Oligo- and Poly-nucleotides 463 electrophoresis. Depurination is facilitated by prior methylation of guanines at N-7 and of adenines at N-3 using dimethyl sulphate whereas depyrimidination is achieved by reaction with hydrazine (see Section 6). The DNA is then broken by treatment with piperidine. Judicious choice of overall reaction conditions further distinguishes bases.The second method'' makes use of primed transcription of DNA with DNA polymerase in the presence of chain-terminating inhibitors in particular 2',3'-dideoxynucleoside 5'-triphosphates. Partial incorporation of just one inhibitor added to each of four separate reactions gives rise to a series of fragments resolvable by gel electrophoresis. The method has been extended for use with double-stranded DNA." The use of a computer considerably aids the storage and processing of DNA sequence inf~rmation.'~ Despite several elegant direct methods of RNA sequencing,14 it is now in most cases quicker to copy mRNA (often unpurified) into its complementary DNA (cDNA) using reverse transcriptase. The crude DNA is engineered into a carrier DNA (plasmid) which is used to transform Escherichia coli cells.Particular colonies (clones) that exhibit characteristics assignable to the presence of the sequence of interest may be selected and the relevant DNA excised and sequenced (e.g.ACTH-P-lipotropin precursor mRNA" and ovalbumin mRNA16). Cloning techniques are developing rapidly for analysis of genomic DNA. New vector classes capable of handling large DNA inserts have been constructed some bearing peculiarly hybrid names (co~mid,'~ phasmid"). Of similar use is the single- stranded circular DNA from filamentous bacteriophages such as M13.19 In 1977the intriguing discovery was made that many eukaryotic structural genes are interrupted by pieces of non-coding DNA (intervening sequences introns). A review and speculative discussion of this topic has recently appeared.20 Functional RNA is seemingly derived by transcription of the genes into RNA precursors which are then processed including the removal of all introns.The non-contiguous nature of mammalian genes has enhanced the cDNA route to analysis and subsequent expression of hormone-specifying sequences (e.g.insuIin2l and growth hormone22). l1 F.Sanger S. Nicklen and A. R. Coulson Proc. Nut. Acad. Sci. U.S.A. 1977,74,5463. l2 J. Maat and A. J. H. Smith Nucleic Acids Res. 1978 5,4537. l3 R. Staden Nucleic Acids Res. 1977,4 4037. l4 G. G. Brownlee and E. M. Cartwright J. Mol. Biol. 1977 114 93; H. Donis-Keller A. Maxam. and W. Gilbert Nucleic Acids Res. 1977 4 2527; J. Stanley and S. Vassilenko Nature 1978 274 87; A.Simoncsits G. G. Brownlee R. S. Brown J. R. Rubin and H. Guilley ibid. 1978 269 833; D. A. Peattie Proc. Nut. Acad. Sci. U.S.A. 1979,76 1760. S. Nakanishi A. Inoue T. Kita M. Nakamura A. C. Y. Chang S.N. Cohen and S. Numa Nature 1979 278,423. L. McReynolds B. W. O'Malley A. D. Nisbet J. E. Fothergill D. Givol S.Fields M. Robertson and G. G. Brownlee Nafure 1978 273 723. I' J. Collins and B. Hohn Roc. Nut. Acad. Sci. U.S.A. 1978,75,4242. G. Cesarini J. Karn and S. Brenner Proc. Nut. Acad. Sci. U.S.A. 1980,77 5217. l9 P. Schreir and R. Cortese J.Mol. Biol. 1979,129,169;J. Messing B. Gronenborn B. Muller-Hill and P. H.Hofschneider in 'Integration and Excision of DNA Molecules' ed. P. Hofschneider and P. Starlinger Springer Verlag Berlin 1978 pp. 29-32. 2o F.Crick Science 1979 204 264. 21 L. Villa-Komaroff A. Efstratiadis P. Broome P. Lomedico R. Tizard S.P. Naber W. L Chick and W. Gilbert Proc. Nut. Acad Sci. U.S.A. 1978,75 3727. 22 P. H. Seeburg J. Shine J. A. Martial J. D. Baxter and H. M. Goodman Nature. 1977,270,486; D. V. Goeddel H. L. Heyneker,T. Hozumi R. Arentzen K. Itakura D. G. Yansura M. J. Ross G. Miozzari R..Crea. and P. H. Seeburg ibid. 1979,281 544. 464 M. J. Gait 3 Synthetic Oligonucleotides in Molecular Biology The completion of the synthetic gene for the E. coli tyrosine suppressor tRNA and its control regions23 required the work of some forty five scientists over ten years. In contrast the inheritors of this technology can now carry out similar operations with considerably more ease.Despite the impressive nature of modern gene synthesis and subsequent expression in bacteria (e.g. somato~tatin~~ there is a and disappointing trend to omif the fine details of the chemical procedures. In the oligoribonucleotide field the determination of the total synthesis of tRNAm"' is nearing completion .26 The synthesis of the lac operon and of a number of analogues with altered sequence or containing modified bases has been de~cribed.~' Studies of repressor binding have identified particular functional groups on the DNA that are important to the interaction. Of great future potential is a new and generally applicable method of site-specific mutagenesis of DNA.28 A synthetic oligonucleotide that is mis- matched in a specific position on a DNA template is used to prime transcription by DNA polymerase.The progeny DNA contains a mutation at the site of the mismatch. Transition28 and transver~ion~~ mutants of 4x174 have been made. Of general use in cloning are self -complementary oligonucleotides (linkers) which after ligation to the end of a DNA may be cut by a restriction enzyme to give a 'sticky end'.30 Other adaptors will perform a similar function without the need for digestion with a restriction enzyme.31 One type of sticky end can also be changed into Oligonucleotides that are 32P-labelled have been used as probes for the isolation of gastrin mRNA32 and for the gene for yeast iso-l-cytochrome-c.33 The first crystal structure of a synthetic deoxytetranucleotide d(A-T-A-T),34 heralds a new era in the determination of structures of DNAs.Interestingly the large difference in torsion angle of the O(3')-P bond observed between the sequences T-A and A-T hints at the importance of conformational effects in the recognition of specific DNA sequences by proteins. A useful review of the uses of synthetic oligodeoxyribonucleotideshas been p~blished.~' 23 H. G. Khorana Science 1979,203,614. 24 K. Itakura T. Hirose R. Crea A. D. Riggs H. Heyneker F. Bolivar and H. W. Boyer Science 1977 198,1056. 25 R. Crea A. Kraszewski T. Hirose and K. Itakura Proc. Nut. Acad. Sci. U.S.A. 1978 75 5765. 26 E. Ohtsuka T. Tanaka S. Tanaka K. Fujiyama A. F. Markham E. Nakagawa T. Wakabayashi, Y.Taniyama S. Nishikawa R.Fukumoto H. Uemura T. Doi and M.Ikehara Nucleic Acids Res. Special Publication No. 6 1979 S195. 27 D. V. Geoddel D. G. Yansura C. Winston and M. H. Caruthers J.Mol. Biol. 1978,123,661;H. Sista R.T. Loder and M. H. Caruthers Nucleic Acids Res. 1979 6 2583. '* C. A. Hutchinson 111 S.Phillips,M. H. Edgell S.Gillam P. Jahnke and M. Smith J.Biol. Chem. 1978 253,6551;H. Kossel R. Buyer S.Morioka and H. Schott Nucleic Acids Res. Special Publication No. 4,1978 S91. 29 S.Gillam P. Jahnke C. Astell S.Phillips C. A. Hutchinson 111 and M. Smith,Nucleic AcidsRes.. 1979 6,2973. 30 R. H.Scheller R. E. Dickerson H. W. Boyer A. D. Riggs and K. Itakura Science 1977,196 177. 31 C. P.Bahl R. Wu R.Brousseau A. K. Sood H. M. Hsiung and S. A. Narang Biochem. Biophys. Res. Comm. 1978,81,695. 32 M.Mevarech B. E. Noyes and K. L. Agarwal J. Biol. Chem. 1979 254.7472. 33 D.L.Montgomery B. D. Hall S.Gillam and M. Smith Cell 1978,14,673. 34 M. A. Viswamitra 0.Kennard Z. Shakked P.G. Jones G. M. Sheldrick S.Salisbury and L. Falvello Nature 1978,273,687. 35 R. Wu C. P. Bahl and S. A. Narang Progr. Nucleic Acids Res. Mol. Biol. 1978 21 101. 465 Biological Chemistry -Part (v)b Oligo-and Poly-nucleotides 4 Synthesis of Oligonucleotides Two general reviews have been published36 and two more deal with phosphotriester methods of ~ynthesis.~’ tech-The advent of both DNA sequencing and h.p.l.~.~* niques has significantly aided the isolation and identification of oligonucleotides and above all has led to an increased awareness of the need for improved synthetic met hods.In the synthesis of oligodeoxyribonucleotidesin solution by the phosphodiester approach the lipophilic t-butyldiphenylsilyl group has been used in place of acetyl for the 3’-protection of oligonucleotide chains.39 The group is alkali-stable but cleaved by fluoride ion in buffered pyridine and considerably aids h.p.1.c. separa- tions of protected oligonucleotides. The triphenylphosphine-carbon tetrachloride complex has been proposed as a condensing agent for the rapid formation of phosphodiester bonds and it is particularly useful for the preparation of 5’-dianilides from nucleoside S-ph~sphates.~’ In coupling reactions the phosphorylpyridinium derivative (1)has been shown to be the most likely phosphorylating agent when either Ph3P-CC14 or arenesulphonyl chlorides are used to activate 3’-0-acetyl-2’- deoxythymidine S-ph~sphate.~~ Phosphodiester groups also become activated in coupling reactions and comparative studies of rates suggest that the use of tri- nucleotide or longer blocks as ‘phosphate components’ leads to a higher probability of side-products being formed.42 The use of short oligonucleotide blocks with protected phosphodiester bonds has been re~omrnended.~~ Phosphotriester methods of oligodeoxyribonucleotidesynthesis are characterized by their greater selectivity in inter-nucleotide coupling reactions.However until recently inadequate phosphorylation and deprotection procedures have resulted in unreliable syntheses. The most popular phosphorylating agent for nucleoside 3’-hydroxyLgroups is the bis-triazolide of p-chlorophenyl phosphate (2).“ Further reaction with 2-cyanoethanol results in the formation of a nucleoside 3’-p-chloro- phenyl 2-cyanoethyl phosphotriester.The cyanoethyl group may be removed 36 V. Amarnath and A. D. Broom Chem. Rev. 1977,77,183;M. Ikehara E.Ohtsuka and A. F. Markham Adv. Carbohydrate Chem. Biochem. 1979,36,135. 37 C. B. Reese Tetrahedron,1978,34 3143; J. H.van Boom,Heterocycles 1977 7 1197. 38 H.-J. Fritz R. Belagaje E. L. Brown. R. H. Fritz R. A. Jones R. G. Lees and H. G. Khorana Biochemistry 1978,17,1257. 39 R. A. Jones H.-J. Fritz and H. G. Khorana Biochemistry 1978,17,1268. 40 G.F. Mishenina V. V. Samukov L. N. Semenova andT. N. Shubina Bioorg. Khim. 1978,4,735,1137. *’ V.F.Zarytova D. M. Graifer E. I. Ivanova D. G. Knorre A. V. Lebedev and A. 1. Rezvukhin. Nucleic Acids Res. Special Publication No. 4 1978 S209. 42 D. G. Knorre V. F. Zarytova A. V. Lebedev L. M. Khalimskaya and E. A. Sheshegova. NucIeic Acids Res. 1978,5 1253. 43 D. G. Knorre G. T. Mishenina and T. N. Shubina Doklady Akad. Nauk. S.S.S.R. 1978 243 662. 44 K.Itakura N. Katagiri and S. A. Narang Canad. J. Chem. 1974,52 3689. 466 M. J. Gait 0 (2) selectively using triethylamine in ~yridine.~’ Monofunctional 3’-phosphorylating agents have also been The 4,4‘-dimethoxytriphenylmethylgroup (dimethoxytrityl) is usual for 5’-protection and it has been shown to be rapidly cleaved by treatment with benzenesulphonic Loss of N-benzoyladenine is substantially reduced compared to treatment with acetic acid.The lability of the 9-phenylxanthen-9-yl protecting group to acid is similar to that of dimethoxytrityl,48 but of greater future potential for 5’-protection is the 2-dibromomethylbenzoyl group (DBMB).49 Treatment with silver perchlorate converts DBMB-protected deoxynucleosides into their 2-formylbenzoyl derivatives which are then readily hydrolysed in the presence of aqueous morpholine (Scheme 1). 0 Scheme 1 Arylsulphonyltetrazoles are rapid new coupling agents that are used in phospho- triester ~ynthesis,~’ and the use of 8-quinolylsulphonyl chloride has also been prop~sed.’~ However 5‘-0-sulphonylation by such coupling agents is a side- reaction that has yet to be fully eliminated.Of much concern is the continued widespread use of ammonia and hydroxide ion for the removal of aryl protecting groups from phosphodiester bonds despite further warnings of the resultant likelihood of inter-nucleotide cleavage” and other side- reaction^.'^ The alternative use of 1,1,3,3-tetramethylguanidiniurn p-nitro-benzaldoximate or of pyridine-2-carboxaldoximatehas been shown to effect deprotection smoothly with minimal formation of side-produ~ts.’~ 4s A. K. Sood and S. A. Narang Nucleic Acids Res. 1977,4 2753. 46 C. B. ReeseandY.T. Y. Kui J.C.S. Chem. Comm. 1977,802;C. B. Reese andL. Yau ibid. 1978,1050. 47 J. Stawinski T. Hozumi S. A. Narang C. P. Bahl and R. Wu Nucleic Acids Res. 1977.4,353. 48 J. B. Chattopadhyaya and C. B. Reese J.C.S. Chem.Comm. 1978,639. 49 J. B. Chattopadhyaya C. B. Reese and A. H. Todd,J.C.S. Chem. Comm. 1979,987. H. Takaku M. Kato M. Yoshida and T. Hata Nucleic Acids Res. Special Publication No. 5 1978 s345. R. W. Adamiak R. Arentzen and C. B. Reese Tetrahedron Letters 1977 1431. 52 J. F. M. de Rooij G. Wille-Hazeleger P. M. J. Burgers and J. H. van Boom Nucleic Acids Res. 1979,6 2237. ’’ C. B. Reese R. C. Titmas and L. Yau Tetrahedron Letters 1978,2727. Biological Chemistry -Part (u)b Oligo- and Poly-nucleotides 467 Phosphotriester routes now predominate in oligoribonucleotide synthesis yet no consensus has been reached concerning the usage of protecting groups. Acid-labile 5’-protecting groups have been mostly chosen in combination with a~etyl,~~ o -nitrobenzyl (removable ph~tolytically),~~ on the 2’-posi- or t-b~tyldimethylsilyl~~ tion.The last group is removable by fluoride ion but serious danger of the formation of side-products has been shown in the deprotection of oligonucleotide phospho- triesters containing 2’-O-t-butyldimethylsilyl groups by fluoride Base-catalysed 2‘-3’ migration of a silyl group is another potential hazard.” An alter- native combination is the acid-labile methoxytetrahydropyranyl group for the 2’-position and the laevulinyl group for the 5’-position (removable with buffered h~drazine).’~ Useful 3’-phosphorylating agents are 2,2,2-trichloroethyl o-chloro- phenyl phosphoro~hloridate~~ and p-chlorophenyl phosphoramid~chloridate.~~ Corresponding nucleoside 3‘- 0-arylphosphates are obtained by treatment of the nucleoside 3’-phosphotriester with zinc and toluene-p-sulphonic acid58 and iso- pentyl nitrite,” respectively.As a warning to those who may have been tempted to couple unprotected nucleosides chemically the preferential formation of 2 -+ 5’ links has been shown to occur.6o The introduction of new resins has revitalized solid-phase synthesis of oligo- deoxyribonucleotides. Copolymers based on polydimethylacrylamide6’ and poly- acryloylmorpholide62 are freely permeated by polar organic solvents. In contrast to polystyrene resins good coupling yields were obtained using a phosphodiester approach. An impervious polymer formed by grafting of uncrosslinked polystyrene to Teflon beads has shown similarly good results in phosphodiester (a polar polymer surface is obtained by high nucleoside loading).Improved yields were obtained by blocking the inter-nucleotide phosphate group after coupling with aniline using the Ph3P-CC14 reagent.63 Phosphotriester methods of solid-phase synthesis have recently been shown to be both rapid and fle~ible.~~.~’ Much higher yields were obtained in the synthesis of octa- and dodeca-deoxy- ribonucleotides on a poly(dimethylacry1amide)resin than could have been expected by a phosphodiester Enzymatic oligonucleotide synthesis has become increasingly important. Poly- nucleotide phosphorylase catalyses the reaction of a nucleoside 5’-diphosphate with the 3’-end of an oligonucleotide primer. Some improvements to addition reactions of ribonucleotides have recently been made,66 but owing to the preponderance of s4 R.W. Adamiak E. Biala K. Grzeskowiak R. Kierzek A. Kraszewski W. T. Markiewicz J. Okupniak J. Stawinski and M. Wiewiorowski Nucleic Acids Res. 1978,5 1889. ’’ E. Ohtsuka T. Tanaka S. Tanaka and M. Ikehara J. Amer. Chem. Soc. 1978,100,4580. 56 K. K. Ogilvie S. L. Beaucage A. L. Schifman N. Y. Thieriault and K. L. Sadana Canad. J. Chem. 1978 56,2768. ’’ S. J. Jones and C. B. Reese J.C.S. Perkin I 1979,2762. ’* J. H. van Boom P. M. J. Burgers C. H. M. Verdegaal and G. Wille Tetrahedron 1978,34 1999. 59 E.Ohtsuka T. Tanaka T. Wakabayashi Y. Taniyama and M. Ikehara J.C.S. Chem. Comm. 1978,824 6o R.Lohrmann and L. E. Orgel Tetrahedron,1978,34,853. M. J. Gait and R. C. Sheppard Nucleic Acids Res.1977 4 1135,4391; 1979 6,1259. 62 C. K. Narang K. Brunfeldt and K. E. Norris Tetrahedron Letters 1977 1819. 63 V. K. Potapov V. P. Veiko 0.N. Koroleva and Z. A. Shabarova Nucleic Acids Res. 1979,6 2041. K. Miyoshi and K. Itakura Tetrahedron Letters 1979 3635. ” M. J. Gait M. Singh R. C. Sheppard M. D. Edge A. R. Greene G. R. Heathc1iffe.T.C. Atkinson C. R. Newton and A.F. Markham Nucleic Acids Res. 1980,8 1081. 66 B. W.-K. Shum and D. M. Crothers Nucleic Acids Res. 1978,5 2297. 468 M. J. Gait multi-addition products only relatively simple syntheses are practical. Greater control is possible in the deoxyribonucleotide case and oligonucleotides of chain length up to 13 have been prepared from a minimum primer length of 3.67 T4-RNA ligase catalyses the joining of a 5‘-phosphate of an oligonucleotide donor to a 3’-hydroxyl of an oligonucleotide acceptor and as distinct from DNA ligase this does not require a template.2‘-0-0 -nitrobenzyl-protected oligoribonucleotide donors will join to oligoribonucleotide acceptors without concomitant self-conden- sation or cyclization. The protecting group is photolytically cleavable.68 Similarly nucleoside 3‘,5’-bisphosphates have been shown to be good After joining them (with RNA ligase) the 3‘-phosphates are removed with phosphatase; stepwise oligoribonucleotide70 and oligodeoxyribonucleotide7’synthesis has been described. The joining reaction is also useful for the 3’-labelling of RNA with 32P,to high specific Mass spectral analysis of synthetic oligodeoxyribonucleotidesis a useful tool that has yet to be fully exploited.It has been used to detect whether or not all blocking groups have been removed at the appropriate stage of a synthesis.73 5 Analogues . of Oligo- and Poly-nucleotides From studies of polypyrimidine nucleoside analogues it had previously been thought that intact 2’-hydroxy-groups were essential for the induction of interferon by poly(I).poly(C). It has now been shown that poly(2‘-deoxy 2’-substituted purine nucleosides) have similar physical properties to their ribose counterparts and that the 1:1 complexes of poly(C) with poly(2’-azid0-2’-deoxy-I),~~ poly(2’-chloro-2’-deo~y-I),’~and p0ly(2’-fluoro-2‘-deoxy-I)~~ are potent inducers of interferon. Poly(2-methylthio-A) and poly(2-ethylthio-A) strongly inhibit viral reverse tran- scriptases and also form Hoogsteen-paired 1:1 complexes with p01y(U).~~ The complexes of 2-aza-analogues of poly(A) and of poly(1) with complementary natural homopolymers are strongly destabilized however owing to repulsion of the lone pair of electrons on ApU analogues containing electron-withdrawing substituents in the 5-position of uridine showed decreased stacking interactions compared to APU.’~ Similarly modified ApApU and ApA(pU) analogues were less effective in stimulating the binding of aminoacyl-tRNA to ribosomes than their natural counterparts.80 Whereas the template activity of ApAp5NH2U was lower than that of ApApU that of ApA(pSNH,U) was higher than that of ApA(pU), suggesting the importance of 67 S.Gillam P.Jahnke and M. Smith J. Biol. Chem. 1978,253 2532. 68 E.Ohtsuka S. Nishikawa A. F. Markham S.Tanaka T. Miyake T. Wakabayashi M. Ikehara and M. Sugiura Biochemistry 1978,17,4894. 69 Y.Kikuchi H. Hishinuma and K.,Sakaguchi Proc. Nut. Acad. Sci. USA. 1978,75 1270. 70 T.E.Eigland and 0.C. Uhlenbeck Biochemistry 1978,17,2069. 71 D.M.Hinton and R. I. Gumport Nucleic Acids Res. 1979 7 453. 72 T.E.England and 0.C. Uhlenbeck Nature 1978,275,560. 73 M.A. Armbruster and J. L. Wiebers Analyt. Biochem. 1977,83 570. 74 T.Fukui N. Kakauchi and M. Ikehara Nucleic Acids Res. 1977,4 4249. ” N.Kakauchi T. Fukui and M. Ikehara Nucleic Acids Res. 1979,6,2627. 76 M.Ikehara N. Kakauchi and T. Fukui Nucleic Acids Res. 1978,5 3315. 77 T.Fukui and M.Ikehara Biochim. Biophys. Acta 1979,562,527. 78 T.Fukui N. Kakauchi and M. Ikehara Biochim. Biophys. Actu 1978,520,441. 79 W. Hillen and H. G. Gassen Biochirn. Biophys. Actu 1978.518 7. Biological Chemistry -Part (v)b Oligo- and Poly-nucleotides correct base overlap in anticodon interactions.80 5 -Methoxyuridine occurs in several tRNAs of Bacillus subtilis but although poly(5-methoxy-U) has been shown to form triplexes with poly(A) it did not direct the synthesis of polyphe in vitro unlike other 5 -substituted homopolymers.81 OH OH (RP) (3) The two diastereomers of 5’-O-adenosyl3’-O-uridylylphosphorothioate (3) have been chemically synthesized via phosphotriester intermediates.82 Only the (Rp) diastereomer is sensitive to digestion with snake venom exonuclease.Phos-phorothioate linkages incorporated enzymatically into DNA do not significantly alter its properties and should be useful for labelling DNAs with heavy metalss3 Chemically synthesized methylphosphonate analogues of oligodeoxyribonucleo- tides are resistant to digestion with an exonuclease and are useful model substrates for studies of the action of restriction enzyme^.'^ Some non-phosphorus-containing carbamate8’ and acetamidate analogues86 of oligonucleotides have also been pre- pared. 6 Chemical Reactions on Polynucleotides Denaturation of DNA with formaldehyde is much used in electron microscopy. A detailed kinetic analysis of this reaction has now confirmed that initially hydrogen- bond rupture and base unstacking takes place at an A-T-rich region in the interior of DNA due to local thermal fluctuations.This is followed by hydroxymethylation of the exocyclic amino-group of adenine and of the endocyclic imino-group of thy- mine.87 The reaction of hydrazine with DNA is pyrimidine-specific and is used in the Maxam-Gilbert sequencing method.” In addition to the expected 3-amino- pyrazole a major product of the reaction of cytosine has been identified as 3-ureidopyrazole (4),88and not NN’-di-(3-pyrazolyl)hydrazine,as first thought. A W. Hillen and H. G. Gassen Nucleic Acids Res. Special Publication No. 4 1978 S149. 81 W. Hillen and H. G. Gassen Biochim. Biophys. Acta 1979,562 207. 87 P. M. J. Burgers and F. Eckstein Biochemistry 1979 18 592. 83 H.-P. Vosberg and F.Eckstein Biochemistry 1977,16 3633. 84 K. L. Agarwal and F.Riftina Nucleic Acids Res. 1979,6 3009. W. S. Mungall and J. K.Kaiser J. Org. Chem. 1977,42 703. 86 M. J. Gait A. S. Jones M. D. Jones M. J. Shepherd and R.T. Walker J.C.S. Perkin I 1979 1389. 87 J. D. McGhee and P. H. von Hippel Biochemistry 1977,16,3276. A. R.Cashmore and G. B. Peterson Nucleic Acids Res. 1978.5 2485. 470 M. J. Gait mixture of semicarbazide and sodium bisulphite reacts specifically with cytosine residues in DNA and RNA to give the transamination product (5). The reaction has been used as a probe for tRNA conformation^.^^ Iodination by sodium or potassium iodide in the presence of thallium(II1) salts is well known for the specific 12'I-labelling of cytosine to high activity.This reaction has recently been used for sequence analysis of RNA9O and as a probe of the tertiary structure of tRNAs." Aminoacylated tRNA has also been 12'I-labelled to high specific activity in a new technique that involves prior acylation of crude tRNA with N-hydroxysuccinimido 3 -(4-hydroxypheny1)propionate. After chromatographic purification the tRNA of interest is iodinated at the newly introduced benzene ring by reaction with ['251]iodide ion and Chloramine T.92 The 5'-termini of short oligoribonucleotides can be determined by cleavage with snake venom phospho- diesterase followed by oxidation with periodate and then allowing the resultant nucleoside dialdehyde to react with p -hydra~inobenzene[~~S]sulphonic acid.93 However more generally useful in RNA sequencing is the new 3'-32P-labelling procedure previously described (Section 4).72 The 3'-32P-labelling of DNA has been effected by the terminal-transferase-catalysed addition of 4-thiouridine followed by thio-specific modification using a-halogeno-acetamide derivatives.Fluorescent radioactive and photoactivatable groups have been attached to DNA by this method.94 Whereas the specific attachment of a fluorescent probe to the minor base Q9' or to its under-modified replacement 7-aminomethyl-7-deaza G,96in E. coli tRNATyr did not destroy the ability of the tRNA to be aminoacylated fluorescent labelling of X base in E. coli tRNAPh" did.97 The reaction of l-fluoro-2,4-dinitro- benzene with tRNAPh' from yeast at pH 8 resulted in labelling of adenine residues only.98 This reaction may prove useful for the introduction of antigenic sites into tRNA.Osmium tetroxide in the presence of pyridine or 2,2'-bipyridyl adds across the 5,6-double-bond of pyrimidines in polynucleotides to give stable osmate esters that are useful in heavy-metal labelling.99 The reaction with isopentenyladenosine is much faster and permits single-site labelling of yeast tRNATy'.'O0 In the absence of 89 K. Negishi F. Harada S. Nishimura and H. Hayatsu Nucleic Acids Res. 1977,7,2283. 90 E. Dickson L. K. Pape and H. D. Robertson Nucleic Acids Res. 1979,6,91. 91 I. L. Batey and D. M. Brown,Biochim. Biophys. Acra. 1977,474,378. 92 G. M. Tener A. D. Delaney T. A. Grigliatti G. J. Cowling and I. C. Gillam Biochemistry 1978,17 741.93 G. 0.Osuji and M. W. Johnson,F.E.B.S. Letters 1977,83,85. 94 H. Eshaghpour D. So11 and D. M. Crothers Nucleic Acids Res. 1979,7 1485. 9s A. Pingoud R. Kownatzki and G. Maass Nucleic Acids Res. 1977 4 327. 96 H. Kasai N. Shindo-Okado S. Noguchi and S. Nishimura Nucleic Acids Res. 1979,7,231. 97 P. W. Schiller and A. N. Shechter Nucleic Acids Res. 1977 4 2161. 98 K. Watanabe and F. Cramer European J. Biochem. 1978,89,425. 99 C. H. Chang M. Beer and L. M. Marzilli Biochemistry 1977,16,33. loo W. R. Midden and E. J. Behrman F.E.B.S. Letters 1979 103 300. Biological Chemistry -Part (u)b Oligo- and Poly-nucleotides 47 1 tertiary nitrogen donors osmium tetroxide reacts preferentially with thymidine in DNA to give 5,6-dihydroxythymidine.Subsequent glycosidic cleavage with piperi- dine forms the basis of a T-specific reaction that is useful in DNA sequence analysis.'O1 A polymetallic agent tetrakis(acetoxymercuri)methane has been used for labelling of 4-thiouridine and 6-thioguanosine residues in tRNA,"* and the use of platinum derivatives as probes of polynucleotide ~tructure''~ and as anti-tumour agent^''^^''^ has been reviewed. Of the known alkylating carcinogens N-ethyl-N-nitrosourea has the highest reactivity with phosphodiester groups compared to other sites in DNA,'" and has been used to help chart the points of interaction of RNA polymerase with DNA promoters.'06 The 2-halogenoethyl-nitrosoureas,on the other hand have been shown to cause intra-strand cross-linking probably between guanine and cyto~ine,''~ and this may be directly related to their antileukaemic properties.108 The binding of ethidium bromide to DNA duplexes is stronger where there is a mismatch and this suggests that this frameshifting agent can function by stabilizing transient mismatched intermediates in DNA.lo9 The interaction of DNA with antibiotics and other drugs is an area of much current activity and has been extensively reviewed."' lo' T.Friedman and D. M. Brown,Nucleic Acids Res. 1978,5,615. lo' K. G.Strothkamp J. Lehmann and S. J. Lippard Proc. Nur. Acad. Sci. U.S.A. 1978,75 1181. Io3 S.J. Lippard Accounts Chem. Res.. 1978 11 211. Io4 J. J. Roberts and A. J. Thomson,Progr. Nucleic Acids Res. Mol. Biol. 1979 22,71. lo' B.Singer J. Toxicof.Enoiron.Health 1977 2 1279; D.H.Swenson P. B. Farmer and P. D. Lawley Biochem. J. 1978,171 375. '06 U. Siebenlist and W. Gilbert Proc. Nut. Acad. Sci. U.S.A.,1980 77 122. lo' K. W. Kohn Cancer Res. 1977,37 1450. '08 J. W. Lown L. W. Mchughlin and Y.-M. Chang Bioorg. Chem. 1978,7,97. lo9 D.C. Helfgott and N. R. Kallenbach Nucleic Acids Res. 1979,7,1011;C. H.Lee and I. Tinoco Nature 1978,274,609. M. J. Waring in 'Drug Action at the Molecular Level' ed. G. C.K. Roberts Macmillan London 1977; R. J. Suhadolnik Progr Nucleic Acids Res. Mol. Biol. 1979,22 193; W.A. Remers in 'The Chemistry of Antitumour Antibiotics' Vol. I Wiley-Interscience New York 1979.

ISSN:0069-3030    

DOI:10.1039/OC9797600462

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

16 Biological Chemistry Part (vi) Enzyme Chemistry By P. F. LEADLAY Department of Biochemistry University of Cambridge Tennis Court Road Cambridge CB2 10W 1 Introduction In the past year useful reviews have been published on chiral methyl groups,’ coenzyme B12-dependent enzymes,2 and positional isotope exchange studies of enzyme mechani~ms.~ Other good articles have appeared on two-dimensional n.m.r.,4 the preparation and uses of immobilized enzyme^,^ cryoen~ymology,~ and the prediction of protein conformation from amino-acid sequence data.’ The proceedings of the Ciba Foundation Symposium on ‘Molecular Interactions and Activity of Proteins’ are now p~blished,~ as are the papers given at the Third European Symposium on Vitamin B12.9Several new books on enzymes have also appeared.Recent X-ray crystal structure determinations include those of citrate synthase from pig heart,” phosphofructokinase from Bacillus stearuthermuphilus,l2 6-phos-phogluconate dehydrogenase from sheep liver,13 and chicken heart mitochondria1 aspartate amin~transferase.’~ Some aspects of natural-abundance 13C n.m.r. as applied to proteins have been re~iewed.’~ Curiously 15Nand l3 C n.m.r. studies have given apparently quite different results concerning the mechanism of action of a typical serine proteinase.16 H. G. Floss and M. D. Tsai Adv. Enzymol. 1979,50,243. B. M. Babior and J. S. Krouwer C.R.C. Crit. Rev. Biochem. 1979,6 35. I. A. Rose Ado. Enzymol. 1979,50 361. K. Wuthrich Trends Biochem. Sci. 1979,4 N178.’G. G. Guilbault and M. H. Sadar Accounts Chem. Res. 1979,6,204. P. Douzou and C. Balny Adv. Protein Chem. 1978,32,77. ’P. Y. Chou and G. D. Fasman Adv. Enzymol. 1979,49,45. Ciba Foundation Symposium No. 60 Excerpta Medica Amsterdam 1978. ‘Vitamin Biz' ed. B. Zagalak and W. Friedrich Walter de Gruyter Berlin and New York 1979. lo (a)C. Walsh ‘Enzymatic Reaction Mechanisms’ W. H. Freeman New York 1979;(b) ‘Transition States of Biological Processes’ ed. R. L. Schowen and R. D. Gandour Plenum Press New York 1978;(c) R. L. Foster ‘The Nature of Enzymology’ Croom Helm London 1980. G. Wiegand D.Kukla H. Scholze T. A. Jones and R. Huber European J. Biochem.. 1979,93,41. l2 P. R.Evans and P. J. Hudson Nature 1979,279,500. l3 M. A. Abdallah M. J. Adams I. G.Archibald J.-F.Biellmann J. R. Helliwell and S. E. Jenkins European J. Biochem. 1979,98,121. l4 G. Eichele G. C. Ford M. Glor J. N. Jansonius C. Mavrides and P. Christen J. Mol. Biol. 1979,133 161. ” A. Allerhand Accounts Chem. Res. 1978,ll. 469. l6 W. Bachovchin and J. D. Roberts J. Amer. Chem. SOC.,1978,100,8041. Biological Chemistry -Part (vi) Enzyme Chemistry 2 Enzyme-catalysed Methyl-transfer Reactions In a large number of enzyme-catalysed reactions methyl groups are either created or destroyed.' The methyl group can also be transferred intact either intramolecu- larly" or from a donor such as S-adenosylmethionine to a wide range of acceptors." In all these reactions the determination of the stereochemical consequences of reaction at the methyl group is of central importance in elucidating the mechanism.This was first made possible by the discovery of synthetic routes to acetyl-CoA (1) containing a chiral methyl group." These molecules are chiral because the methyl group contains each of the three isotopes of hydrogen in a specific configuration. By exploiting the existence of an intramolecular kinetic isotope effect in the malate synthase reaction (Scheme l) a method was developed" to provide both the absolute configuration and a quantitative measure of the enantiomeric excess at the methyl carbon.20 The chirality of any methyl group can therefore be assayed by transforming it chemically into the methyl group of acetate. glyoxylate CoA (1) (D=2H;T=3H) Scheme 1 In order to study methyl transfers in which S-adenosylmethionine (6)is the methyl donor two almost identical synthetic routes to chiral [Me-3H1,2Hl]methionine have been developed,21 and in Arigoni's laboratory a way has also been devised to re-convert methionine into acetic acid to check its chirality.2'" Transferases have now been studied that catalyse methyl transfer respectively to carbon to oxygen or to sulphur but not as yet to and the only methyl donor examined so far is S-adenosylmethionine (6).21QA good example of a study on transfer to sulphur concerns the (essentially irreversible) methylation of homo- cysteine (4) that is catalysed by s-adenosylmethionine homocysteine methyl- transferase (EC 2.1.1.12).*'" Here S-methylmethionine (3) can deputize for S-adenosylmethionine (6) as the methyl donor as outlined in Scheme 2 so that each transfer generates two molecules of methionine (5).Since (3) was synthesized chemically from (2S)-[Me-3H1,2Hl]methionine, the chiral methyl groups in (3)should be distributed equally between the two diastereo- topic positions at sulphur.22 Half the labelled methyl groups in the sample of methionine (5)that is produced will therefore be derived from (3)without transfer G. T. Phillips and K. H. Clifford European J. Biochem. 1976,61,271. G. L. Cantoni Ann. Rev. Biochem. 1975,44435. l9 (a) J. W. Cornforth J. W. Redmond H. Eggerer W. Buckel and C. Gutschow Narure 1969,221,1212; (6)J. Liithy J. RCtey and D. Arigoni Nature 1969,221 1213. 2o H. Lenz and H. Eggerer European J.Biochem. 1976,65 237. (a)D. Arigoni in ref. 8 p. 404; (6) L. Mascaro Jr. R. Hohrhammer S. Eisenstein L. K. Sellers K. Mascaro and H. G. Floss J. Amer. Chem. SOC.,1977,99,273. 22 G. Grue-Sorensen E. Kelstrup A. Kjaer and J. 0.Madsen J.C.S. Chem. Comm. 1980 19. 474 P.F. Leadlay [R= (CH2)2CH(6H3)C02-] Scheme 2 and will retain the original configuration. The other half will have been transferred to (4) and their configuration will depend on the mechanism. In fact as indicated in Scheme 2 the methionine obtained proved on degradation to acetic acid and chirality analysis to be completely racemic. Therefore one can conclude that this methyl transfer involves a net inversion of configuration.21" Schowen and his co-workers have used kinetic isotope effects to examine the nature of the transition state in enzyme-catalysed transfers of methyl groups.23 An enzyme that they have studied in detail is catechol 0-methyl transferase (EC2.1.1.6),isolated from rat liver.The major function of the enzyme in viuo is to provide a route for the inactivation of catecholamines and toxic catechols in the diet. A typical reaction between S-adenosylmethionine (6) and the model acceptor 3,4-dihydroxyacetophenone(7) is shown in Scheme 3. The methylation occurs at either hydroxy-group but not both.23b COMe + )xo~+($oH+ COMe f:o; Me + S OR2 I I OH OR' Ado Ado (6) (7) (8)R' = H,R2=Me (9)R' =Me,R2= H (Ado =adenosyl) Scheme 3 A sample of (6),enriched with 13Cin the methyl group and with the correct chirality at sulphur was prepared by the action of a yeast culture on the correspond- ing (2S)-[Me-13C]methionine.The initial rate of methyl transfer from S-adeno~yl[Me-'~C]methionineto (7) catalysed by catechol O-methyl transferase was compared with the rate of transfer from unlabelled material (6)measured in a separate experiment.This non-competitive method has the advantage that isotope effects on V,,,,,,the maximal velocity can be separated from effects on K, the Michaelis constant. An isotope effect of 1.09 was observed; this is consistent with the methyl transfer being clearly rate-limiting and with other elementary steps (such as product release) being The size of the kinetic isotope effect indicates that the transition state 23 (a) M.F.Hegazi,D. M. Quinn,andR. L. Schowen,inref. 10b,p.413; (6) M. F. Hegazi,R.T. Borchardt and R. L. Schowen J. Amer. Chem. SOC.,1979,101,4359. 24 For a recent review of primary kinetic isotope effects see J. P. Klinman Ado. Enzymol. 1978,46,415. Biological Chemistry -Part (ui) Enzyme Chemistry 475 for the methyl transfer is symmetrical with the methyl group ‘in flight’ between sulphur and oxygen. These authors had previouslyZ5 measured the secondary deuterium isotope effect on the methyl transfer to (7) from (2S)-[Me-2H3]methionine. Secondary deuterium isotope effects are generally considered to arise26 from changes in bending force constant as the transition state is approached. The measured value i.e. Vm,,(CH3)/Vm,(CD3)=0.83 is typical for a rather ‘tight’ transition (short oxygen-sulphur bond distance).Since the secondary isotope effect is even more strongly inverse than in model SN2reaction^,^' steric compression in the transition state has been proposed as a mechanism for the rate enhancement brought about by the enzyme. An assumption in the above treatment is that the methyl transfer is direct and does not involve prior methyl transfer from (6)to an enzyme nucleophile with transfer to the acceptor (7) in a second step. Kinetic evidence against the existence of such a methyl-enzyme intermediate is However it has been shown that S-adenosylmethionine bearing a chiral methyl group transfers this group to adrenal- ine (epinephrine) with net inversion of its on figuration,^^ and this is most easily explained by a direct methyl transfer.An exactly analogous problem the vexed question of the existence of a phospho-enzyme intermediate in the acetate-kinase- catalysed reaction has recently been illuminated by the use of ATP containing a chiral y-phospho-gr~up.~~ 3 Phosphorylase Kinase Phosphorylase kinase (EC 2.7.1.38) is a central component of the enzyme system that controls glycogen breakdown in skeletal muscle. It catalyses the activation of glycogen phosphorylase b to glycogen phosphorylase a by the ATP-linked phos- phorylation of a unique hydroxy-group of serine in each of the two subunits of phosphorylase 6. This was the first recognized example of the control of enzyme activity by covalent m~dification.~’ As shown in Scheme 4 phosphorylase kinase is Protein kinase 1 Phosp horylase -nb Phosphorylase kinaseb* ATP ADP kinasea* 1 Phosphorylase b -,+ Phosphorylasea ATP ADP *a and b represent more-active and less-active forms respectively Scheme 4 25 M.F. Hegazi R. T. Borchardt and R. L. Schowen J. Amer. Chem. SOC. 1976,98 3048. 26 M. H. O’Leary in ref. lob p. 298. ”I. Mihel J. 0.Knipe J. K. Coward and R. L. Schowen J. Amer. Chem. SOC. 1979,101,4349. J. K.Coward E. P. Spisz and F. Y. H. Wu Biochemistry 1973,12,2291. 29 H. G. Floss,in ref. 1 p. 289. 30 W. A. Blattler and J. R. Knowles Biochemistry 1979 18 3927. 31 For recent reviews see (a)P. Cohen Biochem. SOC.Trans.,1979,7,16; (b)G. M. Carlson P. J. Bechtel and D. J. Graves Ado. Enzymol. 1979,50,41.476 P.F. Leadlay activated through ATP-linked phosphorylation by a ‘general protein kinase’ which in turn is activated by 3‘,5‘-cyclic adenosine monophosphate. The synthesis of cyclic AMP from ATP is triggered by the binding of hormones to specific receptors linked to adenylate cyclase. This ‘cascade’ system ensures a very rapid amplification of the initial hormonal stimulus. Phosphorylase kinase activity is also dependent on micromolar levels of calcium ions which are released as a result of nervous stimuli.31 Since this concentration of calcium ions also initiates muscle contraction glyco- genolysis and muscle contraction are synchronized. Recent work3’ has greatly increased our understanding of this complex enzyme. The protein was at first found to contain four copies each of three different types of subunit (a,p and y of M 145 000 130 000 and 45 000 respectively; but see below).Rapid phosphorylation of the kinase by cyclic-AMP-dependent protein kinase occurs on both the a and the p This was the first observation of control by multi-site phosphorylation and a similar pattern has since been found for several other enzymes including glycogen synthase3ln and mitochondria1 pyruvate dehydr~genase.~~ The phosphorylation of /3 subunits occurs first and correlates with the increase in catalytic activity. The slower phosphorylation on a subunits has no direct effect on the activity but greatly increases the rate of dephosphorylation of the p subunits. Recently the important discovery was made3’ that rabbit skeletal muscle phos- phorylase kinase actually has the subunit composition (ap~S)~.The fourth subunit 6,is small (of M 16 000) and highly acidic. It appears to be identical with a protein called calmodulin or ‘calcium-dependent regulator protein’ which was first identified in 1970 as a heat-stable calcium-binding protein that is required as an It activator of one form of brain cyclic nucleotide phosph~diesterase.~~ was subsequently isolated and shown to be largely identical in its amino-acid sequence with troponin C the calcium-binding protein of the complex that controls skeletal muscle on traction.^^ Calmodulin is present in high concentrations in a wide range of animal tissues and has now been clearly implicated in the regulation of several other enzymes including the calcium-dependent ATPase of erythrocyte membrane^,^^ adenylate cyclase in the pancreas,34 and myosin light-chain kina~e.~~ The finding that calmodulin is identical with the S subunit of phosphorylase kinase strongly suggests that it may be the major calcium-binding protein in mammalian cells.In the phosphorylase kinase it is clearly the subunit that confers the sensitivity of the enzyme to calci~m.~’ Four groups have announced” that the major cyclic-AMP-independent glycogen synthase kinase is identical with phosphorylase kinase. In fact additional calmodu- lin stimulates both glycogen synthase and phosphorylase kinase. This provides evidence for direct involvement of calcium ions in the control of glycogen synthesis as well as in its breakdown.32 P. H. Sugden A. L. Kerbey P. J. Randle C. A. Waller and K. B. M. Reid Biochem. J. 1979,181,419. 33 (a)W. Y. Cheung Biochem. Biophys. Res. Comm.,1970,38,533; (b)S. Kakiuchi R. Yamazaki and H. Nakajima Proc. Japan Acad. 1970 46 589. 34 For a review see R. J. A. Grand and S. V. Perry Biochem. J. 1979,183,285. 35 (a)K. X. Walsh D. M. Millikin K. K. Schleuder and E. M. Reimann J. Biol. Chem. 1979,254,6611; (b) A. A. DePaoli-Roach P. J. Roach and J. Lamer ibid. p. 4212; (c)N. Embi D. B. Rylatt. and P. Cohen European J. Biochem. 1979,100,339; (d)T. R. Soderling A. K. Srivastava M. A. Bass and B. S. Khatra Proc. Nut. Acad. Sci. USA. 1979,76 2536. Biological Chemistry -Part (ui) Enzyme Chemistry 4 Enzyme-activated Irreversible Inhibitors An enzyme-activated inhibitor binds at the active site as an inert substrate analogue and is converted by the target enzyme into a reactive species that inactivates the enzyme.36 This type of specific inhibition also referred to as k, or suicide inhibiti~n,~'continues to be used with great success against flavin-linked and pyridoxal-phosphate-linkedenzymes for which the removal of a proton is thought to constitute an integral part of the normal catalytic pathway.For example mono- and poly-fluoro-analogues are found to be efficient inhibitors of inter alia a-dialkyl-amino-acid tran~aminase,~' ornithine decarb~xylase,~' and alanine ra~emase.~' A detailed study has been made4' of the suicide inhibition of the flavin-linked (2R)-lactate dehydrogenase from the bacterium Megasphaera elsdenii.This enzyme catalyses the oxidation of (2R)-lactate to pyruvate with an electron-transferring flavoprotein serving as the natural electron acceptor. The substrate analogue (2R)-2-hydroxybut-3-ynoic acid (10) is both a substrate and an efficient irreversible inhibitor since the enzyme only undergoes an average of five catalytic turnovers in air at pH7.0 before being inactivated. The inactivation is accompanied by the conversion of the enzyme-bound flavin into a stable pink flavin adduct (1l),which can be released from the enzyme by acid treatment and then purified. The novel adduct (1 l) characterized by its spectroscopic and chemical properties and by comparison with model compounds is the result of covalent linkage of the acetylenic inhibitor (10) to positions N-5and C-6 of the flavin nucleus (Scheme 5).This contrasts with (2s)-lactate mono-dxygenase (EC 1.13.12.4) from Mycobacteriurn '2" OH I OH (10) [R= CH2(CHOH)3CH20P03-H] Reagents i (2R)-lactate dehydrogenase; ii (2S)-lactate mono-oxygenase Scheme 5 36 For recent reviews see (a) C. Walsh Ann. Rev. Biochem. 1978 47 881; (b) 'Enzyme-Activated Irreversible Inhibitors' ed. N. Seeler M. Jung and J. Koch-Weser Elsevier/North-Holland Amster- dam 1979. 31 M. C. Summers and S. C. Williams Ann. Reports (B) 1977,74,432 and refs. cited therein. 38 J. W. Keller and M. H. O'Leary Biochem. Biophys. Res. Comm. 1979,90 1104. 39 B. W. Metcalf P. Bey,'C. Danzin M. J. Ji-ng P. Casara and J.P. Vevert J. Amer. Chem. SOC.,1978,100 2551. 40 E. Wang and C. Walsh Biochemisrry,1978,17,1313. 41 S. T. Olson V. Massey S. Ghisla and C. D. Whitfield Biochemistry 1979,18 4724,4733. 478 P. F. Leadlay smegmatis where inactivation by the (2s)-enantiomer of (10) leads42 to formation of the adduct (12) in which the inhibitor is covalently attached to the flavin nucleus through N-5and C-4a. Massey and his co-w~rkers~~ have interpreted this as evidence for the same face of the bound flavin being turned towards the substrate in both enzymes and for a similar geometry of the active site in each case From their results they favour a mechanism for inactivation in which an allenic carbanion derived from (10) by proton abstraction attacks reduced flavin.However alter- native mechanisms for both suicide inactivation and the processing of normal substrate involving radical intermediate^,^^ for example cannot be excluded. The need for thorough characterization of the inactivator-enzyme adduct is underlined by recent on the suicide inactivation of succinate dehydrogenase (EC 1.3.99.1) which catalyses the oxidation of succinate to fumarate. The enzyme is inhibited irreversibly by 3-nitropropionic acid (1 3) and it was originally suggested that the inactivator becomes covalently attached to the flavin nucleus through N-5.45 However re-investigation has now shown that the enzyme first oxidizes the 3- nitropropionate (13)to 3-nitroacrylate (14) [3-nitroprop-2-enoic acid] and this is then trapped by 1,4-nucleophilic addition of a thiol group of a cysteine residue at the active site (Scheme 6)./ kFADH2 H202 02 02N-CH2-CHC02H ,1/ 02N-'=CHC02H 1 Scheme6 The accurate positioning of active-site nucleophiles is apparently critical for efficient suicide inactivation. For example the electrophilic allene deca-2,3- dienoyl-Co A which inactivates 3-hydroxydecanoyl thioester dehydratase within a single turn~ver,~'*~' is a well-behaved substrate for dec-3-ynoyl thioester isomerase from pig liver.46 A similar observation has recently been made4' in Walsh's laboratory with vinylglycine (1 5)[2-aminobut-3-enoic acid] a potent suicide inhibi- tor of many transaminases that require pyridoxal phosphate. The accepted 42 A. Schonbrunn R. H. Abeles C.T. Walsh S. Ghisla H. Ogata and V. Massey Biochemistry,1976,15 1798. 43 S. Ghisla V. Massey and Y. S. Choong J. Biol. Chem. 1979 254 10662 and refs. cited therein. 44 C. J. Coles D. E. Edmondson and T. P. Singer I. Biol. Chem. 1979,254 5161. 4s T. A. Alston L. Mela and H. J. Bright Proc. Nat. Acad. Sci. U.S.A.,1977,74 3767. 46 F. M. Miesowicz and K. Bloch J. Biol. Chem. 1979 254 5868 and refs. cited therein. 47 M. Johnston D. Jankowski P. Marcotte H. Tanaka N. Esaki K. Soda and C. Walsh Biochemistry 1979,18,4690. 479 Biological Chemistry -Part (vi) Enzyme Chemistry H H H2C=CH-C-CO2H I H2C=cYco2H NH2 YH Py-CHO = Pyridoxal phosphate mechanism for inactivation the generation of the electrophilic adduct (16) at the active site.It now appears that this same adduct is a normal enzyme-bound intermediate in the reactions catalysed by cystathionine y-synthase (EC4.2.99.9) and related enzymes that catalyse pyridoxal-phosphate-dependenta#-elimination and y-replacement reactions. These enzymes may have evolved a geometry at the active site that prevents enzyme nucleophiles from causing ina~tivation.~~ A recent explanation for the consistency of the stereochemical course of aldolase- catalysed reactions (a proton is replaced by another group with retention of c~nfiguration~~) has been advanced along the same lines. It is suggested that an aldolase with enzyme bases appropriately placed to bring about inversion of configuration would also be able to catalyse ‘suicide’ reactions such as eliminati~n.~~ Most suicide inhibitors depend for their activation upon the initial removal of a proton and this approach cannot be applied to a large number of enzymes such as hydrolases and group-transferring enzymes.There is great interest therefore in other ways of generating the reactive species; for example by initial nucleophilic attack by a group in the active site of the Impetus for this search has been provided by the realization that several natural toxins and antibiotics appear to function as suicide inhibitors. Clavulanic acid (17) for example a novel p-lactam isolated from Streptomyces clavuligerus and a potent inhibitor of P-lactamases from a variety of both Gram-positive and Gram-negative bacteria both in vivo and in ~itro,~~ appears to function as an enzyme-activated inhibit~r.’~ With the inducible P-lactamase from cell extracts of Staphylococcus aureu~,~~~ the inhibition is active-site-directed as judged by substrate-protection experiments.It is suggested54a that enzyme-catalysed opening of the p-lactam ring to (18) and subsequent cleavage of the oxazolidine ring might expose a reactive carbonyl function in (19) (Scheme 7). Formation of an imine between this carbonyl and an E-amino-group on a lysine residue could then lead to decarboxylation and covalent modification of the active site. The proposed covalent linkage cannot be very stable for excess clavulanate is gradually consumed and the original activity is then regained. Nevertheless low concentrations of inhibitor are effective in vivo in abolishing the resistance of P-lactamase-producing staphylococci to synthetic peni- cillins.K. R. Hanson and I. A. Rose Accounts Chem. Res. 1975,8 1. *9 R. Motiu-DeGrood W. Hunt J. Wilde and D. J. Hupe J. Amer. Chem. SOC. 1979,101 2182. 50 D. V. Santi T. Wataya and A. Matsuda in ref. 366 p. 291. ’’ M. Vilkas in ref. 36b p. 323. ’* C. M. Pickart and W. P. Jencks J. Biol. Chem. 1979 254,9121. 53 T. T. Howarth A. G. Brown and T. J. King J.C.S. Chem. Comm. 1976 266. 54 (a)C. Reading and P. Hepburn Biochem J. 1979 179 67; (b) J. Fisher R. L. Charnas and J. R. Knowles Biochemistry 1978 17 2180 2185. 480 P.F. Leadlay (17) inactivation -X HN (19) Scheme 7 A group at Harvard Univer~ity’~~ has studied an E.coli plasmid-encoded p-lactamase whose crystal structure at 0.4 nm resolution has recently been reported.’’ They found a rather complex pattern of inhibition by clavulanic acid; superimposed on a transient reversible inactivation there was a slow and (in contrast to the S. aureus enzyme) irreversible inactivation. Clavulanate is hydrolysed more rapidly by this enzyme and the average number of turnovers before each inactivation event is about 115. Evidently the formation of (19)is not the only process leading to covalent attachment of the inhibitor to the enzyme since three types of irreversibly inactivated complex could be distinguished on the basis of their spectroscopic properties and chemical 5 Dihydrofolate Reductase Dihydrofolate reductase (EC 1.5.1.3) catalyses the NADPH-linked reduction of 7,8-dihydrofolate (20) to tetrahydrofolate (21).56 Folate (22) is also slowly reduced to (21).Tetrahydrofolate (21) is an essential cofactor in the synthesis of thymidylate inosinate and methionine and specific inhibitors of dihydrofolate reductase such as methotrexate (23) block the synthesis of these metabolites. Methotrexate (23) has proved to be clinically useful in cancer chemotherapy and related compounds are effective antimalarial and antibacterial dr~gs.’~ Dihydrofolate reductase has been isolated from various bacterial source^.'^ The E. coli enzyme is typical in consisting of a single polypeptide chain of M 18 000 containing 159 amino-acid re~idues.’~ It shows extensive amino-acid sequence homology with the enzyme from both Lactobacillus casei and Streptococcus faeci~m.’~Very recently a Wellcome research group has discovered a new type of dihydrofolate reductase encoded by an E.coli plasmid and containing four ’’ J. R. Knox J. A. Kelly P. C. Moews and M. L. DeLucia Microb. Drug Resistance 1979 2 313. 56 (a)R. L. Blakley in ‘The Biochemistry of Folic Acid and Related Pteridines’ ed. A. Neuberger and E. L. Tatum Elsevier New York 1969 pp. 1-569; (b) ‘Chemistry and Biology of Pteridines’ ed. R.L. Kislink and G. M. Brown Elsevier/North-Holland Amsterdam 1978. ” D. Stone A. W. Phillips and J. J. Burchall European J. Biochem. 1977 72 613. Biological Chemistry -Part (ui) Enzyme Chemistry (21a) R’ =H unlabelled (21b) R’=H Hs=D (25) R=CHO NH MeNR apparently identical subunits each of M 8500.This shows no significant sequence homology with the chromosomal enzyme.58 Amino-acid sequences have also been determined for the enzymes from pig and chicken liver and a mouse cancer cell line.59 The vertebrate enzymes typically are monomeric of M ca. 21 000 and resemble each other closely showing an overall sequence identity of 89%. They also show homology with bacterial enzymes particularly in the N-terminal part of the chain that is thought to form the major active-site cleft.60 The crystal structure of L. casei dihydrofolate reductase in a ternary complex with methotrexate (23) and NADPH (24) has been determined by X-ray diffraction SONH2 [R = (2’-O-phosphoryl) ADP-ribosyl] R (24a) unlabeiled (24b) HR =D methods at 0.25 nm resolution and the same group has also determined the crystal structure of the binary complex between E.coli dihydrofolate reductase and methotrexate (23).60Since different enzymes were used comparisons between these structures must be interpreted with caution. In the ternary complex the folate analogue and the cofactor apparently bind to the same domain of the protein. The C-6 of the pteridine nucleus is directly above the C-4 position of the nicotinamide ring of NADPH (24),and only 0.45 nm away. This positioning would favour a direct transfer of hydride ion from the cofactor to C-6. The positioningof the nicotinamide 58 D. Stone and S. L. Smith J. Biol. Chem. 1979 254 10857. 59 S. L. Smith P.Patrick D. Stone A. W. Phillips and J. J. Burchall J. Biof. Chem. 1979,254,11475 and refs. cited therein. 6o D. A. Matthews R. A. Alden S. T. Freer N. Xuong,and J. Kraut J. Biol. Chem. 1978,254,4144 and refs cited therein. 482 P. F. Leadlay ring is also consistent with the established A-side stereospecificity6' of this enzyme of the two diastereotopic hydrogens at C-4 in NADPH (24) the pru-S hydrogen (which is known to be specifically transferred) points towards the pteridine. On the basis of their model Matthews and his co-workers predicted6' that 7,8-dihydrofolate (20) would be reduced at C-6 of the pteridine nucleus from the Si face. Despite the X-ray crystal structure evidence other studies have indicated differences in the binding of methotrexate (23)and dihydrofolate (20)to the enzyme.Methotrexate (23)binds at least 10 000-fold more tightly to dihydrofolate reductase than does (20),and although bound methotrexate is protonated at N-1 while (20)is not,61 this can only account for about a third of the differencee61 Recent n.m.r. work6* also indicates a difference in the binding of methotrexate (23) and dihy- drofolate (20):for example there are large shifts in the 13Cn.m.r. spectrum of a sample of dihydrofolate reductase in which the methyl groups of methionine have been enriched with 13C when (23) binds to it while (20) produces fewer and smaller shifts.62 Matthews and his co-workers60 were careful to point out that their data do not exclude the possibility that methotrexate (23) and the natural cofactor bind differently within the same site.A rotation of 180"about the bond between C-6 and C-9 and slight movements in other angles would present the opposite face of the pteridine to NADPH (24) and still allow close approach of C-6 to the C-4 of nicotinamide. Without knowing which orientation is adopted by the natural cofac- tor it is impossible to interpret sequence data and assign roles to specific residues in the active site with any confidence. A decision between these two possibilities can now be made because of the recent X-ray determinati~n~~ of the absolute configuration at C-6 of both diastereomers of 5,lO-methenyltetrahydrofolate. The biologically active diastereomer was established to have the (6s)configuration and therefore the biologically active diastereomer of 5-formyltetrahydrofolate from which it was derived has the configuration shown in (25).63This knowledge has been used to establish the stereochemical course of the reductase-catalysed reaction.64 Dihydrofolate (20)was reduced with NADPH and dihydrofolate reductase and the product (21)was shown to possess the (6s)configuration by direct chemical correlation with (25).64This proves that attack by NADPH occurs at the Re face of dihydrofolate (20),and not at the Si face as predicted by the X-ray results.Evidently methotrexate (23)does bind 'the wrong way up' compared to dihydrofolate (20) and this weakens the proposal that it functions as an analogue of the transition state of the enzyme.65 The stereochemical course of the much slower reduction of folate (22) was also e~tablished:~~ NADP' was reduced using the B-side-specific enzyme glucose 6- phosphate dehydrogenase and the resulting NADPH (24b) was used to reduce folate (22) in the presence of dihydrofolate reductase.A 'H n.m.r. analysis of the 61 K. Hood and G. C. K. Roberts Biochem. J. 1978,171,357. 62 R. L.Blakley L. Cocco R. E. London T. E. Walker and N. A. Matwiyoff Biochemistry 1978,17,2284 and refs. cited therein. 63 J. C. Fontecilla-Camps C. E. Bugg C. Temple Jr. J. D. Rose J. A. Montgomery and R. L. Kislink J. Amer. Chem. SOC. 1979,101,6114. 64 P.A.Charlton D. W. Young,B. Birdsall J. Feeney and G. C. K. Roberts J.C.S. Chem. Comm. 1979 922. 65 J. W. Williams J. F. Morrison and R.G. Duggleby Biochemistry 1979. 18 2567. Biological Chemistry -Part (vi) Enzyme Chemistry 483 product established that the tetrahydrofolate has the configuration shown in (21b) with deuterium specifically in the (7s) position. Thus hydride transfer is from the 4-pro-R position of NADPH (24) to the Si face at C-7 of folic acid (22) and reduction at C-6 and C-7 occurs on the same face of the pteridine nucleus.64 6 Multi-enzyme Proteins Enzymes in many metabolic pathways are physically associated in multienzyme proteins [cf. Ann. Reports (B) 1977,74,443]. These proteins are of two basic types multi-enzyme complexes (also termed multi-enzyme aggregates) in which some or all of the component enzymes are only held together by non-covalent interactions; and multi-enzyme polypeptides,66" (or multi-enzyme conjugates666) in which all of the associated catalytic activities are carried on the same polypeptide chain.Multi- functional proteins are thought to have arisen as a result of fusion of the structural genes coding for the individual enzymes and this arrangement provides a simple way of co-ordinating the control of their synthesis. The significance of multi-enzyme complexes in general is harder to assess although possible advantages have frequently been The third second and tenth steps in the biosynthetic pathway to histidine in yeast are catalysed by a trifunctional protein which was only isolable when proteinase inhibitors were present during the purification of the enzyme.68 Similarly trypto- phan synthase from yeast has now been shown to be a multifunctional protein rather than a non-covalently associated aggregate by using a rapid purification procedure that is designed to minimize proteolytic damage.69 Such difficulties in the isolation of intact complexes because of the action of endogenous proteinases can however be turned to good account.Brief exposure of a multi-enzyme complex to a specific proteolytic enzyme such as trypsin often leads to chain cleavage at a very limited number of particularly reactive sites. The resulting fragments often retain catalytic activity and their characterization can provide very useful information about the organization of the native complex. This approach has been used for example with glutamine ~ynthetase,~' aspartokinase I-homoserine dehydrogenase I,71 fatty acid syntha~e,~* and tryptophan syntha~e.~~ Brief treatment of the biotin-dependent transcarboxylase from Propionibacterium shermanii with trypsin has the interesting consequence that the part of the biotin carrier protein that bears the prosthetic group is specifically excised from the complex.74 A very similar finding has been made for the pyruvate dehydrogenase " (a)P.Karlson and H. B. F. Dixon Trends Biochem. Sci. 1979,4 N275; (6)F. H.Gaertner ibid. 1978,3 63. 67 (a)K. Kirschner and H. Bisswanger Ann. Rev. Biochem. 1976,45,143; (b) G.R.Welch Prog. Biophys. Mol. Biol. 1977 32 103. 68 J. K. Keesey Jr. R. Bigelis and G. R. Fink J. Biol. Chem. 1979 254 7427. '9 M. Dettwiler and K.Kirschner European I. Biochem. 1979,102 159. 70 A. Dautry-Varsat G. N. Cohen and E. R. Stadtman J. Biol. Chem. 1979,254 3124. 71 P. A. Briley L. Sibilli M.-A. Chalvignac P. Cossart G. Le Bras A. De Wolf and G. N.Cohen I. Biol. Chem. 1978,253,8867. 72 J. K. Stoops P. Ross M. J. Arslanian K. C. .'.une S. J. Wakil and R. M. Oliver J. Biol. Chem. 1979,254 7418,and refs. cited therein. 73 (a) W. Higgins T. Fairwell and E. W. Miles Biochemistry,1979,18,4827; (b)V.Rocha E. F. Brennan and S Plumb Arch. Biochem. Biophys. 1979,193 34. 74 H. G. Wood C.R.C. Crit. Rev. Biochem. 1979.7 143 and refs cited therein. 484 P. F.Leadlay complex from E. ~oli,~’ appears to affect only those where limited prote~lysis~~ subunits (E2) that bear dihydrolipoyl residues.This is surprising because the E2 subunits are regarded as forming the ‘core’ of this complex and might have been expected to be screened from proteolytic attack. Some elegant work has been on mammalian multi-enzyme complexes in the pathway responsible for the production of pyrimidine nucleotides de no00 for DNA biosynthesis. What follows mainly concerns the first three steps in the pathway to uridine 5’-monophosphate in which carbamoyl phosphate is produced and converted (Scheme S) by way of N-carbamoyl aspartate (26),into dihydro-orotate (27). ADP NH~+ HCO~+ ATP 4 H~N-CO-PO$-\Laspartate 0 I1 .OH (27) Scheme 8 The three enzymes involved i.e. carbamoyl phosphate synthetase (EC 6.3.5.5) aspartate carbamoyltransferase (EC 2.1.3.2) and dihydro-orotase (EC 3.5.2.3) have been at least partially purified from a variety of animal tissues and in every case all three activities are associated with a single multi-enzyme complex.77a The amounts of enzyme obtained were too small to permit extensive characterization but the enzyme from mouse ascites hepatoma cells7’ certainly appeared to be a multi- functional protein.Large amounts of this complex have now become available through the use of a simple and effective technique mammalian cells in tissue culture were exposed to gradually increasing concentrations of N-(phosphonoacety1)-L-aspartate (28) which is a substrate analogue and also a potent inhibitor” of the second enzyme in 0 II ,OH C 2-o,P O’N H‘!02H (28) ” M.C. Summers and D. C. Williams Ann. Reports (B) 1977 74,445. 76 (a)G. Hale and R. N. Perham European J. Biochem. 1979,94,119; (b)C. Gebhardt D. Mecke and H. Bisswanger Biochem. Biophys. Res. Comm. 1978,84,508; (c) D. M. Bleile P. Munk R. M. Oliver and L. J. Reed Proc. Nut. Acad. Sci. U.S.A.,1979,76,4385. ’’ (a)P. F. Coleman D. P. Suttle and G. R. Stark J. Biol. Chem. 1977,252,6379; (b)R. A. Padgett G. M. Wahl P. F. Coleman and G. R. Stark ibid. 1979,254,974; (c)D. P. Suttle and G. R. Stark ibid. 1979 254,4602. M. Mori and M. Tatibana J. Biochem. (Japan) 1975,78,239. 79 E. A. Swyryd S. S. Seaver and G. R. Stark J. Biol. Chem. 1974,249,6945. Biological Chemistry -Part (vi)Enzyme Chemistry the pathway i.e. aspartate carbamoyltransferase. Mutant cells were obtained which resist concentrations of this inhibitor 5000 times higher than required to cause 50% inhibition of the wild-type cell line.In these mutant cells all three activities of the complex were increased by nearly a hundred-fold and the complex (constituting nearly 10% of the total cellular protein) could be readily purified and characterized. The pure protein contains only one type of polypeptide of M 200 000,which carries all three enzyme activities of the complex. The isolated multifunctional protein is a mixture of trimers and hexamers. Over-accumulation of this multifunctional protein in the resistant cells has been shown7” to be due to an increased rate of enzyme synthesis and a large RNA purified from mutant cells co-sediments in sucrose gradients with a fraction that has the capacity to direct the synthesis of the multifunctional protein in vitr~.~~~ This approach to obtaining relatively large amounts of mammalian complexes has been extended to a second bifunctional complex in the same biosynthetic path~ay.’~‘ By exposing cells to increasing amounts of specific inhibitors of orotidine S’-phosphate decarboxylase (EC 4.1.1.23) which is the sixth and last enzyme in the pathway resistant mutants have been obtained that over-accumulate both this enzyme and its neighbour orotate phosphoribosyltransferase (EC 2.4.2.lo) by nearly seventy-fold. In prin- ciple this technique is applicable to any enzyme that is essential for cell growth for which a specific inhibitor is available.

ISSN:0069-3030    

DOI:10.1039/OC9797600472

出版商:RSC    

年代:1979

数据来源: RSC

摘要:

Abatjoglou A. G. 273 Abbott B. J. 383 Abbott S. J. 311 Abboud J.-L. 55 Abdallah M. A. 472 Abdulla R. I. 162 326 Abe Y. 210 Abeles R. H. 478 Abenhaim D. 149 Abeysekera B. 357 Abidi S. L. 153 Abiko S. 294 Abou-Gharbia M. A. 248 Abraham M. H. 58 Abramovitch A. 296 Abramovitch D. A. 240 Abramovitch R. A. 240 Abronin I. A. 248 Abu-Rabie M. S. 227 Acheson R. M. 243,248 Ackerman J. J. H. 23 261 Adachi J. 236 Adachi M. 214,298 Adachi T. 454 Adam W. 121,226 Adamcik R. A. 318 Adamiak R. W. 466,467 Adams C. 106 Adams M. A. 367,408,429 Adams M. J. 472 Adams P. E. 429 Adams R. E. 369 Adamsky F. 50 Adlington R. M. 367 Afzal M. 249 Agarwal K. L. 464,469 Agarwal S. K.290 Agopian G. K. 95 Agosin M. 415 Agosta W. C. 19 117 Ahlberg P. 309 Ahlenstiel E. 299 Ahlgren G. 409 Ahlrichs R. 33 Ahmed I. 86 Ai T. H. 375 Aida T. 347 Air G. M. 462 Akada M. 102 Author Index Akagi K. 282 Akashi K. 365 Akermark B. 424 Akhtar M. 381 Akhunova V. R. 419 Akiba K. 220 Akimoto I. 228 295 Akimoto K. 368 Akita H. 431 Akiyama F. 158 Akiyama S. 207 Aksnes G. 312 Albaugh P. 47 Albeck M. 199 Albericci M. 441 Albersheim P. 6 Albonico S. M. 386 Albrand J. P. 21 Albrecht H. 340 Albrecht H. A. 212 Albrecht P. 374 Alcalde E. 232 Alden R. A. 481 Alder R.W. 246 Aldrich J. R.,408 Al-essa R. J. 256 Alexakis A. 325,422 Alexander R.G. 191 Alexanian V. 222 248 Algona G. 43 Al-Hassan J. M. 249 Ali S. F. 60 Allen D. W. 311 313 Allen F. H. 13 14 16 391 Allen N. 407 Aller T. 409 Allerhand A. 19 472 AI-Masad F. N. 249 Almenningen. A. 275 Almond S. W. 52 Alonso M. E. 98 Alper H. 224,257,265 266 Al-Sader B. H.,*181 Alston T. A. 478 Altenbach H.-J. 185,246,357 Altman B. 152 Altman L. J. 21 380 Altmann J. A. 305 Amagaya S. 376 Amarnath V. 465 Amatore C. 108 197 Ambuehl J. 268 Amey R. L. 237 Amin N. 215 Amrein W. 53 Anapolle K. E. 51 Anastasia M. 378 Anastassiou A. G. 181 Ancelle J. 283 Anderegg R.J. 11 Anderson R. J. 408 Anderson W. R. Jr. 9 Ando R.,55 Ando W. 97 99 122 123 129,280,283 Andre D.145 Andreeva L. R. 189 Andreozzi P. 33 Andrews G. D. 324 Andrews G. T. 29 Andrews M. A, 258 Andrieux C. P. 108 Andrus A. 268,359 Anet F. A. L. 22 172 Angele S. 23 1 Angst M. E. 409 Anicich V. 65 Anjo D. M. 300 Ansell J. M. 428 Antczak S. 306,308 Anteunis M. J. O. 222 Antin J. H. 218 Aoki K.,461 Aoki S. 325 Aomori Y. 203 Aoyagui S. 108 Aoyama H. 114,270,357 Appel R. 226 317 ApSimon J. W. 323 Arafat A. 210 Arai S. 220 Aragnuez L. M. 370 Arase A. 291 292 Arbuzov B. A. 238 307 Arcamone F. 227 Archibald I. G. 472 Archie W. C. Jr. 309 Arco M. J. 50 488 Author Index Ardakani M. A. 234 Ardebili M. H. P. 15 Arduengo A.J. 43 Arene E. O. 190 Arentzen R.,463 466 Argile A. 69 70 Arigoni D. 473 Armarego W. L. F. 249 Armbruster M. A. 468 Armitage I. M. 23 Am H.,407 Arnaboldi M. 381 Arnett E. M. 56 218 Arnold B. 97 Arnold E. V. 367,408,436 Arnone C. 195 Arnost M. J. 50 Arnoux B. 375 Arpino P. J. 11 Arslanian M. J. 483 Arthur A. P. 407 Arthur E. V. 374 Asada M. 376 Asbrink L. 33 Ashby E. C. 132,277,279 Ashcroft M. R.,84 Ashe,A. J.,218,243,284,285 299,316 Ashmore J. W. 287 Askakawa Y.,366 Asmus K.-D. 79 Ast T. 5 10 Astell C. 464 Asubiojo 0. I. 72 Atkinson R. S.. 87 222 Atkinson T. C.. 467 Atsumi K. 366 Auffret A. D. 11 Aune K. C. 483 Aurelle H.,8 Ausloos P.5 Avasthi K. 292 Aversa M. C. 190 Ayanoglu E. 443 Ayer W. A. 373 Ayyangar N. R.,248 Aiman A. 43,223 Baban J. A. 78 79 Babior B. M. 472 Babler J. H. 421,424 Babsch H. 53 Bach R.D.. 37 136 147 153 Bachechi F. 268 Bachmann P. 28 Bachovchin W. W. 22,472 Baciocchi E. 69 Back T. G. 347 376 Backlund S. J. 294 295 Baddeley G. V. 375 Baeryschi P. 53 Bahl C. P. 464,466 Bahl M. K. 218,284 Bahr J. 335 Bailey A. S. 248 Bailey B. K. 416 Bailey T. F. 168 Bailey T. R. 123 166 333 356,365 Bain A. D. 26 Baird M. S. 90 91 Baird N. C. 39 Bajwa G. S.,222,460,461 Bak D. A. 135 Bakeeva R.S. 419,424 Baker D. C. 452 Baker J. D. 289 Baker J. T. 219 Baker P. M. 410 Baker R.254 363 404 410 411,412,432 Baker T. C. 405,407 Baker W. R.,349 Bakke A. 409 Balaban A. T. 169 248 Balan A. 152 Balasubramanian K. 223 Balasubramanian K. K. 234 Baldwin B. J. 23 Baldwin D. 377 Baldwin J. E. 50 178 Baldwin J. J. 228 Bale N. M. 388 Balen’kii L. I. 248 Ballard H. H. 86 Bally T. 53 Balny C. 472 Balogh-Nair V. 38 1 Balthazor T. M. 237 Bamkole T. O. 195 Banerjee A. 40 Bankier A. T. 462 Banks R. E. 190 Bannemann D. 79 Bantle S. 33 Banville J. 158 274 Barabas A. 416 Baranak J. 459 Barber J. J. 128 Barbier M. 434 Bard A. J. 105 108 109 110 Bargon J. 21,74 Barker P. J. 76,77 Barlow M. G. 190,243 Barltrop J. A. 50 230 Barluenga J.239 Barnes C. E. 188 Barnette W. E. 137,213,350 380 Barnick J. W. F. K. 152 Barnier J.-P. 15 Barnvos D. 96 Barr P. J. 455 Barrans J. 238 Barrell B. G. 462 Barrett A. G. M. 324 367 395 Barron P. F. 20 Bartetzko R. 176 Barth J. 151 Barth V. 226 Barthelat J.-C. 34.98 281 Bartlett P. A. 428 Bartlett P. D. 306 Barton D. H. R. 157 263 323,324,338,340,349,376 378,381,394,395,398 Barton D. L. 365 Barton J. W. 217 249 Bartsch R. A. 68,69 Baryshnikova T. K. 298 Bass M. A. 476 Basus V. J. 29 Batey I. L. 470 Batra S. W. T. 409 410 Battaile J. 438 Battersby A. R.,156,390,391 392,396,400 Battig K. 380 Baudat R. 345 Bauer M. 248 Baumann H. 35 Baumann T. W.452 Baumgartel O. 168 Baumstark A. L. 306 Bax A. 28 Baxter A. G. W. 90 Baxter D. L. 365 Baxter J. D. 463 Baxter R. L. 382 Baydar A. E. 242 Beacham L. M. 111,456 Beak P. 273 Beaucage S. L. 453,467 Beauchamp J. L. 64 Bechtel P. J. 475 Bechtold R. A. 300 Beck K. 409 Becker A. R. 57 Becker E. D. 20 Becker G. 319 Becker H. D. 200 Becker H. G. O. 201 Becker H. J. 299 Becker H. P. 300 Becker J. 94 Becker K. B. 324 Beckey H. D. 10 Beckwith A. L. J. 334 Bedekovic D. 247 Beechan C. M. 443 Beels C. M. D. 227 Beer M. 470 Beer P. D. 308 Beer R.J. S. 220 Beevor P. S. 407 Begg D. T. 20 Begley M. J. 360 Beheshti I. 14 Behforouz M. 368,444 Behrendt S.235 Behrman E. J. 470 Author Index Beisler J. A. 314 Belagaje R. 465 Belikov V. M. 261 Belin B. 162 Bell G. 462 Bell H. C. 284 Bell R. A. 26 Bellamy F. 87 Bellard S. 13 Bellmann P. 235 BelluS D. 150 Bellville D. J. 243 285 Belokon Yu. N. 261 BelSkii V. E. 31 1 Beltrami H. 240 Bemi L. 245 Bendall M. R. 20 Bender C. O. 53 Benechie M. 328 Benedikt G. M. 23 Benkeser R. A. 277 Bennett D. A. 301 Bennett J. E. 79 Benninghoven A. 9 Benoist C. 462 Benoit F. M. 6 Bentley K. W. 394 Bentley T. W. 57,293 Bentrude W. G. 222 321 318,460,461 Ben-Yakov H. 377 Bercaw J. E. 258 Berclaz T. 321 Berenjian N. 121 Beress L. 434 Bergbreiter D. E. 291 Berge J.M. 127 323 Bergers D. A. 425 Berger R. S. 415 Bergman J. 200 Bergman R. G. 52 85,256 Bergstrom G. 409 410 Bergstrom D. E. 453 Berisford C. W. 407 Berk H. C. 237 Berkowitz W. F. 349 Berlin B. 248 Berlin K. D. 312 Berman D. W. 65 Berman E. 21 360 368 Bernadou F. 142 Bernard D. 307 Bernardi F. 32 37 Bernasconi C. F. 194 218 Bernauer K. 224 Berndt A. 74 Berner H. 220 Bernheim M. 54 Bernstein J. 13 14 Bernstein M. A. 22 Bernstein R. L. 447 Bernstein P. R. 378 Bertero L. 264 280 Bertie J. E. 174 Bertran J. 38 186 Bertrand G. 34,98 281 283 Bertrand M. 360,364,421 Besse J. J. 161 Bestmann H. J. 314,315,404 407,419,421 Bethell D. 96 Beugelmans R.228 Bey P. 477 Beynon 3. H. 5 10 11 238 299 Bhanu S. 145 Bhat V. 248 Bhatt M. V. 301 Bhatt T. S. 205 Bhattacharyya P. 375 Bhattacharyya S. P. 315 Biala E. 467 Bialkowska A. 84 Bianchi G. 49 248 Bichlmayer K. 230 Bickelhaupt F. 152 285 Bieber L. 328 Biellmann J.-F. 472 Biemann K. 11 Bienvenue-Goetz E. 70 Bierbaum V. M. 67 Bierl B. A. 416 Bierl-Leonhardt B. A. 405 407 Biermann M. 208 Biernbaum M. S. 300 Bierschenk T. R. 271 Bigam G. 20 Bigelis R. 483 Bigley D. B. 178 Bigot B. 43 223 Bihlmaier W. 48 Billingham N. C. 127 Billups W. E. 85 Bilton J. N. 11 Bingham A. Jr. 435 Bingmann H. 53 Binkley J. S. 33 36 Binkley R. W. 454 Binkley W.W. 454 Birch M. C. 409 Bird T. G. C. 213,360 Birdsall B. 482 Bisswanger H. 483,484 Biwer G. 405,407 Bjerre C. 237 Blacklock T. J. 93 Blattler W. A. 459 475 Blaicher W. 305 Blais J. 29 Blakley R. L. 480 482 Blatchley R. A. 218 BlaieviC N. 162 248 Bleeke J. R. 251 Bleile D. M. 484 Blessing R. H. 16 Blight M. M. 409 Bloch A. 448 Bloch K. 478 Block E. 160 Blooman C. 108 Blount J.F.,212,350,366,371 Bloy V. 149 Blues E. T. 277 Blum D. M. 374 Blum M. S. 408 409 410 413,415,432 Blum P. M. 78 Blundell T. L. 16 Blurock E. S. 37 173 Boar R. B. 375,394,395 Bobek M. 457 Bocarsly A. B. 178 Boche G. 51,54,275,284 Bochmann M. 299 Bockhoff F. M. 5,311 Bodenhausen G.27 Boeckman R. K. 374 Boeder C. W. 420 Bohle C. 238 299 Bohm M. 48 182 Bohm M. C. 123 173 176 275,333 Boehmer V. 207 Boekelheide V. 206 208 Boekestein G. 320 321 Boersma J. 300 Bosiger H. 30 Boeyens J. C. A. 16,377 Bogenschutz H. 407 Boggs J. E. 36 Bohlmann F. 366,371 Boireau G. 149 Boisdon M. T. 238 Bojesen G. 20 Boldrini G. P. 269 Boldyreva 0.G. 298 Bolivar F. 464 Bolster J. 169 Bolton P. H. 27 Bolton R. 210 Bombala M. V. 160 Bomben K. D. 218,284 Bon R. 461 Bond F. T. 274,356 Bone S. A, 306 Bonett M. 351 Bonneau R. 115 Bonny A. 284 Bonzougou Y. 152 Boor J. 251 Borch G. 435 Borchardt R. T. 474,475 Borchers F. 9 Borden W. T. 39 175 Bordner J.245 315,375 Boreham D. R. 7 Bose A. K. 363 Bosnich B. 150 Botar A. A. 416 Both F. K. 10 Bothner-By A. A. 21 490 Bott K. 162 Bottomley W. 388 Bouas-Laurent H. 117 Boujlel K. 105 Boulton A. J. 2 12 Boulton K. 372 Bouma W. J. 4 39,41 Bourelle-Wargnier F. 245 Bourgois J. 49 Bourgois M. 49 Bouscasse L. 210 Boutagy J. 7 314 Boutkan C. 273 Boutry J. L. 434 Bovill M. J. 366 Bowden B. F. 372 Bowen C. T. 57 Bowen R. D. 4,5 Bowman D. A. 305 Boyd G. V. 242 Boyer H. W. 464 Boykin J. 55 Bozorgzadeh M. H. 10 11 238,299 Bracho R. D. 394 Bradley C. H. 19 Bradshaw J. S. 248 Bradshaw J. W. S. 411 Brady W. T. 135 Braekman J. C.,433,440,441 442 Braenden 0.J.382 Bramblett J. D. 306 Bramwell F. B. 221 Brand J. M. 363 410 413 415,417 Brandenberger H. 8 Brandt S. 89 260 Braslavsky S. E. 53 Brauer D. J. 238 299 Brauman J. I. 72 Braun R. W. 271 Brazier J.-F. 309 Brean D. L. 33 Breathnach R. 463 Bredt D. C. 55 Brener L. 289 Brennan E. F. 483 Brenner S. 463 Brent D. A. 8 10 Brenton A. G. 10 11 Breuninger M. 185 246 Brewster A. G. 376 Brey W. S. 28 Brice M. D. 13 Brich Z. 158 364 Bridges S. D. 453 Brierley J. 304 306 Bright H. J. 478 Briley P. A. 483 Brille F. 255 Briner P. H. 412,432 Bringmann G. 323- Brinker U. H. 91,92,174,179 Brinkmeyer. R. S. 162,326 Brion F. 420 Brittain J. M.190 Britton G. 380 Broekhof N. L. J. M. 340 Broline B. M. 50 Brook A. G. 282 Brookhart T. 53 Brooks B. R. 32 34 41 92 279 Brooks D. W. 152 297 330 343 Broom A. D. 453,465 Broome P. 463 Brophy J. J. 7 Brosche T. 407,419 Brossi A. 201,391 Brousseau R. 464 Brown A. G. 479 Brown A. T. 85 Brown B. O. 380 Brown C. 317 319 Brown C. A. 287 289 332 355 Brown C. H. 291 Brown D. 156 Brown D. C. 279 Brown D. M. 453,470,471 Brown D. W. 52 85 Brown E. 378 Brown E. L. 465 Brown F. F. 23 Brown H. C. 56 140 147 278,287,288,289,290,291 292,297,298,300,333,341 364 Brown L. 7 Brown L. D. 32 Brown M. 208 Brown M. P. 299 Brown N. L. 462 Brown R. A. 273 Brown R.S. 148,463 Brown R. T. 391,401 Brown S. B. 41 Brown T. 458 Brown W. T. 181 Brown W. V. 410,412 Brownbridge P. 353 Browne L. E. 415 Brownlee G. G. 462,463 Bruce M. R. 64 Bruce R. L. 204 Bruck D. 29,63 Bruckmann P. 175 Bruntrup G. 132 326 Bruhn M. S. 291 Bruins A. P. 7 Brunet J.-J. 86 257 Brunfeldt K. 467 Brunke E. J. 377 Brunner P. 30 Brunton G. 79 188 Brussard P. F. 405 Author Index Bryan D. B. 228 Bryantsev B. I. 297 Bryce-Smith D. 277 Bubnov N. N. 322 Bubnov Yu. N. 297 Buchanan J. G. 450 Buchbauer G. 371 Buck H. M. 309,320,321 Buckl K.,54 275 Buckle D. R. 191 Buckel W. 473 Buckley D. G. 156,382 392 Buckley T. F. 228 Budd D. L. 24 Budesinsky M.373,412 Buding H. 173 Budris J. P. 407 Budzikiewicz H. 7 Buchi G. 329 368 Bugg C. E. 482 Bull J. R. 16 377 Buloup A. 265 Bunce N. J. 117 Buncel E. 55,66,278 Bunnett J. F. 68 192 196 197 Bunton C. A. 196 311,365 Burchall J. J. 480,481 Burdon J. 203 Burgada R. 307,309 Burgen A. S. V. 21 Burger U. 53,94 Burgers P. M. J. 466,467,469 Burges P. C. 4 Burke L. A. 42 Burke S. D. 367 Burkholder W. E. 405 Burlingame A. L. 3 Burnett A. R. 400 Burns F. B. 313 Burns P. D. 24 Burreson B. J. 444 Bursey M. M. 6 8 Bursey J. T. 6 Burton L. P. J. 91 Bury A. 84 Burya G. F. 189 Busby R. E. 90,230 Busch A. 255 Bushby R. J. 51 Busker E. 7 Butcher A. R. 6 Busch K.L. 8 Buse C. T. 332 Buser H. R. 407 Butina D. 151 Butler A. R. 223 Butler D. 85 Butler R. N. 232 Butler W. 299 Buyer R. 464 Buynak J. D. 85 Byerrum R. U. 388 Byler R. C. 410 Author Index Cacace F. 66 Caccamese S. 437 Cacchi S. 200 Cachapuz Carrelhas A. 309 Cadiot P. 290 Cadogan J. I. G. 88,201,307 3 24 Cadosch H. 380 Caglioti L. 343 Cahiez G. 325,422 Calderon J. S. 414 Caldwell R.L. 409 Callahan J. F. 368 Cambie R. C. 377 378 Cameron D. 6 Cameron T. B. 217 Cammaertr M. C. 410 Campari G. 256 Campbell A. L. 273 Campbell J. B. 290 Campbell J. D. 300 Campbell N. 204 Campion D. G. 407 416 Campsteyn H. 16 Canadell E. 38 186 Cantoni G.L. 473 Cantrell G. L. 205 Cantrell J. S. 202 Canty A. J. 278 Capinera J. L. 416 Caporusso A. M. 144 Capozzi G. 249 Caramella P. 43 Carde A. M. 405,407,408 Carde R. T. 405,407 Cardellina J. H. Jr. 435 436 Carli J. S. 446 447 Carleer R. 222 Carless H. A. J. 48 Carlsen L. 148 Carlsen N. R. 36 Carlsen P. H. J. 248 Carlson D. A,,407 Carlson G. M. 475 Carlson R. G. 53 119 Carlson S. C. 160 Carlton L. 144 Carnahan E. J. 59 Caro J. H. 416 Caronna T. 123 201 Carpenter B. K. 45 183 Carpenter T. L. 405 Carpino L. A,,330 Carpita A. 406 416 422 Carr D. B. 134,279 Carre D. J. 218 Carroll D. I. 9 11 Carson W. M. 16 Carter C. G. 178 Cartwright B. A. 13 Cartwright E.M. 463 Caruthers M. H. 464 Casara P.,477 Caserio M. C. 4 Casey C. P. 258 Cashmore A. R. 469 Casida M. E. 34 92 279 Casnati G. 346 Cassani G. 141 327 420 Cassar L. 266 267 Casson A. 246 Castellan A, 117 Castillo M. J. 222 Catterall J. F. 462 Caubkre P. 86,257 Cavell R.G. 304 Cavill G. W. K. 411 Cavin W. P. 68 Cawkill E. 236 Cayley P. J. 21 Cazes B. 421 Ceccherelli P. 153 344 Cech F. 119 Celrna M. L. 462 Cere V. 50 Cerfontain H. 189 Ceriotti S. 264 Cesarini G. 463 Cesarotti E. 161 Chaabouni R.,290 Chabala J. C. 246 Chabaud B. 143 Chadha M. S. 150 Chadwick D. J. 14 24 Chae W. K. 217 Chaillet M. 49 Chakraborty D. P. 375 Challis B.C. 198 223 Chaloupka S. 224 Chalvignac M.-A. 483 Chamberlin A. R. 274 356 Chambon J. P. 407 Chambon P. 462 Chan D. M. T. 270,358 Chan T. H. 271 320 347 353,356 Chan W.-T. 218,284 Chandler J. H. 289 324 Chandler R. F. 374 Chandrasekaran S. 290 291 344,372 Chandrasekhar J. 34 35 36 37 38 77 272 Chang A. C. Y. 463 Chang C. H. 470 Chang C. W. J. 372 Chang C.-Y. 205 Chang D. W.-L. 116 Chang K.-T. 93 Chang L. L. 305 318 Chang M. J. 182 Chang M. N. T. 396 Chang V. S. 143 Chang Y.-M.,282,471 Chao E. 300 Chao S. C. 124 Chapman A. V. 240 Chapman J. R. 3 Chapman 0. L. 87 405 407 416 Chapple C. L. 391 Charbonnel Y. 238 Chari S. 95 Charles C. 440 Charlton P.A. 482 Charnas R. L. 479 Charnay P. 462 Charrier J. 225 Chatgilialoglu C. 80 Chatrousse A.-P. 194 Chattopadhyaya J. B. 330 457,466 Chatziiosifidis,I. 353 Chaudhary S. K. 457 Chaussard J. 108 197 Chawla B. 218 Chayabunjonglerd S. 368 Cheeseman G. W. H. 86 Cheetham A. K. 171 Chen B. 118 Chen I. 35 167 Chen J. C.-S. 289 Chen R. 369 Chen S.-C. 301 Chenard B. L. 102 Cheng C.-C. 226 Cheriyan U. O. 169 Chermprapai A. 158 212 Cherrett J. M. 410 Cherry P. C. 227 Cheung H. T. A. 379 Cheung L. M. 42 Cheung W. Y. 476 Cheung Y.-F. 374 Chevolot L. 290 Chick W. L. 463 Chidsey C. E. 178 Chiesi-Villa A. 260 Childs R. F. 117 118 Chiles M. S. 161 Chin E.369 Chini P. 264 Chioccara F. 445 Chiou B. L. 296 Chiprnan D. M. 42 87 173 Chisholrn M. D. 407,416 Chiu K.-W. 295 296 Chizhov 0.S. 3 Cho B. R. 68 Cho N. S. 66 Choi L. L. 376 Choong Y. S. 478 Chou P. Y. 472 Choudhry S. 349 Choudry G. G. 200 Chow F. 130 131 Chow Y. L. 253 Chow Y. S. 407 Chowdhry V. 97 283 Christen P. 472 Christensen B. G. 227 Christensen J. J. 248 492 Christensen L. 107 Christiansen P. A. 32 Christie B. 295 Christmas P. E. 415 Christoph G. G. 176 Christophersen C. 237 439 446,447 Chu C. K. 453,454 Chu P.-S. 368 Chuche J. 245 Chucholowski A. 132 326 Chumana T. 405 Chung S. 252 Chung S.-K. 127 324 Ciattini P. G.326 Cimino G. 373.441 Cimiraglia R. 36 Citerio L. 231 Claramunt R. M. 232 Clardy J. 168 171 Clardy J. C. 319 360 363 367,373,374,408,411,415 436,438,439,441,444 Claremon D. A. 137,350 Clark D. A. 347 Clark D. S. 155 Clark R. D. 47,425 Clark T. 34,77,90 272 Clarke J. K. A. 96 Clarkson K. 447 Clayton A. F. D. 205 Clayton P. J. 229 Clayton S. D. 456 Clifford K. H. 473 Clin B. 29 Clive D. L. J. 301 Closier M. D. 87 Closs G. L. 25 Clough J. M. 380 Coates H. 317 Coates R. M. 214 337 349 368 Cocco L. 482 Coffin R. L. 53 119 Coghlan M. J. 424 Cogolli P. 192 210 Cohen G. N. 483 Cohen J. S. 22 23 Cohen M. L. 67 Cohen P. 475,476 Cohen S. G 120 Cohen S. N.463 Cohen T. 164,301,354 Colb A. L. 120 Coleman B. 35 Coleman P. F. 484 Coleman R. A. 289 332 Colens A. 347 Coles C. J. 478 Coll J. C. 372 Collart-Lempereur M. 441 Colle K. S. 313 Collins A. M. 410 Collins C. J. 290 Collins J. 463 Collins M. S. 412 Collins P. W. 291 Collins S. 347 Collum D. B. 301 Colombo L. 148 Colonna S. 161 Colquhoun I. J. 29 Coluccia S. 256 Comber R. N. 241 Conia J. M. 163 Conn R. S. E. 47 135 Connolly J. D. 375 Conrad M. P. 40 Conrad N. D. 52 Conradi M. S. 73 Consiglio G. 195 268 Contreras R. 462 Cook F. T. 180 Cook L. S. 241 Cook M. J. 158,240 Cooke F. 356 Cooke M. P. 288 Cooks R. G. 5,6,9 10 Cooksey C. J. 84 Cookson R.C. 150,359 Coombes R. G. 188 Coombs M. C. 205 Cooper N. J. 256 Coppel H. C. 416,423 Copsey D. P. 375 Corbridge D. E. C. 303 Cordell B. 462 Cordell G. A. 400 Corey E. J. 147 150 334 340,344,347,348,351,368 372,444 Cori O. 365 Cornforth J. 202 Cornforth J. W. 473 Cortese R. 463 Cortez C. 204 Cory H. T. 453 Cory R. M. 91 Cossart P. 483 Cotter M. L. 369 Cotter R. J. 9 Cough R. L. 121 Coughlin D. J. 118 Coulson A. R. 462,463 Couret C. 89 Cowan D. O. 11 1 Coward J. K. 475 Cowburn D. 19 Cowell A. 269 349 Cowling G. J. 470 Cox W. W. 53,119 Cozens R.J. 308 Crabbt P. 145,365,377 Crain P. F. 452 Cram D. J. 247 Cramer F. 470 Crampton M. R. 194 198 Crandall J.K. 253 Author Index Crawford J. L. 17 Crawford T. C. 295 Crea R. 463,464 Crease A. E. 84 Cremer D. 35 36 38 Creutz C. E. 23 Crick F. 463 Crimmin M. J. 254 Croce M. 55 Crombie L. 141 382 Crombie W. M. L. 382 Cromwell N. H. 248,249 Cross B. E. 372 Cross J. H. 410 Cross T. A. 29 Crothers D. M. 467,470 Crout D. H. G. 388 389 Crow F. W. 7 Crow W. D. 95 Cruse H. W. 188 Cruse W. B. T. 48 Cruz A. 377 Csendes I. G. 152 Csizmadia I. G. 37 39 305 Cueto 0..226 Culver M. G. 401 Cum G. 190 Curran D. P. 116,328 Currie J. K. 266 Curtin D. Y. 14 Czerny V. 377 Dadali. V. A. 186 Daddona P. E. 401 Dahl O. 317 Dahlhoff W. V. 292 Dahm K. H. 407 Dajani E.Z. 281 Dalietos D. 435 Dallas J. L. 24 Dalling J. 181 Daloze D.,412,433,440,441 442 Daly J. J. 185 224 246 Damiano J.-C. 377 Damji S. W. H. 30 194 Damude L. C. 277 Danen W. C. 78,79,133 Danheiser R. L. 344 372 Daniewski W. M. 164 Danishefsky S. 163 360 367 368,384,385 Danzin C. 477 Darensbourg D. J. 23 Darling D. 277 Darm H. 208 da Rocha J. F. 249 Das B. C. 452 Daterman G. E. 424 Dauben W. G. 115,287 Dauber P. 14 Dautry-Varsat A. 483 Dave V. 377 Daves G. D. Jr. 424 Author Index David S. 328 Davidson E. R. 39 175 Davidson R. S. 122 Davies A. G. 76,77,78 Davies D. I. 162,349 Davies G. M. 296 Davies J. 160 Davies J. C. 407 Davies N.W. 41 1 Davies P. S. 296 Davies S. G. 263 Davies B. R. 379 Davis F. A. 211 223 Davis L. P. 185 Davy J. R. 206 Dawber J. G. 312 Dawkins B. G. 11 Day A. C. 50 230 Day R. J. 5 6 Deacon G. B. 280 Dean P. A. W. 277 De’ath N. J. 305 306 De Bernardo S. 449 de Bony J. 29 de Bruijn S. 33 de Capite P. 401 Declercq J.-P. 168 169 225 233,441,442,443 de Clerq P. 367 Decodts G. 420 Dederer B. 215 de Fonseka K. K. 120 De Frees D. J. 33 Degenhardt C. R. 63 De Graw J. I. 393 de Groot A. 431 de Groote R. 366 de Haas G. H. 25 Dehmlow E. V. 90 Deiters J. A. 304 de Jong E. G. 7 Dekerk J.-P. 225 Dekmezian A. H. 22 Delamar M. 110 de la Mare P. B. D. 189 190 Delaney A.D. 470 Delseth C. 434 De Lucia M. L. 480 De Lue N. R. 291,300 de Mayo P. 118 121 123 217,239 de Meijer A. 15 De Micheli C. 49 248 Demole E. 381 Demuth M. 53 Dendramis A. 39 Denis J. N. 130 335 364 Denney D. B. 305 306 308 310,318 Denney D. Z. 305 306 308 Dennis N.,49 248 De Noto F. M. 462 De Paoli-Roach A. A. 476 d’Epifanio L. 87 DeprCs J.-P. 135 164 Depuy C. H. 67 de Rooij J. F. M. 466 de Rossi R. H. 197 Dervan P. B. 49,217 des Abbayes H. 265,266 Descoins C. 405 407 420 42 1 de Silva A. P. 124 De Silva K. T. D. 400 Deslongchamps P. 169 de Sousa B. F. S. E. 234 De Souza J. P. 425 des Roches D. 265 de Stefano S. 373,441 De Talvo W. 277 Dettner K.412 Dettwiler M. 483 Deuchert K. 248 Deutschmann A. 47 Devaprabhakara D. 290.291 292 Devaquet A, 43,223 Devi P. 231 De Ville G. 212 337 Devlin B. R. J. 90 Devos A. 347 De Vos M. J. 364 de Vries J. G. 21 1 Dewar M. J. S. 31 33 35,41 42,223 Dewey H. J. 51 de Wilde H. 367 de Wit A. D. 225 De Wolf A. 483 Dhaenens L. 6 Dhar R. 462 Diakiw V. 7 Diamond S. E. 239 Dianova E. N. 238 Diaz A. F. 109 Diaz S. 311 Dickens J. C. 415 Dickerson J. E. 202 Dickerson R. E. 464 Dickson E. 470 Dickstein J. I. 304 Diderberg O. 16 Diederich F. 206 Diehl D. R. 53 114 Diehl P. 30 Dignam K. J. 43 Dill J. D. 33 39 272 Dill K. 19 Dillon J. 144 164 Dime D.S. 166,356 Di Miele G. 308 Dimitrijevich S. D. 456 Dimroth K. 320 Di Ninno F. Jr. 227 358,368 Dinur V. 381 Di Pasquale F. 298,353 Dixon H. B. F. 483 Djerassi C.,378,434 443 Doddi G. 195 Doddrell D. M. 20 Dodson E. J. 17 Dodsworth D. J 86 Dorre R. 233 Dogadaeva L. V. 307 Doggett B. R. 29 Doi T. 464 Dolbier W. R. 51 181 Dolphin J. M. 129 326 Dolson M. G. 102 Domagala J. M. 153 Dombek B. D. 258 Domelsmith L. N. 85 Donaldson W. A. 178 Donis-Keller H. 463 Doppler T. 234 Dorofeenko G. N. 248 Dorokhov V. A. 298 Dossena A. 346 Doubleday A. 13 Dougherty C. M. 94 Dougherty D. A. 15 33 Douzou P. 472 Dowle M. D. 162,349 Doyle Daves G. Jr. 9 Drabowicz J. 318 Drahnak T.J. 99,280 Drapier J. 222 Drauz K. 338 Dreiding A. S. 92 164 357 Dressaire G. 420 Drouin J. 462 Drozd V. 215 Duax W. L. 16 Dubois J.-E. 69 70 110 152 Dubois R. J. 314 Duboudin J. G. 275 276 Duckworth D. M. 391 Duffield R. M. 413 Duggan A. J. 429 Duggleby R. G. 482 Dumas-Bouchiat J. M. 108 Dumont W. 130,355 Dunaway-Mariano D. 214 Dunbar R. C. 65 Dunitz J. D. 14 Dunn A. W. 373 Duong K. N. V. 84 Duong T. 334 Dupont L. 16 Dupontlooser E. 452 Dupuis M. 32 Durner G. 381 Durst T. 335 Duus F. 148 Dye J. L. 247 Dyer S. F. 233 Dykstra C. E. 43 93 Dyllick-Brenzinger C. 219 Dyong I. 341 Dzakpasu A. A. 14 Dzidic I. 9 Earl R. A. 450 Easler E.M. 118 Eastlands G. W. 320 321 Eaton P. E. 324 Ebata T. 153 Eberson L. 101 Echter T. 166 Eckstein F. 456,469 Edgar A. R. 450 Edge M. D. 467 Edgell M. H. 464 Edmondson D. E. 478 Edwards M. 87 Edwards R. C. 308 Edwin J. 299 Eeles M. F. 96 Effenberger F. 271,338 Efstratiadis A. 462 463 Egan W. 29 Ege G. 124,235 Eggerer H. 473 Ehlers J. 47 Ehret A. 120 Ehrhardt M. 395 Eichele G. 472 Eichenauer H. 424 Eickwort G. C. 409 Eiki T. 55 Einhorn J. 407 Eisch J. J. 276,300 Eisenstein S. 473 Eisner T. 379,412 El Abed M. 70,144 Elgavish G. A. 19 Elguero J. 232 Eliel E. L. 148 221 273 Ellames G. 372 Elliott M. 364 Elliott R. H. 415 Elliott W.J. 428 Ellis D. 87 Ellis P. D. 29 Ellison J. 6 219 Elmes P. S. 261 El Mouhtadi M. 49 Elsenbaumer R. L. 147 El-Sheikh M. 282 Embi N. 476 Emery S. E. 289 Emsley J. W. 303 Encinas M. V. 120 Enders D. 424 Endres W. 316 Engbert T. 61 Engberts J. B. F. N. 55 Engel P. S. 217 Engelke G. 299 Engen D. V. 441 England T. E. 468 Englert G. 380 English A. D. 259 Engman L. 200 Engstrom S. 36 Enkaku M. 123,245 Enke C. G. 12 Enngist P. 381 Ennifar S. 452 Entwistle D. 453 Epiotis N. D. 37 118 Epstein W. W. 363 376 Epsztajn J. 212 Erasmuson A. 372 Erden I. 121 226 Erdman T. R. 441 Erickson G. W. 158,364 Ernest I. 227 228 Emst R. R. 28 30 Esaki N. 478 Eschenmoser A.348 35 1 EscudiC J. 89 Eshaghpour H. 470 Essiz M. 86 Etaix E. 461 Etheredge S. J. 367 Eugster C. H. 216,371 380 Eustache J. 328 Evans C. A. Jr. 9 Evans D. A. 295 297 330 346,355,363,404,412,414 432 Evans D. H. 171 Evans F. J. 7 372 Evans J. R. 156 Evans P. R. 472 Evans S. L. 413 Everett J. R. 26 Evitt E. R. 256 Evtikhov Z. L. 307 Eweiss N. F. 158,212 335 Ewig C. S. 35 174 Ewing G. D. 206 Faber A. C. 203 Fabricius D. M. 52 183 Fabry L. 282 Fadel A. 163 Fairhurst S. A. 79 96 Fairwell T. 483 Fakley M. E. 265 Falck J. R. 147 Fales H. M. 408 409 410 413,432 Falvello L. 17 464 Fanso-Free S. N. Y. 22 Fantina M. E. 92 Fargerlund J.408 Farmer P. B. 471 Farnsworth N. R. 383 Farrall M. J. 335 Faruk A. E. 381 Fasman G. D. 472 Faulkner D. J. 372,441,442 Faust Y. 377 Fauth D. J. 266 Fava A, 50 Favre E. 297 Fayos J. 437 Fedorynski M. 89 Author Index Feeney J. 21,482 Fehr C. 329 Feibush B. 152 Feigenbaum A. 118 Feldman K. S. 187 188 Feldmann R. J. 19 Feller D. 39 Fellmann J. D. 255 Fenical W. 373,378,433,434 436,438,439,444 Fenselau C. 7 9 Fenzl W. 297 Ferguson M. G. 284 Fernell J. W. 290 Feron A. 222 Ferrario F. 201 Ferreira T. W. 325 Ferrell J. E. 223 Ferretti J. A. 20 Ferridge A. G. 27 FCtizon; M. 424 Fetter C. L. 178 Fiato R. A. 288 Ficini J. 268 Fiddes J. C. 462 Fiecchi A.378 Field D. J. 51 Field F. H. 6 7 8 Fields S. 463 Fienemann H. 47 Fiefs W. 462 Fiksdahl A. 434 Filippo J. S. Jr. 161 Fillion H. 145 Finar J. 373 Finch M. A. W. 330 Finch N. 206 Findlay J. B. 43 Finer J. 168,438,441 Finer J. S. 444 Finiels A. 55 71 Fink G. R.,483 Finkelmeier H. 175 Finney R. W. 11 Fischer A. 189 Fischer B. E. 461 Fischer C.-H. 79 Fischer E. 116 Fischer H. 77 120 Fischer H. D. 366 Fischer M. H. 366 Fischman A. J. 19 Fish R. H. 415 Fisher J. 479 Fisher J. D. 76 Fisher R. P. 294 Fisk T. E. 93 Fissekis J. D. 219 Fitoussi F. 462 Fitt J. J. 273 354 Fitzsimmons B. J. 428 Flammang R. 6,219 Fleischhauer I. 91 Fleischhauer J.48 Author Index Flemal J. 225 Freidfelder M. 251 Fleming. I.. 48 129 228 271.. Freitaa W.. 171 .. 326,352; 353,356 Frejd,-T. 236 Fletcher A. S. 238,299 Frenking G. 33 Fletcher T. L. 190 Frerot B. 407 Flippin L. A. 67 Frey H. M. 48 Flockerzi D. 155 Frey M. H. 29 Flood E. 42 Frey P.A. 459 Floor J. 377 Frick W. 9 Floriani C. 260 Fridey S. M. 461 Floss H. G. 472,473,475 Fridh C. 33 Fluck E. 318 Fried J. 428 Fludzinski P. 328 Friedman H. S. 243,285 Foa M. 266,267 Friedman R. A. 21 Forner W. 38 Friedman T. 47 1 Fogarasi G. 36 Friedmann T. 462 Foglia T. A. 152 Friedrichsen W. 167,242 Fonken G. J. 180 Friesen M. D. 7 Fontecilla-Camps J. C. 482 Frimer A. A. 45 Font Freide J. H. M. 310 Fringuelli R.153 344 Fookes. C. J. R. 320 Frisque-Hesbian A.-M. 347 Foote C. S. 121 Fristad W. E. 123 166 333 Forbus T. R. Jr. 62 356,365 Ford G. C. 7,472 Fritsch N. 360,439 Ford G. P. 31 35,41 223 Fritschel S. J. 261 Ford W. T. 67,275 Fritz H. 185 246 Fornarini S. 195 Fritz H.-J. 465 Foroughi K. 309 Fritz H. P. 108 Forrester A. R. 82 Fritz R. H. 465 Forsen S. 21 Froborg J. 290 Fortunak J. M. 263 Fruchey 0.S. 62 Fortunato J. M. 287 Fryzuk M. D. 150 Foster R. L. 472 Fu P. P. 204,205 Foster R. W. G. 377 Fuchikami T. 226,282 Fothergill J. E. 463 Fuchita T. 130 335 Foucaud A. 223,225 Fueno T. 41 Foulkes J. A. 159 Fujihira M. 109 Fountaine J. E. 317 Fujii H. 55 Fourrey J.-L. 454 Fujimori T. 15 381 Fox D. L. 435 Fujimura M.208 Fox J. J. 241,453,454 Fujita E. 354 371 Fox M. A. 45 54,117 Fujita K. 414 Fraenkel A. M. 275 Fujita R. 242 Fraenkel G. 275 Fujita T. 371 Franceschi G. 227 Fujita Y.,262 Francke W. 409,410,427 Fujiwara H. 363 Franck-Neumann M. 93,420 Fujiwara S. 90 135 Franckowiak G. 395 Fujiwara Y.,141 Francois J.-P. 152 Fujiyama K. 464 Francotte E. 328 Fukami H. 405,421 Frank A. 299 Fukuda E. K. 72 Frank J. 6 167,219 Fukui K. 282 Frankie G. W. 410 Fukui T. 468 Franklin R. T.. 415 Fukumoto K. 376 380 397 Franz J. E. 237 Fukumoto R. 464 Fraser R. R. 158,274 Fukunaga T. 43 Fraser-Reid B. 428 Fukushima D. 55 Frater G. 424 Fukushima T. 217 Frazee W. J. 148 Fukuzawa A. 436 Frechet J. M. J. 335 Fukuumi S. 284 Freeman H.P. 416 Fulcher J. G. 178 Freeman J. P. 220 Fumaki H. 408 Freeman R. 20,26,27,28 Funabiki T. 84 337 Freer S. T. 481 Funaki K.,153 Funfschilling P. C. 378 Fung C. H. 19 Funk R. L. 380 Furst G. T. 22 Furubayashi T. 294 Furukawa Y. 116 Furusaki A. 15 Furuta R. 452 Furuta T. 85 Fustero S. 239 Fyfe C. A. 29,30,63,194 Fyles T. M. 320,424 Gabe E. J. 376 Gacs-Baitz. E. 370 Gadian D. G.. 23 Gaertner F. H. 483 Gait M. J. 467,469 Gajewski J. J. 46 52 179 180,182 Galankiewicz K. 448 Galeeva R. I. 419 424 Galenkamp H. 203 Galibent F. 462 Gall J. H. 181 Gallagher M. 310 320 Gallagher P. T. 48 87 248 Gallagher T. C. 235 Galle J. E. 276 300 Gallenkamp B. 53 185 246 Galli C.197 Gallina C. 326 Gallois M. 405,407 Games D. E. 7 Gammill R. B. 360 Gandillon G. 94 Gandolfi R. 49,248 Gandour R. W. 175 Ganem B. 287,301,335 Ganjian I. 416 Gannett T. P. 53 113 Ganter C. 71 Gapinski R. E. 301 354 Gara W. B. 79 Garbe J. E. 288 Garcia B. J. 416 Gardini G. P. 21 74 Gardlik J. M. 171 172 Gareev R. D. 307 Garegg P. J. 213 Garratt P. J. 207 Garrigues B. 307 Garrity M. P. 407 Garrone E. 256 Garst M. E. 374 Gamey D. S. 297,331 Gase R. A. 211 Gaskell. S. J. 11 Gasparrini F. 343 Gassen H.-G. 468,469 Gassman P. G. 94 103 168 Gates B. C. 264 Gaudemar A. 84 Gaudemar M. 297 Gaudioso L. A. 363 Gavrilova G. V. 284 Gawinowicz M.A. 381 Gebhardt C. 484 Gebreyesus T. 443 Geckle M. J. 275 Gee V. 96 Geeraerts J. 416 Geiss R. H. 109 Geissman T. A. 388 389 Geittner J. 48 Gelbard G. 161 Gemal A. L. 150,252 333 Gemenden C. W. 206 Gence G. 310 Geneste P. 55 71 Genestier G. 407 Genet J. P. 268 Gennari C. 148 Geoffrey M. 321 Georgarakis E. 234 George M. V. 248 Gerdes H. M. 355 Gerdes J. M. 346 Gerlach H. 429 Germain G. 168 169 225 233,441,442,443 Germino F. J. 407 Gervay J. E. 395 Gerwick W. H. 439 Gewald K. 235 Ghiotti G. 256 Ghisla S. 477,478 Ghosez L. 347 Ghosh A. C. 11 Ghosh P. K. 462 Ghosh S. S. 292 Giacomelli G. 144 264 280 Giamalva D. 92 Giannetto P. 190 Gibbons W.A. 20 Gibbs D. E. 461 Gibson B. 194 Gibson J. A. 304 Gibson K. H. 391 Gielen M. 283 Gieren A. 215 Giese B. 279 315 Gieselmann M. J. 408 Giessmann U. 9 Giffney J. C. 188 Gil-Av. E. 152 Gilb W. 246 Gilbert B. C. 79 80 Gilbert J. C. 92 Gilbert K. 124 235 Gilbert W. 462,463 471 Gilchrist,T. L. 87,88,239,336 Giles J. R. M. 79 80 Gill H. S. 203 Gill M. 82 Gill W. D. 109 Gillam I. C. 470 Gillam S. 464,468 Gillen M. F. 453 Gillespie R. J. 98 229 Gilpin A. B. 279 Gilyarov,V. A. 306 Gimzewski J. K. 218,284 Ginsburg D. 48 Ginsburg H. 228 Gioia B. 231 Giovannini E. 234 Girard J. E. 407 Girard Y. 236 Gisby G. P. 243 Gittos M. W. 152 Givens R. S.53 119 206 Givol D. 463 Gladysz J. A. 178 260 288 Glaser E. 308 Glass R. S. 104 Gleason J. G. 228 Gleiter R. 123 173,176,275 333 Glickson J. D. 24 Glidewell C. 283 Glor M. 472 Glotter E. 377 Glusker J. P. 205 Goad L. J. 433,434 Gocan A. 416 Godar D. E. 237 Godbee J. F. 407 Goddard J. D. 32 39,40 Goddard W. A. 36 Godleski S. A. 138 328 Godson G. N. 462 Godtfredsen W. O. 374 Goeddel D. V. 463,464 Goel A. B. 132,277 Goering H. L. 292 Gorner H. 53,116 Goetz H. 33 Goetz M. 412 Gogte V. N. 248 Gokel G. W. 265,355,416 Gold V. 193 Gol’dfarb Ya. L. 248 Goldhill J. 353 Golding J. G. 188 Goldsack R. J. 7 Goldschmidt,Z. 113 Goldsmith D. J. 431 Golob N. F.425 Gombatz K. 360 368 Gomez M. 98 Gomi M. 240 Gompper R. 229,230,241 Gonbeau D. 307 Goncalves A. M. R..425 Gonzales A. G. 437 Gooch E. E. 290 Goodman H. M. 462,463 Goodwin D. 122 Goodwin T. W. 380,434 Gopalakrishnan B. 365 Gopalan B. 344 372 Author Index Gopichand Y. 442 Gordon A. S. 180 Gordon P. F. 88 Gore J. 423,424 Gore P. H. 191 Gorenstein D. G. 43 222 Gorvin J. H. 195 Gorzynski-Smith J. 372 Gosney I. 88 Gossauer A. 8 Gosteli J. 227 346 Goto R. 202 Goto T. 367,449,450 Gotor V. 239 Gould K. J. 293 294 Gowland F. W. 345 Grabowski,J. J. 67 Grade H. 9 Graebe J. E. 372 Gratzel M. 247 Graf H. 47 Graf W. 350 Graham R. A. 415 Graham R. J. A.24 Graifer D. M. 465 Grand R. J. A. 476 Granot J. 19 Granoth I. 237 Grant H. G. 203 Gras J.-L. 344 360 372 Grathwohl C. 23 Graves D. J. 475 Green M. 97,283 Green M. L. H. 256 Greenberg A. 33 38 272 Greenblatt J. 58 Greene A. E. 135,164 Greene A. R. 467 Greenstein J. P. 387 Greer S. 147 288 289 Gregson R. P. 437 Gribble G. W. 22 289 Griebsch U. 174 Grieco P. A. 155 367 378 Griesbaum K. 70 137,144 Griffin G. W. 95 Griffin J. F. 16 Griffiths L. 24 Grigg R. 164 358 Grigliatti T. A. 470 Griller D. 74,75,79,220,320 Grimme W. 167 Grimminger,W. 375,415 Grimshaw J. 104,124 Gronenborn B. 463 Gronowitz S. 236 Gross B. 288 Gross H. J. 452 Grossel M. C. 171 Grossi L.79 Groth U. 211 Grove T. H. 23 Grubbs R. H. 96 Grue-Sorensen G. 473 Author Index 497 Grutzmacher H.-Fr. 5 Halat M. J. 241 Harlow R. L. 241 Grugel C. 81,83,284 Halazy S. 128 324 Harnisch J. 168 169 Grund H. 212 Gruntz U. 158,212,335 Grzeskowiak K. 467 H H H ale G.. 484 aley M. J. 173 238 299 algren T. A. 32 Harper M. E. 11 Harpp D. N. 347 Harring C. M. 415 Gschwend H. W. 273,354 Hall B. D. 464 Harris C. J. 87,381 Guanti G. 148 Hall C. 30 Harris J. M. 57 Guastini C. 260 Hall C. D. 303 306,308,314 Harris J. W. 282 Guest A. W. 229 Hall C. R. 311 318 Harris R. K. 19 Guest D. W. 379 Hall D. R. 407,416 Harrison A. G.. 5,6 Guidry R. M. 185 Guilbault G. G. 472 H H all E. A. H. 381 all H. K. 47 Harrison C. R. 293,294 Harrison J.F. 39 Guillaumet G. 86 Hall J. H. 32 Harrison R. 193 Guilley H. 463 Guiochon G. 11 Hall L. D. 18 20 22 25 26 27 Harrison R. G. 405 Harrit N. 237 Guittet E. 421 Hall S. S. 140 Harruf L. G. 208 Gummerson R. J. 30 Hall T. N. 55 Hart H.. 114 118 169,208 Gumport R. I.. 468 Gundu Rao C. 291,341 Gunn B. P. 262,345 Gunnarsson G. 21 H H H H allberg A. 236 allenstvet M. 434 alstenberg M. 226 alterman R. L. 292 Hart N. K. 383 Hartford T. W. 300 Hartmann H. 248 Hartwell J. L. 383 Guo W.. 40 92 Hamada Y. 339 Hartwig W. 211 Gupta B. D. 84 Gupta B. G. B. 283,343 Gupta P. 20 H H H amana H. 214,298 amana M. 240 amashima Y. 227 Haruki K. 379 Harusawa S. 339 Harvan D. J. 7 Gupta R. K. 20 Gupta R. N. 389 Gusel’nikov,L. E. 282 Gustafsson K. 200 H H H H ambly G. F. 97 amel P.,236 amflray A.A. 204 ammar W. J. 278 Harvey R. G. 204,205 Hase T. A. 324 Hasegawa T. 114 Haselbach E. 53 Gut R. 348 Hammerich O. 105 Hashiba N. 15 Guthrie R. D.. 66 Hammond P. J. 306,314 Hashihama M. 187 Gutsche C. D. 207 Hammoud A. 420 Hashimoto H 259.369 Gutschow C. 473 Hanack M.. 59 186 Hashimoto. K. 422 Guy M. H. P. 366 Hanafusa M. 262 Hashimoto S. 47 268 359 Guzman A. 369 HLanafusa,T. 187,203 Hashimoto Y. 433 Hanaya K. 253 Hashizune T. 452 Handoo K. L. 96 Haskins N. J. 7 Haaks D. 8 Handy N. C. 32 Haslinger E. 18 Haaland A. 275 Hanke M. 208 Hass J. R. 7 8 Haas A. 74 Hanlan A. T. L. 178 Hasselaar M. 142 Habib M. M. 266 Habich D. 271 H H anley R. N. 236 anna G. 210 Hassner A. 144 164 222 248,290,428 Hache K. 381 H ansen B. 237 347 Haszeldine R.N.. 90,243 Hachey D. 365 Hackert M. L. 16 H H ansen G. 9 ansen H.-J. 234 Hata T. 223 346,466 Hatanaka K. 356 Haddadin M. J. 220,231 Hansen J. 220 Hatem J. 91 Haddon R. C. 148,185,221 Hanson J. R. 363 369 370 Hauptmann S. 235 Haddon W. F. 11 Hadjigeorgiu P. 188 Haegeman G. 462 Hafner K. 248 Hagadone M. R. 444 Hagaman E. 401 Hagaman E. W. 452 Hagan J. P. 332 Hagar M. E. 117 H H H H H H H H anson K. R. 479 ao N. 177 appel G. 207 ara S. 295 arada F. 470 arada N. 370 arada S. 371,451 arada T. 214,354 372,377,378 Hauw C.. 115 Hawkes R. 30 Hay R. S. 321 Hayakawa Y. 268 359 450 Hayami J. 60,61 Hayano K. 368,451 Hayashi E. 248 Hayashi J. 110 453 Hagelee L. A. 294 Harayama T. 360 368 Hayashi N. 405 Hagen J. P. 50 Hager L. P. 437 Hagiwara. T. 97,283 Hagler A. T. 13 14 Hagmann W.K. 215 Hahn B. 124 H H H H H H archelroad F. 300 arding L. B. 36 argis J. H. 222 argrave K. D. 222 ari T. 336 arita K. 379 Hayashi S. 366 373 Hayashi. S.-I. 234 Hayashi T. 227,254 Hayashi Y.,370 Hayashiya,K. 4 15 Hayatsu H. 470 Hajos G. 232 Harkema S. 225 244 Haymore B. L. 89 498 Hay Motherwell R. S. 323 Haynes L. R. W. 412 Hayward R. C. 247,378 Hearn L. 16 Heathcliffe G. R,,467 Heathcock C. H. 222 331 332 Heatley F. 218 Hecht H. J. 374 Heck R. F. 202,251 Heckendorf A. H.,401 Hecker E. 372 Hedberg F. L. 111 Hedgecock. H. C. 291 Hedin P. A. 405,416 Hedstrand D. M. 211 Heerma W. 7 Heermann D. 347 Hefetz A. 409,410,415 Hegarty A. F. 43 Hegazi M. F. 474,475 Heggs R. P. 335 Heh J.C. K. 161 Hehemann D. G. 454 Hehre W. J. 31 33 37 42 173,282 Heidenhain F. 284 Heimbach P.. 255 Heimgartner H. 224 Heinzel F.P. 460 Heise K.-P. 8 Heitmann W. R. 253 Heitzmann M. 208 Helfgott D. C. 471 Helgeson R. C. 247 Helliwell J. R. 472 Hellwinkel D. 305 308 310 Helmchen G. 155 Helquist P. 89 131 165,260 420 Hemmersbach P. 175 Hendriks B. M. P. 120 Hendry L. B. 415,416 Hengartner V. 152,228 Hengesbach,J. 299 Henkel V. 74 Henne A. 119 Hennessee G. L. A. 245 375 Hennig L. 235 Henrici-Olive G. 257 Henrick C. A. 408 Henries H. E. 190 Henriksen L. 317 Henriquez R. 209 Henry E. 88 Henry G. 454 Henry-Basch E.. 149 Henton D. R. 102 Hepburn P. 479 Herberich G.E. 299 Herbert R. B. 383 392 394 400 Herin. M.. 374 Hermann,'H. 192,208 Hermann R. 341 Hernandez O. 457 Herold T. 297 Herrmann W. A. 96 Herron N. R. 210 Hershberger J. 337 Hertel M. 209 Herz W. 366,371 Hess B. A. 35 174 Hesse R. M. 376 378 Hester R. E. 73 Heuck K. 279 Heuschmann M. 222 Heyneker. H. L. 463,464 Hiberty P. C. 49 217 Hibi T. 259 H.igashino T. 248 Higgins W. 483 Higgs H. 13 Higgs. M. D. 411,414 Higuchi T. 226,282 Hihara N. 60 Hildebrand J. G. 407 Hill A. S. 407 Hill E. A. 276 Hill H. D. W. 18,27,29 Hillen W. 468,469 Hillier I. H. 218 Hiltbrunner K. 34,90,272 Hindorf G. 410 Hine K. E. 118 Hinney H. R. 49,337 Hinton D.M. 468 Hinze R.-P. 8 Hirai K.,155 Hirai Y.,376 407 Hiraki N. 90 Hirama M. 297,331,360,368 Hirano C. 419 Hirao T. 270 357 Hirata K. 351 Hirata T. 456 Hirata Y. 7 445 Hiroi. M. 373 Hirose T. 464 Hirota K.,241,453 Hirotsu K.,371 Hirsch A. F. 369 Hirst J. 195 Hirtosu K. 373,441 Hishinuma H. 468 Hitchcock P. B. 14 370,372 Hiyama,T. 280,357 Hlasta D. J. 226 Hlavaty. J. 101 Ho H. T. 459 Ho T. L. 251 Ho Y.K. 389 Hoard J. A. 52 Hobbs S. J. 301 Hoberg H. 174 Hochmann J. 20 Hodgkin D. C. 17 Hodosan F. 416 Author Index Hohener A. 30 Horhammer R. 473 Hoff W. D. 30 Hoffmann H. M. R. 47,183 Hoffmann R. W. 50,297,332 429 Hofheinz W. 378,434 Hofmann A.A. 216 Hofmeister P. 243 281 Hofschneider P. H. 463 Hohn B. 463 Hohurst H. J. 311 Holden K. G. 228 Holick W. 227 Holl P. 308 Holland G. N. 30 Holand J. F. 10 Holldobler B. 410 Hollenbeak K. H. 443 Holliday A. K. 299 Hollitzer 0..159 Holm A. 233,237 Holmberg K.,347 Holmes J. L. 5 Holmes R. R. 304,305 Holmsen H. 23 Holubka J. W. 136 147 Holy N. L. 253 Home D. E. 74 Hommes H. 4 Hongo H. 242 Honig. B. 381 Hood D. M. 40 Hood K. 482 Hood R. A. 211 Hooper S.N. 374 Hooz J. 294 Hope D. A. O. 171 Hopf H. 206,207 Hopfinger. A. J. 33 Hopkinson A. C. 39 Hopkinson M. J. 125 Hoppin C. R. 96 HorBk D. V. 51 Hordvik A. 220 Horiai H. 442 Horicke M.419 Horikawa H. 101 Hornby J. C. 190 Hornby J. L. 288 Homer L. 311 316,317 Homing E. C. 9 11 Homing M. G. 9 Horvath K. 212,323,335 Hosai K.,8 Hosaka. K. 442 Hoshi M. 292 Hoshimo M. 217 Hosomi A. 164,352,364,421 Houghton P. G. 231 Houghton R. P. 251 Houk K.N. 40,43,53,85,92 175 Houle F. A. 64 Author Index Houlla D. 307 Hoult D. I. 30 Hounshell W. D. 170 Houriet. R. 65 House D. W. 146 Houser D. J. 234 Huvey M. C. 113 Howard B. M. 436,447 Howard R. 405 Howarth T. T. 479 Howe I. 3 Howe J. A. G. 407 Howse P. E. 410,411 Hozaki H. 359 Hozumi 463,466 Hrabe J. 349 Hrdy I. 412 Hromnak G. 428 Hsiung H. M. 464 Hsu C. L. 407 Hsu Y.F. 306 Huang G.-F.453 Huang Shu 201 Hubbard J. L. 287 290 Huber H. 215 Huber R. 472 Hubert A. J. 222 Hudlicky,T. 96 Hudson C. E. 4 Hudson H. R. 62 Hudson P. J. 472 Hudson R. F. 317,319 Hunig S. 248 Huesmann P. L. 214 Huettemann R. 369 Huttenhain S. 353 Hufnal J. M. 355 Hughes A. N. 248 Hughes C. A. 388 Hughes D. W. 26 Hughes L. 293 Hughes R. J. 295,296 Hughes R. P. 178 Hui K.-Y.. 265 Hui R. A. H. F. 349 376 Huisgen R. 46 47 48 183 215,216 Hull S. E. 17 Hull W. E. 18,22 Hulshof L. A. 248 Hummelin T. 13 Hummelink-Peters B. G. 13 Humphry-Baker R. 247 Humski K. 55 Hung F. A. 118 Hunkler D. 53 Hunt D. F. 7 10 Hunt W. 479 Hunter D. H. 316 Hupe D.J. 479 Hurst K. M. 346 355 Hussain S. M. 230 Husson H.-P. 400,401,402 Hutchings,C. W. 214 Hutchings M. G. 293 Hutchings M. G. 272 293 Hutchins R. F. N. 415 Hutchins R. 0.. 222 319 Hutchins R. R. 354 Hutchinson,C. A. 111,462,464 Hutchinson C. R. 363 401 415 Hutley B. G. 311 313 Huttner G. 226,299 Hutton J. 159,333 Hutzinger 0..200 Huybrechts L. 225 Huyton P. 407 Hvistendahl G. 4 Hwang K.-J. 347 Hyono T. 370 Ichihara A. 153 Ichikawa H. 5,6 Idacavage M. J. 298,353 Iddon B. 87,248 Ide Y.,227 Iengo A. 444 Igarishi K. 257 Iguchi K. 442 Iguchi M. 369 Iida H. 86 Iio M. 367 Iitaka Y.,366 376 Ikawa T. 352 Ikegami S. 330,446 Ikehara M. 460 464 465 467,468 Ikekawa N.379 Ikemi-Kono Y.,243 Ikeno M. 99,280 Ikizler A. A. 158 Illuminati G. 195 Imai R. 456 Imaida M. 423 Imanaka T. 141 Imazawa M. 456 Imre S. 436 Imuta M. 136 223 Inagaki T. 97 Inanaga J. 351 Inch T. D. 311 318 Ingold K. U. 75 79 82 220 320 Inhoffen H. H. 8 Inokuchi T. 102 Inomata K.,228 297 Inoue A. 463 Inoue I. 454 Inoue K. 351 Inoue M. 342 Inoue S. 439 Inoue T. 297 Inoue Y.,259 Inubushi T. 280 Invergo B. J. 421 Inwood M. R. 410 Ippen J. 138,328 Iqbal M. 90 230 Ireland C. 435 Ireton R. 180 Irving C. S. 23 Irving E. 50 230 Isaacs N. S. 190 Isaacs N. W. 16 391 Isab A. A. 28 Isagawa K. 133 Isemura M. 278 Ishibashi,M.8 Ishido Y. 457 Ishidoya M. 291 Ishiguro M. 368,444 Ishii S. 405,408 Ishii Y. 147 336 Ishikawa H. 133 280 Ishikawa M. 114 226 280 281,282,437 Ishikura H. 451 Ishikura K. 227 Ishimori M. 262 Ishitoku T. 225 Ishitsuka M. 439 Ishizu J. 257 Iskander M. N. 206 Isobe M. 367 Isoe S. 207 Isono K. 451 Israel G. 201 Issidorides,C. H. 231 Itakura K. 463,464,465,467 Itaya K. 105 Iten P. X.,216 Ito R. 8,450 Ito S. 446 Ito Y.,228,270 357 Itoh A. 280 Itoh K. 372 Itoh M. 292 294 296 Itoh N. 289 Ittel S.D. 259 Ivanova E. I. 465 Iversen P. E. 107 Iwakuma T. 289 Iwamura H. 23 Iwanaga M. 8 Iwano Y. 155 Iwasa A. 130 335 Iwasaki F. 220 Iwasaki T.101,454 Iyoda M. 207 Izac R. R.,366,433,437 Izatt R. M. 248 Izawa Y. 97 Izumi M. 102 Jackman L. M. 18 Jackson B. 234 Jackson D. K. 102 Jackson F. B. 383 Jackson K. 193 Jackson R. A. 127 Jackson W. P. 431 Jackson W. R. 261 Jacob P. 290 292 Jacobsen J. P. 220 Jacobsen N. 438 Jacobson R. M. 339,356 Jacobson S. E. 147 Jacobus J. 127,290 Jacquemin H. 375 Jacquesy R. 379 Jaeger C. D. 109 Jager H. 341 Jager V.,212 Jaffe R. L. 32 Jaglan S. S. 55 Jagtap R. S. 248 Jahnke P. ,464,468 Jaisli F. 351 Jakobsen H. J. 28 James D. R. 374 James N. F. 364 James R. 398 Jankowski D. 478 Janousek Z. 73 Jansen E. H. J. M. 25,321 Jansonius J. N. 472 Jansson A.409 Jaouen G. 199,260 Jaques B. 86 Jarema M. C. 21 Jarvest R. L. 459 Jasperse J. L. 313 Jawdosiuk M. 159 Jayalekshmy P. 85 Jean Y.,49,217 Jeener J. 28 Jeffares M. 118 169,208 Jeffrey G. A. 14 36 37 Jehangir M. 191 Jemmis E. D. 34 37,38,272 Jen T. L. 406,409 Jencks W. P. 479 Jenkins P. R. ,348 Jenkins R. 21 1 Jenkins S. E. 472 Jennings J. R. 308 Jensen F. R.,279 Jesson J. P. 259 Jesthi P. K. 300 Jew S.-S. 151,211 Jewett D. M. 423 Jezierski A. 79 Jick B. S. 288 Jigajinni V.B. 291 Jirieny J. 343 Joanny M. 283 Jochem R. 208 Jonsson B. 36 Jonsson. L. 101,200 Johansen R. 275 John D. I. 227,323 Johns S. R. 383,396 Johnson A. W. 378 Johnson C. R.130,147,149 Johnson D. L. 260,288 Johnson G. C. 52.85 Johnson H.D. 300 Johnson K. J. 152 Johnson K. K. 228 Johnson L. K.. 171 Johnson L. P. 7 Johnson M. A. 268,359 Johnson M. D. 84 Johnson M. R. 247 Johnson M. W. 188,470 Johnson,T. H. 168 Johnson W. L. 405 Johnson W. S. 374 Johnston M. 478 Johnstone R. A. W. 373 Jojima T. 242 Jolly P. W. 174 Jonczyk A. 163 Jones A. 301 Jones A. S. 453,455,469 Jones D. W. 51 Jones G. 89 Jones G. H. 457 Jones I. F. 415 Jones J. B. 160 Jones J. R. 218 Jones M. Jr. 35 95 97 283 Jones M. D. 469 Jones M. E. 55 Jones P. 193 Jones P. G. 17,464 Jones P. R. 203 Jones R. A. 465 Jones R. C. F. 392 Jones R. L. 407 Jones S.J. 467 Jones S. R. 311 Jones T. A. 472 Jones T. H. 432 Jones T. M. 432 Jones W. M. 181 Jonkers F. L. 131 340 Jordan F. 23 Jordan M. 316 Joshi B. S. 16,370 Jouin P. 454 Joullii M. M. 248 Jousseaurne B. 275,276 Joussot-Dubien J. 115 Judkins B. D. 87 222 Jug K. 42 Juhlke T. J. 271 Julia M. 325 Julia S. 421 Julliard M. 201 Jullien J. 230 Jung M. J. 477 Jurlina J. L 378 Justus R. 143 Jutsum A. R. 410 Jutz Ch. 208 Author Index Jutzi. P. 283 Jynge K. 220 Kabachnik M. I. 320 322 Kabachnik M. P. 306 Kabalka G. W. 289,290,291 324 Kabe Y.,123 Kabuto C. 15,366 Kadir K. 458 Kagi J. H. R. 21 Kaemmerer H. 207 Kaftory M. 48 Kahn A. H. 413 Kahn G.,409 Kainosho M. 23 Kaiser J. K. 469 Kaisin M. 433,443 Kaissling K. E. 404,407,416 Kaito M. 421 Kajfez F. 162 248 Kaji A. 60 61 Kaji K. 422 Kakauchi N. 468 Kakimoto M. 214,338 Kakisawa H. 214,414,439 Kakiuchi S. 476 Kakui T. 138 327 Kallenbach N. R. 471 Kalrnan J. R. 4 284 Kaloustian M. K. 71 Kalvoda L. 449 Kalyanam N. 203 Kamemura I. 90 163 Kametani T. 359 376 380 397 Kamigata N. 248 Kamijo N. 366 Kamkar N. M. 106 Kamlet M. J. 55 Kamm J. A. 407 Kammula S. L. 97,283 Kanai H. 90 Kanakarajan,K. 204 Kanayasu T. 437 Kanazawa K. K. 109 Kane V.V.,369 Kaneda K. 141 Kaneda M.,366 Kaneko C. 228,240,379 Kaneko H. 15,381,427 Kaneko K. 379 Kanemasa S.236 Kanemura I. 134 Kan-Fan C. 400,401,402 Kanno H. 416 Kano S. 153 Kanojia R. M. 369 Kantardjiew I. 407,419 Kantor E. A. 248 Kao J. 37 Kao P. N. 170 Kapadia G. J. 363 Kaplan F. 96 Author Index Kaplan M. A. C. 378 Kaplan M. L. 221 Kaptein R. 25 Karakanov R. A. 248 Karimpour H. 277 Kariya A. ,404,407 Karle I. L. 17 Karlson P. 483 Karlsson R. 17,440 Karlstom G. 36 Karpf M. 92,164,357 Karpfen A.. 220 Karn J. 463 Karrenbrock F. 107 Karton Y. 57 Kasai H. 470 Kasai P. H. 279 Kasai. T. 456 Kasang G. 404,407 Kashima C. 249 Kashimura S.,356 Kashman Y. 434,440,441 Kasuga R. 15 Katagiri N. 465 Katakuse I. 8 11 Kato H. 242 Kato K. 381,405 Kato M.352,466 Kato. S. 32 Kato T. 15 256 366 Katoh M. 23 Katritzky A. R.. 6 49 158 159,212,219,221,240,241 248,323,335,337 Katsuki T. 35 1 Katsumura A. 254 Katterman L. C. 357 Katz J.-J. 290 Katzhendler J. 55 Kauffmann T. ,249 Kaufmann D. 182 Kaupp G. 207 Kawa. A. 379 Kawabata N. 90 134 135 Kawada M. 101,102 Kawada Y.,23 Kawai T. 55 119 Kawamoto K. 256 Kawasaki K. 407 Kawashima T. 311 Kazanskii B. A. 297 Kazior R. J. 305 Kazlauskas R. 366 392 440 44 1 Keates C. 89 Keay J. G. 240 Kebarle P. 65 Keck G. E. 53,113,344,372 Kees K. 309 Keese R.,169 Keesey J. K. Jr. 483 Keinan E. 152 Keller J. W. 477 Keller W. E. 265 Kellerhals H. P. 186 Kellogg R.M. 169 211 351 Kelly D. R.,330 Kelly J. A. 480 Kelly W. J. 289 Kelm H. 46,183 Kelsey R. G 366 Kelstrup E. 473 Keman E. 338 Kemp D. S.,246 Kemp J. E. G. 87 Kempsell S. P. 26,27,28 Kende A. S. 116,328 Kennard O. 13,48,391,464 Kennard P. 17 Kennedy G. Y. 434 Kenny D. H. 158,335 Kerbey A. L. 476 Kern C. W. 43 Kerr J. B. 109 Kerton N. A. 141 Kerwin J. F. Jr. 156,226 Kessel C. R. 75 Keul H. 137 Kevill D. N. 57 63 Keyser T. 261 Khalil F. Y. 312 Khalimskaya L. M. 465 Khan I. M. 191 Khan M. A. 90,230,249 Khanna J. M. 204 Khanna V. S. 204 Khatra B. S. 476 Khatri N. A. 280 Khodak A. A. 322 Khorana H. G. 464,465 Khouri F. 71 Kibayashi C. 86 Kienzle F.381 Kierzek R. 467 Kijima S.,200 Kikkawa I. 227 342 Kikuchi H. 442 Kikuchi O. 33 Kikuchi Y. 468 Kikukawa T. 416 Killian L. 294 Kim C. U. 228 Kim J. K. 4 Kim M. S.,65 Kimura H. 407 Kimura K. 452 Kimura M. 379 Kimura R. 153 Kimura Y. 266 Kinas R. W. 459 Kinast G. 345 King G. K. 67 King H. F. 32 King P. F. 169 King R.M. 366 King T. J. 373,436,479 Kingsbury C. A. 248 Kingston D. G. I. 6 Kinoshita M. 368 Kinoshita T. 414,439 Kinoto T. 242 Kinugasa T. 15 Kira M. 75 76 Kirby G. W. 398 Kirchen R.P. 63 175 Kirchhoff R. A. 130 Kirin V. N. 272 Kirk C. M. 80 Kirk D. N. 363,378 Kirkpatrick D. 293 Kirkup M. 373,436,438 Kirmse W. 61 Kirschner K.483 Kiselev V. D. 46 Kiselev V. G. 298 Kisiel Z. 173 Kislink R. L. 482 Kissinger P. T. 107 Kissonerghis A.-M. 205 Kistemaker P. G. 9 Kistenmacher T. J. 11 1 Kistii T. 451 Kita T. 463 Kitade Y. 241 Kitagawa A. 298 Kitagawa I. 446 Kitahara T. 360 367 Kitahara Y. 205 Kitai M. 294 Kitao M.. 415 Kitao T. 122 Kjaer A. 473 Klaar M. 374 Klabunde K. J. 271 Kladko I. 89 KlaCbC A. 309,310 Klarner F.-G. 50,51 181 Klebach T. C. 285 Kleier D. A. 32 Kleijn H. 420 Klein A. J. 171 Klein E.. 3 Klein H. A. 301 Klein M. W. 136 147 Klein P. D. 3 Kleiner E. 119 Kleinpeter E. 233 Kleinschroth J. 206 Klessinger M. 175 249 Kliegel W. 299 Klima W. L.420 Klinger R.J. 284 Klingl H. 309 Klinman J. P. 474 Klopman G. 33 Kliinenberg H. 424 Klug J. T. 104 Klumpp G. W. 273 Klun J. A. 405,407,416 Kluth. J. 255 Knabe. J. 199 502 Author Index Knauf W. 407,419 Knight D. W. 228 Knipe A. C 192 Knipe J. O. 475 Knozinger H. 264 Knorre D. G. 465 Knothe L. 53 Knowles J. R.,311 453 459 475,479 Knox J. R.,480 Kobayashi K. 228 Kobayashi M. 207,342 Kobayashi T. 99 220 280 28 1 Kobayashi Y. 379 Koch W. 299 Kochansky J. P. 407 Kochi J. K. 251 284 Kocienski P. J. 128 326 379 Kocovsky P. 377 Kodama H.,133 Kohler F. H. 308 Kohler H. J. 37 38 39 Koll P. 183 Kolle U. 299 Koenig K. H. 202 Konig L. 92 179 Koenig M.307 309,310 Koeniger N. 410 Konnecke A. 233 Kossel H. 464 Koster R. 292 294 297 Koga K. 47,151,211 Koga M. 9 Kogure T. 254 Kohashi Y. 243 Kohl F,. 283 Kohli D. K. 218 Kohmoto S.,122 Kohn K. W. 471 Kohno M. 405 Kok R.A. 311 Kokke W. C. M. C. 378,434 Kokubo T.,160 Kolb M. 151 Kolbah D. 162 248 Koll A. 30 194 Koller J. 43 223 Kollmar H. 42 Kolodner R.,462 Kolpak F. J. 17 Komae H. 405 Komamura T. 353 Komatsu M. 125 Komeshina N. 47 Komoda Y. 437 Komori T. 366 Komornicki A. 32 Konda K. 297 Kondo K. 132,291,418 Kondo S.,452 Kondo T.. 203,450 Kondrat R.W. 10 Konishi M. 254 Konno K. 451 Konno T. 439 Konzelmann F. M.,212 Kool M.273 Koomen G. J 455 Koplick A. J. 62 Kopp R.,59 Korn S.R.,168 Kornblum N. 160 Kornrumpf W. 108 Koroleva 0.N. 467 Kortekaas T. A. 189 Korver G. L. 52 Koschatzky K. H. 407,419 Kosfeld H. 297 Koshino J. 295 Kost A. N. 228 Kostelc J. G. 416 Koster D. F. 113 Kosugi M. 210 Kotake H. 228 Kotsuki H. 439 Kovacic P. 200 Kowerski R. C. 380 Kownnatzki R.,470 Koyama Y. 352 Koyanagi T. 60,61 Koz'min A. S.,272 Kozminskaya T. K. 297 Kozuka S.,119 Krabbenhoft O. 47 Kraemer M. 416 Kralj B. 5 Kramer E. 404 Kramer G. W. 288 289 290 297 Kramer V. 5 Krapp W. 305,308,310 Kraszewski A. 464,467 Kraus G. A. 242 Kraus W. 375,415 Kraut J. 481 Krebs E.-P.324 Krecek J. 412 Kretschmer M. 235 Krief A. 128 130 324 335 355,364,374 Krieger C. 206 Krinsky P. 377 Krishnamurthy S. 147 287 288,289,333 Kristensen L. H. 108 Krogh-Jespersen K. 35 38 Krolikiewin K. 352 Kroshefsky R.D. 311,317 Krouwer J. S.,472 Krowczynski A. 59 Kriiger. C. 238,242,283.299 Krueger F.R. 9 Kriiger H. W. 42 Kruithof K. 420 Kruizinga W. H. 211 351 Kryger R.G. 210 Ksander G. M. 268.359 Ku A. Y. 53 Kubisen S.J. Jr. 304 Kubo I. 371,404,415 Kubo Y. 225 Kubota T. 227 371 Kuck D. 5 Kudo H. 9 117,253 Kuhne R. O. 30 Kuhlmann H. 358 Kui Y.T. Y. 466 Kujath E. 242 Kukla D. 472 Kulikov N. S. 272 Kulkarni G. H. 248 Kulkami. S. U. 289 291 298 341 Kulkowit S.,166 Kurnada M.138 226 254 280,281,282,327 Kumar A. 290 Kumar C. V. 292 Kumar G. 234 Kumar N. 366 Kumazawa M. 415 Kumer Y. 117 Kunai A. 324 Kunert D. 47 Kunimoto K. 15 Kunitake T. 55 Kuo M. 20 Kupchan S.M. 375 Kuramoto N. 122 Kurashima A. 55 Kurita J. 123 244 245 Kuriyama K. 366 Kurobe H. 359 Kurokawa T. 418 Kurosawa E. 436 Kursanov D. N. 261 Kurshakova N. A. 307 Kushi Y. 366 Kusumi T. 214,414,439 Kutzelnigg W. 33,42 Kuwahara Y. 405,408,414 Kuwajima I. 137 341 352 Kuznetsov M. A.. 248 Kuzuya M. 114 Kwak J. F. 109 Kwast A. 163 Kwikari R.,324 Kwok P.Y.,191 Kwong C. 431 Kyba E.P. 317 Kyogoku Y.,446 Kyriakidis N.. 11 Laas H.8 Labbe C. 375 L'abbC G. 225,233 Lacave C. 8 Lacaze P.-C. 110 Lacey M. J. 11 Lacoste J.-M. 117 Author Index Ladner W. 429 Lagow R. J. 271 Lahm G. P. 356 Lai S.-T.F. 9 Laidig W. D. 34 Lalanne P. 29 Lalezari I. 249 Lalima N. J. 295 Lam K.P. 171 LaMar G. N. 24 Lambert J. B. 52 183 Lambert Y. 169 Lamberton J. A. 383 396 Lammertsma K.,189 Lamotte G. 157 323 338 Lamotte J. 16 Lancer G. N. 428 Landini D. 341 Landis M. E. 306 Lane D. M. D. 189 Lang M. 227 Lang S. A. 231 Lang T. J. 37 Langdon S. P. 23 Lange G. L. 368 Lange L. M. 375 Langer I. 107 Langley P. A. 407 Langlois Y. 420 Langry K. C. 24 Lanier G. N. 409 Lanyiova Z.53 Lapham D. J. 217 Lapidot. A. 23 Larcheveque M. 358 Lardicci L. 144,264,280 LaKner J. 476 Larrieu C. 49 Larscheid M. E. 152 228 Larsen D. T. 68 Larsen S. D. 344 372 Larson J. R. 37 Lasch M. 297 Lashford A. G. 391 La Torre F. 200 Laub R.J. 293 Lauer G. 33 Lauher J. W. 412 Laungani D. R. 21,380 Laurenco C. 307,309 Laurent A. 290 Laurie W. A. 365 Lauwers M. 335 Lawaldt D. 54 Lawley P. D. 471 Lawson J. A. 393 Lawton R.G. 153 Lazare C. 424 Leadbetter G. 424 Leardini R. 324 Lebedev A. V. 465 Le Bras G. 483 Lecas A. 228 Lechtken P. 113 Leckonby R. A. 217 Led J. J. 22 Leddy B. P. 158 Lee A. W. M. 361,432 Lee C. 341 Lee C. H. 471 Lee C.M. 240 Lee D. G. 136,143 Lee H. H. 377 Lee H. W. H. 188 Lee J. G. 69 Lee J. S. 282 Lee K.-H. 118 Lee M. G. 7 Lee S. 303 Lee S.-L. 400,401 Lee Y. S. 32 Lees R. G. 465 Leete E. 383 Le Goff M. 228 Legon,A. C. 173 Lehmann J. 471 Lehmann W. D. 8 Lehn J. M. 247 Leibner J. E. 127 Leitloff M. 311 Lemanceau B. 29 Lenkinski R. E. 24 Lennon J. 282 Lenz G. R. 118 Lenz H. 473 Leonard J. 391,401 Leong T. S. 125 Leresche J.-P. 365 Lerman C .L. 306 Leroi G. E. 39 Le ROUX, J.-P. 87 Leroy F. 115 Leroy G. 42,43 Lesiak K. 318,459 Lessinger L. 373 Lester D. J. 340 349 376 Lester R. 407 416 Letcher R. 388 Lettere M. 407 Leung C. W. F. 240 Leung H.-W.5 6 Leung T. 294 Levi B. A. 33 37 173 Levin J. I. 248 Levin R. H. 85 Levine S. D. 369 Levine S. G. 365 Levinson A. R. 406,409 Levinson H. Z. 406,409 Levitt M. H. 20 26 27 28 Levitt T. E. 301 Levitz R.,339 Levsen K.,3 9 Levy A. B.. 228,293,295,296 Levy G. C. 20 Lew G. 290 Lewis E. S. 313 Lewis J. 158 212 Lewis L. 159 Lewis N. G. 391 Lewis T. W. 14 Lewy A. J. 8 Lex J. 167 185 246 Ley S. V. 16 160 349 370 376,431 Leznoff C. C. 417,424 Li E. 374 Li W.-K. 24 Li Y.-H. 5 Liaaen-Jensen S. 433 434 435 Liang G. 64 Liaw S.-J. 161 Libbey L. M. 409 Lichter R. L. 22 Liebezeit G. 242 Liebman J. F. 33,39,272 Liebscher L. 248 Liedtke R. C. 39 Liehr J.G. 451 Lien M. H. 39 Lifson S. 14 Liles D. C. 283 Limburg K.,452 Lin C. 52 Lin C.-C. 314 Lin G. M. L. 57 Lin H.-S. 10 Lin S. 252 Lin Y.-I. 231 Lin Y. M. 407 Lin Y. Y. 7,383 Lindholm E. 33 Lindley P. F. 242 Lindon J. C. 27 Lindoy L. F. 24 Linek E.V. 227 Ling C.-F. 310 Lingley D. J. 48 Link H. 224 Linley J. R. 407 Lion C. 152 Liotta C. 265 Liotta R. 140 289 290 Lipkowitz K.B. 35 174 Lipnick R. L. 219 Lippard S. J. 471 Lippmann E. 233 Lipscomb W. N. 32 Lischka H. 37,38,39 Lisichkin G. V. 251 Lissel M. 90 Lister J. H. 249 Little R. D. 360 Liu L. C. 278 Live D. H. 19 Livinghouse T. 167 Livingston R. 73 Ljungqvist A. 424 Lloyd D. 104 Lloyd H.A. 363 408. 413 Lloyd R. V. 74 Lobo A. M. 223 Locher R. 346 Lockhart T. P. 52 85 Loder R. T. 464 Lodge S. P. 48 Loehr T. M. 424 Loew G. H. 223 Lowe. V. 353 Lofqvist J. 409 Lofthouse R. 455 Lofti M. 47 Logan J. A. 109 Loginova G. M. 307 Lohmann J. J. 93 Lohrmann R. 460,461,467 Loim N. M. 261 Lombardi P. 227 Lomedico P. 462,463 London G. M. 338 London R. E. 482 Longhurst C. 410 411 Longoni G. 264 L6pez-Ortiz J. F. 239 Lorand J. P. 210 Lotter H. 372 Loubinoux B. 257 Louie H. W. 24 Loutfy R. O. 120 Lovell F. M. 376 Lovell M. F. 231 Lowe G. 23,459 Lown J. W. 471 Loza R. 93 Lu,L.D.-L. 152,297,331,343 Lu P.,21 Luber J. 238 Lucchetti J.355 Lucchini V. 249 Luche J.-L. 145 150 252 333,365,377 Luche M.-J. 377 Lucken E. A. C. 321 Luckenbach R. 303,313,316 Lueken H. 299 Liithy J. 473 Lutolf J. 341 Liittke W. 175 Lugade A. G. 248 Luh T.-Y., 179 Luibrand R. T. 441 LukhE J. 224 Lunazzi L. 79 Lund H. 108 Lundeen J. T. 143 Lunsford R. A. 202 Lusby W. R. 407 Lusztyk J. 275 Luther H. 191 Lutomski K. 273 Luton P. R. 57 Luxon B. A. 43 Luzikov Yu. N. 272 Lyerla J. R. 29 63 Lynch G. J. 278 Lythgoe B. 142 379 Maas G. 52. 178 Maas G. E. 248 Maass G. 470 Maat J. 463 Maatta E. A. 89 McAdoo D. J. 4 McAllister D. R. 258 McCapra F. 395 McCarthy F. C. 368 McCay I. W., 113 McCloskey J.A. 448 451 452,453 McClusky G. A. 10 Maccoll A, 4 McCorrnick J. P. 365 McCready R. 335 McCullagh L. 5 1 McCullough J. J. 120 McCurry P. 360 McDermott A. 187 Macdonald C. G. 11 McDonald E. 396 MacDonald J. A. 413 Macdonald J. E. 347 MacDonald L. M. 41.3 McDonough L. M. 407 McDougal P. 335 McDowell D. C. 294 McDowell P. G. 412 McElvain S. S. 358 368 McEvoy T. 232 McEwan W. E. 317 MacFarlane R. D. 9 McFarlane W. 29 McGahan T. J. 152 McGarvey B. R. 24 McGee J. 264 McGhee J. D. 469 McGlinchey M. J. 177 McGregor D. N. 228 McGuinness S. J. 192 McGuirk P. R. 131 420 McHale D. 365 Machiguchi T. 174 Machin J. 232 McHugh C. R. 378 McIlwaine W.R. 79 McIntyre D. E. 441 McIntyre P. D. 190 McIver R. T. Jr. 72 Mack A. G. 203 MacKay M. F. 16 McKay R. A. 29 McKean D. R. 283,352 McKee M. L. 31 McKee R. 384 385 McKeever B. 303 310 Mackenzie G. 455,457 458 MacKenzie W. M. 209 McKervey M. A. 166 McKibben G. H. 405 Author Index McKillop A. 162 323 McKinley W. H. 89 McLafferty F. W. 5 11 39 31 1 McLain S. J. 256 McLaughlin L. W. 471 MacLean D. B. 389 McLennan D. J. 41 McLeod D. 279 MacLeod J. K. 4,39 McLick J. 161 McLoughlin R. G. 5 65 McManus S. P. 33 McMichael K. D. 52 MacMillan J. 372 McMonagle D. 220 McMorris T. C. 378 McMurry J. E. 268 359 McNab H. 95 McNeil M. 6 MacNicol D. D. 181 McPartlin M.205 McPhail A. T. 222 McPhail N. 209 MacPhee J. A. 152 McQuade K. J. 264 McQueen R. G. 379 McReynolds L. 463 McVeigh L. J. 407 McVey J. 11 3 Maddocks P. J. 293 Madsen J. Id. 438,473 Maeda K. 452 Maeda Y. 82 Markl G. 243 281 316 Magid R. M. 62 Magnus P. 342 356,427 Magnusson G. 290,423 Mahaffey R. L. 181 Mahendran M. 439 Maiden R. P. 437 Maier W. K. 353 Maillard B. 79 Main P. 17 Maini S. 405,416 Maiolo F. 192 Majetich G. 367 Majewski P. J. 312 Majurndar D. 300 Makasza M. 159 Maki Y. 85 Malavaud C. 238 Malek F. 127 Malhotra R. 283 Mallet M. 86 Mallinson P. R. 293 Malorni A, 434 Malrieu J. P. 43 125 223 Malysheva M. A. 322 Marndapur V.R. 150 Marnrnarella R. E. 274 Mancinelli P. A. 223 Mandai T. 269,421 Mandal. A. K. 289.364 Author Index Mandart E. 462 Mander L. N. 372 Mangold D. 202 Manrnade A. 11 Mann G. 235 Manriquez J. M. 258 Mantel N. 462 Manwaring R. 379 Manzer L. E. 259 Maquestiau A. 6 219 Maracek J. F. 303 307 310 Marcacci F. 144 Marchelli R. 346 Marcotte P. 478 Marcuzzi F. 70 Mares F. 147 239 Marfat A. 131 165,420 Mariano P. S. 214 Marinari A. 116 Marinelli E. R. 228 295 Marinelli G. P. 267 Marino J. P. 357 399 Marinovic N. 367 Markey S. P. 8 Markgraf J. H. 218 Markham A. F. 464,465,467 Markiewicz W. T. 457,467 Markovetz A. J. 415 Marks R. J. 416 Marner F.-J.435 Maron A. 3 19 Marples B. A. 363 377 Marquet B. 290 Marriott P. R. 74 79 80 Marschner F. 33 Marsel J. 5 Marshall A. G. 29 Marshall J. H. 221 Marsi K. L. 313 Martens D. 51 54 275 Martial J. A. 463 Martin D. 248 Martin G. E. 18 Martin J. C. 62 237 Martin J. D. 437 Martin S. F. 162 341 Martin V. S. 437 Martinek H. 70 Martinez M. 407 Martinez-Ripoll M. 437 Martre A. M. 108 Maruoka K. 268 359 Maruyarna K. 202 225 291 295,296,300 Marvell E. N. 52 Marwood J. F. 437 Maryanoff B. E. 222 Maryanoff C. A. 319 Marzilli L. M. 470 Masaki Y. 422 Masamune S. 152 174 297 330,331,343 Mascaro K. 473 Mascaro L. Jr. 473 Maschwitz U. 413 Masilarnani D.3 19 Mason R. W. 337,368 Massardo P. 141 327 420 Massey I. J. 378 434 Massey V. 477,478 Matsumoto T. 451 Masuda I. 371 Masuda K. 236 Masuda S. 423,427 Masuda Y. 291,292 Masui M. 103 320 Mateescu G. D. 23 Mateos J. L. 369 Mathias L. J. 162 347 Matson J. A. 18 372 Matsubara F. 342 Matsuda A. 479 Matsuda H. 8 11 Matsuda I. 147 336 Matsuda M. 67 Matsue T. 109 Matsugo S. 226 Matsui K. 51 Matsui M. 421,423,424,426 Matsurnoto H. 138,327 380 Matsurnoto K. 7 101,243 Matsurnoto T. 15 119 342 368,369,370,371 Matsumura F. 405 416 423 Matsurnura H. 227 Matsurnura Y. 107 110 128 356 Matsunaga I. 379 Matsuo A. 366 373 Matsuo T. 8 11 364,422 Matsuura T. 226 Matten D.S. 354 Mattes K. C. 416 Matteson D. S. 300 Matthews D. A. 481 Mattingly P. G. 156 226 Matwiyoff N. A. 482 Maurer W. 199 Mauze B. 274 Mavrides C. 472 Maxarn A. M. 462,463 Maxwell R. E. 195 May G. L. 284 May J. T. 284 Mayer H. 38 381 Mazerolles P. 283 Mazur S. 85 Mazur Y. 21 Mecke D. 484 Medved M. 5 Megarity E. D. 116 Mehlkoff A. F. 28 Meier B. H. 28 Meier H. 166 Meijer E. W. 196 Meinwald J. 379 404 411 412,429,432 Mela L. 478 Melloni G. 70 Mellor J. M. 107 Mellor M. 360 Mellor M. T. J. 311 Menchen S. M. 301 Mendoza A. 300,354 Menger F. M. 341 Menicagli R. 264 280 Menon B. 66 Menzer R. E. 407 Meot-Ner M. 218 Mercer F. 47 Mercier J.-C.169 Mertnyi R. 73 Merkley J. H. 276 Merrill R. E. 296 Mertens M. L. 21 Merz A. 108 Meshularn H. 375 Mesnard D. 142 Messing J. 463 Messrner A. 232 Messrner W. 383 Mtszaros Z. 6,219 Metcalf B. W. 477 Meth-Cohn O. 87 239 248 Metzger J. 183,201,210 Meuzelaar H. L. C. 9 Mevarech M. 464 Meyer C. J. 82 Meyer G. T. 198 Meyer M. W. 341 Meyer R. 255 Meyer R. B. 460 Meyers A. I. 158 273 364 Mezheritskii V. V. 248 Michaelakis S. 407 Michalski J. 308 312 Micha-Screttas M. 137 273 Michel U. 186 Michelotti E. L. 325 Michida T. 103 Michl J. 51 99 280 Midden W. R. 470 Middlemiss N. E. 6 Midland M. M. 147,288,289 292 293,294 Miesowicz F. M. 478 Migata T. 283 Miginiac L.142 Migita T. 97 210 Mignani G. 334 Mihel I. 475 Mijarez A. 369 Mijnheer R. 367 Mikarni K. 98 Mikhailov B. M. 297 298 Mikolajczyk M. 308,311,318 Milborrow B. V. 381 Milbrath D. S. 319 Mildvan A. S. 19 Miles D. E. 355 Miles E. W. 483 506 Millard B. J. 3 Miller A. L. 240 Miller J. 192 Miller J. G. 46 Miller J. R. 416 Miller L. K. 109 Miller M. J. 156 226 Miller R. D. 182 283 352 Miller R. J. 25 Miller R. W. 407 Millet G. H. 158 240 Millikin D. M. 476 Millington D. S. 11 Milner J. A. 396 Milner J. R. 379 Milstein D. 284 Mimura T. 418 Minale L. 373 434,438 441 Minami N. 200 Minamikawa J. 201 Minato T. 42 Minder R. E. 381 Ming Shen 215 Minta A.392 Minter D. A. 180 Miozzari G. 463 Misco P. F. 228 Mishenina G. T. 465 Mishibida K. 321 Mishina T. 130 187 203 335 Misiti D. 343 Mislow K. 15 33 170 Mispreuve H. 6 219 Misumi S. 369 Misuraca G. 445 Mita N. 132 Mitchell E. B. 405 Mitchell E. P. 210 Mitchell M. L. 96 Mitchell S. J. 372 Mitchell T. R. B. 164 358 Mitchell W. R. 230 Mitchener J. C. 116 Mitra A. 418 Mitra R. B. 248 Mitsuhashi H. 379 Miura I. 411,415 Miura K. 456 Miura M. 133 280 325 Miura T. 379 Miyake T. 468 Miyamoto F. 373 414 Miyamoto S. 226,282 Miyasaka T. 453 Miyase T. 371 Miyata N. 205 Miyaura N. 139 292 294 296,327 Miyazaki H. 8 122 160 Miyoshi H.280 Miyoshi K. 467 Miyoshi M. 101,454 Miyoshi N. 282 Mizoguchi M. 1 10 Mizuguchi K. 102 Mizumachi N. 426 Mizuta E. 451 Mlotkiewicz J. A. 369 Mnatsakanian V. A. 370 Mochida K. 284 Mochizuba K. 341 Mochizuki A. 270 357 Mochizuki K. 137 Modak H. M. 248 Modena G. 70,249 Moerke W. 79 Moews P. C. 480 Moffatt J. G. 456 457 Moffatt J. R. 57 Mohr S. 242 Moiseev I. I. 200 Molander G. A. 290 Moldowan J. M. 376 Molinari H. 161 Momose T. 220 Mondon A, 395 Money T. 395 Mongelli N. 212 335 Montanari F. 161 267 341 Monterra C. 256 Montgomery D. L. 464 Montgomery F. E. 9 11 Montgomery J. A. 456,482 Moodie R. B. 189 Moody C. J. 88 Moody R. J. 300 Moon M.P. 197 Moore B. P. 410 412 Moore D. R. 378 Moore G. M. 152 Moore H. W. 47 Moore R. E. 363 373 434 435,436,438 Moore W. S. 30 Mootz D. 304 Moran T. A. 379 Morbach W. 317 Moreno D. S. 408 Morera E. 59 377 Morgan B. A. 16 Morgan E. D. 410 Morgan N. J. 191 Morgan R. P. 238 299 Morgans D. J. Jr. 360 Mori K. 147 364 416 421 422,423,424,425,426,427 428 Mori M. 484 Mori S. 297 330 342 Mori Y. 133 134 332 Morioka S. 464 Morisaki M. 379 Morishima I. 280 Moritani I. 289 296 297 Morokuma K. 32,41 Moro-oka Y. 352 Morris G. A. 28 Morris J.. 360 Author Index Morrison J. D. 5 Morrison J. F. 482 Morrocchi S. 123 Mortimer R. 294 Morton D. R. 301 Moseley M.E. 19 Mosher H. S. 147,435 Moskal M. 318 Moss G. P. 380 381 Moss R. A. 40,89,92,93 Mosselman C. 208 Motherwell W. B. 157 263 323,338,340 Motherwell W. D. S. 13 14 39 1 Motiu-DeGrood R. 479 Motto M. G. 381 Mudd A. 413 Mudryk B. 159 Muehle H. 186 Miillen K. 34 90 272 Mueller H. W. 53 Miiller K. 41 Muller K.-H. 185 246 Muller L. 30 Mueller L:G. 153 Miiller N. 3 16 Miiller P. 94 Mueller R. H. 291,431 Muetterties E. L. 251 Mukaiyama T. 149 211 297 347 Mukherjee-Miiller G. 224 Mulholland D. A. 375 Muller G. W. 360 Muller M. C. 194 Muller-Hill B. 463 Mulot P. 358 Mulzer J. 132 326 Mumma R. O. 416 Mungall W. S. 469 Munjal R. C. 40 89,92 93 Munk P.484 Munoz A. 307,310 Munroe E. 405 Munson B. 9 Mura A. J. 301 Muragaki H. 446 Murahashi S.-I. 132,288,289 291,296,338,418 Murai S. 251 256 352 Murakami M. 342 Muraki M. 297 Muraki S. 15 366 Muramatsu T. 253 Murao K. 451 Muraoka K. 439 Murari R. 366 Murata I. 208 243 Murata S. 147 333 336 Muratake H. 228 Murdock T. O. 271 Murofushi N. 372 Murphy P. T. 366 440,441 Author Index Murphy R. 292,293 Murray-Rust J. 98 218 227 229,369 Murray-Rust P. 14 98 218 227,229,369 Musina A. A. 307 Musker W. K. 104 Musser J. H. 268 359 Musso H. 173 Muthard J. L. 176 Muthukrishnan R. 207 Mutuura A. 405 Myers M. M. 276 Myerson J. 428 Myhre P. C. 187 188 Mynderse J.S. 435 436 Myngheer R. 6 Naber S. P. 463 Nadir U. K. 223 Naemura K. 173 Nagai T. 87 Nagakura N. 401 Nagamoto N. 220 Nagao Y. 354 Nagaragan K. 248 Nagarajan M. 94 235 Nagarajan R. 452 Nagase S. 32,41,43 103 Nagashima T. 122 Nagata S. 205 Nagata W. 227 342 Nagayama K. 21,27,28 Nahrn S. 245 Naimann A. 218 Nair M. 234 Naisby T. 88 Naito T. 431 Naka M. 90 134 163 Nakadaira Y. 99 280 281 Nakagawa E. 464 Nakagawa K. I. 280 Nakagawa M. 207 Nakahara S. 173 Nakai S. 320 Nakai T. 98 418 Nakajima H. 476 Nakajima M. 346 Nakamizo N. 456 Nakamoto Y. 203 Nakamura A. 142 Nakamura E. 351 Nakamura M. 463 Nakamura S. 97 Nakane M. 363,415 Nakanishi A, 147 321 445 Nakanishi K.367 381 404 408,415,416,431 Nakanishi S. 266,463 Nakano A. 351 Nakano K. 227 Nakashima S. 203 Nakashima T. 20 28 148 Nakata T. 431 Nakatsu K. 15 Nakatsuka S. 449 Nakayama E. 227 Nakayama J. 217 Nakayama M. 366,373 Nakayarna N. 9 Nakazaki M. 173 207 Nakazaki N. 457 Nakazawa T. 208 Nalepa C. J. 217 Nambudiry M. E. N. 379 Nametkin N. S. 282 Namkung M. J. 190 Naoki H. 373,414 Napier R. J. 82 Napoli J. J. 52 183 Narang C. K. 467 Narang S. A. 464,465,466 Narang S. C. 157 283 338 343 Narbonne C. 379 Nardi G. 446 Narine B. 239 Narisano E. 148 Naruse M. 294 379 Naruto S. 452 Nasirov R. 320 Nasu. I. 453 Natalie K.J. 364 Natsume M. 228 Nawi V. 454 Nay B. 88 Naya Y. 373,414 Nayyir-Mazhir R. 24 Nazer M. Z. 231 Ncube S. 296 Neal W. 405 Negishi E. 290,295,296,298 353 Negishi K. 470 Nelson D. 7 Nelson D. J. 41 Nelson J. V. 297 330 Nelson R. B. 22 Nelson S. F. 75 Nemoto H. 359 380 Nesbitt B. F. 407,416 Nesmeyanova 0.A. 297 Neszmelyi A. 232 Neuenschwander M. 182,186 Neumznn W. P. 81,83,284 Neumeister J. 137 Nevestveit O. 225 Newall C. E. 227 Newhart A. T. 416 Newkirk D. D. 79 Newman M. S. 204 Newman R. H. 19 Newsam J. M. 171 Newton C. R. 467 Newton M. D. 14 35 37 85 Newton M. G. 222,461 Newton R. F. 330 Newton R. J. 247 289 290 Nguyen M. T. 43 Niccoli A.406 416 Nicholas S. A. 279 Nicholls B. 192 Nicholson I. T. 383 Nicklen S. 463 Nicolaisen F. M. 237 Nicolaou K. C. 137,213 350 351,380 Nie P.-L. 158,212 335 Nigh W. G. 143 Nikanorov V. A. 284 Nikawa J.-I. 333 Nill G. 155 Nilsson C.-A. 8 Nimgirawath S. 345 Nio N. 153 Nisbet A. D. 463 Nishi S. 67 Nishida J. 415 Nishida R. 408 Nishida S. 179 Nishida T. 262 363 Nishiguchi I. 353 Nishikawa H. 55 Nishikawa N. 370 Nishikawa S. 464,468 Nishimura S. 448,452,470 Nishino K. 243 Nishino T. 446 Nishitani Y. 227 342 Nishiyama K. 95 Nishizawa M. 268 359 367 370 Nitta K. 366 Niwa H. 147 Niwa M. 369 Noack K. 441 Noakes T. J. 190 Noding S. R. 279 Noell J.O. 35 85 Noggle J. H. 21 Noguchi H. 404,407 Noguchi M. 15,381,405 Noguchi S. 470 Nokami J. 101 102 Nollen D. A. 55 Nomoto T. 460 Nomura K. 236 Nomura Y. 439 Nonaka T. 110 Nonhebel D. C. 73,209 Noriega L. 369 Norin T. 369 409 Norman R. 0.C. 80 Normant J. F. 142 325,422 Norris A. R. 278 Norris K. c.,467 Norstrom A. 8 Norte M. 437 North R. A. 307 Noth H. 298 Noto R. 195 Novellino E. 445 Nowacki E. 388 Nowakowski M. 307 Nowlin J. G. 9 11 Noyes B. E. 464 Noyori R. 177,251,268 333 359,450,453 Nozaki H. 131 139,268,280 283,294,296,357,366,373 Numa S. 463 Nutakul W. 208 Nwe K. T. 320 Nyberg K. 101 Nyburg S. C. 282 Oates C. L. 93 Obayashi M. 131,283,296 Oberhansli W.E. 441 Ochi K. 379 Ochi M. 439 Ochi N. 102 O’Connor J. P. 264 Oda M. 282 Oda T. 423 Odinokov V. N. 419,424 O’Donohoe C. 96 Oertle K. 429 Oeser H. G. 202 Oesterheit G. 378,434 Oztunc A. 436 Offermann W. 190 Oganessian,G. B. 370 Ogata H. 478 Ogawa M. K. 453 Ogden R. C. 453 Ogihara Y. 376 OgiIvie K.K. 453 467 Ogino K. 119 Ogino T. 137 341 Ogunwole,J. 210 Oguri T. 367 Oguro K. 342 O’Hare K. 462 Ohashi M. 9 116 117 Ohfune Y. 367 368,369 Ohgi T. 449,450 Ohige M. 133 Ohki E. 227 Ohloff G. 329 369 Ohmori H. 103,320 Ohno M. 452 Ohnuma T. 366 Ohnuma Y.,142 Ohnumen T. 15 Ohtsuka E. 460 464 465 467,468 Ohtsuka T. 369 Ohya K. 8 Oida S. 227 Oikawa K.378 Oikawa T. 133 Oishi T. 431 Ojima I. 254 Okada K. 227,294,342 Okahara M. 161 Okahata Y. 55 Okamoto M. 46 Okamoto T. 205 Okamoto Y. 55 Okamura H. 325 Okano K. 446 Okano M. 160,280 Okano T. 253 Okawa M. 338 Okawara R. 101 102 Okaware M. 325 Okay G. 244 Okazaki M. 114 Okeda. Y. 415 Okorie D. A. 375 Okuda T. 114 Okukado N. 35 1,420 Okupniak J. 467 Okutsu M. 448 Olah G. A. 64 65 283 343 O’Leary M. H. 475,477 OlivC S.,257 Olivella S. 42 232 Oliver R. M. 483,484 Oliveros E. 43 125,223 Olivier E. J. 366 Olli L. K. 143 Ollis W. D. 236 374 Olofson R. A. 94 Olsen R. J. 206 Olson R. E. 352 Olson S. T. 477 Olsson T. 185 O’Malley B. W. 462 463 Omelanczuk,J. 318 Ornote Y.114 Ona H.,227 Onishi,T. 262 Onopchenko A. 253 Onuska F. I. 6 Onyido I. 195 Opella S. J. 21 29 Opferkuch H. J. 372 Oppenheimer N. I. 455 Oppolzer W. 150 213 328 360,379,380 Oram R. K. 304 Orere D. M. 343 Orgel L. E. 460,461 467 Ortar G. 59 377 Orton W. L. 221 Osa T. 109 Osamura Y. 42 Osawa E. 369 Oshida J.-I. 379 Oshima K. 280 Oskam A. 260 Ostrowski P. 369 Osuji G. O. 470 Otomasu H. 157 Otsuji Y. 133 266 Otsuka S. 253,262 Otsuka T. 99 280 Author Index Ottenhegm H. C. 17 Otter A. 186 Ottersen T. 443 Ottridge A. P. 392 Otvos J. D. 23 Ouchida S.,35 1 Ouellette D. 164 Oughton B. M. 17 Ourisson G. 374 Ovenall D. W. 96 Overman L. E. 214 231 Owens K.,337 Pacansky J.74 Padgett H. C. 152 Padgett R. A. 484 Padias A. B. 47 Padwa A. 53,93,245,248 Paetzold P. 297 Paget W. E. 238,296,299 Pahlmann G. 299 Pahor B. 203 Paik H.-N., 265 Pak M. C. 378 Pakuiski M. 308 Palermo R. E. 365 Palmer J. R.,291 Palmer R. A. 16 Palmer R. F. 7 Palmieri G. 343 Palumbo A. 446 Pan J. 462 Pandit U. K. 211,455 Panetta J. A. 22 Panichanum,S. 345 Pankova M. 69 Pankratov V. A. 248 Pant P. 374 Pantaleo N. S. 222,461 Panunto T. W. 21 1 Panunzio M. 269 Paolucci C. 50 Paolucci G. 200 Papaioannou D. 395 Pape L. K. 470 Papoula M. T. B. 340 Pappo R. 291 Paquette L. A. 53 123 166 169 171,172,176,333,356 365 Paradisi M. P. 377 Parg A. 311 Parham M. E. 338 Park C.31 1 Park H. 169 Pirkbnyi C. 210 Parker C. E. 7 Parker D. W. 288 Parker W. 57 369 Parkinson C. 90 Parlman R. M. 288 Parnaud J. J. 256 Parnes Z. N. 261 Parrick J. 90 230 Author Index Parrish F. W. 22 Parry G. V. 391 Parry K. 410 Parry R. J. 390,396,400,457 Parshall G. W. 96 Parsons C. A. 93 Parsons I. W. 203 Parsons P. G. 400 Parthasarathy R. 461 Paryzek Z. 375 Pascard C. 15 16 375 Paschal J. W. 452 Pasquali M. 260 Pasteels J. M. 412 Pasto D. J. 42 87 173 Patel R. C. 158,212,221,337 Paternostro M. P. 370 Paterson I. 129,326,352,353 Patey C. A. H. 459 Patin H. 334 Paton R. M. 230 Patrick J. A. 23 Patrick P. 481 Patrick T. B. 205 Pattenden G. 114 141 360 Pau J. K. 4 Paul E.G. 201 Paul H. 77 Paul I. C. 14 Paul V. J. 444 Paulmier C. 194 Pavia M. R. 351 Payne J. A. 405 Payne T. L. 407 Pazoles C. J. 23 Peach J. M. 248 Pearce H. L. 351 368 Pearlman B. A. 342 Pearson A. J. 261 Peattie D. A. 463 Pecherle R. G. 91 Pechet M. M. 376,378 Pechine J. M. 230 Pedersen C. T. 220 Pedersen. T. 220 Pedlar A. D. 374 Peele G. L. 8 Peled M. 48 Peliuetti E. 247 Pellacani L. 87 Pellicciari R. 153 344 Pelter A. 287 289 291 293 294,295,296,301,364 Penn R. E. 160 Pennings M. L. M. 225 Penton J. R. 199 Percy J. E. 413 Perez F. 230 Perham R. N. 484 Peries R.,426 Perkins M. J. 171 Perkinson N. A. 231 Perriot P. 142 Perry S. V.. 476 Persico M. 36 Person H.225 Persoons C. J. 367,408 Petasis N. A. 351 Pete J.-P. 118 Peter G. 311 Peters A. J. G. M. 431 Peters J. A. 163 Petersen H. 166 Petersen S. B. 22 Peterson G. B. 469 Peterson M. R.. 37 Petre J. E. 292 Petriehazy I. 318 Petro C. 56 Petrov A. A. 307 Petrovsky P. V. 322 Petrilka M. 345 380,429 Pettei M. J. 371 415,416 Pettit G. R. 375 Pettus J. A. 437 Pezzanite J. O. 242 Pfaendler H. R. 227,346 Pfaff K. 340 Pfeffer P. E. 22 Pfenninger A. 169 Pfister-Guillouzo G. 307 Pfluger R.W. 324 Pfund R. A. 71 Phillips A. W. 480,481 Phillips B. 249 Phillips G. T. 473 Phillips L. R.,364 Phillips S. 464 Phoenix F. H. 121 Piade J. J. 230 Piatak D. M. 378 Picard J. P. 282 Piccardi P. 141 327,420 Pickart C.M. 479 Pickett J. A. 404 Picman A. K.,415 Pictet R.,462 Pidcock A. 265 Piedrahita C. A. 181 Pierantozzi R. 264 Pierce D. 349 Pierini A. B. 197 Piers E. 357 Pietro W. J. 282 Piggott. F. 152 228 Pike A. W. 11 Pillersdorf A. 55 Pinet-Vallier M. 275 Pingoud A. 470 Pinhey J. T. 284 377 Pinkus A. G. 203,227 Pinnick H. W. 217 Pino P. 256 Pinson J. 108 197 Piozzi F. 369 370 Pipal J. R. 317 Pipe D. F. 88 231 Piper E. A. 21 Pirkle W. H. 146 420 424 429 Pirrung M. C.. 332 360 Pitman G. B. 409 Pittman C. U. 264 Pitzer K. S. 32 Pitzer R. M. 40 Pizzorno M. T. 386 Place P. 423,424 Placucci G. 79 Plank J. 96 Plati J. T. 212 Platti R. 391 Platz H. 407,419 Plau B. 212 323 335 Plaumann D.E. 428 PlesniEar B. 43,223 Pletcher D. 341 Plevyak J. E. 202 Plimmer J. R.,405 407 424 Plum H. 48 Plumb S. 483 Plummer B. F. 125 Pocar D. 231 Pohl S. 238 Pohmakotr M. 348 355 Pointner A. 132 326 Polezhaeva N. A. 307 Pollack S. K. 33,284 Pollard H. B. 23 Pollicino S. 50 Polonsky J. 375 Polyrakis J. 407 Pommer H. 3 14 Pons B. S. 107 Ponticello G. S. 228 Poon Y. C. 282 Pople J. A. 31 33 35. 36,37 38 Popova 0.A. 215 Popovici N. 416 Popp F. D. 249 Poppinger D. 32 35 Porter A. E. A. 98 229 Posthumus M. A. 9 Potapov V. K. 467 Potter C. J. 394 Pottinger R. 48 Potts K. T. 236,237 Poulton D. J. 62 Poupat C. 392 Powell D. W. 50 Powell L. A. 106 Power M. J.450 Prager R.H. 292,293 Prakasa Rao A. S. C. 225 Prakash G. K. S. 343 PrangC T. 15 16 Prasad K. 227 Prasad R.S. 443 Prasad V. A. V. 310 Pratt S. B. 391 Pregosin P. S. 268 Prelog V. 150 247 Press L. S. 93 Preston K. F. 74 Prestwich G. D. 404,411,412 Preus M. W. 378 Price E. M. 222 Priesner E. 407 Prince R. H. 21 1 Prinzbach H. 53,185 246 Proehl G. S. 94 Prokep’eva T. M. 186 Prokof’ev A. I. 322 Prokopiou P. A. 324 Prokopy R. J. 414 Prome J. C. 8 9 Pross A. 57 Prota G. 445,446 Pruett R. L. 288 Puddephatt R. J. 256 Pudovik A. N. 307 Pulay P. 31 36 Punzar R. V. 246 Purdum W. R. 312 Pusset J. 228 Putt S. R. 452 Puzo G. 8,9 Pyle J. L. 202 Pyne S. G. 372 Quast H. 222 Qutguiner G.86 Quici S. 161 Quigley G. J. 17 Quijano L. 414 Quillam M. 453 Quin L. D. 221 314 Quinkert G. 119 381 Quinn D. M. 474 Quinn R. J. 437 Raab W. 340 Raaen V. F. 290 Raba M. 452 Rabenstein D. L. 20,28 Rabolt J. F. 109 Racz W. J. 278 Radda G. K. 23 Rademacher P. 249 Radhakrishna A. S. 338 Radics L. 370 Radley P. 89 Radom L.,4,31,36,37,39,41 Radzikowska T. A. 240 Ragault M. 378 Rahimi P. M. 81 Raines D. 377 Rainville D. P. 291 Rajagopalan K. 234 Rajananda V. 20 Raju M. 125 Rakhmankulov D. L. 248 Ramage R. 229 Ramamurthy V. 11 3 Ramana Rao V. V. 290 291 292 Ramasubbu A. 164 358 Ramirez F. 303 305 307 310,312 Ramos J. J. M. 58 Ramsden C. A. 236,241 Ramsey B. G.300 Ramunni G. 42 Randle P. J. 476 Rao C. G. 56 Rapoport H. 152 Rappoport Z. 58 Rastetter W. H. 245 Rastogi R. P. 374 Rastrup-Andersen N. 374 Rathay D. 207 Rathke M. W. 300 Rau A. 163,181 Raucher S. 347 Rauscher S. 407 Rautenstrauch V. 425 Ravanal L. 117 Ravi B. N. 372 Ravid U. 410 429 Ravindran N. 289 Ravindranath K. R. 16 370 Rawdah T. N. 172 Rawson D. I. 183 Rayment I. 299 Razumova N. A. 307 Re A. 161 Read G. 144 Read R. A. 68 Reader G. 236 Reading C. 479 Rebek J. Jr. 85 335 Rechsteiner C. E. Jr. 8 Record K. A. F. 319 Reddy K. V. S. 407 Reddy V. B. 462 Redfield A. G. 21 Redmond J. W. 473 Reed L. J. 484 Rees C. W. 87 88 231 239 248 Rees J. C. 365 Reese C. B. 330 343 457 465,466,467 Reetz M.T. 50 73 353 Reeves P. C. 161 Regen S. L. 161 162 Reger D. L. 266 Regitz M. 52 97 Regnier B. 335 Rehm D. 119 Rehman Z. 70 144 Reich H. J. 67 130 131 352 Reichardt C. 55 Reichman U. 453,454 Reid K. B. M. 476 Reimann E. M. 476 Rein R. 33 Reinecke M. G. 86 Author Index Reinhoudt D. N. 225 244 Reiss J. A. 206 Reisse R. 58 Reissig H.-U. 48 215 216 Reith W. 410,427 Remers W. A. 471 Remion J. 347 Remmer G. 215 Renga J. M. 50 Renold W. 369 Renon M. 407 Renwick J. A. A. 409,415 Rttey J. 473 Reuben J. 23 Reutov 0.A. 284 Reutrakul V. 345 Revelle. L. K.. 160 Rewcastle G. W. 379 Reynolds D. P. 330 Reynolds W. F. 282 Rezende M. C. 158,212,335 Rezvukhin A.I. 465 Rheinwald M. 407,419 Rhouati S. 239 Riccio R. 373,434,438,441 Rice K. C. 393 Rich A. 17 Richard J. P. 459 Richard T. J. 245 Richards K. E. 189 Richardson M. F. 24 Richardson S. G. 454 Riches K. M. 188 Ridd J. H. 188 193 Riddell F. G. 221 369 Rideout J. A. 446 Ried W. 163 Riediker M. 350 Riemann J. M. 51 Riemann U. 215 Riftina F. 469 Riggs A. D. 464 Riggs N. V. 36 Riggs R. M. 338 Righini A. 325 Riley J. P. 218 Rilling H. C. 380 Rinaldi P. L. 424 Rinehart K. L. Jr. 437 Rings R. W. 407 Rios T. 414 Risbood P. A. 149 Ritter F. J. 408 Riviere M. 43 125 223 Rizvi S. M. H. 230 Rizvi S. Q. A. 21 1 Roach P. J. 476 Robert A, 223 Roberts B. P. 78 79 80 81 320,321 Roberts D.A. 213 379 Roberts D. K. 68 Roberts G. C. K. 21,482 Roberts J. D. 22 219,472 Author Index 511 Roberts J. J. 471 Roberts J. S. 369 Roberts P. J. 391 Roberts R. M. G. 47 Roberts S. M. 127,323,330 Roberts T. D. 216 Roberts T. G. 336 Robertson H. D. 470 Robertson M. 463 Robertson M. A. 462 Robertson P. L. 41 1 Robien W. 18 Robins D. J. 249 384 386 Robins R. K. 458 Robinson D. H. 455,458 Robinson D. S. 387 Robinson H. 366 Robinson P. J. 90 Robinson S. W. 410 Roboz J. 3 Rocha V. 483 Rochester C. H. 194 Rodgers J. R. 13 Rodini D. 418 Rodini D. J. 47 135 Rodrigues J. A. R. 239 Rodriguez B. 370 Rodriguez-Hahn L. 365 Rodwell W. R. 36 Roe D. C. 29 Roeller H. 407 Rollgen F.W. 9 10 Roelofs W. L. 405 407 408 415,416 R~nneberg,H. 435 Roepstorff P. 11 Rosel P. 419 Roesky H. W. 215 Roesle A. 169 Roessler K. 198 Rogers D. 16 370 Rogers D. N. 240 Rogers M. T. 74 Rogiers R. 462 Rohmer M. 374,434 Rohrer D. C. 16 Rokach J. 236 Rolfe S. 79 220 Rolison D. 51 Rolla F. 341 Roller P. P. 438 Romeo A. 377 Romeo G. 190 Romsted L. S. 196 Rondan N. G. 40,85,92 Roof A. A. M. 200 Rooney J. J. 96 Roosendaal E. 260 Ropers H. J. 372 Rosanske R. C. 20 Rose A. F. 433 Rose A. W. 120 Rose I. A. 472,479 Rose J. D. 482 Rosenberger M. 335 Rosenthal N. 462 Roskam J. M. 431 Ross M. J. 463 Ross P. 483 Ross R. A. 379,442 Rossi M. 11 1 Rossi R. 314 373 406 416 417,422,424 Rossi R.A. 197 Rotem M. 441 Roth H. D. 116 Roth J. A. 252 Roth W. R. 208 Rothermel W. 238,299 Rothschild G. H. L. 422 Rothstein S. M. 24 Roumestant M. L. 423,424 Rousch P. B. 79 Roush D. M. 47,222,349 Rousseau R. J. 458 Roussi G. 228 Roux D. 43,223 Rowe B. A. 284 Rowe K. 293,301 Rowell R. 222 Rowland R. 90 Rowley A. G. 307 Rowson G. P. 236 Roy G. 342,427 Roy T. A. 7 Royall S. E. 243 Rozeboom M. D. 53 Rozen S. 377 Rozenberg V. I. 284 Ruasse M. F. 69 70 Rubin J. R. 463 Rubio V. 239 Ruchirawat S. 392 Rudashevskaya T. Yu.,297 Rudinsky J. A. 409 Ruchardt C. 73 Ruchardt G. 315 Ruedenberg K. 42 Ruedi P. 371 380 Rueffer M. 401 Ruel O. 421 Ruest L. 169 Rugg P. W.455 Ruggera M. B. 4 Ruhmann W. 264 Ruisinger R. 54 Rupprecht G. A. 255 Rusek J. J. 352 Russell G. A. 159 337 Russell G. B. 415 Russell R. A. 113 Russell S. W. 381 Russo R. 169 Ruston S. 379 Ruthven D. M. 149 Rutledge P. S. 377 378 Rutter W. J. 462 Ryan M. D. 104 161 Ryan R. C. 264 Rycroft D. S. 375 Ryder D. J. 289 364 Ryhage R. 8 Ryker L. C. 409 Rylatt D. B. 476 Ryntz R. A. 136 147 Ryschkewitsch,G. E. 300 Rzepa H. S. 31 35,41,42 Sabanski M. 290 Sabino de Oliveira J. 410 Sabourin E. T. 253 Saccarello M. L. 231 Sadana K. L. 467 Sadar M. H. 472 Sadd J. S. 82 Sadier P. 91 Saegusa T. 228,270,357 Saeki H. 351 Sagitullin R. S. 228 Saito H. 240,451 Saito I. 226 Saito K. 122 Saito M.364,421 Saito Y.,278 Saji T. 108 Sakaguchi K. 468 Sakai N. 296 Sakairi N. 457 Sakakibara M. 428 Sakakibara T. 213,224,257 Sakamoto T. 55 Sakamura S. 15 153 Sakan T. 370 Sakdarat S. 386 Sakuma K. 422 Sakurai A, 364 Sakurai H. 75 76 99 164 280,281,352,421 Salamone S. Jr. 23 Salaun J. 163 Salazar J. 179 180 Salem G. F. 343 Salem L. 40 42 115 Saliot A. 434 Salisbury S. 17 464 Salisova M. 265 Salomon R. G. 118 Saltiel J. 116 117 Saluja P. P. S. 65 Salvadori P. A. 406,416,422 424 Samaan H. J. 375 Samaan S. 316 Samain D. 42 1 Samanen J. H. 399 Samitov Yu.Yu.,238 Sammes M. P. 240 Sammes P. G. 86 243 Sampathkumar P. S. 349 Samuelsson B. 213 Samukov V. V. 465 5 12 Sana M.43 Sancasson F. 24 Sanchez M. 307 Sanders J. K. M. 18,20,22,25 Sandford H. F. 299 Sandhu J. S. 231 Sandra P. 374 Sandri E. 50 Sanger F. 462,463 Sanner R. D. 258 Sano M. 8 Santacrose C. 444 Santi D. V. 479 Santiago C. 53 175 Santilli D. S. 49 217 Sarma R. 303 310 Sasaki K. 352 Sasaki M. 46 353 364 426 427 Sasaki N. 292 Sasaki S. 280 Sasaki T. 366 Sasakura K. 298 Sasse M. J. 235 Sasson I. 349 Satake M. 259 Satgt J. 89 Sato A. 456 Sato F. 133 134 280 332 342 Sato M. 133 134 280 332 342 Sato R. 404,407 Sato S. 227 Sato T. 149 211 427 450 453 Satoh F. 316 Sattar A. 369 Sau A. C. 330 Saucy G. 335 Sauer J. 48 182 223 Sauter H. 53 Saveant J.-M. 105 108 197 Savelli G.196 Savin V. I. 271 Savona G. 369,370 Sawanishi H. 123 245 Sawitzki G. 375,415 Sawyer J. F. 177 Saxena M. P. 137 Sayer B. G. 177 Sayo N. 110 Sayre L. M. 279 Scaiano J. C. 120 Scala A. 378 Scamehorn R. G. 197 Scarborough R. M. 137 Schaad L. J. 35,174 Schaap A. P.. 121,309 Schaefer H. F. 111 32 34 39 40,41,92,93,279 Schafer H. J. 199 341 424 Schaefer J. 29 Schafer L. 37 Schaefer W. 404,407 Schafer H. J. 105 107 Schaffhauser,T. 30 Schaffner K. 53,119 Schakel M. 273 Schaltegger H. 182 Schang P. 173 Schanze K. S. 117 Scharf H.-D. 48 Schaumann E. 47 Schecker R. 74 Schecter A. N. 29 Scheffer J. R. 14,357 Scheidl F. 152 228 Scheinmann F. 145 Scheller R. H. 464 Schenk H.260 Schenkluhn H. 255 Schermer D. 17 Scheur P. J. 379 434 435 441,442,443,444 Scheve B. J. 121 Schiebel H. M. 8 Schiess P. 208 Schifman A. L. 467 Schiller P. W. 470 Schilling F. C. 221 Schilling M. 65 Schilling M. L. M. 116 Schlegel H. B. 32 35 Schleker W. 48 Schleuder K. K. 476 Schleyer P. von R. 31 34 35 36 37 38 56 77 90 169 272 Schloman W. W. 125 Schloss F. 275 Schlosser K. 74 Schlosser M. 220 228 Schlotthauer B. 317 Schluetter K. 74 Schmid G. H. 69 Schmid H. 224,234 Schmid P. 194 Schmid U. 224 Schmidbaur H. 305 308 Schmidpeter A. 308 Schmidt A. H. 163 Schmidt G. 150 340 348 Schmidt H. 75 159 Schmidt H.-J. 199 341 Schmidt J. H. 375 Schmidt U. 319 347 Schmidpeter A.238 Schmieder K. R. 381 Schmitt R. J. 6 67 Schmitt W. 199 Schmitz E. 249 Schmitz,F. J. 442 443 Schmitz R. F. 273 Schmutzler R. 304 Schnaithmann M. 246 Schneider C. S. 229 Schneider D. 404,407 Author Index Schneider D. R. 54,275 Schneider F. W. 124 Schneider H. 70 144 Schneider H.-J. 171 365 Schneider M. 163 Schneider M.P. 181 246 Schneider P. 220 Schnell A. 312 313 Schnorrenberg G. 159 Schoberth W. 59 Schoch J. 315 Schoeller W. W. 92 174 Schollkopf U. 211,271 Schoen A. E. 10 Schonholzer P. 185,224,246 44 1 Schoening R. C. 288 Schofield K. 189 Scholler D. 118 Scholz D. 346 Scholze H. 472 Schoofs A. R. 62,359 Schonbrunn A. 478 Schott H. 464 Schowen R. L. 474,475 Schreiber B.70 Schreir P. 463 Schriewer M. 284 Schrock R. R. 255 256,257 Schroder G. 246 247 Schroder N. 8 Schroer W.-D. 167 Schubert U. 215 Schuda P. F. 360 367 368 Schueler B. 9 Schuhle W. 155 Schulte K. W. 33 Schulte-Frohlinde D. 116 Schulten H.-R. 3 8 Schultz A. G. 215 Schulz D. N. 317 Schulz R. 217,233 Schuster I. I. 219 Schuster P. 70 220 Schutz A. 226 Schwab J. N. 396 Schwab W. 212 Schwartz,J. 134 279 Schwartz L. H. 15 Schwartz R. E. 443 Schwartz R. H. 161 Schwartz S. J. 295 Schwarz H. 4,65 Schwarz M. 407 Schweig A. 33 35 183 217 233 Schweitzer D. 206 Schwendemann V. M. 206 Schwier J. R. 289,290 364 Schwindeman,J. 356 Scoby J. 216 Scolastico,C. 148 Scott A. I. 395,400,401 Scott C.A. 317 Author Index Scott G. 306 Scott J. W. 152 228 Scott K. J. 68 Scouten C. G. 140,289 Screttas C. G. 137,273 Scriven E. F. V. 87,248 Scrocco E. 43 Seabrook W. D. 415 Sealfon S. 47 135 Searle R. J. G. 90 Seaver S. S. 484 Sebastiani G. V. 69 Sedmera P. 373,412 Seebach D. 34 74 90 272 323,338,346,348,355 Seeburg P.H. 463 Seewald A. 159 Sefcik M. D. 29 Seff K. 435,436 Segal G. 42 Segall Y. 237 Segaloff A. 16 Seguin R. P. 323 Seiter W. 70 144 Seitz S. P. 137 350 Seki E. 217 Seki Y. 256 Sekiguchi,A. 97,123,129,283 Sekiguchi S. 194 Sekine M. 346 Sekine T. 110 Seko N. 228 Sellers H. L. 37 Sellers L. K. 473 Selover J. C. 288 Selwitz C. M. 253 Semenova L.N. 465 Senda S. 241 Seno K. 354 Serafinowski,P.,455 Servi S. 201 Servin R. 101 Servoss W. C. 277 Sessions R. B. 246 Seto H. 366 Setzer R. B. 437 Seufert A. 300 Sevenet T. 402 Sevin A. 43 223 Seyferth D. 274 Shabanowitz J. 10 Shabarova Z. A. 467 Shackleton C. H. L. 3 Shaddock V. M. 10 Shafer S. G. 57 Shafiee A. 249 Shafizadeh F. 366 Shah S. K. 130,131,337,368 Shaik S. 118 Shakked Z. 17,464 Sham H. L. 368,444 Shanks C. T. 450 Shannon J. S. 7 Shanzer A. 151 Shapiro R. H. 6 Sharma G. M. 395 Sharma R. A. 457 Sharom F. J. 194 Sharpless K. B. 143 336 365 Sharrocks D. N. 301 Shashkova E. M. 298 Shaw B. L. 265 Shaw C. 369 Shaw C. J. G. 90,230 Shaw G. 455,457,458,459 Shaw R.A. 314 Shchegoleva T. A. 298 Shea K. J. 167 Shearer H. M. M. 299 Shearing D. J. 316 Sheats W. B. 143 Shechter A. N. 470 Shechter H. 93,94 234,235 Shefi M. 113 Sheikh H. 335 Sheinkman A. K. 228 Sheldrick G. M. 17,464 Sheldrick W. S. 305 371 Shelnut J. G. 203 Shepard R. 40 Shepherd M. J. 469 Sheppard J. H. 289 364 Sheppard R. C. 467 Sheridan R. S. 87,416 Sherwin P. F. 178 Sheshegova E. A. 465 Sheth J. P.,96 Sheves M. 21,381 Shevlin P. B. 233 Shiau W.-I. 317 Shiba T. 333 Shibasaki M. 330 Shibata S. 8 Shibata Y.,439 Shibayama F. 442 Shibuya M. 351 Shibuya S. 153 Shieh W.-C. 89 Shiekh H. 158 Shim S. C. 239 Shimazaki M. 452 Shimizu F. 268 359 Shimizu H. 149 21 1 Shimizu M. 137 341 Shimizu N.179 Shimizu Y. 433 Shindo H. 23 Shindom M. 379 Shindo-Okado N. 470 Shine J. 463 Shiner V. J. jun. 55 Shiney C. D. 358 Shingaki T. 87 Shinoda M. 357 Shinoda S. 278 Shioiri T. 339 Shipchandler M. T. 162 337 Shirahama H, 368 369,451 Shirahata A. 164 F52 Shirai E. 8 Shirataki Y. 125 Shiratori. Y. 376 Shirwaikar G. S. 248 Shold D. M. 5 Shono T. 107 110 128 353 356 Shortnacy A. T. 456 Shu P. 111 Shubina T. N. 456 -Shudo K.,205 Shuey C. D. 368 Shuker D. E. G. 198 Shukla Y.N. 363 Shulman R. G. 23 Shum B. W.-K. 467 Sibilli L. 483 Sicherer C. A. X.G. F. 7 Sichtermann W. K. 9 Siddiqui M. S. S. 220 Sidot C. 257 Siebenlist U. 471 Siebert W. 238 299 Siefert W. K. 376 Siegbahn P.E. M.32 Siegel H. 34 90 272 Siew N. P. Y. 119 Sifniades S. 219 Sigal I. S. 308 Sigsby M. L. 5.6 Siler P.,228 Silveira A. 296 298 353 Silverstein R. M. 363 410 417,427,429 Sim G. A. 16,366,370 Simes J. J. H. 375 Simmonds D. J. 382 Simmons C. J. 435,436 Simon P. 288 Simon W. 199 Simoncsits A. 463 Simonet J. 105 108 Simons J. 40 Simonsen S. H. 241 Simpkin D. J. 243 Simpson K.L. 380 Simpson T. J. 373 Sims J. J. 366 433,437 Sinclair J. A. 294 295 Singaram B. 289,290,364 Singer B. 47 1 Singer H. 79 Singer S. P. 50 Singer T. P.,478 Singh A. 290 Singh J. 372 Singh M. 467 Singh. R. K. 360 384 385 Sioumis A. A. 396 Sipic W. J. 350 Siret P. 344 372 Siroi T. 102 Sisani E.153 344 5 14 Sista H. 464 Sitton P. G. 218 284 Siv C. 201 Sivapalen P. 407 Siverns M. 369 Skancke P. N. 42 Sket B. 114 203 Sklarz B. 373 Skowronska A. 308 Skulnick H. 450 Skulnick H. I. 152 344 Skvortsov I. M. 249 Slattery S. A, 383 Sleeper H. L. 444 Sleigh S. K. 401 Sliwa W. 249 Slocombe P. M. 462 Slopianka M. 90 Slotin L. A. 312 Smalley R. K. 234 Smidt J. 28 Smirnov V. V. 307 Smit A. L. C. 8 Smith A. B. 137 Smith A. J. H. 463 Smith D. 194 Smith D. G. 317 Smith D. J. H. 317 Smith D. L. 453 Smith D. M. 232 Smith G. 122 Smith G. C. 377 Smith G. D. 16 Smith G. N. 400 Smith G. W. 376 Smith I. G. 74 75 Smith 1. S. 236 Smith J. 175 Smith J. G. 334 Smith K.238 287 290 291 293,295,296,299,300,301 Smith K. M. 24 Smith L. C. 378 Smith L. L. 7 Smith L. M. 424 Smith L. R. 427,429 Smith M. 462,464,468 Smith M. R. 33 Smith N. B. 446 Smith N. P.,89 Smith R. C. 160 Smith R. G. 424 Smith R. H. 234 Smith S. A. 150 359 Smith S. L. 481 Smith W. B. 363 Smolanoff,J. 429 Smothers W. K. 117 Sneden A. T. 375 Snider,B. B.,47,135,349,418 Snieckus V. 245 Snyder L. C. 34 Soai K. 149 211 Soda K. 478 Sodano G. 444 Soderling T. R. 476 Soderquist J. A. 290 So11 D. 470 S~rensen,U. 439 Sohn J. E. 332 Sokoloski E. A. 413 Sokolov S. D. 249 Solheim B. A. 171 Solodovnikov S. P.,320 322 Solomonovici,A, 55 Soltmann B. 10 Somasundaram S. 439 Somei M.228 Somekh L. 151 Somfai l. 314 Sommer S. 214 215 Songstad J. 317 Sonnet P. E. 407,416,422 Sonoda A. 288,289,296 Sonoda N. 251,256,352 Sood A. K. 464,466 Soper C. J. 372 Sopher D. W. 106 Sordo T. 38 186 Sorensen T. S. 63 175 Sotoyama T. 298 Soucy P. 169 Soulii J. 290 Souto-Bachiller F. A. 174 Spangler C. W. 300 Sparks A. N. 405,407 Speed W. 410 Speight J. G. 90 Spencer I. D. 389 Speranza M. 66 Spielvogel B. F. 300 Spinelli D. 195 Spisz E. P. 475 Springer J. P. 171 319 Sridharan S. 68 Srikirin Y.,345 Srikrishnan T. 461 Srinivasan N. S. 136 143 Srinivasan P. R. 22 Srivastava A. K. 476 Srivastava P. C. 458 Srouji G. 431 Staab H. A. 206 Staal L. H. 260 Stacey B. E. 29 Staden R.462,463 Stadtman E. R. 483 Stahle M. 228 Staemmler V. 42 Stahl D. 7 Stallard M. O. 444 Stang P.J. 93 Stanley J. 463 Stanovnik B. 249 Stapleton B. J. 4 5 Stark C. J. Jr. 149 Stark G. R. 484 Starks C. M. 265 Author Index Starowieyski K. B. 275 Starratt A. N. 407 Staudig B. 284 Staunton J. 156 390 392 Stawinski J. 466,467 Stec W. J. 459 Steck W. F. 407 416 Steenken S. 74 Stefaniak L. 219 Stegel F. 195 Stegelmeier H. 185 246 Stegk A. 381 Steglich W. 159 374 Stejskal E. O. 29 Stella L. 73 Stephenson G. P. 455 Sternbach D. 351 Sternhell S. 284 Sternrup H. 101 Stetter H. 358 Stevens I. D. R. 89 Stevens J. D. 18 Stevens R. V. 167,361,432 Stewart N. J. 88 Stibbard J. H. A.107 Stierle D. B. 378,434 441 Stilbs P. 19 Still I. W. J. 125 Still W. C. 367,408,418.430 Stille J. K. 261 269 284 349 Stillwell R. N. 9 Stobart S. R. 284 Stock L. M. 179 189 191 Stocks R. C. 314 Stoddart J. F. 248 Stockigt J. 400 401,403 Stoecklin G. 198 Stofko J. J. Jr. 52 85 Stokie G. J. 372 Stolle W. T. 129 326 Stone D. 480,481 Stone P. G. 120 Stone T. E. 460 Stoodley R. J. 249 Stoops J. K. 483 Stork G. 62 339 351 359 360,372 Storr R. C. 235 Stotbloorn A. F. 25 Stout R. 143 Stradi R. 231 Stransky W. 419 Stravrakis G. N. 407 Street G. B. 109 Streith J. 87 Strong P. D. 16 Strothkamp K. G. 471 Strozier R. W. 43 175 Struble D. L. 407 Struck R. F. 311 Stults B. R. 237 Stupnikova T.V. 228 Styles P. 23 Sub J. 419. 421 Author Index Subba Rao G. S. R. 342 Subba Rao S. C. 7 Subrahmanyam C. 289 293 301,364 Subramaniam C. S. 150 Subramanian K. 59 Subramanian K. N. 462 Subramanian L. R. 59 Sudoh R. 213 Suetsugu A. 371 Suga S. 203 Sugasawa T. 214 298 Sugawara T. 23 Sugden P. H. 476 Suggs J. W. 267 Sugie H. 404,407 Sugihara Y. 107 128 Sugimoto H. 242 Sugimoto M. 372 Sugimoto T. 160 Sugisawa H. 281 Sugita K. 369 Sugiura M. 468 Sugiyama T. 452 Suguro T. 422,423,427 Suhadolnik R. J. 471 Suire C. 366 Suksamrarn A, 396 Sukumar S. 25,26 27 Sukumaran K. B. 204 Sullivan G. R. 27 Sum F. W. 347,417 Sum P. E. 427 Sumita M. 228 Summers M. C. 23,477 484 Sun H.H. 438,439,444 Sun R. C. 152,228 Sundar N. S. 342 Sundberg K. R. 42 SunjiC V. 162 248 Surya Prakash G. K. 64 Suschitzky H. 87 203 240 248 Sustmann R. 48,75 182 Sutcliffe L. H. 79 96 220 Sutcliffe R. 77 78 Sutherland I. O. 247 Sutherland J. W. H. 29 Sutherland M. D. 446 Sutherland 0.R. W. 415 Suttle D. P. 484 Suzuki A, 139 228,291,292 294,295,296 327 Suzuki H. 130 187 203,335 352 Suzuki K. 149,211,359 Suzuki M. 8,9 85 333 Suzuki S. 442,45 1 Suzuki T. 15 366 Svensson B. G. 410 Swaminathan K. 238 299 300 Swaminathan S. 234 Swanson D. D. 104 Swartz J. E. 197 Sweat F. W. 376 Sweeley C. C. 10 Sweeney J. R. 389 Swenson D. H. 471 Swenton J. S. 102 241 Swenton L. 118 Swier S.R. 407 Swindell C. S. 325 Switz S. P.,.351 Swyryd E. A. 484 Sydnes L. K. 123,239 Symons M. C. R. 74 75 320 321 Szakal G. 318 Szalkiewicz A. 239 Szeimies G. 36 168 169 Szeimies-Seebach U. 169 Szele I. 199 304 Szendrei K. 382 Szymanska A. 407 Tabata M. 291 295 Taber D. F. 262 345 Tachibana T. 426 Tada M. 378,379 Tada T. 366 Taeger T. 298 Taft R. W. 55 Tagaki W. 55 Taggart A. D. 208 Taguchi M. 125 Taguchi T. 379 Tai A. 423 Tait S. J. D. 341 Takacs J. M. 346 355 Takagi H. 379 Takagi S. 14 Takahashi H. 157 Takahashi K. 15 161 366 Takahashi M. 239 Takahashi N. 372 Takahashi Y. 133,280 292 Takakis I. M. 117 Takaku H. 460,466 Takano S. 445 Takao S. 371 Takaoka D. 373 Takasabi T.342 Takaya M. 177 Takayama K. 210 Takeda R. 137 Takeda S. 371 Takeda T. 376 Takei H. 325 Takeichi T. 262 Takemoto T. 366 373 414 Takeshiba H. 242 Takeuchi S. 366 Takeuchi T. 7 Takigawa T. 364 378 422 424 Takimoto S. 351 Talman E. 408 Tam C. C. 354 Tam W. 288 Tamada S. 416,423,426,427 Tamaki Y. 404,407 Tamao K. 138,327 Tamaru Y. 214,354 Tamary T. 199 Tamas J. 232 Tamura A. 452 Tamura Y. 55 Tan H. 438 Tan R. Y. S. 113 Tanaka H. 102,110,453,478 Tanaka M. 379 Tanaka N. 60 Tanaka S. 139,464,467,468 Tanaka T. 220,460,464,467 Tanaka Y. 462 Tanamachi S. 55 Tani H. 142 Tani K. 262 Tanigawa Y. 335 Taniguchi H. 289 Taniguchi M. 439,457 Tanikaga R. 202 Tanimoto M.90 135 Tanimoto S. 160 Tanis S. P. 431 Taniyama Y.,464,467 Tanner D. D. 81 Tanouchi M. 419 Tarburton P. 248 Tarchini C. 378,434 Tardella P. A. 87 Tardy D. C. 180 Tarnowski B. 239 Tarnowski T. L. 247 Taschenberg E. F. 416 Tashiro H. 408 Tashiro M. 202 Tatematsu H. 438 Tatibana M. 484 Tatsuki S. 416 Tatsumi K. 133 Tatsuta K. 368 Taylor A. W. 229 Taylor D. A H. 190,375 Taylor E. C. 53,248 Taylor K. F. 39 Taylor M. R. 29 Taylor P. G. 189 Taylor S. E. 218 278 Tebbe F. N. 96 Tebby J. C. 312,313 Teddler J. M. 73 Tegg D. 457 Teichteil C. 43 125 223 Teitel S. 391 Temple C. Jr. 482 Templeton D. H. 222 Templeton L. K. 222 Tener G. M. 470 5 16 Tengo J. 409 Ten Noever de Brauw M.C. 9 Terada T. 379 Teranishi S. 141 Terashima S. 151 211 Terayama Y. 153 Terem B. 106 Terlouw J. K. 4 5 Terrier F. 194 Testaferri L. 192,210 Teuerstein A. 169 208 Teufel E. 207 Tewson T. J. 201 Texier F. 49 TeyssiC P. 222 Thacker J. D. 315 Thaisrivongs S. 289 Thayer A. L. 121 309 The K. I. 304 Thenot J.-P. 9 11 Thiebault A. 108 197 Thiel W. 35 183 Thiellier H. P. M. 455 Thieriault N. Y. 467 Thimmappaya B. 462 Thind S. S. 212 Thivolle-Cazat J. 255 Tho Y. P. 413 Thomas C. B. 6 Thomas E. J. 227,323 Thomas M. T. 223,245 Thomas P. J. 150 Thomas P. S. 455,459 Thomas R. 7 314 Thomas R. C. 295 Thomas S. A. 370 372 Thomas S. E. 459 Thomas T. D. 218 284 Thommen H. 381 Thompson D.W. 279 Thompson J. T. 198 Thompson M. E. 431 Thompson R. H. 82 Thompson T. B. 67,275 Thomson A. J. 471 Thomson R. H. 436,439 ThorCn S. 290 Thornber C. W. 392 Thorstenson T. 317 Threlkel R. S. 258 Thulin B. 314 Thummel R. P. 208,218 Thyagarajan G. 231 Tickle I. J. 16 Tideswell J. 379 Tiecco M. 192,209,210 Tien H.-J. 110 Tietze L.-F. 345 Tikhonina N. A. 306 Tingoli M. 192 210 Tinker L. A. 110 Tinoco I. 471 Tiollais P. 462 Tippett J. M. 391 Tipping A. E. 90 Tischer. E.. 462 Tischler S..A. 213 TiSler M. 249 Tissie G. 8 Titmas R. C. 466 Tizard R. 462,463 Tkatchenko I. 255 Tobe M. L. 193 Tobias R. S. 278 Todd A. H. 330,466 Torok F. 36 Togami M. 370 Toi H. 288 289 Toke L.318 Tokoroyama T. 439 Tokuda M. 292 Tolela L. 434 Tolman C. A. 259 Tolstikov G. A. 419,424 Tomis M. 239 Tomasi J. 36,43 Tomasik P.,240 Tomioka H. 95 97 Tomisawa H. 242 Tomita K. 157 Tomita Y. 266 Tomuro Y. 133 Tondeur Y. 283 Top S. 260 Toppet S. 225 Torchia D. A. 29 Torgerson D. F. 9 Tori K. 227 Torii S. 102 110 Torimoto N. 87 Torisawa Y. 330 Torrence P. F. 453 Toube T. P. 3 Toubro N. H. 237 Toullec J. 193 Tovar L. 369 Towers G. H. N. 415 Townsend J. M. 152,228 Townsend L. B. 450 Townshend R. E. 42 Toyne K. J. 131 Toyoda. Y. 214,298 Toyota M. 366 Traeger J. C. 5 65 Traldi P. 123 Tramontano A. 147 288 Traynham J. C. 73 Traynor S. G. 158 364 Treimer J.400 Tremper A. W. 226 Trenary M. 34 92 279 Trenbeath S. L. 292 Trend J. E. 85 Tretzel J. 124 Trewella J. C. 18 Trinquier G. 34 98 281 Trippett,S. 303,304,306,308 310 Author Index Trocha-Grimshaw J. 104 Trompenaars W. P. 225,244 Trost B. M. 138 152 154 263,270,328,335,338,345 358,368,378 Tsai M. D. 472 Tschinkel W. R. 413 Tse A. 148 Tse M.-W. 76 Tse Y.-C. 37 Tsiryapkin V. A. 261 Tsubata K. 107 128 Tsuboi S. 231 Tsuchiya T. 123 220 244 245 Tsuda Y. 366 Tsuge O. 249 Tsuji H. 371 Tsuji J. 128 269 325,421 Tsuji T. 342 Tsujimoto K. 116 Tsukitani Y. 442 Tsuruta T. 262 Tsuzuki H. 46 Tsyban A. V. 297 Tuck D. G. 271 Tucker K. W. 410 Tuinman A. 16 377 Tuinstra A. 313 Tun H. W.318 Tunaley D. 280 Tundo P. 161 247 Turchi I. J. 53 248 Turner A. B. 379 Turner D. W. 398 Turner P. H. 170 Turro N. J. 113 Tursch B. 433,440,441,442 443 Tuttle R. C. 434 Tuttobello L. 373 Tweddle N. J. 88 Tyler R. C. 410 Tyrrell N. D. 227 323 Tyrrell J. 37 Uchic J. T. 459 Uchida K. 296 Uchida M. 42 1,422,426 Uchida T. 243 Uchiumi K. 416 Uchiyama T. 141 Uda H. 370 Uebel E. C. 407 Ueda C. 103 Ueda T. 456 Uegaki R. 381 Ueji S. 15 Uemura D. 445 Uemura H. 464 Uemura M. 370 Uemura. S. 280 Unal G. G. 16 Author Index Ueno Y. 325 Ueyama M. 227 Ugi I. 226 305 312 Ugolick R. C. 178 Ugurbil K. 23 Uhlenbeck 0.C. 468 Uijttewaal A. P. 131 Ukida M. 110 Ullrich A.462 Umani-Ronchi A. 269 Umezawa H. 452 Umino N. 289 Unal G. G. 370 Underhill E. W. 407,416 Untch K. G. 47 Uramoto M. 45 1 Usuif S. 371 Utirnoto K. 131,283,294,296 Utley J. H. P. 106 381 Utrapiromsuk N. 55 Uyehara T. 15,49 217 366 Uyeo S. 227 Uzar H. C. 345 Uzawa J. 366,45 1 Uznanski B. 318 Vadasz A. 379 Valcho J. J. 94 Valenti P. C. 121 Valentine D. 152 228 Valentine K. M. 22 van Bergen T. J. 21 1 van Boom J. H. 17,456,466 van de Langkruis G. B. 55 Van den Berg J. 462 van der Baan J. L. 152 Vanderbilt J. J. 170 van der Gen A. 131 340 van der Ham D. M. W. 244 Vander Jagt D. L. 56 van der Kerk G. J. M. 300 van der Kerk S. M. 300 van der Marel G. 17 van der Stouwe C. 105 Vanderwalle M.367 Van de Sande C. C. 6 Van de Voorde A. 462 van Dongen H. 285 van Eenoo M. 335 van Engen D. 363,415 Van Fleteren G. M. 311 Van Gaever F. 6 Vangedal S. 374 Vanhaelen M. 416 Vanhaelen-Fastre R. 416 van Haverbeke Y. 6,219 Vanhear G. 376 Van Herreweghe J. 462 Van Heuverswyn H. 462 Van Horn D. E. 297,330,420 van Hummel G. J. 244 Vankov Y. D. 343 Van Meerssche M. 168 169 225,233,441,442,443 Van Ooyen A. 462 van Riel H. C. H. A. 115 van Rooyen P. H. 16 van Scharrenburg G. J. M. 25 van Schie D. M.J. 337 van Tamelen E. E. 374 Vargaftik M. N. 200 Varon Z. 375 Vasak M. 21 Vasil’ev V. V. 307 Vassilenko S. 463 Vawter A. T. 405 Vedejs E. 50 129 326 Veiko V. P. 467 Veith H. J. 9 410 Venanzi L.M. 268 Venturello P. 161 Verdegaal C. H. M. 467 Verhelst G. 453 Verheyden J. P. 456 Verhoeven T. R. 154 263 Verkade J. G. 311,317,319 Verkruijsse H. D. 142 Vermeer P. 420 Vernin G. 201 210 Verpeaux J.-N. 325 Verwiel P. E. J. 408 Vevert J. P. 477 Vezza M. 40,92 Viala J. 364 421 Vidal J. L. 288 300 Vidal J. P. 402 Viehe H. G. 73 Vierhapper E. W. 221 Vierling P. 247 Vigneron J.-P. 149 Vilarrasa J. 232 Vilkas M. 479 Villa-Kornaroff L. 463 Villieras J. 142 Vincent C. A. 104 Vincent M. 245 Vincent M. A. 41 Vine J. 7 Vinson S. B. 410 Viriot M.-L. 86 204 Vishveshwara S. 36 37 Viswamitra M. A. 17,464 Vita R. A, 407 Vittimberga B. M. 123 Voegtle F. 190 Voerman S. 407 422 Vogel E.185 246 297 330 Vogeli U. 380 Vogler H. 35 185 Volckaert G. 462 Vollhardt K. P. C. 175 218 314 380 Vollmer J. J. 441 Voncken W. G. 309 Vonderheid C. 340 von Hippel P. H. 469 von Jouanne J. 46 183 von Kiedrowski G. 341 von Seyerl J. 226 Vorbriiggen H. 352 Vosberg H.-P.. 469 Vose C. W. 7 Voss B. 185 246 Voss S. 48 Vostrosky O. 404 407 419 42 1 Vrieze K. 260 Vroc J. 373,412 Vuilhorgne M. 452 Vysotskii Yu. B. 186 Wachter M. P.. 369 Waddling R. E. L. 310 Wade L. G. Jr. 346 Wade P. A. 49,337 Wadhams L. J. 409 Wadsworth H. 377 Wachter G. 191 Waegell B. 91 Waelder S. 21 Waespe-Sarcevic N. 378 Wagenknecht J. H. 103 Wagner G. 21 Wagner H.-U. 36 54,275 Wagner P. J. 121 Wahl G.M. 484 Waight E. S. 11 Wakabayashi T.,464,467,468 Wakamura S. 407 Wakefield B. J. 203 240 241 Wakil S. J. 483 Walker F. J. 218 360 Walker J. A. 295 Walker R. T. 453 455 469 Walker T. E. 482 Wall M. E. 375 Wallace J. B. 413 Wallace T. W. 202 Waller C. A. 476 Wallmeier? H. 33 Walsh C. 472,477,478 Walsh C. T. 478 Walsh K. X.,476 Walter R. I. 120 Walton D. J. 104 Walton J. C. 73 75 Walz P. 353 Wan W. 400 Wang A. H.-J. 17 Wang C.-L.J. 367 Wang E. 477 Wang J. T. 75 Wang K. K. 289 Wang P. S.-C. 201 Wani M. C. 375 Wanner H. 452 Ward D. L. 169 208 Wardleworth J. M. 296 Warin R. 222 Waring M. J. 471 518 Warnhoff E. W. 377 Warren F. L. 388 Warren K. E. 400 Warrener R.N. 113 Wartew G. A, 317 Washburn W. N. 35 167 Wasserman A. L. 248 Wasserman H. H. 226 Wasserman Z. R. 34 Watabe Y. 213 Watanabe H. 423 Watanabe K. 470 Watanabe K. A. 241,453,454 Watanabe M. 75,76,223,453 Watanabe S. 239 Watanabe T. 8 Watanabe Y. 239 Wataya T. 479 Waterhouse I. 142,379 Watson D. G. 13 Watson F. 242 Watson N. S. 227 Watson T. R. 379 Watson W. D. 190 Watt C. I. F. 57 Watt D. W. 81 Watts W. E. 192 Waugh J. S. 29 Wax R. 419 Way G. M. 299 Weatherston J. 413,424 Weber E. 247 Weber R. J. 182 Weber W. 15 Weber W. P. 265 Webster R. P. 414 Weedon A. C. 121,217 Weedon B. C. L. 314 380 381 Weerasooriya U. 92 Wehrli F. W. 363 Weidenhammer K. 96 Weigand E. F. 365 Weigele M.449 Weiler L. 213 347,417,427 Weinberg K. G. 317 Weinheimer A. J. 18 372 Weinkam R. J. 10 Weinmaier J. H. 238 308 Weinman S.A, 311 Weinreb S. M. 248 280 Weinstein B. 375 Weisenfeld R. B. 354 Weiss G. H. 20 Weiss J. 410 Weiss R. 209 Weissman S. M. 462 Weissmann C. 462 Welch G. R. 483 Welch M. J. 201 Welch S. C. 225 368 Wells R. J. 366,434,440,441 Weltwisch D. 79 Wen L.-S. 200 Wenham M. J. 409 Wenkert A. 125 325 401 425,452 Wennerstrom H. 21 Wennerstroem O. 185,314 Wenska G. 123,239 Wentrup C. 94,230 Wentrup-Byrne E. 94 Wentworth R. A. D. 89 Werenga W. 344 Wesdemiotis C. 65 West C. T. 78 West R. 99,280 Westaway K. C. 60 Westerman I. J. 47 Westheimer F. H. 97 283 304,308,309,311 Westmijze H.420 Wette M. 50 51 181 Wetter H. 348 Wexler A. J. 241 Whalley D. P. 195 Whangbo M.-H. 315 Wheeler J. W. 409 410 White C. T. 331 White D. N. J. 293 366 White J. G. 15 223 White R. A. 415 White R. C. 216 Whitehead E. V. 376 Whitesides G. M. 128 Whitfield C. D. 477 Whiting D. A. 382 Whiting M. C. 57 192 Whittaker D. 365 Whitten J. P. 240 Whittle A. 188 Whybrow D. 114 Wiberg K. B. 33 Wicha J. 378 Widmer J. 160 Widdowson D. A. 394 395 398 Wieber M. 304,309 Wiebers J. L. 10 11,468 Wiegand G. 472 Wieland T. 17 Wiemer D. F. 379,411,412 Wiener L. F. 416 Wierenga W. 152 Wiersig J. R. 378 Wiewiorowski M. 467 Wightman R. M. 106 Wilcox C. F. 45 Wilcsek R.J. 300 Wilde H. 235 Wilde J. 479 Wilhelm M. 185 246 Wilke G. 174 Wilkie D. W. 435 Willard G. F. 132 Wille G. 467 Wille-Hazeleger G. 466 Williams D. C. 477 484 Author Index Williams D. H. 4,5 11,20,22 379 Williams D. J. 16 293 370 Williams D. L. H. 198 Williams F. 75 Williams G. H. 210 Williams G. M. 288 Williams J. J. 427 Williams J. L. D. 409 Williams J. R. 368 Williams J. W. 482 Williams P. J. 156 Williams R. J. H. 380 Williams R. M. 290 Williams T. H. 152 228 Williams W. J. 90 Williamson M. P. 20 Willis C. 128 Willis C. L. 37 Willocx A. 233 Wilshire C. 376 Wilson G. S. 104 Wilson H. 55 Wilson N. 295 Wilson N. H. 204 Wilson S. R. 364 Wind R. A. 30 Winkler F. J. 7 Winston C.464 Winter J. N. 80 81 Wirthlin T. 416 Wise S. 167 Wiseman J. R. 170 Wisian-Nielson P. 300 Wismonski-Knittel T. 116 Wistrand L.-G. 101 200 Withers G. P. 155 Withers N. W. 378 434 Witiak D. N. 4 Witt W. 247 Wittig G. 314 Wohleb R. H. 424 Wokaun A. 30 Wolczanski P. T. 258 Wolf H. 209 Wolf M. 264 Wolf R. 307 309 310 Wolf U. 241 Wolfe J. F. 197 Wolfe S. 32 Wolfhagen J. L. 153 Wolford T. L. 79 Wolkoff P. 5 Wollenberg R. H. 426 Wolschann P. 70 Wong G. G. 23 Wong G. S. K. 217 Wong K. F. 18 Wong T. C. 284 Wong T. T. Y. 414 Wong V. K. 288 Wood C. D. 256,257 Wood D. E. 74 Wood D. L. 415 Author Index Wood H. G. 483 Wood J. L. 280 Woodgate P. D. 377,378,379 Woodward R.B. 227 346 Woolard F. X. 363,438 Woolfson M. M. 17 Woolias M. 228 Woolley R. G. 31 Wooten J. B. 22 Worden H. A. 407 Wrackmeyer B. 294 Wratten S. J. 442 Wright G. J. 189 Wright P. W. 379 Wright T. L. 189 191 Wu F. Y. H. 475 Wu G. 300 Wu J. S. 226 Wu R. 462,464,446 Wuest H. 329 Wuest J. D. 289 Wiithrich K. 21 28,472 Wunderlich H. 304 Wursthorn K. R. 274 Wykypiel W. 338 Wylie P. L. 206 Wynberg H. 169,248 Wynne-Jones Lord 193 Wyrsch-Walraf I. 216 Wyssbrod H. R. 19 Xuong N. 481 Yabuki Y. 294 Yakogawa K. 452 Yalpani M. 249 Yamabe S. 42 Yamabe Y. 282 Yamada F. 228 Yamada K. 139 292 296 327,438 Yarnada M. 213 Yamada S. 9 117 Yamada Y. 442 Yamaguchi M. 342,351 Yamaguchi R.103 Yamaguchi S. 427 Yamaizumi Z. 452,453 Yamakawa M. 177 Yamakawa T. 128,269,325 Yamamaichi A. 355 Yamamoto A. 240 257 Yamamoto H. 139 268 280 359,368,444 Yamamoto K. 207 243 281 Yamamoto M. 239 Yamamoto T. 102 257 338 Yamamoto Y. 220 288 289 291,295,296,297,300,366 Yamamura M. 132 Yamamura S. 369 Yamaoka R. 42 1 Yamato T. 202 Yamato Y. 8 9 Yamauchi M. 142 Yamazaki A. 415,448 Yamazaki M. 102 Yarnazaki R. 476 Yamazaki Y. 337 Yambushev F. D. 271 Yameda K. 220 Yamisaki Y. 376 Yan C. F. 360 Yanagida S. 161 Yanagisawa K. 132 Yang D. T. C. 289 Yannoni C. S. 29 30,63 Yano S. 243 Yano T. 227 296 338‘ Yano Y. 55 Yansura D. G. 463,464 Yarwood A. J. 115 120 Yaslak S.50 51 181 Yasuda A. 139 Yasuda H. 142,421 Yatagai H. 291 295 296 Yates G. 39 Yates J. H. 37 Yates K. 305 Yates P. 97 120 Yau L. 466 Yeats R. B. 365 Yee B. G. 121 Yoda N. 254 Yogo T. 295 Yokoe I. 125 Yokota T. 220 Yoneda K. 214 Yonehara H. 366 Yoon N. M. 289 Yoshida A. 227 Yoshida J. 138 Yoshida K. 103 Yoshida M. 466 Yoshida T. 15 253 290 296 366,373 Yoshida Y. 55 Yoshida Z. 214 354 Yoshioka H. 15 342 Yoshioka M. 342 Yost R. A. 12 Young D. W. 162,323,482 Young J. C. 363,417 Young S. D. 332 Youngless T. L. 8 Yousset M. S. K. 155 Ysebaert M. 462 Yuasa K. 292 Yuasa Y. 86 Yuffa A. Y. 251 Yunker M. B. 443 Yur’eva N. M. 272 Yushima T. 407 Zacharias D. E. 205 Zahler R.35 167 Zahra J.-P. 91 Zaidlewicz M. 289 Zain B. S. 462 Zakaria Z. 241 Zakett D. 10 Zaklika K. A. 121 Zamarlik H. 249 Zambonelli L. 268 Zambri P. M. 147 Zandler M. F. 39 Zaretskii Z. V. I. 21 Zarytova V. F. 465 Zavada J. 69 Zavitsas A. A. 210 Zavitsas L. R. 210 Zbiral E. 314 Zderic S. A. 147 288 292 Zdero C. 366,371 Zecchina A. 256 Zechlin L. 374 Zefirov N. S. 272 Zeisberg R. 371 Zeiss H.-J. 297 332 Zeldes H.,73 Zeller K.-P. 96 Zel’tzer I. E. 261 Zemskii B. P. 228 Zenk M. H. 400,401 Zentgraf R. 294 Zerby G. A. 355 Ziegler F. E. 354 Ziegler J.-C. 288 Ziegler J. R. 414 Ziegler M. L. 96 Zielinski T. J. 33 Ziffer H. 136 223 Zilenovski J. S. R. 140 Zimmerman H. E. 53 113 114 Zimmermann H.30 Zimmermann H. J. 297 Zinner K.,226 Zitter R. N. 113 Zollinger H. 199 Zolopa A. R. 292 Zoutendam P. H. 107 Zupan M. 114,203 Zurawski B. 42 Zutterman F. 367 Zviely M. 440 Zweifel G. 294 295 Zylber J. 456 Zylber N. 456

ISSN:0069-3030    

DOI:10.1039/OC9797600487

出版商:RSC    

年代:1979

数据来源: RSC