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8 Organometalfic Chemistry The Transition Elements By G.R. STEPHENSON School of Chemical Sciences University of East Anglia Nurwich NR4 7TJ UK 1 Introduction Not every year produces results which point to new directions in organometallic chemistry. During 1993 however significant advances have been made in the use of supercritical fluids as solvents for preparative-scale organometallic synthesis. At Nottingham Bannister Howdle and Poliakoff ' have developed a flow reactor to perform photochemistry under supercritical conditions. In the Nottingham set-up an infrared flow cell is placed in series with the reactor vessel to allow on-line study of the reaction process (Figure 1). In this way the pentacarbonylchromium complex of ethene was isolated for the first time.This experiment used supercritical ethene as the solvent in the flow reactor. Figure 1 (Reproduced with permission from J. Chem. Soc. Chem. Cornmun. 1993 1814) At CIernson University in the USA supercritical water has been used as a reaction solvent. Dicarbon y1(cyclopen tadien yl )co balt-catal ysed cyclo trimerizat ion of a1k ynes was studied under these conditions. At 374 "Cgood yields of aromatic products were obtained with regioisorner distributions comparable to those observed in the organic solvents more customarily employed for this type of reaction. The temperature conditions were important. At 140°Ca diverse mixture of products was The cyclooligomerization and cooligomerization of alkynes has always been an J.A. Banister S. M.Howdle and M.PoIiakoff J. Chem. Soc. Chem. Commun. I993 1814. K.S. Jerome and E. J. Parsons Orgonometallics 1993,12 2991. 217 G. R . Stephenson 70% OTBDMS -OTBDMS Reagents i rPd(dba)J; ii TBDMSCI CO [RU~(CO)~J Scheme I important topic in organometallic chemistry. Alkynes are highly reactive starting materials and so participate readiIy in a great variety of reactions. During the year there has been particular progress with the development of the organometaiiic chemistry of alkynes for controlled carbonsarbon bond formation. Few of the reactions under study are new in type but looking back over the year it is clear that this continues to be an exciting and rapidly deveIoping area of organornetallic chemistry.In this year's Report we will look in detail at the most recent developments in this field.2 Alkynes in C-C Bond Formation DicarbonyIfcyclopentadieny1)cobalt is the most common reagent used for the cyclotrimerizationof alkynes. An alternative based on organopalladium chemistry is remarkable for its chemical selectivity (Scheme 1). Palladium catalysis produces a dimer from a bispropargyl ester of an alkyne-containing dicarboxyclic acid .3 Combination of two alkynes with two molecules of carbon monoxide can produce a 1,2-dioxygenated aromatic ring. Ru,(CO) and tricyclohexylphosphine are used to promote this cyclization rea~tion.~ When two alkynes are joined within a larger ring these can be dimerized using a (cydopentadieny1)cobalt system to form a superphane containing q4-cyclobutadiene CoCp complexes at each end.Yields are low (less than 1%) but this interesting product was characterized by X-ray ~rystallography.~ Enyne cyclizatim-When an alkene and an alkyne are combined by a palladium catalyst the typical product is a 1,3-diene. An example from the Trost group forms a six-membered ring in this way? When an extra alkyne is present in the starting material further carbon-carbon bond formation forms a triene which cyclizes C. Stephan and H.Torn Dieck J. Mot. Cotal. 1993 81 313. 'N. Chatani Y. Fukumoto,T. Ida and S. Murai J. Am. Chem. Soc. 1993 115 11614. R.Gleiter G. Pflasterer and B. Nuber J. Chem. Soc. Chem. Commun. 1993,454. B. M.Trost and 0.J. Gelling TetrahedronLert. 1993,34,8233. Organomtalk Chemistry I 4 Med Med 68% (11 0 0 63% Reagents i [Pd(OAc),] Py; ii Pd[(dba),] CH,CO,H,P(O-tol) scheme 2 thermally thus providing a cycIohexa-l,3-diene ~ynthesis.~ If the alkene is a vinylbrom- ide,' cocyclization with an additional alkyne affords an aromatic product.Enyne cyclization can be performed on elaborate substrates as evidenced by the formation of (1) (Scheme 2).9 Inclusion of acetic acid among the reagents allows the formation of an alkene [e-g. (211 rather than a diene. The product (2) was used as an intermediate in the total synthesis of chokol C." There are now many variants on the enyne cyclization. A combination of the cyclization reaction with a metathesis step is of particular note. Palladium-catalysed cycfization of (3) affords (4) in 85% yield.The CHMe unit originating in the alkene has been transferred to the atkyne-end of the carbon chain." In some cases a cyclobutene for example (3, can be isolated." Use of a palladium chloride catalyst in the presence of five equivalentsof copper(11) dichloride allows the introduction of two ' B.M. Trost and Y. Shi J. Am. Gem. Soc. 1993 115 12491. * E.-i. Negishi M. Ay and T.Sugihara Tetrahedron 1993 49 5471. F.-H. Wartenberg B. Hellendahi and S. Blechert SYNLETT,1993 539. lo 8.M. Trost and L.T. Phan Tetrahedron Lett. 1993 34,4735. 'I B. M. Trost and V.K. Chang Synthesis 1993 824. B.M. Trost M. Yanai and K. Hoogsteen J. Am. Chem. SOL 1993,115,5294. 220 G.R. Stephenson chlorine atoms one to the alkene and one to the a1k~ne.l~ The potential for further elaboration of the alkenyl and the alkyl chloride groups in such products will make them attractive as intermediates in organic synthesis.To gain access to a precursor of isohinokinin hydrogenation conditions were employed to remove both halides and the carbonsarbon doubIe bond.14 In a further variant P-ketoester and alkyne coreac- tants in an intermolecular process combine in a new synthesis of 2,3,4-trisubstituted furans.' Allylic alcohols acetates and chlorides have been examined as starting materials in intramolecular cyclizations with terminal alkynes. Lithium chloride is included as a coreactant. In the case of the allylic alcohol depending on the substitution at the CHOH centre either hydrogen or OH transfer to the metal is observed.Bulky substituents favour hydrogen transfer forming an enol ether and hence ultimately a ketone. With a methyl group the only product is that of oxygen transfer. In both cases a chlorine atom becomes attached forming an alkenyl ch1oride.l6 Allylic acetates show more general selectivity for leaving group displacement in this type of rea~ti0n.l~ Allylic chlorides have aIso been used as starting rnaterials.l8 In the presence of carbon monoxide the reaction takes a different course. This is a palladium-catalysed version of the Pauson-Khand reaction. The dienone (6) was formed in 43% yield.lg Progress continues to be made in the development of the organocobalt Pauson-Khand reaction. Dimethyl sulfoxide and other polar solvents have been shown to promote cyclopentenone formation from alkyne hexacarbonyldicobalt complexes.20The dry-state adsorption conditions developed by Smit and Caple have been employed in a version of the Pauson-Khand cyclization of N-protected ally1 propargyl amines which in the absence of oxygen give rise to saturated bicyclic cyclopentanone products rather than the usual cyclopentenones.2 The use of coordinating ligands has also been evaluated,2 and a 1-alkynylcycfopropanoI has been shownz3 to be an alternative starting material for this type ofcyclization.In this case a catalytic amount of octacarbonyldicobalt and triphenylphosphite was em-ployed. In the patent literature reports of catalytic versions of the Pauson-Khand cyclization have appeared. An intermolecular reaction between hept- 1-yne and ethene has been performed.Pentacarbonyliron may be used in combination with the dindear cobalt catalyst (Scheme 3). The reaction is described as regioselective and useful on an industrial scale. Another catalytic version of the reaction used dicyclopentadienyltitanium(trimethylphosphine)in place of the cobalt complex and an isocyanide in place ofcarbon monoxide.25 Since the recently reported first catalytic l3 S. Ma and X.Lu J. Org. Chem. 1993,58 1245. lo X. Eu and G. Zhu SYNLETT 1993 68. N. Greeves and J. S. Torode Synthesis 1993 1109. l6 S. Ma and X. Lu J. Organornet. Chem. 1993 447 305. l7 G. Zhu S. Ma and X. Lu J. Chem. Res. (S) 1993 366. la S. Ma G.Zhu and X.Lu,J. Org. Chern. 1993,58 3692. i9 N.C.IhIe and C. H. Heathcock J. Org. Chem. 1993,58 560. 2o Y.K. Chung B. Y. Lee N. Jeong M. Hudecek and P. L. Pauson Organometalks 1993,12 220. '' D. P.Becker and D. L. Flynn Tetrahedron Lett. 1993 34 2087. 22 M.E. Krafft I. L. Scott R. €3. Romero S. Feibelmann and C. E. Van Pelt J. Am. Chem. Soc. 1993,115 7199. 23 N. Iwasawa and T. Matsuo Chem. Lett. 1993 997. 24 W. Keim Potentschrift (Switz.),CH 681224 1993 (Chem. Abstr. 1993 119 95004). 25 S.C. Berk R. B. Grossman and S.L.Buckwald J. Am. Chem. Soc. 1993 115,4912. Organometaliic Chemistry 221 (6) 43% 0 51% Reagents i [Pd,(dba)J PPh,,LiCl,CO; ii ethene CO [Co,(CO),] (cat.) [Fe(CO),] Scheme 3 Me (7)91% 62% Reagents i [Co,(CO),];ii [Mo(CO),] DMSO toluene Scheme 4 version of a Pauson-Khand cyclization considerable progress has been made.Under stoichiometric conditions cyclizations of electron deficient alkynes have been examined. The enedione product (7) was obtained in excellent yieldsz6 (Scheme 4). With three equivalents of a simple propargylketone and (octacarbonyl)dicobalt a compound with a dinuclear ‘flyover bridge-type’ structure has been obtained and characterized by X-ray crystallography .” The use of other transition metal systems in cydopentenone formation continues to be developed. Both tungsten’ and moIyb- denum2’ complexeshave been used to effect the intramolecular cyclization of enynesto form cyclopentenones. In the tungsten case a pentacarbonyltungsten-THF complex was used. The hexacarbonylmolybdenum method on the other hand employed the recently developed DMSO promoter conditions.The second example shown in Scheme 4 includes a potential allylic leaving group but unlike the reaction leading to T. R. Hoye and I.A. Suriano J. Urg. Chem. 1993 58 1659, ’’ G. Gervasio E. Sappa and L. Marko J. Organomet. Chem. 1993,444 203. 28 T. R. Hoye and J.A. Suriano J. Am. Chem. SOC.,1993 115 1154. 29 N. Jeong S,J. Lee B.Y. Lee,and Y.K.Chung Tetrahedron Lett. 1993 34,4027. G.R. Stephenson (6) (Scheme 3) in this benzyl ether case the ether is retained in the product. Indenones can be prepared with palladium catalysts from alkynes and substituted benzal- dehydes. O There have been further developments with cyclopentadienone f~rmation.~ Cyclization of diynes with carbonyl insertion initially formed an q2-cornplex from which the metal can be removed by oxidation with trimethylamine N-oxide.The tetrasubstituted cycfopentadienone (8) can be prepared in 46% yield in this way from 1,7-bistrimethyIsi~ylhept-I$-diyne. Four equivalents of the amine oxide reagent are used. When a large excess of amine oxide is employed (9) is obtained in an improved yield of 67%. It has been shown that (8) is converted into (9) by the action of trimethylamine N-oxide. In the case of the thioether (lo),cyclopentadienone formation affords the q4-compIex in 76% yield. On metal removal bath double bonds muve to produce the substituted thiophene (1 1 ) (Scheme 5). I-SiMej s -2d-L smo dSiMe3 (10) (11) 22% Reagents i [Fe(CO),]; ii Me,NO Scheme 5 When the starting material is the tricarbonyliron complex of a vinylketene intermolecular reaction with an alkyne can under the correct conditions produce a 2,2-disubstituted cyclopent-4-ene-l,3-dione.Phenolic products are also obtained in this way particular€y when electron-rich alkynes are An example of phenol production is given in Scheme 6. This type of cyclization is related to the Dotz-WulR cyclizationof vinylcarbenes with alkynes which is also believed to involve coordinated ketene-type intermediates. In the case of (12) however the usual 1,4-oxygenation pattern on the aromatic ring is replaced by a 1,3-regiochemistry. The Dotz-Wulff cyclization has itself been undergoing further development. The direct preparation of differentially protected hydroquinone complexes has been demon~trated,~~ and the dry-state adsorption conditions discussed above for the 30 R.C.Larock M.J.Doty and S. Cacchi J. Org. Chem. 1993,58,4579. 31 H.-J. Knolker and J. Heber SYNLETT 1993 924. 32 K. E.Morns S. P.Saberi and S. E. Thomas J. Chem.SOC.,Chem. Comun. 1993,209; K.G.Moms,S. P. Saberi M.W.Salter S.E.Thomas and M. F.Ward Tetrahedron,1993,49 5637. 33 S. Chamberlin W. D. Wulff and B.Bax Tetrahedron 1993 49 5531. 223 Organornetallic Chemistry Reagents i EtOC-CH A Scheme 6 Reagents i Ceriumfrvf;ii PPh Scheme 7 Pauson-Khand reaction have been shown to be effective.34 In a variant under examination in the Herndon group a cyclopropylcarbene complex (13) is used (Scheme 7).Opening of the cyclopropyl ring forms a cydoheptadienone product (14).35 Fluorinated vinyfcarbene complexes afford fluorinated hydroq~inones.~~ 1,4-Dioxygenated 1,3-dienes can be obtained from molybdenum carbene complexes and alkyne~.~~ With aminocarbenes bearing a pendant alkyne tricyclic five-membered lactams are ~btained.~' 3 Palladiumcatalysed Cross Coupling There are many palladium-catalysed procedures to effect coupling reactions. Most involve aryI or vinyl halides (or equivalents)with alkenes or hetero-substituted vinyl compounds or arenes. Heck and Stille/Suzuki (organotin/organoboron) coupling reactions are among the most widely used. In the Heck procedure an alkene receives the incoming group. After carbon<arbon bond formation fl-elimination detaches the " J.P. A. Harrity W. J. Kerr and D. Middlemiss Tetrahedron 1993 49 5565. 35 J. W. Herndon and M. Zora SYNLETT 1993 363. 36 K.H. Dotz and J. GIanzer J. Chem. Soc. Chem. Commun. 1993 1036. 37 D.F. Harvey and D.A. Neil Tetrahedron 1993,49 2145. '' E. Chelain A. Parlier M. Audouin H. Rudler J.-C. Daran J. Vaissermann J. Am. Chem. SOC.,1993,115 10568. G.R. Stephenson cc__) Ar-X f i Reagents 1 Palladium(o) L 65 "C Scheme 8 metal and replaces the unsaturation in the product. In the Stille/Suzuki cross- couplings the alkene is substituted with a heteroatom (tin in the Stille case boron in the Suzuki case) to allow oxidative addition to transfer an alkenyl substituent to the metal. In this case carbon-carbon bond formation occurs by reductive elimination.When the substrate is a simple vinylboronate ester it is an open question whether reaction with an aryl halide will proceed by a Heck or a Suzuki process (Scheme 8). A study of the selectivity of this reaction3g has shown that the nature of the aryl halide exerts a considerabIe influence. With iodobenzene the ratio of (15) (16) was greater than 95 :5. With 4-iodoanisoie on the other hand reaction was slower and selectivity was reversed (10 :90) to favour product (16). Acrylic esters are commonly used substrates for the Heck coupling. Bates and Gabel have applied this reaction to good effect in a short synthesis of phcatin B (17) (Scheme 9).40Styrenes are also typical receiving groups. The effect of chelating ligands in Heck coupling to styrenes has been studied in detail under base-free c~nditions.~' A recent trend is to apply Heck coupling in heterocyclic synthesis.4-Vinylpyridine has been combined with 4-brornoiodobenzene urfdet the normal palladium acetate triethylamine conditions?* Indoles have been coupled to a~rylates.~~ Oxidative addition to an iodopyridine by a triphenylphosphine complex formed from palladium acetate begins a short total synthesisof (+_)-epibatidine.Coupling to the alkene (18) is followed by a reductive procedure using formic acid to complete the substituted ring system in 35% yield (Scheme 10).Deprotection at nitrogen completed the synthesis of epibatidine (19) (R = 39 A. R. Hunt S. K. Stewart and A. Whiting Tetmhedron Lett. 1993,34,3599.*O R. W. Bates and C. J. Gabel Tetrahedron Lett. 1993 34 3547. 41 M. Portnoy Y. Ben-David and D. Milstein Organametallics 1993 12 4734. *' J. Burdeniuk and D.Milstein J. Organornet. Chem. 1993,451 213. 43 Y. Yokoyama M. Takashima C. Higaki K. Shidori S. Moriguchi C. Ando and Y. Murakami Heterocycles 1993 36 1739. 44 S.C. Clayton and A.C. Reagan Tetrahedron Lett. 1993 34 7493. Organometallic Chemistry Reagents i methyl acrylate [PdfOAc),] PR, NEt,; ii K,CO, MeOH Scheme 9 Reagents i [Pd(OAcj,(PPh )J,piperidine formic acid 2-chloro-5-iodopyridine Scheme 10 (20) -72% Reagents i [Pd(OAc),] AgJO, PPh, DMF Scheme 11 Attention is currently turning to more unusuai substitution on the alkene. Examples involving vinylphosphine and enamine~~~ illustrate this trend.The alkene linkage in a 1,3-dioxep-5-ene is also suitabIe (Scheme 13).47 In this case silver carbonate was used as the base in place of the more norma1 triethylamine. The product (20) was employed in a synthesis of 4-arylbutyrolactones. 45 K. M. Petrusiewicz M. Kuznikowski. and M. Koprowski Tetrahedron:Asymmetry 1993,4 2143. 46 C. A. Busacca R. E. Johnson and J. Swestock J. Org. Chem. 1993 58 3299. 4’ T. Sakamoto Y. Kondo and H. Yamanaka Heterocycles 1993 36 2437. G.R. Stephenson (21)98% RNm OBn lii t)Bn (24) 60% Reagents i [Pd(OAc),] NEt, CH,CN; ii [Pd(OAcf,] PPh, KOAc; iii [Pd(OTf),(PPh,),] toluene Scheme 12 Intramolecular Heck reactions work well (Scheme 12). Tndoles can be made by cyclization of N-aIlyl-2-iodoanaline derivatives.The #?-elimination step completes the methylene substituent at C-3. The reaction has been used in the synthesis of the CC- 1065/duocarrnycin pharmacophore?8 Cyclization of an N-arylenamine also works. The highly efficient formation of (21) illustrates that ester substituents on the receiving alkene are not restricted to the far end of the double bond.49 Polycyclic indoIe derivatives are accessibk by use of the C-2 C-3 double bond as the receiving unit.50 Acrylic amides obtained from iodoanilines offer similar coupling possibihties. Larger rings [e.g. (23)] can be formed by attachment of the allylamine portion via a spacer unit as in (22).52More elaborate po~ycyclic structures are obtained in a similar way.53 The example leading to (24) empIoys the relatively unusual palladium trifluoroacetate catalyst.The alkene links in the products (23) and (24)illustrate the importance of the b-elimination step at the conclusion of the coupling process. A highly functionalized substrate has been used in an intramolecular Heck arylation to give rapid access to 48 T. Sakamoto Y. Kondo M. Uchiyarna and H. Yamanaka J. Chem. Soc. Perkin Truns.1,1993 1941. 49 J. P. Michael S.-F. Chang and C. Wilson Tetrahedron Lett. 1993 34 8365. ’* P.Melnyk J. Gasche and C. ThaI Tetruhedron Lett. 1993 34 5449. 5* A. Arcadi S. Cacchi F. Marinelli and P. Pace SYNLETT 1993 734. 52 L. F. Tietze and R. Schimpf Synthesis 1993 876. ’’ C.Y. Hong N,Kado and L. E. Overman J. Am. Chem. Soc. 1993,115 11028.Organometallic Chemistry 227 congeners of FR900482.54An allylic leaving group an N-0 bond and an aziridine were all present as structural features in the substrate in this case yet side reactions did not prevent the effective application of the process. Regiocontrol has been studied. Depending on the reaction conditions coupling to vinyl ethers can occur at either end but pendant amines in the alkyl group of the enol ether promote far-end attack by chelation control.55 The regiocontrol of the b-elimination step in the Heck coupling of allylamines has been st~died.'~ When a vinyl epoxide is the receiving group carbon-oxygen bond cleavage replaces #3-elimin- ation at the metal-removal step5' A reductive base-free version of the Heck reaction has been reported.Half an equivalent of zinc is included in the reaction mixt~re.~' The reaction conditions shown in Schemes 9-11 are typical of those currently employed in Heck coupling reactions. Normally palladium acetate and triethyIamine are used in polar aprotic solvents such as DMF or acetonitrik. Common variants on the base include other alkylamines silver carbonate or an acetate. The palladium complex need not be the diacetate. Other palladium(i~) and fo) complexes are also employed. The use of aryl triflates in place of aryl halides is common. An example with an en01 ether again employs a coordinating group in the alkyl side chain of the receiving unit. In this case an alkyldiphenylphosphine was used. The enoI ether couples with the triflate of €-naphthol.59 An intramolecular coupling involving an aryI triAate has been used to build benzofluoranthenes." Turning to cross-coupling similar trends are clear.Aryl bromides are again typical building blocks but are now combined with tin- or boron-containing aIkenes. Scheme 13 shows a typical Bromobenzene couples with the vinyltin reagent (25)to afford (26) in 95% yield. The reaction has been applied to the preparation of seven-membered azaheterocydes e.g. (27) using bromobenzaldehydes. The pallad- ium@) catalyst [Pd(PPh,),] is typical for this type of coupling. Product (26) is formed efficiently in the presence of the free amine but a version of the reaction using a bistrimethylsilyl-protected amine has also been reported.62 An advantage of the cross-couplingis that regiocontrol in the coupling step can be dictated by the location of the carbon-tin bond.Coupling 4-iodonitrobenzene with an a-stannyl acrylate affords a branched product in 76% yield.63 The reaction has been applied to 2-bromo-6-methoxynaphthalene, again to afford a branched coupling product. This requiresonly reduction and ester hydrolysis to complete a short synthesis of naproxen a commercially important inhibitor of cyclooxygenase. An intramolecular version of vinyltin coupling has been reported.64 This type of coupling reaction is useful in heterocyclic synthesis. 2,6-Dibromoaniline couples with a tributyltin derivative of an " K. F. McClure and S. J. Danishefsky J. Am. Chem. Soc. 1993 115 6094. 55 M. Larhed C.-M. Anderson and A.Hallberg Acta Chem. Scad. 1993,47 212. s6 L. Filippini M. Gusrneroli and R. Eva Tetrahedron Len. 1993 34 1643. '' R.C. Larock and S. Ding J. Org. Chem. 1993,58 804. '* M. Portnoy,Y. Ben-David and D. Milstein OrganornetaNics,1993 12 4734. 59 D. Badone and U. Guzzi Tetrahedron Left. 1993 34 3603. 6o J.E. Rice and 2.-W. Cai J. Org. Chem. 1993,58 1415. R.J. P.Corriu B.Geng and 1.J. E.Moreau J. Org. Chem. 1993,58 1443. 62 R.J. P. Corriu G. BoIin and J. J.E. Moreau Bull. SOC.Chim. Fr. 1993 273. 63 J. I. Levin Tetrahedron Left. 1993 34 6211. H. Finch N.A. Pegg and 3. Evans Terrahedron Lett. 1993 34 8353. G.R. Stephenson i X=H / (26) 95% oBr X i X=CHO c (27) 89% Reagents i (25),[Pd(PPh,)J Scheme 13 OprlI BnO BnoYY"'Bu3 78% Reagents i [Pd(OAc),J AsPh Scheme 14 enol ether providing bromoindoles for use in a short synthesis of hi~padine.'~ With tetramethyltin alkyl groups are transferred.Methylation of an iodo derivative of a purine nucleoside has been effected in this way.66 Cross-coupling reactions can be performed on highly elaborate intermediates. The combination of (28) with the tin-substituted chiral. dihydrofuran derivative (29)provides a good example (Scheme 14).67The catalysts in these cases were palladiumfxt)complexes. Stannylquinones can 65 T. Sakamoto. A. Yasuhara Y.Kondo and H. Yamanaka Heterocycles 1993 36,2597. 66 A. A. Van Aerschot P. Marnos N.J. Weyns S. Ikeda E. De Clerq and P.A. Herdewijn,J. Med. Chem. 1993 36,2938. 67 H.-C.Zhang M. Brakta and G.D. Daves Jr. Tetrahedron Lett. 1993 34,1571. Organometallic Chemistry 86% &B(O&)2 (31) n= 1 78%; n=2 30% Reagents i [PdCl,(PPh,)] NaOEt; ii [Pd(PPh,),] NaCO Scheme 15 be coupled with aryl iodides,68 and heteroaryltin derivatives couple similarly.69 Tin derivatives of BOC-protected anilines couple with bromochlorobenzenes in the first step of a new carbazole synthesis. The bromine in the haloarene takes part in the coupling step and the chlorine is eliminated with strong base to complete the carbazole by a benzyne rnechani~m.~~ The use of carbon-boron bonds in cross-coupling is now common (Scheme 15). A trifluoromethyl-substituted dime (30) has been linked to 4-iodonitrobenzene in this way.71In this case a boronate ester was used though often it is a simpIe boronic acid that is employed.An azacarbazole synthesis is based on this approach using iodoff uoropyridines in combination with N-protected boronic acid derivatives of aniline.72 The reaction has been employed in a synthesis of the antimicrobial arene sponge pigment fa~caplysin.~~ A bisboronic acid can be used to produce symmetrical 68 L.S. Liebeskind and S. W. Riesinger i.Org. Chem. 1993 58 408. 69 S. Gronwitz P. Bjork J. Malm and A.-B. Hornfeldt J. Orgonomer. Chem. 1993 460,127. ’O M.Iwao H. Takehara S. Furukawa and M. Watanabe Heterocycles 1993 36 1483. ” F. Jin Y. Xu and B. Jiang J. Fluorine Chem. 1993 65 11I. 72 P. Rocca F. Marsais A. Godard and G. Queguiner Tetrahedron 1993 49,49. 73 P.Rocca F. Marsak A. Gadard and G. Queguiner Tetrahedron Lett. 1993 34 7917. G.R. Stephenson (32) (33) 80% Reagents i [Pd(OAc),] K,CO,; ii [PdfOAc),] K,CO, DMF Scheme 16 doubly-extended structures such as the tetrapyridine-substituted triphenyl derivative (31)(n = l).74Aryl triflates have been employed in the same way as aryl halides. The reaction can couple a porphyrin-substituted aryl triflate with 2,4-dimethoxyphenyl- boronic acid providing an alternative access to elaborated quinone~.~~ Couptingwith Vinyl Halides and Triflates.-Vinyl halides work well in Heck couplings (Scheme16).The reaction proceeds in the presence of unprotected OH groups even in allylic alcohols and has been performed without racemization on optically active ally1 alcoholin an enantioselective direct synthesis of dien~ls.’~ Palladium acetate and silver acetate or carbonate were used in this coupling.In a simiIar reaction (using palladium acetate and potassium carbonate) intramolecular cyclization of (32) to form the taxoI intermediate (33) proceeded with concomitant oxidation of the allylic alcohol in the produ~t.~’ Another intramolecular Heck coupling7’ is notable because of the inversion of geometry in the exocyclic alkene in the product (34). Vinyl halides are useful in cross-coupling. Combination with vinyl tin coupling partners provides an attractive route to conjugated polyenes (Scheme 17).The tetraene building block for calyculins has been prepared in this way.79 Intramolecular coupling of the same type closes the macrocyclic ring in (35).80 A still more ambitious 74 M.Beley S.Chodorowski,I.-P. Collin and J.-P. Sauvage Tetrahedron Lett. 1993,34,2933. 75 C.-S. Chan C. C. Mak and K. S. Chan Tetrahedron Lett. 1993,34 5125. 76 T. JefFery TetrahedronLert. 1993,34 1133. 77 1.J. Masters D. K. lung,W. G.30rnmann S. J. Danishefsky and S.de Gala Tetrahedron Lett. 1993,34 7253. 78 V.H. Rawal and C. Michoud J. Org. Chem. 1993,58,5583. 79 F. Yokokawa Y. Hamada and T. Shioiri Tetrahedron Lett. 1993 34,6559. 80 G. Pattenden and S. M. Thorn SYNLETT 1993,215. Organometallic Chemistry 231 SnBu3 88% Ncpf (35) 37% Reagents 1 [PdCl,(CH ,CN),] DMF ; ii [Pd(AsPh )J ; iii trans-1,Z-bis( tributyIstanny1 fethyne [PdCl,tCH,CN),j DMF-THF Scheme 17 cross-coupling constitutes the key step in a total synthesis of raparnycin (36).Here 1,2-di(tributylstannyl)etheneis coupled with a pair of vinyl iodide end-groups to complete a triene and close the macrocycle in the target Palladium dichloride or triphenylphosphine complexes are generally used in these reactions though in the case of the formation of (35)triphenylphosphine proved ineffective and the triphenylarsine analogue of the catalyst was required. Enantiomerically pure *’K. C.Nicolaou T. K. Chakraborty,A. D. Piscopio N. Minowa and P. Bertinato J. Am.Cltern. Soc. 1993 115 1 IS,4419. 232 G R . Stephenson dienylsulfoxides can be obtained by coupling tributylvinyltin with a sulfoxide-substituted vinyl bromide.’’ An unusual coupling of distannylethene was used to link two bromocyclooctatetraenes.83Boronic acids are often used in coupling with vinyl halides.In a synthesis of belamcandaquinones a substituted arylboronic acid is coupled with a bromoquinone derivative by [Pd(PPh,),J catalysis and sodium carbonate.84 This reaction is the converse of the quinone elaboration illustrated in the preceding section. Vinyl triflates are used in coupling reactions with vinyltin reagents.85 This type of coupling has been applied to polyene synthesiss6 and the elaboration of aromatic rings87 by organotin reagents. Vinyltriflates couple with alkyl- alkenyl- and aryl- boronic acid derivatives and other organoboron compounds.88 3-Indoleboronic acids have been used in similar couplings to form 3-substituted indoles.89 Carbapenems have been obtained by Suzuki cross-coupling between boronic acid derivatives and vinyltriflate functionality in the carbapenem unit.90 Nucleophilic Reagents in PalIadiurn-catalysed Cross-coupling.-NucleophiIic species are commonly used in cross-coupling reactions.One of the most general procedures employs acetylide reagents. TypicaI conditions involve besides the palladium catalyst the presence of copper([) iodide and an amine base in the reaction mixture. Coupling with aryl halidesg1 and with heterocyclic derivativesg2 illustrate this reaction. Considerable attention has been paid to the elaboration of uracils and pyridines. Protected uracil derivatives couple with propargyl alcohols and ketones under the typical copper iodide condition^.^^ This type of coupling can be performed with en01 triflate derivatives of pyrimidinucle~sides.~~ Propargyl alcohols couple with aryl haIides in a reaction that has been used in the early stages of the synthesis of water-soluble phthalocyanine derivatives destined for use in the photosensitized inactivation of cancer cells and vir~ses.’~ Chiral propargyl alcohoIs (37) have been employed,96 and retain their stereointegrity during the coupling process (Scheme 18).The product was taken on in another palladium-cataiysed alkyne addition step to complete a synthesis of lipoxin B,. The use of a coupling step to circumvent the need for protecting groups on the alcohols in this synthesis of (38) (of which only reduction is required to complete the tetraene heart oflipoxin B4)is an important advantage.The synthesis of polyenynes in a fashion similar to that illustrated in Scheme 17 is a typical application of this type of 82 R. S. PaIey and A. de Dios Tetrahedron Lett. 1993,34 2429. 83 D.A. Siesel and S. W. Staley Tetrahedron Lett. 1993,34 3679. 84 Y. Fukuyama Y. Kiriyama and M. Kodama Tetrahedron Lett. 1993,34 7637. 85 I.N. Houpis L. DiMicheIe and A. Molina SYNLETT 1993 365. 86 B.H. Lipshutz and M. Alami Tetrahedron Lett. 1993,34 1433. ” V. Farina B. Krishnan D. R. Marshall and G.P. Roth J. Org. Chem. 1993,58 5434. ” T.Oh-e N. Miyaura and A. Suzuki .I. Org. Chem. 1993,58 2201. R9 Q.Zheng Y. Yang and A. R. Martin Tetrahedron Lett. 1993,34 2235. yo N.Yasuda L. Xavier D. L. Rieger Y.Li A. E. Decamp and U.-ff. Dolling Tetrahedron Lett. 1993,34 3211. 91 B.V. Nguyen 2.-Y. Yang and D. J. Burton J. Urg. Chem. 1993 58 7358. 92 G.GaIarnbos C. Szintay J. Tarnas and C. Szantay Heterocycles 1993,36 2241. 93 N.G.Kundu and S. K. Dasgupta J. Chem. Soc. Perkin Trans. 1 1993,21,2657. ’‘ G.T. Crisp and B. L. Flynn J. Urg. Chern. 1993 58 6614. y5 R. W. Boyle and J.E. van Lier SYNLETT 1993 351. 96 M. AIarni B. Cronsse G. LinstrumeIle L. Mambu and M. LarchevEque SYNLETT 1993 217. Organometallic Chemistry OH (37) SiMe SiMe, I Reagents i [PdCI,(PhCN),] CuI piperidine; ii [Pd(PPh,),] CuI piperidine Scheme 18 reaction. The procedures to form dienediyne system^^',^^ are effective and provide the starting point98 for work related to the neocarzinostatin series of natural products.Tribenzocyclotriynesg9 and higher polybenzopolydehydroannulenes have been pre- pared by sequences of coupling reactions (Scheme 19)between arylalkynes and aryI halides. The formation"' of (39) (n= 5) provides another fine example of large ring closure using palladium-catalysed coupling methods. In these reactions it has always been thought that the combination of organic base and copper salt produced traces of copper acetylides as the active nucleophile. In a route to building blocks for functionalized butenolides coupIing at the alkyne was performed in the presence of a 1,3-dicarbonyl compound that could also be easiIy deprotonated."' Coupling of alkynes with aryl halides however can be efficient in the presence of a typical amine base such as pyrrolidine without the presence of a copper salt.lo2 In a synthesis of aryl-and alkynyI-linked pyridine systems a key coupling between a functionalized alkyne and a similarly functionalized aryl halide was found to proceed efficiently (71-79% yield) in the presence of n-propylamine.When copper salts were used side reactions were observed.' O3 97 J. Suffert A. Eggers S. W. Scheuplein and R. Bruckner Tetrahedron Lett. 1993,34 4177. 98 K. Nakatani K. Arai and S. Terashima Tetrahedron 1993 49 1901. 99 J. D. Kinder C.A. Tessier and W. J. Youngs SYNLETT 1993 149. "O K. P.BaIdwin J.D. Bradshaw C.A. Tessier and W.J. Youngs SYNLETT 1993 853. "' A. Arcadi S. Cacchi G. Fabrizi and F. Marinelli SYNLETT 1993 55. ID' M.Alami F. Ferri and G. LinstrnrnelIe Tetrahedron Lett. 1993 34 6403. G.R. Stephenson + (39) n=5 Reagents i [Pd(PPh,),] CuI NEt Scheme 19 Not all aryl halides participate in coupling with alkynes. Efficient homocoupling of the acetylide (to form a diyne) has been reported in the presence of the iodoarene portion of 2-nitro-3-hydroxy-4-iodophenol~104 Coupling of acetylides to a second alkyne carrying a propargylic leaving group has proved to be an efficient route to 1,2-dien-$-ynes. O5 Two examples have appeared where silylalkynes participate in coupling with 2-iodoanilines (and related heterocyclic systems) to provide effective syntheses of heterocondensed pyrroles106 and substituted trypt~phans."~ In these '03 V. Grosshenny and R.ZiesseI J. Organonref. Chem. 1993 453 C19. Io4 N.G. Kundu M. Pal and C. Chowdhury J. Chem. Res. (S) 1993,432. S. Gueugnot and G. Linstrumelle TetrahedronLett. 1993 34 3853. D. Wensbo A. Eriksson T. Jeschke U. Annby S. Gronowitz and L. A. Cohen Tetrahedron Lett. 1993 34,2823. '13' T. Jeschke D. Wensbo U.Annby S. Gronowitz and L.A. Cohen Terruhedron Lett. 1993 34 6471. Organometailic Chemistry examples the silicon is retained during the coupiing step which involves palladium transfer to the alkyne and ring closure with the nitrogen atom. Frequently more potent nucleophiles are used in coupling reactions. In many cases a carbon-zinc bond initiates reaction with a palladium complex. This has been employed in the elaboration of serine-derived iodozinc derivatives of amino acids O8 and imidazole-derived organozinc lo9 and vinylzinc' lo*l reagents.Vinylzincs are often prepared in situ for example from a vinyl halide,'12 or vinyltin reagent.' Their use thus provides a direct alternative to the combination of the halides and tin compounds themselves in cross-coupling steps. Heterocyclic systems have been used. Deprotonation of N-protected indoles followed by addition of zinc chloride prepares the way for coupling with iodobenzene.' l4 In this reaction the protecting group is an electron-withdrawing group. Similar zinc chloride derivatives of indoles have been used in coupling with pyridines.' Grignard reagents have also been used even in the presence of alcohol functional groups. Boron is a Iess-common precursor for metallation but there are examples of the use of trivinylboron derivatives in transmetallation with diethylzinc prior to coupling under palladium-catalysed conditions.' 'Electrochemically prepared arylzinc halide derivatives have also been successfully employed.* Double Heteroatom Attachment.-The use of palladium-catalysed coupling conditions to form bonds to heteroatoms rather than to carbon is of growing importance (Scheme 20). Coupling of 2-brornotrifluoromethyIbenzene with hexarnethyldisilane affords (40) in 50% yield.' l9 Double silylation with concomitant dimerization of 1,3-dienes to form (41) has also been reported.'20 In the case of formation of (421 a dimethylsilyl group is introduced during the cyclodimerization of two alkynes.'" An intramolecular process adds an 0-tethered R2Si-SiR unit across an alkene.' 22 With a mixed trimethyltin-trimethylsilyl reagent tin and silicon add across n~rbornene.'~' Wexarnethyiditin can be used to replace an enol triflate by a trimethyltin unit.124 Thioboration of alkynes proceeds under palladium-catalysed conditions.12s Iodine can be introduced in place of an S02Ph group by the use of zinc iodide with [PdCl,(PhCN) J.25 The examples given in Scheme 20 indicate that all the typical lo* M. J. Dunn R. F. W. Jackson J. Pietruszka,N. Wishart D. Ellis,and M. J. Wythes S YNLETT 1993,499. '09 R. M. Turner S. V. Ley and S. D. Lindell SYNLETT 1993,748. 'Io T.L. GiIchrist and M. A. M. Healy Tetrahedron 1993 49,2543. ''I R. Rossi A. Carpita F.Bellina and P. Cossi J. Organornet. Chem.. 1993,451 33. '" E.4. Negishi M. Ay Y. V. Gulevich and Y. Noda Tetrahedron Lett. 1993,34 1437. B.H. Lipshutz M. Alami and R. B. Susfalk SYNLETT 1993,693. lL4 T. Sakamoto Y. Kondo N. Takazawa and H. Yamanaka Heterocycles 1993,36 1993. 'I5 M. Amat S.Hadida and J. Bosch Tetrahedron Lett. 1993 34 5005. R. W. Hoffman V. Giesen and M. Fuest Liebigs Ann. Chem. 1993.629. 'I7 K. A. Agrios and M. Srebnik 3. Organornet. Chem. 1993,444 15. S. SibiIle V.Ratovelamanana J. Y. NtdtIec and J. Pkrichon SYNLETT 1993,425. 'I9 P.Babin B. Bennetau M. Theurig and J. Dunoguts J. Organomet. Chem. 1993,446 135 ''O Y.Obora Y. Tsuji and T. Kawamura Organometallics 1993 12 2853. ''I K. Ikenaga K. Hiramatsu N. Nasaka and S. Matsumoto J. Org Chem.1993,58 5045. "'M. Murakami M. Suginome K. Fujimoto H. Nakamura P.G. Andersson and Y. €to,J. Am. Chem.SOC. 1993 115 6487. lZ3 Y. Obora Y. Tsuji M. Asayama and T. Kawamura Organometallics I993,12,4697. ''' T.A. Tius G.S.K. Kannangara M.A. Kerr and K. J.S. Grace Tetrahedron 1993,49,3291 T.Ishiyama K.-i. Nishijima N. Miyaura and A. Suzuki J. Am. Chem. Soc. 1993 115 7219. '" T.Satoh K. Itoh M. Miura and M. Nomura,Bull. Chem. Soc. Jpn. 1993,66,2121. T. Satoh K. Itoh M. Miura and M. Nomura Bull. Chem. Soc. Jpn. 1993 66,2121. G.R. Stephenson (40) 50% (41) 85% Reagents i Me,SiSiMe, [Pd(PPh,),J HMPT; ii Mc,SiSiMe, [Pd(dba),] DMF; iii HMc,SiSnBu, CPdCI,(PPh,)J Scheme 20 types of palladium(0) and palladium(I1) catalysts can be empIoyed Multi-step Coupling Reactions-A simple two-step process adds two coupling partners across an alkene.Norbornadiene couples with 4-methoxyiodobemzene and a tributyl- tin acetylide. Effectively this is a Heck coupling reaction intercepted by a Stille coupling. Pyrolysis of the product effects a retro Diels-Alder reaction to place a cis-alkene between the acetylene and the aromatic ring.127The second double bond in norbornadiene can also participate in coupIing. A new carbon+arbon bond is formed across the base of the norbornadiene framework and a second coupling reaction completes the process. A combinationof zinc zinc dichIoride and an alkyl iodide have been used in the final stage of this reaction.128 Reaction of norbornadiene with 3-iodocyclohexenone attached two enone units to the same alkene.In the presence of triethylamine these products then cycIizedin a normal aldol reaction. A vinylzinc reagent provides the starting point for an unusual double coupling (Scheme 21) to a diiodobiaryl coreactant with axial chirality and C symmetry. The product (43) arises from a sequence of metal-rnediated stepsending in p-elimination to pIace the alkene in the five-membered ring. Since a quaternary centre has been formed the alkene moves to the next place around the ring.130 An iodocinnamate ester couples with norbor- nadiene by a double Heck process. In this reaction too an aikene is put back into the 'I' M.Kosugi T.Kimura H.Oda and T. Migita Bull. Chem. SUC.Jpn. 1993,66,3522. ''13 c.s. Li,D.C. Jou and C.H. Chcng Organometdlics 1993 12 3945. 'I9 C.-S. Li D.-C. Jou C.-H. Cheng F.-L. Liso and S.-L. Wang OrganornetaNics 1993,12 3553. lJoT.J. Katz A.M. Gilbert,M.E.Huttenloch G. Min-Min and H.H. Brintzinger TetrahedronLett. E993 34,3551. Organometallic Chemistry Q-"" (43) 66% Reagents i [Pd(PPh,),] THF Scheme 21 OMe Reagents i HCEX.,H,OH EPdCl,(PPh,),] CuI NEt Scheme 22 product by #%eIirninati~n.'~' Heteroatoms can participate in the final bond formation. Coupling of a monosubstituted alkyne with 3-bromoacrylic acid under the copper iodide-triethylamine conditions affordsbutenolides by a sequence of carbonxarbon and carbon-oxygen bond formations. I 32 2-Iodobenzoic acid couples with alkynes in a similar fa~hi0n.I~~ The quinolinofuren (44)can be prepared by attachment of an acetylide to a vinylhalide and trapping of the oxygen atom after tautomerization of the amide (Scheme 22).Benzofurans can also be obtained.134 1,3-Dicarbonyl compounds are precursors to furan ring systems in a tandem coupling pracess in which tautomerization to the enol form completes the product structure.13s In all these reactions an intermolecular initial coupling is followed by an intramolecular process. With a l-en-6-yne a sequence of three carbonxarbon bond formations is possible to effect a [2 + 2 -k 21 cycIoaddition.'36 An alternative way to combine inter- and intramolecular steps is to place both the initial site of reaction and the first receiving carbon-arbon multiple bond within the 13' R.Grigg P. Kennewell A. J. Teasdale and V. Sridharan Tetrahedron Lett. 1993 34 153. 132 X. Lu X. Huang and S. Ma Tetrahedron Lett. 1993 34 5963. 13' N.G. Kundu and M. Pal 1.Chem. Soc. Chem. Commun. 1993 86. 134 J. Reisch P. Nordhaus and T. Pfiug J. Heterocydic Chem. 1993,30,1161; I. Candiani S. Dekrnardinis W. Cabri M. Marchi A. kdeschi and S. Penco SYNLETT 1993 269. A. Arcadi S. Cacchi R.C. Larock and F. Marinelli Tetrohedron Lett. 1993 34 2813. 13' S.&Own. S. Clarksan R. Grigg and V. Sridharan Tetrahedron Lett. 1993 34 157. G.R.Stephenson (45) 50% Reagents i Bu,SnC=CCH,OTBDMS [Pd(PPh,),j THF; ii [PdCI,(PPh,),],CuI,Et,NH HC=CCH(OEt) Scheme 23 same molecule. Reaction in the presence of an external coreactant traps the final organometallic intermediate.A dienediyne motif has been obtained in this way from a 1,l-diiodoalkene equipped with a terminal alkyne group (Scheme 23). These two unsaturated portions become the 1,3-diene moiety in the dieneldiyne. The acetylides became attached in different ways. One by direct coupling with the vinyl iodide and the other in the trapping step following the closure to the pendent alkyne to complete (45).13'The control of stereochemistry at the exocyclic alkene in this reaction is an important feature and is determined by the syn stereochemistry of metal-mediated doubIe addition to the alkyne. In a variant of the reaction a 1,1-dibromoalkene was used with palladium acetate and triphenyIphosphine as the catalyst system. One equivalentof a tributyltin derivative of a protected propargyl alcohol was employed to complete the coupIing reaction.The intermediate obtained in this way contained one remaining vinylbromide unit and was coupled with a second propargyl alcohol derivative using the copper iodide method.138 The final trapping can also use a copper-mediated acetylide addition. An example that starts through transmetallation to produce an aIkyizinc reagent from an alkyl iodide proceeds by intramolecular cyclization to a pendent alkene. This produces an intermediate that couples to a propargyIic ester.139 A similar strategy but in a different ring size and with the vinyl halide at an internal position (Scheme 241 gives access to an exocyclic 1,3-diene which can couple to a vinyltin derivative.In this way a route to the diene portion of vitamin D can be achieved.14' In a similar cyclization an exocyclic vinylbromide derived from a steroidal CD fragment has been used to terminate the coupling pro~ess.'~' Since the metal moves through the molecule with each successive carbon-carbon bond formation an extensive series of new bonds can be made in a single reaction. This forms the basis of the palIadium zipper polycyclization process (Scheme 25).142Three new carbon<arbon bonds and three rings are formed in the cyclization leading to (46). In the route to (47),reaction is initiated at the vinyl halide with cyclization occurring in J. M. Nuss R.A. Rennels and B. M. Levine J. Am. Chem. SOC. 1993 115,6991. 136 S. Torii H.Okumoto T. Tadokoro A. Nishimura and M.A. Rashid Tetrahedron tett. 1993,34,2139. 13' H. Stadtmiiller C.E. Tucker A. Vzupel and P. Knochei Tetrahedron Lett. 1993,34,791 I. J. M. Nuss M. M. Murphy R. A. Rennels B. H. Heravi and B. J. Mohr Tetrahedron Lett. 1993,34,3079. B. M. Trost and J. Dumas Tetrahedron Left. 1993 34 19. B.M.Trost and Y. Shi J. Am. Chem. Soc. 1993 115 9421. Organometallic Chemistry TBDMSO TBDMSO 72% Reagents i [Pd(PPh,),] THF Scheme 24 89% majordiastemisomer (4) turn at each of the two alkene links in the right-hand portion of the substrate.143 This type of cyclization has been used in the first total synthesis of ( f)-scopadukic acid B. 144 In this case oxidative addition to an aryl halide initiated the reaction sequence. Heteroatom groups can become involved in the termination of tandem palladium coupling reactions.Intramolecular Heck cyclization of a vinyl bromide to an alkene has been combined with carbon-nitrogen bond formation to a terminal NHTs '43 D.3. Kucera S.J. O'Connor and L.E. Overman 3. Org. Chem. 1993 58 5304. 144 L. E. Overman D. J. Ricca and V. D Tran 3. Am. Chem. SOL 1993 115 2042. 14' G. D. Harris Jr. R.J. Herr and S. M. Weinreb J. Org. Chem. 1993,58 5452. G.R. Stephenson Q- N I SO2Ph R (49) 73-8296 Reagents i Pd(OAc), PPh, CH,CN CO(latm) TIOAc; ii PdCI, CuCI, LiC1 CH,CN Scheme 26 Carbanion centres can also terminate coupling reactions (Scheme 26). Car-bon-carbon bond formation by cyanide ion capture provides a good e~amp1e.l~~ In another case carbonylation is combined with Heck coupfing and anion capture to form spirocyclic derivatives of indole (49).'47 Capture by halide ions is also possible.An unusual example employing copper(I1) chloride and lithium chloride in the presence of a catalytic amount of palladium(I1) chloride couples an alkyne and two terminal alkenes with the introduction of two halide ions to form (49). Under different conditions a monocyclic product predominates indicating that halide trapping had occurred at an earlier stage in the reaction sequence.148 Unusual Coupling Processes.-In the previous sections developments over the year in the most common types of coupling reactions have been surveyed. Clear trends are emerging for the pairing of coupling partners.The same patterns apply with the more unusual coupling processes.For example a diazonium salt takes the place of the iodide or triflate in a Heck coupling process performed using palladium acetate in aqueous media.14' Vinyltin reagents have ken coupled with acid chlorides,150 and with dienes with concomitant silylation by a hexaalkyldisilane.' "Coupling of acid chlorides and Several investigations have examined cyclobutane- 1,2-diones and their haloketone analogues. Both vinyItin-acid chloride coupling with a palladium(n) catalyst in the 146 R.Grigg V.Santhakumar and V.Sridharan TetrahedronLett, 1993,34 3153 147 R.Grigg and V,Sridharan Tetrahedron Lett. 1993,34,7471. 14' J. Ji and X.Lu,SYNLETT 1993 745. lr9 S. Sengupta rtnd S.Bhattacharya J. Chem.SOC.,Perkin Trans I 1993 17 1943. IJ0J.-L. Parrain I. Beaudet A. DuchEne S. Watrelot and J. P. Quintard Tetrahedron Lett. 1993,34,5445. lJ1Y. Obora Y. Tsvji and T.Kawarnura J. Am. Chem. Soc. 1993 115 10414. W. Shihua Y. Shenggang H. Xinquan and G. Hefu Huaxue Xuebao 1993,51 393. '2 aromatic halides with heterocyclic tributyltin reagents has been examined.' Organornsta2lic Chemistry 241 Me3Si SiMe (51) 83% Me Me. Reagents i Me,SnC=CCzCSnMe,; ii Me,SiCECSiMe, [Pd,(dba),] AsPh, DMF; iii MeCECSnMe Scheme 27 presence of copper iodide” and the reverse reaction with a chlorocyclobutenone combined with a tin derivative of a quinone154 succeed. A tin-siIicon disubstituted furan has been combined with a chlorocyclobutenone in a new synthesis of benzofurans.Benzothiophenes are also accessible. 5s Hydrosilylation and pallad- ium-catalysed cross-coupling have been combined in a one-pot reaction sequence. 56 During 1993there have been a series of investigationsof palladium-catalysed coupling to heteroatom-substituted x-bound ligands (Scheme 27). The bimetallic product (50)15’and the tetrayne (51)15’ were prepared by coupling reactions of iodocyc-lobutadiene complexes. Similar coupling with a (pentaiodocyclopentadieny1)manga-nese complex leadsto (52).15’ Products (50)and (51)have been characterizedby X-ray L.S.Liebeskind M. S. Yu and R. W. Fen& 3. Org. Chem. 1993,58,3543. Is* J. P.Edwards D. J. Krysan and L.S.Licbeskind J. Am. Chem. Suc. 1993,115,9868. Is’ L.S. Liebeskind and J. Wang 3.Org. Chem. 1993 58 3550. K. Takahashi T. Minami Y. Ohara and T. Hiyama Tetrahedron Lett. 1993,34 8263. ’’’ J. E. C,Wiegelrnann and U. H. F. Bunz Orgmumetallics 1993,12 3792. ’” U.H.F. Bunz and V. Enkelmann Angew. Chem. Int. Ed. Engl. 1993,32,1653. 159 LJ.H. F. Bunz V. Enkelmann and J. Rader Organornetaliics,1993,12,4745. G.R. Stephenson (53) 45% yield 74% e-e. Me (54) 70% yield 80% e.e --OH OR (55) 76% yield 86%e.e. Reagents:i [Pd,(dba),] (R,S) -BPPFOH,CaCO, AgPO,; ii Pd(OAc), (S)-BINAP Bu,NOAc DMSO; iii [Pd,(dba),] (RFBINAP Bu'OH QCH,CH,C1 Scheme 28 crystallography. Cross-coupling to tricarbonylchromium arene compIexes is welt precedented. An asymmetric version has been reported in which the symmetrical tricarbonylchromium complex of 1,Zdichlorobenzene is coupled in the presence of a chiral auxiliary to introduce a vinyl group in place ofone of the chlorines.The resdting metal complex is chiral and is formed in 44% enantiomeric excess.16o Asymmetric Palladium-catalysedCross-coupling reactiona-At the end of the preced- ing section an example of palladium-catalysed cross-coupling induced asymmetry to form a product with planar chirality The asymmetric modification of pallad-ium-catalysed cross-coupling has been a topic of growing importance. Most work in this area concentrates on the induction of asymmetry at chiral centres at carbon. Further examples of enantiofacial differentiation in coupling with dihydrofurans have appeared.'61.162 In both cases BINAP was used as the chiral auxiliary.An I6O M. Uernura H. Nishimura and T. Hayashi Tetrahedron Lett. 1993,34,107. 16' S. Hillers and 0.Reiser Tetrahedron Lett. 1993 34 5265. F. Ozawa Y. Kobatake and T. Hayashi Tetrahedron Lett. 1993,34 2505. Organometaltic Chemistry 243 intermediate in an efficient synthesis of (-)-eptazocine also relied on BINAP to differentiate the enantiofaces ofa silyl-protected allylic alcohol. After the /&elimination step a silylenol ether was produced. Enantioselectivity in the coupling step was 91 A simiIar strategy employing a pendant ally1 alcohol and BINAP was used in an enantioseIective synthesis of physostigmine. The en01 ether product was hydrolysed to position an aldehyde correctly for a condensation reaction with methylamine in the foHowing step.64 Enantiofacial differentiation leading to the asymmetric formation of (53)(Scheme 27) has been studied in detail. Variation of the chirat auxiIiary and the use of silver additives produced a pronounced variation in the efficiency of asymmetric induction. Enantiomeric excesses ranged from 5-86% and the chemicaI yields from 444%. An additional complication was the possibility of formation of mixtures of or,/% and #?,y-unsaturated lactams. In the first example illustrated in Scheme 28 complete selectivity fur (53)was achieved.'65 Enantiotopic group differentiation holds the key to the asymmetric synthesis of (54);'66 the same strategy afforded (55),'67 which was required as a key intermediate fur a synthetic route to vernolepin.'68 An example of enantioselective Grignard cross-coupling employs a chiraI ferrocenylaminophosphine Iigand to effect an asymmetric transformation during the coupling of a chiral Grignard reagent with a vinyl bromide.'69 4 Use of Other Metals in Couphg Reactions Zirconium complexes are effective at forming carbonxarbon bonds between alkenes and alkynes.Because of the stoichiometric nature of these reactions functional groups can be introduced by exploiting the carbon-metal bonds in the final metallocyclic intermediate. Protonation can simply repIace the metal by a hydrogen. The use of iodine produces vinyl halides.' 70 The chemoselectivity of functionalization of zirconacyclopentenes has been exam- ined.I7l When a pendent alkyl halide is included in the alkene cyclization to form cyclopropanes can Two alkenes can also be coupled using dicyclopenta- dienylzirconiurn dichloride.A study with an unsymmetrical dialkene has demonstrated that the cycIization step is reversible at 75 "C. An initial kinetic product (dimerization) is converted into an intramolecular cycloaddition product over a period of time.' 73 Non-conjugated dimes have been converted into conjugated dienezirconocenes. '74 Organornetallic nucleophiles can be combined with alkynes by the reaction of dicyclopentadienylzirconiumdichloride. Carboahmination can be effected even in the presence of water.'75 163 T. Takernoto M. Sodeoka H. Sasai and M. Shibasaki J. Am. Chem. Soc. 1993 115 8477. A. Ashirnori T. Matsuura L.E. Overmann and D.J.Poon J. Org. Chem. 1993 58 6949. S. Nukui M. Sodeoka and M. Shibasaki Tetrahedron LRtt. 1993,34,4965. K Kagechika T. Ohshima. and M.Shibasaki Tetrahedron,1993,49 1773. 16' K. Kondo M. Sodeoka M.Mori and M. Shibasaki Synthesis 1993 920. K. Kondo M. Sodeoka M. Mori and M. Shibasaki Tetrahedron Lett. 1993,34 4219. 169 €3. Jedicka C. Kratky W. Weissensteiner and M. WidhaIm J. Chem. Soc. Chem. Commun. 1993 1329. 17' T. Takahashi N. Suzuki,M. Kageyarna D. Y.Kondakov and R.Hara Tetrahedron Lett. 1993,34,4811. "' T. Takahashi K. Aoyagi R. Hara and N.Suzuki J. Chem. Soc. Chem. CO~~UR., 1993 1042. 17' T. Takahashi D. Y. Kondakov and N. Suzuki Tetrahedron Lett.. 1993 34,6571. 173 D. F. Taber J. P. Louey and J. A. Lim Tetrohedron Lett. 1993 34 2243. 174 1.P.Maye and E.-i. Negishi Tetrahedron Lett. 1993,34 3359. 17' P. Wipf and S. Lim Angew. Chem. Int. Ed. Engi. 1993,32 1068. 16' G.R. Stephenson Reagents i CpJrMeC1; ii hept-1-ene; iii CO Scheme 29 Catalytic amounts of dicyclopentadienylzirconiurn dichloride have been used to promote the addition of alkyl Grignard reagents to alkyne~.'~~ Oxygenated vinyl- lithium reagents cart also be linked to alkynes. The resulting metallocycies are cIeaved to dienes in protic solvents or can be carbonylated in a cyclojmtenone synthesis. The bicyclic product (56) was obtained in this way (Scheme 29).'" Dimethyltitanocene reacts with alkynes to form metallocyclobutenes. Subsequent addition to a ketone provides a route to homoallylic alcohols.17* Organic nitriles can replace the alkyne in this reaction sequence.There has been a structural study of a titanium ester homoenolate derivative. 79 Dicyclopentadienyltitaniurn derivatives of arenes also react well with alkynes. After protonation substituted styrenes such as (57) are obtained (Scheme 30). This reaction sequence proceeds through a titanium aryne intermediate (58) and the metallocycle (59).' 8o Nickel catalysts couple aryl triflates to form biaryls in the presence of zinc or potassium iodides. *' A combination of nickel dichloride and chromium dichloride has been used to convert vinyl triflates into nucleophilic species for reaction with carbonyl groups in work that completes the tricyclic framework needed for the taxane ring system.'82 The dimerization of alkynes using a rhodium catalyst can proceed in two different fashions.Under acidic conditions followed by exposure to carbon monoxide enynes are produced. On the other hand if reaction with carbon monoxide occurs prior to acidification a disubstituted butatriene is obtained.'83 A dicationic benzene(ethy1- tetramethylcyclopentadieny1)rhodiumcomplex promotes oxidative coupling of phen-ol~.'~~ (PentamethyIcyclopentadieny1)rutheniumcomplexes are used to codimerize conjugated dienes with 1,5-dienes. Intermediate complexes can be obtained or catalytic conditions afford direct access to the free pulyenes.l8' A mechanistic study has been made of reactions between cyclopentadienyl- and (pentamethylcyclopenta- dieny1)ruthenium cations and conjugated dienes and ethyne.IB6 ''' T.Takahashi K. Aoyagi V. Denisov N. Suzuki,D. Choueiry and E.-i. Negishi Tetrahedron Lett. 1993 34,8301. M.C. J. Harris R. J. Whitby and J. BIagg SYNLETT 1993 705. 178 N.A. Petasis and D.-K. Fu Organometallics 1993 12 3776. P. G. Coui T. Carofiglio and C. Floriani Organometallics 1993 12 2845. J. Campora and S. L. Buchwald Organomerallics 1993 12 4182. A. Jutand and A. Mosleh SYNLETT 1993 568. M.H. Kress R. RueI W. H. Miller and Y. Kishi Tetrahedron Lett. 1993 34 6003. i83 M. Schafer N. Mahr J. Wolf and H. Werner Angew. Chem. Int. Ed. Engl. 1993 32 1315. 184 A.G. M. Barrett T. Itoh and E. M. Wallace Tetrahedron Lett. 1993 34 2233. K. Masuda H. Ohkita S. Kurumatani and K. Itoh J. Organornet. Chem. 1993,454 C13. K.Masuda H. Ohkita S. Kurumatani and K. Itoh Urgonometallics I993 12 2221. 245 Organometallic Chemistry Reagents i hex-3-yne; ii MeOH Scheme 30 Unusual I ,1-dizinc carbenoid organometallics have been under investigation in Paris."' These species can be combined with Grignard reagents and after copper modification propargylic esters to produce coupling products. Full details have appeared of homologations of copper reagents using (iodomethy1)zinc iodide.' '* Boron-zinc transmetallation has also been investigated. 89 Zinc/copper chemistry gives rise to new a-amino acid y-amine equivalents and so to direct methods for the synthesis of enantiomerically pure protected amino acids.lgO 5 The Nicholas Reaction The chemistry of dicobalt-stabilized propargyl cations continues to deveIop.The main stepforward comesfrom the laboratory of Nicholas himself where chid metal clusters [(HC~CR)CoL(CO),Co(Co,llhave been used in stereoselective propargyl addition rea~tions.'~' ChiraI allylboron reagents have also been empIoyed with propargyl aldehyde complexes."' Diastereoselectivity is good in Lewis-acid promoted aldol reactions between trimethylsilylenol ethers and dicobalt complexes of pr~pyna1s.'~~ Stereoselectivity is also good in the addition of boron enolates to (propargyl ether)dicobalt c~mplexes.'~~ This reaction (Scheme 31)has been employed in a formal total synthesis of thienarny~in.'~~ After the enolate addition step oxidative removal of 18' F. Chemla 1. Marek J.-F. Normant SYNLETT 1993 445.188 A. Sidduri M.J. Rozema and P. Knochel J. Org. Chem. 1993,58 2694. 18' F. Langer J. Was and P. Knochel Tetrahedron Lett. 1993,34 5261. 19' R.F. W. Jackson N. Wishart and M.J.Wythes SYNLETT 1993 219. 19' A.J. M. Caffyn and K.M. Nicholas J. Am. Chem. SOL 1993 115,6438. lg2 P. Ganesh and K. M. Nicholas J. Org. Chem. 1993 58 5587. C. Mukai 0.Kataoka and M. Hanoaka J. Chem. SOC.,Perkin Trans. 1 1993 563. P.A. Jacobi and W. Zheng Tetrahedron Lett. i993 34 2581. 19' P. A. Jacobi and W. Zheng Tetrahedron Lett. 1993 34 2585. G.R. Stephenson t ii I OSi$uPr (60)79% Reagents I Bu,BOTf; ii ceriurn(1v) scheme 31 the metal with ceric ammonium nitrate afforded the key building block (60). Intramolecular reactions between silyl end ethers and propargyl cations have been Arnine~’~’ and indoles’98 react well with propargyI cations.A crystal structure study of metal-cluster-stabiIized propargyl cations has been performed. 99 AIkynyl derivatives of pyranoses easily invert their stereochemistry when converted into hexacarbonyIdicobaIt complexes.”* Carbon-oxygen bond cleavage under acidic conditions must be combined with the interconversion of stereoisomeric propargyl cation complexes to account for this observation. The effect of modification of the alkyne portion of estradiol on the binding of organometallic units in the estradiol receptor provides evidence fur the irreversible covalent attachment of the metal- labelled steroid to its specific receptor.’*’ The Pauson-Khand reaction was discussed in Section 2.A format total synthesis of loganinehas made use first of stabilization of positive charge CL to the cobalt complexed alkyne and second a Pauson-Khand step to complete a bicyclic cyclopentenoneZo2 196 E. Tyrrell P. Heshmati and L. Sarrazin SYNLETT 1993 769. 19’ K.-D. Roth and U. Muller Tetrahedron Lett. 1993 34 2919. 198 K.-D. Roth SYNLETT 1993 529. IP9M. GruselIe H.EI Hafa M. Nikolski G. Jaouen J. Vaissermann L. Li and M.J. McGlinchey Organometallics 1993 12 4917. S. Tanaka T. Tsukiyama and M. Isobe Tetrahedron Lett. 1993 34 5757. D. Osella G. Dutto G. Jaouen A. Vessieres P. R. Raithby L. De Benedetto and M. J. McGlinchey Organometallics 1993 12 4545. ’” N. Jeong B.Y. Lee S.M.Lee Y.K. Chung and S.-G. Lee Tetrahedron Lett.i993,34,4023. Urganometallic Chemistry 77% Reagents i NaCH(C0,Et)(C02Bu') NEt, [PdCl,(CH,CN,)]; ii CO;iii Me,SnCH=CMe scheme 32 6 Transition Metal Alkeue and Arene z-Cornplexes q2-Cornplexes-Pa11adium-catalysed nucleophilic addition to alkenes and pallad- ium-catalysed coupling reactions are closely related by the similarity of their reaction products though mechanistically the reactions are distinct. Intramolecular versions are popular. An example leading to 2-alkenyltetrahydrofurans uses one double bond link of an alIene as the metal-bound electrophilic centre.203 Combining nucleophile addition with a subsequent cross-coupling step provides a good use for the metakarbon a-bond that is formed when a 7t-bound alkene acts as an electrophile.Intramolecular closure of a pendent amine to an allene has been combined with coupling to an aIkyl halide.204 A similar procedure again using an allene but in the presenceof carbon monoxide and methanol combines nucleophilic attack by a NHTs group with carbonyl insertion to place an ester at the end of the double bond to promote the site of nucleophile addition.20s Unlike the preceding examples which used palladium@) catalysts and a base (typical conditions for coupling reactions) this carbonyl insertion example employs palladium dichloride with copper(i1) chloride as an oxidant. These are typical conditions for a Wacker oxidation modified for carbonylation. Intermolecular nucleophilic addition to an enone carrying a cyclic chiral auxiliary at nitrogen is followed by carbonyl insertion in the early steps of an enantioselective total synthesis of ( + )-negamycin (Scheme 3Q206 An intramolecular closure to a 1,3-diene combined with chlorination by the action of lithium chloride under palladium acetate catalysis illustrates further extensions of the methods for 1,6difunctionaIization of dienes under investigation in Backvall's Hexacarbonylmolybdenum-TMNO has been reported to affect cyclization of pendent OH groups to alkynes to afford substituted dihydrofuran compIexes.208 '03 R.D.Walkup L. Guan M. D. Mosher S.W. Kim and Y. S. Kim SYNLETT 1993,88. M. Kimura N. Saeki S. Uchida,H. Harayama,S. Tanaka K. Fugami and Y. Tamaru TetruhedronLert. '*' I. W. Davies D.I.C. Scopes and T. Gallagher SYNLETT 1993,85.1993,34 7511. '06 J.J. Masters and L. S. Hegedns 3. Org. Chem. 1993,58 4547. '07 J. E. Bickvall K. L. Cranberg P.G.Andersson R. Gatti and A. GogolI J. Org. Chem. L993,58,5445. '** F.E. McDonald C. B. ConnoIly M. M. Gkason T. B.Towne and K. D. Treiber,J.Org. Chem. 1993,SS. 6952. G.R. Stephenson (COhF:'Yp '-BF3 I (61) 45% Reagents i KOBu' CH,CI,; ii cerium(rv) CO MeOH Scheme 33 In stoichiometric examples development of the chemistry of cationic dicar- bonyl(cyc1opentadien y1)iron-alkene complexes continues. Again intramolecular nuc- leophile attack has been the focus of attention (Scheme 33). Suitable electrophiles can be obtained by the reaction ofketones with allyliron complexes in the presence of BF,. Treatment of the resuiting q'-complex with base effects cyclization which under oxidative carbonylation conditions can ultimately replace the iron atom by an ester group.In this way (61) can be obtained.209 Cyclopentadienylruthenium-nitrosyl-phosphine complexes of 1,3-dienes and enynes provide interesting q2-cornplexes that undergo linkage isomerism.' ' Work continues on q2-styrene complexes" and side-on aldehyde q2-Enone complexes have also been investigated." Following work on tricarbonyliron complexes of enones the Thomas group has now extended this investigation to B,y-unsaturated esters and amide~.~'~ New examples of cyclic alkyne complexes have employed the dicarbonyl(cyclopentadieny1)manganese group to form an q2-adduct which rearranges to a 1,2-~yclooctadiene complex.' ' q3-Complexes.-The regioselectivity of nucleophilic addition to q3-transition metal complexes is a topical issue.Further results with cationic iridium complexes from the Stryker group illustrate the generality of reaction pathways for nucleophilic addition at the centre ofthe q3-unit.'l6 Examples with neutral q3-palladium chloride dimers have now also been Both examples use ketone enolates as the nucleophile though in the palladium case the presence of TMEDA is important and the use of a carbon monoxide atmosphere improves yields which can be as high as 70%. With an ally1 bromide as the starting material central attack has been observed in a '09 S. Jiang and E. Turos Organometallics 1993 12 4280. 'Io T.-S. Peng Y. Wang A.M.Arif and J.A. Gladysz Organometallics 1993 12 4535. M. A. Dewey Y&Zhou Y.Liu and J. A. Gladysz Urganametallics 1993 12 3924. 'I2 D. P. Klein,N. Q. Mendez,J. W. Seyler,A. M. Arif,and J. A. Gladysz J. Organornet. Chem. 1993,450,157. Y.Wang F.Agbossou D. M. Dalton Y. Liu A.M. Arif and J.A. Gladysz Organometallics 1993 12 2699. C.Alt S. L. Griffiths C. F. Marcos M. M. Salter A.M. Z. Slawin S.E.Thomas and D.J. Williams J. Chem. Soc. Chem Comun. 1993 201. *I5 S. M. Coughlan and G.K. Yang J. Organornet. Chem. 1993,450 151. '16 K. E. Schwiebprt and J. M. Stryker Organometallics 1993 12 600. 'I7 A. Wilde A. R. Otte and H. M. R. Hoffmann J. Chem. SOC.,Chem. Curnun. 1993 615. Organometallic Chemistry aO”-im 249 I (62) 70% Reagents i Pd(OAc), PPh, NaHCO Scheme 34 palladium-catalysed process; selectivity to favour central attack can be as high as 97 :3 under the correct conditions though in other cases exclusive terminal attack was observed.The nucleophile was a trimethylsilylketene acetal and the reactions were performed in the presence of thallium acetate.218 The centre of an q3-dienyl complex corresponds to the vinyl-substituted end of the q3 unit. Stabilized-enolate addition under palladium acetate catalysis can be manipulated to favour central attack by the presence of trib~tylphosphine.~”The position of the acetate leaving group in the starting material has also been found to influence regiochemistry showing that the approach of the nucleophile can be influenced by the nature of the ion pair after departure of the leaving group.22* Manipulation of synlanti ratios continues to receive attention.There has been a detailed investigation of dynamic processes in q3-paIladium complexes,22 and molecular mechanics parameters fur the n-ally1 palladium moiety have been re-ported.z22 As with q2-chemistry so too with q3-examples; Combination of z-ally1 chemistry with coupling reactions is an important progression (Scheme 34). Silylation of an allylic acetate with hexamethyldisilane can be achieved with a palladium catalyst.223 In another example coupling to an alkene followed by a hydrogen shift forms a y3-allyl complex which is picked up by an internal nucleophile. In this way the cyclic ether products (62) can be obtained.224 Allylic acetates and alcohols can be cyclized to pendent alkenes.In the first case,225 the reaction is a metallo-ene process and was combined with coupling to a vinyltin species. In the second example the tether between the alIyl moiety and the alkene was short and a substituted cyclopentadiene was Ring opening of viny10xetanes~~~ and #3-lactams228 has been combined with palladium-catalysed coupling reactions. AlIylic displacement can be accompanied by 218 M. Formica A. Musco and R. PonteIlini J. Mol. Card. 1993 84 239. ’I9 Y.I. M. Nilsson P. G. Andersson and J. E. BiickvaIl 1.Am. Chem. SOC.,1993 115 6609. ’” B.M. Trost and R.C. Bunt Tetrahedron Lett. 1993 34 7513. ’” S. Hansson P.-0.Norrby M. P.T. Sjogren and 3.Akermark M. E. Cucciolito F. Giordano and A. Vitagliano Organometullics 1993 12 4940.12’ P.-0. Norrby B. Akermark F. Haeffner S. Hansson and M. Blomberg J. Am. Chem. SOC. 1993 115 4859. 223 Y. Tsuji S. Kajita S. Isobe and M. Futano J. Org. Chem. 1993 58 3607. 224 R.C. Larock N.G. Berrios-Pefia C. A. Fried E. K. Yum C. Tu and W. Leong J. Org. Chem. 1993,!58 4509. 225 W. Oppolzer and J. Ruiz-Montes Helu. Chim. Am 1993 76 1266. 2z6 T. Zair C. Santelli-Rouvier and M. Santelli Tetrahedron 1993 49 3313. ’” R.C. Larock S. Ding and C. Tu SYNLETT 1993 145. ”* R. C. Larock and S. Ding Tetrahedron Lett. 1993 34 979. G.R. Stephenson OH Reagents i [PdCI2(C,H,),] EtOH CO Pr’,NEt NaBr rnaleic anhydride Scheme 35 carbonylation as illustrated for the opening of the vinyl epoxide (53)(Scheme 35).229 In this case palladium catalysis was used but alIylic carbonylation (with a phosphate Ieaving group) employing catalysis by a rhodium carbonyl duster has also been reported.230 Work continues to extend the range of nucleophiles that can be employed in palladium-catalysed allylic displacement.Trirnethylsilyl~yanide,~~ triphenyisilanol (as a water and an ahminate formed in situ froman aluminium acetylide and dimethyl ethylidenemal~nate,~~~ have a11 been used. Interest in bisphosphonates as enzyme inhibitors has revived work on their use as nucleophiIes in pallad-ium-catalysed aIlylic di~pIacernent.~ 34 N-protected amines carrying two Boc groups have been employed as nudeophiles in a reaction that forms intermediates which afford esters of N-protected amino acids after ozonolysis of the alkene formed by aIlylic substitution.235 This approach has aIso been used in a synthesis of (+)-N6-hy-dro~ylysine.’~~ By the use of BPh, an oxyborane leaving group has been brought into play to provide a new way to use allylic alcohols directly in palladium-catalysed aIlylic substitution.237 Less-common substitution patterns have been introduced on stoichiornetric q3-ligands in palladium chIoride dimers.Trialkyl~ilyI~~~ and formyl and acetal substituent~~~~ have been examined. Synthetic applications this year (Scheme 36) have featured some of the less cummun types of nucIeophiles. Palladium-catalysed allyiic rearrangement of propenyI-3-py- rimidinyl carbonatesz4’ have been used in the preparation of pyrimidine nucleoside analogues I The Boc-protected hydroxylamines (referred to earlier) have been used in a synthesis of ( + )-laminine.242 In syntheses of buspirone (65)and gepirone a 1,4-disubstituted but-Zene is used to introduce a simple C,H strap by a sequenceof two palladium-catalysed allyIic displacements followed by hydrogenation to remove 229 I.Shimizu T. Maruyama T. Makuta and A. Yamamoto Tetrahedron tett. 1993,34 2135. 230 Y. Imada 0.Shibata and S.4. Murahashi J. Orgonomet. Chem. 1993 451 183. 231 Y. Tsuji N. Yamada and S. Tanaka J-Urg. Chem. 1993,sS 16. 232 B.M,Trost N. Ito and P. D. Greenspan Tetrahedron Lett. 1993 34 1421. 233 B. M. Trost and C.-J. Li Tetrahedron Lett. 1993 34 2271. 234 R. Sulsky and D. R. Magnin SYNLETT 1993 12 933. ”’ R.lumnah J. M.J.Williams and A. C. Williams Tetrahedron Lett. 1993 34 6619. ”15 J. P. Genet S. Thorimbert and A.4. Touzin Terrohedron Lett. 1993 34 1159. 237 I. Starj I.G. Stari and P. KoEovlky Tetmhedron Lett. 1993 34 179. S. Ogoshi W. Yoshida K.Ohe and S. Murai Organometallics 1993 12 578. 239 S. Ogoshi K. Hirako J. Nakanishi X.Ohe and S. Murai J. Orgonomet. Chem. 1993 445. C13. 240 M. L. Falck-Pedersen T. knneche and K. Undheim Acto Chem. Scad. 1993 47 63. ’*’ M. L.Falck-Pedersen T. Benneche and K. Undheim Acto Chem. Scond. 1993 47 72. ’‘’ J. P. Genet S. Thorimbert S. Mallart and N. Kardos Synthesis 1993 321. OrganometaHic Chemistry 25 1 (64) 95% 80% (65) 70% Reagents:i [PdCl,(PhCN),],THFor DMF; ii 4-chiorobut-2-enyl acetate [Pd(PPh,)J; iii [Pd(PPh,),]; iv H,,Pd EtOH Scheme 36 An intramolecular N-alkylati~n'~~ the central alkex~e.~~~ has made use of the selectivity between halide and oxygen leaving groups at the two ends of an alkene.An example (Scheme 37) that illustrates the use of q3-complexes to prepare optically active silylallylamines makes use of the trimethylsilyl directing group in a catalytic process.245 Similar silicon-directed displacements of (EtO) PO from chiral allyl-phosphates with methyImagnesium bromide proceed in a highly regiocontrolled manner.246In another example with optically active allylic acetates manipulation of leaving-group selectivity gives access to both R and S products from a biologically derived monoester of a rnes0-2-ene-l,4-diol.~~' Since biotechnology is used to gain 243 D.L.Kuo Heterocycles 1993 36,1463. 244 K. Tadano K. Takao Y. Nigawara E. Nishino I. Takagi K. Maeda and S. Ogawa SYNLETT 1993 565. *" H.Inarni T. 110 H.Urabe F. Sam Tetrahedron Lett. 1993 34,5919. *" H. Urabe H. Inarni and F. Sato J. Chem. Soc. Chem. Comun. 1993 1595. 247 J.-E. Backvall R. Gatti and H.E. Schink Synthesis 1993 343. G.R. Stephenson Me$i 1 NHBn OKoMe 0 99%(< 98%e.e.> Reagents i,BnNH, [Pd,(dba),] PBu Scheme 37 entry to the optically active allylic acetate the stereodivergence of the two routes is an important feature. Further advances have been made in reactions employing trimethylenemethane complexes. Cycloaddition to N-to~ylimines,~~’ and to sugar-derived to ynone~,’~~ acrylates’ are developments this year.The chemistry of (oxodi-methy1enemethane)paMadium and -platinum complexes has been reported. * The complexes form metallacyclobutanones. A mild and selective method for palladium-catalysed dealIylation has been Allyloxycarbonyl protecting groups have been removed by pallad- ium-catalysed reactions253 and the procedure (performed in aqueous media) has been applied to liberation of N-protected amino acid derivative^.^'^ EnantioselectivePalhdium-catalysed AllyIic Displacement.-The use of chiral auxili- ary Iigands to direct palladium-catalysed allylic displacement is a major growth area. A range of chefating phosphine auxiliaries have been applied to the differentiation of enantiotopic allylic leaving groups.By use of a 1,Zarninoalcohol as the nucleophile the asymmetric construction of chiral morpholines and piperazines has been achieved.255A more common substrate is a 1,3-diphenyI substituted allylic alcohol which becomes prochiraI once the leaving group has been displaced. A range (66bf74) of heteroatom-functionalized chiral bisphosphine ligands has now been employed in this reaction.256 The best optical yieId was obtained with (66)(BHMP-COOH) which proved much more effective (49% e.e.1 than the corresponding t-butyl ester. This indicates a role for the pendent carboxylic acid group. The 1,2-diamine derivative (57) with a C,-symmetric pyrrolidine at each end has also proved effective with an e.e as high as 91%.2s7A more unusual nitrogen-containing chelating Iigand (68) has been prepared from menthone.Asymmetric aflylic substitution proceeded in 84% e.e.258 248 B. M. Trost and C. M. Marrs J. Am. Chem. SOC.,1993 115 6635. 249 B. M. Trost S. Sharma and T. Schmidt Tetrahedron Lett. 1993 34 7183. 250 M. Janson I. Kvarnstrom S. C.T. Svensson B. Classon and 3.Samueisson Synthesis 1993 129. 251 A. Ohsuka T. Fujirnori,T. Hirao H. Kurosawa and I. Ikeda J. Chem.SOC. Chem.Commun. 1993 i039. 252 F. Garro-Helion A. Merzouk and F. GuiM J. Org. Chem. 1993 58 6109. 253 J. P.Genet E. Blart M. Savignac,S. Lerneune S. Lernaire-Audoire and J. M. Bernard SYNLETT 1993 680. 254 J. P. GenEt E. Hart M.Savignac S. Lemeune and J.-M. Paris Tetrahedron Lett. i943 34 4189. 255 Y. Uozumi A. Tanahashi and T. Hayashi J. Org. Chem.1993 58 6826. 256 A. Yamazaki T. Morirnoto and K. Achiwa Tetrnhedron Asymmetry 1993,4 2287. ”’ H. Kubota M. Nakajirna and K. Koga Tetrahedron Lett. 1993 34 8135. M.Bovens A. Togni and L. M. Venanzi J. Organomer. Chern. 1993 451 C28. Organumetallic Chemistry 253 Reiser2" has been using the ligand (69) which combines two nitrogen atoms with a pair of pendent oxygen donors. i$.vN4 Me Me Me Me I %> PPhz N OSiMq'Bu OSiMQ'Bu R TBDMSO (69) 00) (71) Work continues on ligands in which phosphorus and nitrogen donors are combined with a view to distorting the coordination sphere of palladium metal. The groups of Helmchen260and Williams2" have evaluated (70) while Pfaltz262 has afso worked with (71). Optical yields greater than 37% enantiomeric excess are now obtained in these reactions.Sulfur and nitrogen centres are combined in the thiophene derivative (72)263and in the thiophenol derivative (73) (X = SMe)254 and the corresponding phenol (X = OH)265and diarylthioether (73) (X = SPh).266 In (74) the spacing between the sulfur and nitrogen atoms is varied.266 The range of chiral auxiliaries illustrated is a clear indicator of how important this aspect of asymmetric synthesis has become. Stoichiornetric iron carbonyl complexes have also been used as cationic electrophiles 259 0. Reiser Angew. Chern. Int. Ed. Engl. 1993 32 547. J. Sprinz and G. Helmchen Tetrahedron Lett. 1993 34 1769. 260 261 G.J. Dawson C.G. Frost J. M. J. Williams and S. J. Coote Tetrahedron Lett.1993 34 3149. 262 P. von Matt and A. Pfaltz Angew. Chem. Int. Ed. Engl. 1993 32 566. 263 C.G. Frost and J. M. J. Williams Tetrahedron Lett. 1993 34,2015. 264 C. G. Frost and J. M. J. Williams Tetrahedron Asymmetry 1993 4 1785. 265 B. Yang M. A. Khan and K. M. Nicholas Organometallics 1993 12 3485. 266 G. J. Dawson C.G. Frost C.J. Martin J. M. J. Williams and S. J. Coote Tetrahedron hit. 1993 34 7793. 254 G.R. Stephenson in the q3-series. Acy€ directing groups direct enol ether nucleophiles to the far end of the allyl system.267 Optically active acrylates268 and pyrrolin-2-0nes~~~ have been employed in enantioselective aIlylic functionalization steps. Amines and allylsilanes respectively were used as nucleophiles and products had enantiomeric excesses greater than 95%.q3-Ally~(dicarbonyl)cyclopentadienylmolybdenumcomplexes have been prepared from allylicdiphenylph~sphinates;'~' ruthenium complexes have been examined as catalysts for allylic di~piacement;~~' rhodium complexes to carbonylate aIlyl phosphate and an q3-propargyl complex of platinum has been studied.273The bent geometry of the q3-1-ene-2-yne unit corresponds to that of the cationic rhenium example discussed last year. Anionic $-complexes have also received attention. Functional and crystaIlographic studies have been made of the tricarbonyl(cyc1oheptatrienyl)iron complex,274 and with a new twist to palladium allyl chemistry an q3 intermediate has heen converted (by use of a dialkylzinc reagent) into an allylzinc nucleophile effectively providing the iimpolung of the electrophilic ally1 complex.275 A neutral cyclopentadienylmolyb- denum complex with an q3-ligand and chirality at the metal atom has been resolved.276 This neutral reagent serves as a nucleophile in a stereocontrolled reaction with benzaldehyde.In another organomolybdenum example a pendent enone was used in a stereoselective MichaeI reaction.277 Enolates next to dicarbonyl(q3-cyclopen-tadienyl)molybdenum complexes have been used in aldol reactions. Subsequent CO replacement by NO' prepares for a cyclization forming isoxazoles and conjugated die none^.^ q'-Complexes-New structural studies of a well-known organometallic complex is a rare event. Tricarbonyl(butadiene)iron was one of the earliest of the n-complexes to be studied; in 1993 microwave spectroscopy has provided an exceptionally detailed structural characterization of this material.279 A new heterocyclic tricarbonyliron complex containing a silacyclopentadiene ligand has been prepared.280 Ruthenium dicarbonylphosphine complexes of q4-enune ligands can be made by photolysis of tet racarbon ylru theniumphosp hine complexes.*' When nucleophiles are added to q4-ligands cationic molybdenum complexes are often used to promote electrophilicity. Indenyl(dicarbony1)molybdenurn complexes help functionalize spirocyclopentadiene by reaction with dimethyl cuprateZs2 26' T. Zhou and J. R.Green TetrahedronLett. 1993 34,4497. 268 D. Enders and M. Finkam SYNLETT 1993,401. 269 W.-J. Koot H.Hiemstra and W.N.Speckamp J. Chem. Soc. Chem. Cotnmun. 1993 156. 270 J. S. McCallurn J. T. Sterbenz and L. S. Liebeskind Organomerallics 1993 12 927. 271 S.-W. Zhand ".-a. Mitsudo T. Kondo and Y. Watanabe J. Urgnnonter. Chem.. 1993 450 197. 272 Y. Imada 0.Shibata and %-I. Murahashi J. Urganomer. Chem. 1993 451 183. 273 P. W. Blosser D.G. Schimpff J.C.GaIlucci and A. Wojcicki OrganometaMics 1993 12 1993. 274 M. AiroIdi G. Deganello G. Gennaro M. Moret and A. Sironi Organometdlics 1993 12 3964. 275 K.Yasui,Y. Goto,T. Yajima Y.Taniseki,K. Fugami,A. Tanaka,and Y.Tarnaru Tetrahedron Lett. 1993 34,7619. 276 J. W. Faller J.T. Nguyen W. Ellis M. R. Mazzieri Organometallics 1993 12 1434. 277 S.-H. Lin W.J. Cheng Y.-L. Liao S,-L. Wang,C.-H. Lee,S.-M. Peng,and R.S. Liu,J. Chem. SOC.,Chem. COMK~. 1993 1391. 278 S.-H. Lin G.-H. Lee,S.-M. Peng and R.4. Liu Organometallics 1993 12 2591. 279 S. G. Kukolich M. A. Roehrig D. W. Wallace and G. L. Henderson J. Am. Chem. Soc. 1993,115,2021. 280 M. Kako S. Oba and Y. Nakadaira J. Organometni. Chem. 1993 461 173. 281 A. Marcuzzi A. Linden and W. Von Philipsborn Helv. Chim. Acta 1993,76 976. 282 D.J. Norris J. F. Corrigan Y. Sun N. J. Taylor and S. Collins Can.J. Chem. 1993 71 1029. Organometailic Chemistry (75) 55% OR (COhFe Reagents i LDA CO; ii CF,CO,H; iii ArLi Et,O -50°C; iv Et,OBF,; v PPh,; vi [HBEtJ-; Vii SnMe,C1 Scheme 38 Neutral tricarbonyliron complexes can also react with nucleophiles (Scheme 38).An intramolecular example invoIving enolate addition to an inner position on the diene afforded the bicyclic product (75).Carbonyl insertion followed by protonation at iron and reductive elimination completes the cyclopentenone ring.283With aryllithium reagents nucleophile addition occurs at a carbonyl group.The product can be trapped with Meerwein’s reagent to form a carbene which in the presence of an incoming ligand adds to the q4-ligand to produce (76).284 Hydride addition to neutral q4-tricarbonyliron compIexes affords q3-anionintermediates and can be trapped with trimethyltin chloride.285 The anti,syn product (77) interconverts into the preferred syn,syn structure (78). Examples of highly stereoselective nucleophiIe addition at ketone groups adjacent to neutral q4-tricarbonylirondiene complexes have been reported.286 Methyllithium and triethylaluminium gave complimentary stereoselectivity .Similar reactions at imines have also been de~cribed.’~’ Stereoselective synthesis of diols from alkenes adjacent to the tricarbonyliron diene unit is now well known but an unusual epimerization at the 283 M.-C. P. Yeh B.-A. Sheu H.-W. Fu S.4. Tau and L.-W. Chuang. J. Am.Chem. Suc. 1993,115 5941. ’”J. Chen Y. Yu L. Hu and Z. Jin J. Organmet. Chem. 1993,447 113. S. Chang P.S.White and M.Brookhart Organometallics 1993 12 3636. 286 Y. Takernoto J. Takeuchi and C. Iwata Tetrahedron Lett. 1993 34 6067. ’” Y. Takemoto J. Takeuchi and C. Iwata Tetruhedron Lett. 1993,34,6069. G. R. Stephenson ii-tv e Reagents:i 2-methylpropafia1 BF,.OEt,; ii dimethyl malonate enolate; iii NO+;iv NaCO %hem&39 a-carbon has been reported through the action of tetrabutylammonium fluoride at -20 0C.288Friedel-Crafts acylation of 1,3-diene tricarbonyliron complexes has been extended to alkoxyalkylation using EtOCH,Cl with aluminium tri~hloride.~~~ In cycloheptadienone chemistry enolates developed towards an allylic position between the ketone group and the alkene can be alkylated stereoselectively with methyl iodide.290 Nitrile oxides and nitrile imides have been used in the synthesis of bicyclic derivatives of cycloheptadiene by dipolar cycloaddition reactions with tricarbonyl(q'- cyc10heptatriene)iron.~~'Cationic q4-diene cornpiexes are obtained by the reaction of electrophiles (formed from aldehydes and boron trifluoride etherate) with (q3-cy- clohexadienyl)dicarbonyl(cyclopentadieny~)molybdenum complexes.The q4 products can be taken on in reactions with nucfeophiles foIlowing a linear sequence of steps to form the bicyclic product (79)with efficient stereocontrot (Scheme 39).'" The product from the initial Lewis-acid-catalysed reaction with the aldehyde is an q4-diene complex formed with complete stereoselectivity. q5-Complexes.-Tricarbonyl(pentadienyl)iron complexes often show different proper- ties to their cyclic counterparts. In particular since they are nut locked in a ring switching between cisojd and transoid products complicates work in the acylic series. A series of disubstituted examples have now been studied in detail (Scheme 40).In the case of and (81) (X = Me293and O~bfe~~'), additiotl of triphenylphusphine affords products which retain their cisoid geometry. Carbon+arbon bond formation from (81) (X= OMe) with allyltrimethylsilane affords a transoid product with a stereodefined methyl substituent originating from the methyl group at the terminus of the dienyl system. Triphenylphosphine addition to the indenyl tricarbonyliron complex (82) however proceeds with displacement of a carbonyl group from the 288 J.-P.Lellouche A. Gibou-Barbedette and R. Grke J. Orgonomet. Chem. 1993 461 167. M. Frank-Neumann P.Bissinger and P.Geoffroy Tetrahedron Lett. 1993 34 4643. A.J. Parson and K. Chang J. Urg. Chem. 1993 58 1228. 29' A. Gambe R. Gandolfi and P. Grunanger Gnzz. Chim. Itat. 1993 123 209.Wang Y.-C. Cheng G.-H. Lee S.-M. 292 S.-H. Peng and R.3. Liu Organornetallics 1993 12 3282. "'W.A. Donaldson M.J. h,and P.T. Bell Organometaflics 1993 12 1174. 294 W. A. Donaldson and M.-J.Jin Bull. SOC.Chim. Belg. 1993 102 297. 295 D.A. Brown N.1. Fitzpatrick W.K. Glass H.A. Ahmed D. Cunningham and P. McArdle J. Organornet. Chem. 1993,455 157. 257 Orgunometaliic Chemistry MeYm7 In hde’ Me’ X = Me OMe + Reagents i PPh Scheme 40 Substituted cyclohexadienylones react with hydroxide (sodium carbonate in water) to introduce an OH group at the far end of the q5unit. Oxidation affords a diene4one complex. Substituents include methyl phenyl and a chlorine atom the last of which provides a rare example of a 1-chloro substituted dienyl complex of tricarbonylir~n.~~~ Double functionalization of cyclooctadienyl systems extends methods developed in the heptadienyl series.297 The two nucleophile addition steps foilow an iterative sequence alternating between cationic dienyl cornpIexes and neutral q4-addition products.With smaller ring sizes the reformation of the dienyl complex following nucleophilic addition is bIocked. A strategy for reactivation that overcomes this disadvantage has been reported.298 Protonation of a side-chain alkene followed by a hydrogen shift reforms the dienyl salt. A kinetic study of the electrophiIicity of cationic y’-tricarbonyliron complexes has been published.299 Several natural product syntheses starting from tricarbonyliron4ienyf complexes have been described during the year (Scheme 40).Knolker has utilized in addition the substituted aniline (83) in a short synthesis of carbazomycins A and B.300A variety of oxidative cyclizations of this type have been rep~rted.~” The Donaldson group has completed an enantioselective lipoxygenase-inhibitor synthesis in which the dkylation ofa pentadienyliron complex provides a key step.302 296 N. Morita S. Ito and T. Asao 3. Organomet. Chem. 1993,460 67. 297 A. J. Pearson S. Balasubramanian and K. Srinivasan Tetrahedron,1993 49 5663. 298 I. J. Alexander N. J. Hales and G. R. Stephenson 1.Organornet. Chem. 1993 453 11 1. 299 H. Mayr K.-H. Muller and D. Rau Angew. Ckem. Int. Ed. Engl. 1993 32,1630. 300 H.-J. Knolker and M. Bauermeister Helu. Chirn. Am 1993 76,2500.301 H.-J. Knolker M. 3auermeister and J. B. Pannek Tetrahedron 1993 49 841. ’02 C. Tao and W.A. Donaldson 3. Org. Chem. 1993,58 2134. G.R.Stephenson ?Me OMe 0 (84) Reagents i MeCN; ii MnO,; iii 4-methoxyphenylithium; iv; HPF,; v (84) Scheme 41 The sequence oftwo nucleophile additions to a cyclohexadienyl complex completes a synthesis of ( +_ )-0-methyljoubertiamine (85). Again an iterative reaction sequence was used. In this case the reactivation step employed a leaving group in place of hydrogen abstraction. 30 Tricarbonyl(cyclohexadieny1)iron compIexes have been used as selective labels in reactions with peptides and even with the protein ly~ozyrne,~~~ and as a recoverable protecting group in peptide synthesis.305 New exampies of spirolactone formation based on cyanide addition to q5-tricarbonyliron complexes empIoy trimethyIsily1 cyanide to introduce the nitrile.3*6 303 G.R. Stephenson H. Finch D.A. Owen and S. Swanson Tetrahedron 1993 49 5649. 304 J.A. Carver B. Fates and L. A. P. Kane-Maguire J. Chem. Soc. Chern. Conrmun. 1993 928. '05 S. Fu J. A. Carver and L.A.P. Kane-Maguire J. Organornet. Chem. 1993 454 C11. '06 C.W. Ong and C.J. Chien Organometallics 1993 12 241. Organumetallic Chemistry Reagents i MeLi; ii Ph,CHLi; iii 0,; iv. Me,CfCO,Ef)Li; v 0 Scheme 42 Progress with nucleophilic addition to neutral q 5-tricarbonylmanganese complexes has opened the way for a linear double functionalization leading to 5,S-disubstituted cyclohexadienes.A range of nuckophilic additions to the q5 intermediates have been examined. When the starting material for the reaction sequence is a cationic q6-arene complex a sequence of two nucleophilic additions (first to form a neutral q5 intermediate and then to an anionic q4 adduct with two substituents) can provide a successful synthetic route if the final anionic intermediate is oxidized in sit^.^'^ Two examples are illustrated in Scheme 42. Thisreaction sequence represents a considerable step forward since previous attempts to promote electrophilicity for the second nucleophile addition by replacement of carbon monoxide by NO ,while affording cationic q5 intermediates had not proved successful in the identification of general nucleophik addition reactions to introduce the second substituent.Among the unusual q5-complexes reported this year two heterocyclic examples tricarbonyl(pentamethylpyrrole)chromium308 and pentacarbonyl(2,5-dimethylbis-rnoIyl)mangane~e,~~~ are notable. q'-Complexes.-By attachment of a transition metal to an aromatic ring methods are now well established to manipulate the reactivity not only of the metal-bound ring itself but also at positions more remote from the site of metal attachment. Some of the developments highlighted in the preceding sections with small metal complexes advance these methodologies in this direction but it is in the chemistry of t]6-tricarbonylchromium complexes in particular that the most highly developed general methods that utilize the metal in a variety of ways have become established as procedures for organic synthesis.Natural product syntheses reported during 1993 ihstrate the power of the methodology. The Schmalz group have completed a total synthesis of (1S,4S)-7,8-dihydoxycalamenene(Scheme 43).310 The ability of tricar-bonyIchromium complexes to facilitate metallation of the arene and to stabilize benzylanions and benzyl cations are all brought into play in this synthesis. The optical 307 B.C. Roell Jr. K.F. McDaniel W. S. Vaughan and T.S. Macy Urganornetallics 1993 12 224. 308 N. Kuhn J. Kreutzberg E.-M.Larnpe D. Blaser and R Boese,J. Organornet. Chem. 1993 458 125. 309 A. J. Asbe 111 J. W. Kampf and D.B. Puranik J. Organornet. Chem. 1993 447 197. 310 H.-G. Schmalz J. Hollander M. Arnold and G.Diirner Tetrahedron Lett. 1993 34 6259. G. R . Stephenson OMe i ii iii iv (COhCr SiMe OMe -P % 99%e.e. (86) 99% 95% Reagents:i BuLi; ii SiMe,Cl; iii BuLi THF HMPA; iv MeI; v Bu*Li,THF;vi €‘?I HMPA; vii,TBAF; viii BuLi; ix Mel; x I,; xi BBr Scheme 43 purity of the final product was checked at the metal-free diether stage and was found to be greater than 99%. The key to the synthesis is the control of sites of metallation. First a silyl group was introduced on the aromatic ring to block the most acidic site. The product (86)was then elaborated through a sequence of two bemyl anion complexes with complete regio- and stereocontrol. Very high yields are reported for this route to (87). The trimethyIsily1 blocking group was then removed (TBAF),and a repeat of the initial metallation foilowed by reaction with methyi iodide completes the substitution pattern on the aromatic ring.All that remains is removal ofthe chromium with iodine and ether cleavage to complete the target molecule (88). Enantioselective modification of this route employed a dimethoxytetralone as a prochiral starting material. Enantioselective oxazaborolidine-catalysedboron hydride reduction was followed by diastereoselective complexation. It is here that the benzyl cation complexes come into play. The unnecessary OH group was removed by silane reduction (HSiEt,) in trifluroacetic acid. In this step protonation of the OH group foIIowed by loss of water created a chromium-stabilized benzyl cation which was reduced by the silane.This enantioselective synthesis of (88) uses established bond-forming methods in an elegant and efficient way and provides an excellent demonstration of the superb control of diastereoselectivity available from the use of the tricarbonylchrumium group. Planar chirality of tricarbonylchromiurn complexes is exploited in an initial aldol reaction to control stereocentres 01 and p to the metal-bound ring at the start of a synthesis of (+)-goniofufurone (91).311In this synthetic route (Scheme 44),the silyl 311 C. Mukai I.J. Kim and M. Hanaoka Tetrahedron Lett. 1993 34,6081. Organornetallic Chemistry 26 1 (co),cr I Reagents i desilylation; ii metal removal; iii steps; iv 2-(trimethyIsilyloxy)furan Scheme 44 group on the aromatic ring of (89) is necessary to introduce chirality.The later steps after removal of the chromium utilize conventional chemistry to elaborate a further chiral centre and complete the carbon chain in (90).The relative stereochemistry in the intermediate (901 obtained in a racemic series of experiments was proved by X-ray crystallography. Organochromium routes towards (-)-indolactarn V312 and teleocidin A313 have been investigated. 4-Fluoroindole complexes react with amines replacing the fluorine atom but extension of this procedure to the ester amino acids for a route to indolactam V was unsuccessful. The target molecule however was completed by an alternative route. The preparation of the fluoroindole complex used an interesting trick. The ethylzinc adduct (at nitrogen) of the fluoroindole was formed prior to complexation adding electron density to the ring.Only ethylzinc was suitable for this purpose. Copper sodium magnesium and even zinc bromide were unsuccessful. Nonetheless the yield of the indole complex was low. In the case of teleocidin (93) an 3'z M.P. Sernrnelhack and H. Rhee Tefrahedron Lett. 1993,34 1395. 313 M. F. SemmeIhack and H. Rhee Tetrahedron Lett. 1993,34 1399. G.R. Stephenson Me Reagents i 2-methyl-6-cyanohept-2-en-6-yllithium; ii I,; iii steps Scheme 45 organochromium-based route (Scheme 45) was successful. The tricarbonylchromium group was needed to promote eIectrophiIicity on the indole ring. Nucleophilic addition followed by oxidation of the resulting metal anion afforded (92) which was elaborated to complete a formal total synthesis of the target molecule.Without a nitrogen substituent at C4 of the indole nucleophiIic addition occurs preferentially there. This has been used (Scheme 46) in a synthesis of (94),a key intermediate in a route to cIavicipitic acid. l4 An unusual cycloaddition reaction has been reported involving an aniline-derived imine a pendent alkene and one carbon-carbon double bond of a chromium-bound aromatic ring. Lewis acids are employed to promote this hetero cycloaddition process and the final product is a tricyclic chromium arene complex.315 Electrocyclic addition at pendent groups on tricarbonylchromium complexes are more common. Stereoselec- tive nitrile oxide addition3I6 and the reverse process,317 in which a metal-free alkene is combined with a nitrile oxide unit attached to a tricarbonylchromium complex illustrate new developments.Under photolytic conditions isocyanate adds to the 3'4 M,F. SemrneIhack P. Knochel and T. Singieton Tetrahedron Lett. 1993,34,5051. 3'5 S. Laschat R. Noe,M. Riedel and C. Kriiger Organometallics 1993,12,3738. 316 C.BaIdoli P. Del Buttero S. Maiorana G. Zecchi and M. Moret Tetrahedron Lett. 1993,34,2529. 317 C. Mukai 1.J. Kim W.J. Cho M. Kido and M. Hanaoka J. Chem. Soc. Perkin Trans. I 1993,2495. Organometallic Chemistry Reagents i Bu,NH Scheme 46 tricarbonylchromium complex of cycl~heptatrienes.~’’Activated alkene dienophiles aIso react in a 16 + 2) cycloadditionto complexesof seven-memberedring triene~.~” An intramofecular version has been reported.In this case no electron withdrawing end-group was present on the dienophile and photochemical conditions were employed A [6 + 41 cycloaddition is also described. This reaction involves a pendent There are examples of electrocyclic ring openings involving tricarbnyl(o- quinodimethane)chromi~rn~~~ obtained from an alkoxybenzocyclobutane complex and related reactions employing dihydroxybenzo~yclobutanes.~~~ Stereocontrolled nucleophile addition adjacent to a chromium arene complex continues to be developed in work on acetylide addition,323 and also in carbanion addition to aldehydes and irnine~.’~~ A more unusual reaction involves cydopropanation in the presence of the tricarbonylchromium complex .32 An asymmetric oxidation of a chromium-bound aryh hioet her affords a sulfin yl substituted complex with high diastereoselectivit y .326 In another oxidation a 1,Zdione replaces the carbonxarbon double bond in a bis(tricarbony€)chromiumcomplex of a trimeth~xystilbene.~~~ Conformational studies of the Cr(CO) tripod units in phenanthrene complexes have been made.32B ConformationaI preferences in fluorobiphenyl complexes contain- ing tricarbonylchromiurn units have been studied by I3C and ‘’F NMR spectros-Restricted rotation in polysubstituted aromatic complexes has been inves- 318 J.H. Rigby G. Ahmed and M. D. Ferguson Tetrahedron Lett. 1993,34 5397. 319 J.H. Rigby H.S. Ateeq N.R. Charles J.A. Henshlwood K.M.Short and P.M. Sugathapala Tetrahedron 1993,49 5495.320 f. H. Rigby and V. P. Sandanayaka Tetrahedron Lett. 1993,34,935. 321 E. P. Kiindig and J. Leresche Tetrahedron 1993 49 5599. 322 M. Brands R. Goddard H.G. Wey and H. Butenschon Angew. Chem. Int. Ed. Engf. 1993,32 267. 323 C. Baldoli P.Del Buttero E. Licandro S. Maiorana,A. Papagni and M.Torchio TetrahedronLett. 1993 34,7943. 324 E.P.Kiindig L. H. Xu P.Romanens and G. Bernardinelli Tetrahedron Lett. 1993,34,7049. 325 S. Ganesh K.M. Sathe M. Nandi P. Chakrabarti and A. Sarkar,J. Chem. Soc. Chem. Comun. 1993 224. 326 A. Perez-Encabo S.Perrio A. M.Z. Slawin S.E. Thomas A.T. Wierzchleyski and D.J. Williams J. Chem. Soc. Chem. Commun. 1993 1059. 327 Z.V.Todres and E. A. Ionina 1.Orgonomet. Chem. 1993,453 193. 32% D.J. Peitz R.T. Palmer L. J. Radonovich and N.F. Woolsey Organometallics 1993 12 4580. 329 P. Szczecinski and J. Zachara J. Organomet. Chem. 1993 447 24i. G.R. Stephenson tigated by variable temperature NMR spectroscopy.330 FTIR spectroscopy is usefuI for the trace measurement of the presence of organometalcarbonyl tags on biologicalIy active substances. A new contribution to this area which previously had been almost the excIusive preserve of the Jaouen group in Paris has involved the preparation of tricarbonylchromium and dicarbonyl- chromiumphosphite derivatives of aminoglycoside antibiotics such as (95). The compIexes will be used as metallotracers for immunoassay work.331 (CO)& /OH fl OH OH Access methods to optically pure tricarbonylchromium units include the use of a microorganism to effect an asymmetric reduction of an a~etophenone,~~~ and direct metallation of a prochiral chromium-bound aromatic ring in the presence of a chirat auxiliary that promotes orth~metallation.~~~ Organochromium-based auxiliaries are effective as asymmetric catalysts for the addition of an ethyl group from diethylzinc to aldehydes.Examples include chiral auxiliaries with two chiral centres in a side chain attached to an achiral tricarbonyl(arene)chromium complex,334and a case where the two coordinating groups that bind the zinc are in separate substituents in a chromium complex of a 1,2-disubstituted benzene ring.335 In this latter case planar chirality is present on the aromatic ring.From the point of view of asymmetric synthesis the main thrust this year has been the use of tricarbonylchrornium units as chiral auxiliaries for example in a catalytic enantioselective synthesis of (R)-(+)-lasi~diplodin,~~~ and asymmetric DieIs-Alder reactions.337 The chemistry of other metal complexes of aromatic rings develops in a similar way. Cyclopentadienyliron cations promote nucleophilic replacement of halides from aryI halide compIexes from mono-and dichloroarene~.~~~,~~~ Nucleophile addition to tricarbonylmanganese complexes of indoles has been examined,340 as has the regiocontrol of nucleophilic addition to silyl-substituted manganese-bound aromatic 330 J. A. S. HowelI M.G. Palin P. McArdIe D. Cunningham Z. Goldschmidt H.E. Gottlieb and D.Hezront-Eangerman,Organometa!lics 1993 12 1694. 331 J. Szymoniak B. El Mouatassim J. Besanqon C. Mdise and P. Brossier Tetrahedron 1993 49 3109. 332 Y. Yamazaki and H. Kobayashi Terrahedron Asymmetry 1993 4 1287. 333 Y. Kondo J.R. Green and J. Ho J. Org. Chem. 1993 58 6182. 334 G. B. Jones and S. B. Heaton Terruhedron Asymmetry 1993 4 261. 335 M. Uemura R. Miyake K. Nakayama M. Shiro and Y. Hayashi J. Org. Chem. 1993 58 1238. 336 G. B. Jones and R.S.Huber SYNLETT 1993 367. 33' M. Uemura Y. Hayashi and Y.Hayashi Tetrahedron Asymmetry 1993 4 2291. 338 A.S. Abd-El-Aziz and C. R. de Denus J. Chem. SOC. Perkin Trans. 1 1993 293. 339 S. Motallebi and P. Muller Organometollics 1993 12 4658. 34a W.J. Ryan P. E. Peterson Y. Cao P.G. Williard D.A. Sweigart C.D.Baer C. F. Thompson Y. K. Chung and T. M. Chung Inorg. Chim. Acta 1993 211. Organometaliic Chemistry CpFe CGFe Reagents i paIladium(o)(cat.) SnPhBu,; ii palladium(o) (1 eq.);iii SnPhBu Scheme 47 rings,341 the use of Wittig reagents as nucleophiles with manganese arene com- ~lexes,~~’ and electrochemical reduction in the presence of phosphines (which converts tricarbonyl(arene)manganesecomplexes into the dicarbonylphosphine adducts but does not proceed with the corresponding rhenium complexes).343 The formation of ruthenium arene complexes by demethylation of steroids344 has received further attention and bimetallic cyclopentadienylruthenium complexes of dibenzo-p-quinodimethane Iigands have been prepared.345 Two unusual reports conclude this section.Trifluorophosphine is often used in place of carbonyl groups because of its roughly comparable electron-withdrawing effect. Hydride reduction of tris(trifluorophosphine)chromium complexes has produced an intermediate with agostic hydrogens shared between the aromatic ligand and the metal,346 In the cyclopentadienyliron complexes an unusual coupling reaction has been performed. Palladium-catalysed cross-coupling (Scheme 47) replaced a chlorine atom from the cationic chlorobenzene complex with a substituent transferred from a tributyltin reagent. When one equivalent of a palladium complex was used a stoichiometric bimetallic product could be isolated in 65% yield. This is the cyclopentadienyliron complex of a palladated aromatic ring.This intermediate reacts with tributyltin reagents to afford the same product as those arising from the cross-coupling reaction.347 7 Other Aspects Not all areas of organometallic chemistry can be covered in detail every year in an 3L’ S. S. Lee J.-S. Lee and Y. K. Chung Organometallics 1993 12 4540. 342 S. Lee Y. K. Chung T.3. Yoon and W. Shin Organometallics 1993 12 2873. 343 C.C. Neta C.D. Baer Y.K. Chung and D.A. Sweigart J. Chem. Soc. Chem. Comrnun. 1993 816. 344 F. Urbanos M.A. HaIcrow J. Fernandez-Baeza F. Dahan D. Labroue,and B. Chaudret J. Am. Chem. SOC., 1993 115 3484; M.A. Halcrow F. Urbanos and B. Chaudret Organornetallics 1993 12 955. 345 D. T. Glatzhofer Y. Eiang and M. A. Khan Organometallics 1993 12 624. 346 E. P. Kiindig D. Amurrio G.Bernardinelli and R. Chowdhury Orgonornerallics 1993 12 4275. 347 N. Jevnaker T. Benneche and K. Undheim Acta Chem. Scand. 1993,47 406. 265 G.R. Stephenson Annual Report.The main theme this year has been a discussion of alkyne chemistry and coupling reactions. Nonetheless in each year there are developments in all aspects of organometallic Chemistry. During 1993 there has been considerable progress with organometallic dendrimers containing iron348.349 and ruthenium.349 In one case iron complexes have been placed at the centre and the periphery of the tentacled structures. In the fiefd of ferrocene chemistry much synthetic work has been performed. The most notable products are designed for special purposes such as thermotropic crystals;35 53 as end groups on a structure along which a cyclophane moiety as polydecker pentalene complexes linked in stacks at opposite faces of the back-to-back five-membered rings,355 or even larger stacked structures (formed by palladium-cataIysed cross-coupIing to ferrocenylzinc derivatives to produce a range of ferrocene units linked by naphthalenes356 or by binaphth~l~~~ units) or dimeric metallocenes connected by a (dicyclopentadieny1)-methyleneunit.358 Ferrocenes span rnacrocy~les~~~*~~~ and in a smaller ring system the iron participates as a fourth ligand in an interaction with a palladium acetonitrile complex.36 Tetrathi~fulvalene,~~~ f~lgides,~~~ systems have been prepared.Boronic acid and tetrazole hydra~one~~~ substituents on ferrocene units can participate in cross-coupling in the presence of the metal attached to the cyclopentadienyl liga~~d,~~’ but in (arene)tricarbonylchromium complexes coupling is prevented by the presence of the Chiral centre^^^'*^^' including an example at sulfur,349 have been formed and in one case asymmetry was induced by microbial reduction.370 Ferrocene-based chiral auxiliaries are usefuI in and Grignard37 cross-coupling reactions.Work on acyliron complexes has continued with their utility being illustrated by 348 F.MouIines L. Djakovitch R. Boese,B. Gioaguen W. Thiel J.-L. Fillaut M.-H. Delville and D. Astruc Angew. Chem. Int. Ed. Engl. 1993 32 1075. 349 Y.-H.Liao and J. R. Moss J. Chem. SOC.,Chem. Commun.,1993 1774. 350 J.-L. Fillaut and D. Astruc J.Chem. SOC.,Chem. Commun. 1993 1320. 35 I R. Deschenaux M. Rarna and J. Santiago Tetrahedron Lett. 1993 34 3293. 352 C. Loubser C. Imrie and P. H. Van Rooyen Ado. Mater. 1993 545. 353 R. Deschenaux and J. Santiago J. Mater. Chem. 1993 3 219. 354 A. C. Benniston and A. Harrirnan Angew. Chem. Int. Ed. Engl. 1993 32 1459. 355 B. Oelckers I. Chavez J-M. Manriquez and E. Romin Organometallics 1993 12 3396. 356 H. M. Nugent and M.Rosenblurn J. Am. Chern. SOC. 1993,115 3848. 357 B. M.Foxman M. Rosenblum V. Sokolov and N. Rhrushchova Organomerollics 1993 12 4805. 358 M. Watanabe S. Iwamoto S. Nakashima H. Sakai 1. Motoyarna and H. Sano,J. Orgonomet. Chem. 1993,448 167. 359 P.D. Beer Z. Chen M.G.B. Drew J. Kingston M. Ogden and P. Spencer,J. Chem. Soc.Chem. Commun. 1993 13 1046. 360 R.A. Holwerda J.S. Kim,T. W. Robison R. A. Bartsch,and R. P.Czech J.Organornet.Chem. 1993,443 123. 361 M. Sato H. Asano and S. Akabori J. Organomet. Chem. 1993,452 105. 362 A. J. Moore P. J. Skabara M. R. Bryce A. S. Batsanov J. A. K.Howard and S.T.A.K. Daley J. Chem. SOC.,Chem. Commm. 1993 417. 363 R. W. McCabe D. E. Parry and S. P. Saberi J. Chem. SOC. Perkin Trans. 1 1993 1023 364 W. Shaozu L. Benyan Z. Yulan and L. Zenglu Synth React. lnorg. Met. Org. Chem. 1993 23 1139. 365 R. Knapp and M. Rehahn J. Org. Chem. 1993,452 235. 366 M.A. Beckett R. J. Gilmore and K. Idrees J. Organomet. Chem. 1993,455,47. 367 H. Wally,C. Kratky W. Weissensteiner M.Widhalm,and K. Schogl J. Organornet.Chem. 1993,450,185. 368 0.Riant 0.Samuel and H.B.Kagan J. Am. Chem. Soc. 1993,115 5835. 369 F. Rebikre 0.Rian! L. Ricard and H. B. Kagan Angew.Chem. Int. Ed. Engl. 1993,32 568. 370 Y. Yarnazaki A. Maruyama K. Hosono T. Higashihara H. Kobayashi Z. Noturforsch. BioSci. 1993,48 451. 371 B. Jedicka C. Kratky W. Weissensteiner and M.Widhalm J. Chem. Soc. Chem. Commun. 1993 1329. 372 Z.-X.Wang and Z.-Y. Cheng Youji Huaxue 1993,13,496. Organometalfic Chemistry their role as intermediates in syntheses of (-)-actin~nin,~~~ (S)-(-)-methyl tr~pinate,~~~ and a precursor for erap pa mil.^'^ The triphenylphosphine(cyc1open-tadieny1)iron complex has been used as a chiral auxiliary to induce stereoselective reactions in dihydronicotinoyl systems.376 Two resohtion procedures for this iron-based auxiliary have been reported,37 and pentarnethylcy~lopentadienyl~~~ and diphenylalkylph~sphine~~~ anaiogues have been studied.Acknowkdgement. I am grateful to Professor S. Maiorana and his coworkers and to the Library of the Dipartimento di Chimica Urganica e Industriale for assistance with bibliographic work during my visit to the Universita degli Studi di Milano in 1993. 373 G. Bashiardes G.J. Bodwell and S. G.Davies J. Chem. Soc. Perkin Trans. 1 1993 459. 374 T. M. Baker G. J. Bodwell S.G.Davies A.J. Edwards,and M.R. Metzlev Terrahedron 1993,49,5535. 37s H. Brunner S. Forster and B. Nuber Organomeruliics 1993 12 3819. 376 R. P. Beckett V. A. Burgess S.G. Davies and M.Whittaker Tetrahedron Lett. 1993 34 3617. 377 R.W.Baker and S.G. Davies Tetrahedron Asymmetry 1993,4 1479; S.C.Case-Green J. F. Costello S.G.Davies N. Heaton C. J. R. Hedgecock and J. C. Prime J. Chem. Soc. Chem. Commun. 1993,1621. 378 J.-P. Barras S.G. Davies M.R.Metzler A. J. Edwards V. M. Humphreys and K. Prout J. Organomel. Chem. 1993,461 157. 379 H.Stepowska and A. Zamojski J. Organornet. Chem. 1993,456 221.

ISSN:0069-3030    

DOI:10.1039/OC9939000217

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

9 Synthetic Methods By N.J. LAWRENCE Department of Chemistry UMIST PO Box 88 Manchester M6Q 700 UK 1 Introduction One of the year's more interesting accounts of organic synthesis may be found in John Cornforth's Robert Price lecture entitIed 'The TroubIe with Synthesis'.' He discusses the changing reasons for undertaking a synthesis and the development of organic synthesis. The recurrent theme of most papers describing synthetic methods this year has undoubtedly been catalytic asymmetric synthesis. The need for efficient asymmet- ric synthetic methods is driven in part by the pharmaceutical industry's need for enantiopure intermediates; several reviews describing chiral drugs2s3 have appeared this year. Among the most notable total syntheses of the year are those of the immunosuppressant rapamycin achieved by the groups of Ni~olaou,~ Schrieber,' and Danishefsky,6 and the synthesis of strychnine by Overman and coworkers.' An excellent behind-the-scenes account of Nicolaou's' synthesis of calicheamicin 7; has also been pubIished this year.Specialist reference works that have been published this year include Volumes 43' and 44'' of Organic Reactions which review carbonyl alkylidination using titanium reagent^,^" anion-assisted sigrnatropic rearrange- ment~,~' the Baeyer-Villager oxidation," selenoxide elimination,1ou and enone-olefin [2 + 23 photochemical cyclization.' Ob Two Tetrahedron Symposia-in-print describe synthetic methods; 'synthesis of optically active compounds -prospects for the 21st century'' and 'transition meta1 organometallics in organic synthesis'.' * Books published this year include works describing asymmetric catalysis in organic syn- J.W.Cornforth Aus. J. Chem. 1993,46 157. ' S.C. Stinson Chern. Eng. News September 27 t993 38. ' H.-J. Federsel CHEMTECH December 1993,24. K. C. Nicolaou T. K. Chakraborty A. D. Piscopio N. Minowa,and P. Bertinato,J. Am. Chem.SOC.,1993 115,4419. ' D. Romom S.D. Meyer D.D. Johnson and S. L. Schrieber J. Am. Chem. Soc. 1993 115,7906. 'C.M. Hayward D. Yohannes and S. J. Danishefsky J. Am. Chem. SOC. 1993 115,9345. 'S.D. Knight L. E. Overman and G. Paraudeau J. Am. Chem. Sac. 1993,115,9293. ' K.C.Nicolaou Angew. Chem. Int. Ed. Engl. 1993 32 1377. (a)S. H.Pine,Org. React. (N.Y,),1993,43,1; (b)S. R.Wilson ibid.1993,43,93; (c)G.R. Crow ibid. 1993 43 251. lo (a)H. J. Reich and S. Wollowitz Org. React. (N.Y.) 1993,44 1; (b) M. T. Crimmins and T. L. Reingoid ibid. 1993 44 297. *I Tetrahedron 1993,49 1711. Tetrahedron,1993 49 5415. 269 N.J. Lawrence thesis;I3 stereoselective synthesis;‘’*’ catalytic asymmetric ~ynthesis;*~*’~ chiral auxiliaries;” oxidative enzymes;” industrial chirality;*’ natural products;* ’ and stereochemistry.22 The use of enzymes in organic synthesis23 continues to be popular but is not reviewed here since it is well covered in chapter 10. 2 Carbodarbon Bond Formation The asymmetric allylation of aldehydes has been achieved in several ways.24 Keck et al. describe in a series of papers,2s the remarkably efficient allyIation of aldehydes using a catalyst derived from binaphthol and titanium tetraisopropoxide (Scheme la).0 R = PM=H 9812 (92 %) R = P+&4 303(90%) Scheme 1 Tagliavani Umani-Ronchi and coworkers report equally impressive enantioselectiv- ity when the reaction is catalysed by the BINOL-TiC1 complex.26 Tetraallyltin reacts selectively with aldehydes in the presence ofketones in aqueous acidic media (THF-aq. HCl);’’ the extremely high chemoselectivity (> 98.98 :0.02)is not observed with Lewis acids such as BF,-OEt,. Allyltrichlorosilanes add efficiently to aldehydes in DMF without cataIyst under neutral conditions; DMF is thought to coordinate to silicon to l3 R. Noyori ‘Asymmetric Catalysis in Organic Synthesis’ Wiley Chichester 1993.I’ Atta-ur-Rahman and Z. Shah ‘Stereoselective Synthesis in Organic Chemistry’ Springer-Verlag Berlin * 1993. E. Ottow and K.Schoeilkopf ‘Stereoselective Synthesis’ Springer-Verlag Berlin 1993. l6 ‘Catalytic Asymmetric Synthesis’ ed. I. Ujima VCH New York 1993. I’ H. 3runner and W. Zettlrneier ‘Handbook of Enantioselective Catalysis’ VCH New York 1993. J. Mulzer and E. Berger ‘Chiral Auxiliaries; Applications in Organic Synthesis’ Ballen Vieveg and Sohn Int. Germany 1993. l9 H. L. Holland ‘Organic Synthesis with Oxidative Enzymes’ Verlag Berlin 1993. zo ‘Chirality in Industry’ ed. A. N. CoHins Wiley Chichester 1993. z* ‘Dictionary of Natural Products’ Chapman and Hall London 1993. 22 E. Eliel and S.H. Wilen ‘Stereochemistry of Organic Chemistry’ Wiley.Chichester 1993. ” For an illustration of current research into the use of enzymes in organic synthesis see Tetrahedron Asymmetry 1993,4 Nos. 4 and 5. ’* Y.Nishigaichi A. Takuwa Y. Naruta and K. Maruyama Tetrahedron,1993,49 7395. ’’ G. E.Keck K. H. Tarbet and L. S. Geraci J.Am. Chem. Soc. 1993,115,8467; G. E. Keck and L. S. Geraci TetrahedronLert.. 1993,34,7827;G.E. Keck D. Krishnamurthy and M.C. Crier J. Org. Chem. 1993.58 6543. 26 A L. Costa M.G. Piazza E. Tagliavini C. Trombini and A. Umani-Ronchi J. Am. Chem. Suc. 1993,115 7001. ’’ A. Yanagisawa H.Inoue M. Morodome and H. Yamamoto J. Am. Chem. SOC.,1993,115 10356. Synthetic Methods 27 1 produce a hypervalent allylsilicate.28 Allylation of the chiral glyoxalate (1) is highly diastereoselective and very sensitive to the nature of the protecting changing from benzyl to triisopropylsilyl reverses the selectivity (Scheme 1b).Catalytic asymmetric cyanohydrin synthesis has received considerable attention this year.30 Corey and Whangdescribe the use of a pair of chiral catalysts (2)to activate the aldehyde and (3) to provide an equivalent of chiral cyanide ion (Scheme 2a) to achieve the asymmetric silylcyanation of aldehyde^.^ The chiraI cyanide donor is thought to be a complex formed between (3) and trace HCN. A related synthesis of cyano ethers involves the ring opening of the oxazolidinium salt (4)with sodium cyanide to give the cr-hydroxy acid (5)after quaternization and treatment with hydrochloric acid (Scheme 2b).32A more conventional synthesis of cyanohydrin derivatives has been described by de Vries and coworkers.They use the pantolactone-derived titanium complex (4)to catalyse the asymmetric silylcyanation of aldehydes with modest selectivity (Scheme 2+33 The asymmetric catalytic addition of organozinc reagents34 to aldehydes has proved as popular as ever this year (Figure 1).Some of the catalysts used include the azetidine (7),35the thiophosphorarnidate (8),36 the j3-hydroxysulfide (9),3' the hydroxyrnethyl oxazoline the diethanolamine (I 1),39 and the chromium arene complex (l2)." The study of organolanthanoid complexes has also seen great activity this year. Organocerium reagents add selectively to SAMP hydrazones (13) thereby providing an afficient route to 8-amino aldehydes and acids (Scheme 31." Similarly a-amino aldehydes are synthesized from the SAMP monohydrazone of protected gly0xa1.~~ A new method for the preparation of anhydrous lanthanoid chlorides from the metal and hexachloroethane should prove useful for the synthesis of the corresponding or- ganolanthanoid reagents.43 SeveraI groups have reported the use of chiraI ligands to control the stereochemistry of palladium-catalysed allylic substitution (Scheme 4).The groups of Helmchen Pfaltz and Williams have each used similar bidentate ligands phosphines (14),4446 sulfides (15),47 and thiophenes (16),48 which all incorporate a chirality-controlling 28 S. Kobayashi and K. Nishio Tetrahedron Lett. 1993 34,3453. 29 A. B. Charette C. Mellon L. Rouillard and E.Malenfant SYNLETT 1993 8i. 30 M.North SYNLETT 1993,807. 31 E.J.Corey and Z. Whang Tetrahedron Lett. 1993,34,4001. 32 C. Andrks M. Delgado R. Pedrosa and R. Rodriguez Tetrahedron Lett. 1993,34 8325. 33 D.Callant D.Stanssens and J.G. de Vries Tetrahedron Asymmefry 1993,4,185. 34 P.Knochei and R. D. Singer Chem. Rev. 1993,93,21 17. 35 W.Behnen T. Mehler and J. Martens Tetrahedron Asymmetry 1993,4 1413. 36 K.Soai Y.Hirose and Y. Ohno Tetrahedron Asymmetry 1993,4,1473. 37 M.C.Carreiio J. L. Garcia Ruano M. C. Maestro and L.M. Martin Cabrejas Tetrahedron Asymmetry 1993,4,727. 38 J. V.Allen C.G. Frost and J. M. J. Williams Tetrahedron Asymmetry 1993 4 649. 39 E. F.J. de Vries J. Brussee C.G. Kruse and A. van der Gen Tetrahedron Asymmetry 1993,4 1987.40 G.B. Jones and S. B. Heaton Tetrahedron Asymmetry 1993 4 261. 41 D. Enders M. Klatt and R. Funk SYNLETT 1993 226. 42 D Enders R. Funk,M. Klatt,G. raabe and E. R. Hovestreydt Angew. Chem. Int. Ed. Engl. 1993,32,418. 43 C.B.Deacon T. Feng S. Nickel €3. W. Skelton and A. H. White J. Chem. Soc. Chem. Commun. 1993 132%. 44 P.von Matt and A. Pfaltz Angew. Chem. Int. Ed. Engl. 1993 32,566. 45 J. Sprinz and G. Helmchen Tetrahedron Lett. 1993,34 1769. 46 G.J. Dawson C.G. Frost J. M.J. Williams and S. J. Coote Tetrahedron Lett. 1993,34 3149. 41 G.J. Dawson C. G.Frost C. J. Martin J. M. J. Williams,and S. J. Coote Tetrahedron Lett. I993,34,7793. 48 C.G.Frost and J. M. J. Williams Tetrahedron Lett. 1993,34 2015. N.J.Lawrence CN 88 x,$5 % m. Scheme 2 oxazoline group. Substitution of the acetate in (17) with dirnethyl malonate is impressively enantiuselective with (14) and (15) (ex. > 95%). Allylic alcohols may be used in this type of reaction by prior reaction of the allylic alkoxide with triphenyI- boron.49Zhou and P€altz50 have also used the mercaptoaryl-oxazoline (18)as a ligand for the asymmetric copper-catalysed conjugate addition of Grignard reagents to +unsaturated ketones (e.e. > 50%). Several new Lewis-acid catalysts for aldol reactions have been described. Tris(pentafl~oropheny1)boron~and lanthanum trdate5' are excellent air-stable water-tolerant Lewis-acid cataIysts fur the aldol and Michael reactions of silyl enol ethers. The methods can be used for the direct reaction of aldehydes supplied commercially as aqueous solutions (e.g.formaldehyde).On the other hand Kobayashi O9 I.Stary I.G. Stara and P. Kocovsky TetrahedronLett. t993,34 179. Q.-L. Zhou and A. Pfaltz Tetrahedron Lett. 1993 34 7725. '' K. Ishihara N.Hananki and H. Yamamoto SYNLETT 1993 577. '' S. Kobayashi I. Hachiya and T. Takahori Synthesis 1993,371. Synthetic Methods 5 mOr %; 57 86 8.e. (11) (4; (10) (9; 5 mot %; @5% e.e. (12) (A) 10 md %; El96 8.8. Figure 1 Selectivity in the addition of Et,Zn to PhCHO (33) 97 % 99 76 d.%. Scheme 3 S I 8 I Scheme 4 k k (14) X= Pph (16) (15) x=sPh (18) x=sH N. J. Lawrence and Nishio report the use of dimethyl(trifly1)silyI enol ethers as enolate equivalents for aldol and Michaef reactions without Lewis-acid catalysis.53 The asymmetric nitro- aldol reacti~n~~~~~ (Henry reaction) has been used by Shibasaki and coworkers to synthesize the /I-blocker (S)-propranolol (19) (Scheme 5).56 Scheme 5 The disclosure of new chiraI auxiliaries always generates great interest.Such is the case of a new paper from Yarnamoto and coworkers. They have found that 2,2,6,5-tetramethyI-3,5-heptanedioI(TMHDiol) derivatives such as the monobenz-oate (20) are excelIent conforrnationaIly rigid acylic chiral auxiliaries. The a,b-unsaturated ester (21) is highly selective in the conjugate addition of lithium amides [(21) 3 (22)] and Diels-Alder reactions. The high selectivity is associated with the rigid structure (21) as evidenced from X-ray and NMR analysis (Scheme 6a).Vedejs et aL5* report an interesting and highly efficient method for the alkyIation of chiral a-amino acid enolate equivalents involving transfer of chirality from starting material to product oia the transient boron complex (25) (Scheme 6b). The oxazaborolidinone (24) prepared selectiviely from the a-amidino carboxylate (23) and PhBF in situ is deprotonated and alkylated [(24) + (25)l with in most cases exceptionaI stereoselec- tivity. Symmetrical or-diones have been prepared in excellent yield by conventional reaction of organometallic reagents with the C-2 units 1,l'-oxalylimidazole59 and N,N-dimethylpipera~ine-2,3-dione.~~ Alkene Synthesik-Many important improvements to the Wittig reaction have been made this year.Vedejs et al. have shown that the phosphole-derived ethylide (26)61is extremely E selective in the reaction with both aldehydes and ketones.62 In comparison the reaction of Ph,P=CHCH exhibitsZ selectivity whilst the reaction with ketones is very much substrate dependent (Scheme 7a). Patil and Schlosser have introduced a new class of phosphorane (271 derived from tris(2-methoxymethoxy)- phosphine with enhanced cis selectivity (Scheme 8b). Stabilized ylides (X= C0,Me) 53 S. Kobayashi and K. Nishio 1.Org. Chem. 1993 58,2647. '* H. Sasai T. Suzuki,N. Itoh K. Tanaka,T. Date K. Okamura and M.Shibasaki,J. Am. Chem. SOC.,1993 115 10372. " H Sasai T. Suzuki N. Itoh S. Arai and M,Shibasaki,Tetrahedron Lett. 1993 34 2657. 56 H.Sasai N. Itoh T. Suzuki and M. Shibasaki Tetrahedron Lett. 1993,34,855. " I. Suzuki H. Kin and Y. Yamamoto J. Am. Chem. SOC. 1393 115 10139. '' E. Vedejs S.C. Fields and M. R. Schrimpf J. Am. Chem. SOC.,1993 115 11 412. '' R.H.Mitchell and V.S. lyer Tetrahedron Lert. 1993,34 3683. 6o U.T. Mueller-Westerhoff and M. Zhou Tetrahedron Lett. 1993 34 571. E. Vedejs and M.J. Peterson J. Org.Chem. 1993 58,1985. '* E. Vedejs 3. Cabaj and M.J.Peterson J. Org. Chem. 1993 58 6509. Synthetic Methods Scheme 6 show a curious solvent effect; in methanol the reaction is cis selective,whilst in hexane it is trans selective.63 When the phosphorane bears an a-heteroatom the reaction is again impressively cis selective -much more so than when a triphenylphosphine derived reagent is €:Z 22:78 with PtrJkCHCH €296:4 with(26) R2CH0 R2T (6)'-" X Scheme 7 Asymmetric Wittig reactions are proving to be popular.The chiral phosphonate (28) derived from 8-phenylmenthol reacts selectively with the meso dialdehyde (29)65to give the a,#.l-unsaturated ester (30) with the expected E selectivity (Scheme 8a). The chiral phosphonate (31) also shows high selectivity in the Horner-Wadsworth-Emmons (HWE) reaction with the meso 1,2-diketone (32) (Scheme 8b). The reaction is highly enantioselective (e.e. ;2( 100%) and somewhat surprisingly for an HWE reaction Z 63 V.Patil and M. Schlosser SYNLETT 1993 125. " X.P.Zhang and M.Schlosser Tetrahedron Lett. 1993 34,1925. 65 N.Kann and T.Rein J. Org. Chem. 1993,58,3802.I?. J. Lawrence selective.66 Chiral ketones have been kinetically resolved by HWE reaction with the phosphonate (33) derived from ~-mannitol."~ The groups of Paterson68 and Ko-skinen6' report the use of barium hydroxide and potassium carbonate in acetonitrile respectively as mild bases for the HWE reaction of Q-ketophosphonates. The modifications are particularly advantageous when base-sensitive aldehydes are used. Baldwin ef a!.have described an interesting Wittig reaction of 8-lactams; stabilized ylides react with N-Boc protected monocyclic p-lactarn~.'~ I I TBDMS I Denmark and Amburgey have reported a general stereoselective method for the synthesis of trisubstituted alkenes (Scheme 9a).7' They found that both the aikylation of the racemic fi-keto phosphonamidate (34)and subsequent reduction of the carbonyl group are highly diastereoselective.The customary base-induced HWE elimination of (35)proved problematic; however simple thermal cyc~oelirnination proceeded cleanly K. Tanaka Y. Ohta K. Fuji and T. Taga TetrahedronLett. 1993 34 4071. '' K. Narasaka E. Hidai Y. Hayashi and J.-L. Gras J. Chem. SOC.,Chem. Comun. 1993 102. 68 I. Paterson K.-S. Yeung and J. 3.SrnaIll SYNLETT 1993 774. 69 A.M. P.Koskinen and P. M. Koskinen SYNLETT 1993 501. 70 J. E. Baldwin A. J. Edwards C N. Farthing and A. T. Russell SYNLETT 1993,49. 71 S. E. Denmark and J. Amburgey J. Am. Gem. Soc. 1993,115 A0386. Synthetic Methods to give the trisubstituted alkene. Le Corre and have shown that a-metallo phosphine-boranes7 react with aldehydes in a Horner-Wittig-like manner to give E alkenes; when butyllithium is used as the base the intermediate hydroxy phosphine- borane can be isolated after work-up (Scheme9b).Most Wittig-like reactions proceed by syn elimination. However Lawrence and Muhammad have shown that Horner-Wittig intermediates (36) undergo anti elimination by reduction (LiAlH,-CeCl,) and phosphorus trichloride mediated elimination [(37) + (38)] (Scheme -ph ??% €2,955 0 It ((.) PhPiOH LiAH,,CeCI PCIa NEto -"'tC" CH,CI& rat.. 2 h =-R* R Ph R Ph Ph Scheme 9 Chiral alkenes are produced by enantioselective dehydrohalogenation of prochiral alkylbromides by chiral alkoxides derived from N-methylephedrine (Scheme 10a).75 Similarly asymmetric oxidation of the prochiral selenide (39) using Davis' chiral oxaziridine gives a reactive selenoxide (40)of undefined configuration which eliminates to the chiral alkene (41) (Scheme 10b).74 Several examples of silicon-rnediated alkene synthesis have appeared.The di-bromovinylsiktne (42) provides a useful synthon for the construction of a variety of geometrically pure alkenes. For example both bromides react with higher order cuprates to give a vinylsilane (43) that is easily desilylated with iodine in wet benzene (Scheme 1i).77Chauret and Ch~ng~~ have shown that a-epoxy(triethy1silane) serves as '' Y.Gourdel A. Ghanimi P. Pellon and M. Le Corre Tetrahedron Lett. 1993 34,1011. 73 T. Imamoto Pure and Applied 1993 65,655.74 N.J. Lawrence and F. Muhammad J. Chem. Suc. Chem. Commun. 1993 1187. 75 J. Vadecard J.-C. Plaquevent L. Duhamel and P. Duhamel J. Chem. SOC.,Chem. Commun. 1993 116. '6 €4. Komatsu S. Matsunaga T. Sugita and S. Uernura J. Am. Chem. SOC.,1993 115 5847. " R. Angell P.J. Parsons and A. Naylor SYNLETT 1993 i89. 78 D.C. Chauret and J. M.Chong Tetrahedron Lett. 1993,"34,3595. N.J. Lawrence But ph' (41) 96% 33% 8.8. Scheme 10 Scheme 11 an excellent precursor to E and 2 disubstituted alkenes by Hudrlik-Peterson chemistry. Finally Fry et al. have shown that benzal chloride (PhCHCl,) is converted to stilbene (87% E 2 1 :1.1) by the action of electrochemically generated cobalt(1) ~alen.~~ Cyc1oadditioas.-Kobayashi has shown that scandium(Ii1) triflate is an excellent catalyst for the Diels-Alder reaction." The reaction is endo selective and can be performed in both organic and aqueous media.In addition the catalyst is easily recovered and may be used at low concentrations (1mol%). Chiral Lewis acids that have been used as cataiysts for the asymmetric Diels-Alder reaction*' (Figure 2) include the copper(rr) complexes of the bis(imine) (44)82and bis(oxazo1ine) (45);83 the substituted biaryls (46)84 and (47)85 (which forms an interesting titanium(1v) helical 79 A.J. Fry U. N. Sirisoma and A.S. Lee Tetrahedron Lett. 1993 34 809. S. Kobayashi I. Hachiya M. Araki and H. Ishitani Tetrahedron Lett. 1993 34,3755. aL U. Pindur G. Lutz and C. Otto Chem. Rev. 1993 93 741. D.A. Evans T.Lectka and S. J. Miller Tetrahedron Lett. 1993 34 7027. 83 D.A. Evans S. J. Miller and T. Lectka J. Am. Chem. SOC. 1993 115,6460. 84 J. Bao W.D. Wulff and A. L. Rheingold J. Am. Chem. SOC. 1993,115,3814. 85 K.Maruoka N. Murase and H. Yamamoto 1.Org. Chem. 1993 58,2938. Synthetic Methods complex); and the 2-amino-1-indanol (48).86It0 and KatsukiS7 have used the copper(1) complex of the chiral bipyridine (49) to catalyse the asymmetric cyclopropanation of aikenes (Scheme 12). The reaction proceeds with good trans cis selectivity and excellent enantioseiectivity. (44) Figure 2 Scheme 12 Radical-based Method%-Many advances have been made this year in the use of synthetic methods that invoIve radical Ryu Sonoda and co-workers8' have shown that tris(trimethylsi1yl)silane(TTMSS) is an excellent reagent E.J. Corey T. D. Roper K. Ishihara and G. Sarakinos Tetrahedron Lett. 1993 34 8399. 87 K.Ito and T. Katsuki Tetrahedron Lett. 1993 34 2661. P. Dowd and W. Zhang Chem. Rev. 1993 93 2091. 89 1. Ryu M. Hasegawa A. Kurihara A. Ogawa S. Tsunoi and N.Sonoda SYNLETT 1993 143. N. J. Lawrence for the free-radical formylation of alkyf halides (Scheme 13). Additionaly when an electron-deficient alkene is present unsymmetrical ketones (50)are produced. TTMSS is superior to tin hydrides for this purpose due to its modest ability to donate a hydrogen atom to both the intermediate alkyl and acyl radical. TTMSS also effects the isomerization of some 2 alkenes to their E isomers by an addition-elimination path~ay.~' Finally tributylstannyl radicals may be generated in the absence of tin hydride species by mild photochemical methods employing acetone as a triplet ~ensitizer,~' or by thermal decomposition of 0,O'-bistributyItin benz~pinacolate.~~ 3 Reduction Oxazaborolidine catalysts have seen widespread use for the reduction of ketones [(Sl) + (5211 (Scheme 14).New oxazaborolidine catalysts introduced this year include the phenylglycine-derived (53),93 the hydroxysulfoximine (54),94 and the erythro 2-amino-1,2-diphenylethanol derived (55).95 Interestingly the complex (56) derived in situ from the corresponding amino alcohol behaves in the same way as the alkyIated complex (55);96the method therefore avoids the potentially troublesome isolation of the oxazaborolidine.Liotta and coworkers have published the results of a theroreticaf study of such oxazaborolidine-catalysed ketone reductions and suggest that hydride transfer occurs via a chair-like transition state (58) in contrast to the previously proposed boat transition state (57) (Scheme 15).97It has also been shown that the use of oxazaborolidine-borane complexes in combination with triethylamine leads to increased levels of enantioselectivity. The origins of this curious effect are not entirely clear although it appears the amine might trap the initial monoaIkoxyborane which itself may show lower selectivity than the oxazaborolidinone-borane complex.9B Evans ef al. report a highly efficient asymmetric version of the Meer-wein-Pondorf-Verley (MPV) reduction [(SS) + (60)] (Scheme 16).They found that the samarium complex (61)? obtained from samarium(Ir1) iodide and a styrene-oxide-derived tridentate ligand catalyses the hydrogen transfer from isopropanol to a range '* C. Ferreri M. BaIlestri and C. Chatgilialoglu TetrahedronLett. 1993,34,5147. 91 M. Harendza J. Junggebauer K. Lessrnann W. P.Neumann and H. Tews SYNLETT 1993,286. 92 M.J. Tomaszewski and J. Warkentin J. Chern. Soc. Chern. Commun. 1993 1407. 93 C.Dauelsberg and 3. Martens Synth. Comun. 1993,23,2091. "C.Bolm and M. Felder TetrahedronLett. 1993,34,6041. 95 G.J. Quallich and T. M. Woodall Tetrahedron Lett. 1993,34,4145. 96 G.J. Qualljch and T. M.WoodalI SYNLETT 1993,929. 97 D.K.Jones D. C. Liotta I. Shinkai and D.J. Mathrt J. Urg. Chem. 1993,58 799. 98 D.Cai D. Tschaen Y.-J. Shi T.R.Verhoeven R.A. Reamer and A. W. Douglas Tetrahedron Lett. 1993 34.3243. Synthetic Methods 28 1 0 I! HO 1 3H3*THF catalyst (53)88 % e.e.,2 mol % (S) (54) 76 % 8.8.-10md % (R) (55) R = Me 94 % ee (56) R=H94%ee Scheme 14 (57) Scheme 15 of aromatic ketone^.^' The chiral ruthenium and rhodium complexes (62)loo and (63)"' have also been used in a similar manner to obtain moderate selectivity. Molander and McKie report the highly stereoselective samarium(IxI)-catalysed intramolecular MPV reaction. lo2 Other modified MPV catalysts include silica gel-supported zirconi~rn(iv)~~~ fur the reduction of carboxyhc and zir~onia/titania'*~ acids and sterically hindered ketones.The year has seen significant developments in the area ofasymmetric hydrogenation reactions. Buchwald and coworkers have used the titanocene catalyst (64) to achieve the asymmetric hydrogenation of unfunctionalized trisubstituted alkenes (Scheme 17a).lo5Prior to this disclosure only alkenes that possessed a chelating substituent could successfulIy be reduced stereoselectively . The same catalyst has been used to reduce cyclic irnines to the corresponding cyclic amine.Io6 Faller and Parr have 99 D. A. Evans S.G. Nelson M. R. Gagne and A. R.Muci J. Am. Chem. SOC. 1993,115,9800. loo J.-P. Genet V. Ratovelornanana-Vidal and C. Pinel SYNLETT 1993 34 478. lo' P. Gamez F. Fache P. Mageney and M. Lernaire Tetrahedron Lett. 1993 34 6897. G.A.Molander and J.A. McKie J. Am. Chem. Soc. 1993 115 5821. Io3 K. Inada M. Shibagaki Y. Nakanishi and H. Matsushita Chem Lett. 1993 1795. Io4 K. Takahasi M. Shibagaki H. Kuno and H. Matsushita Chem. Lett. 1993 839. Io5 R. D. Broene and S. L. Buchwald J. Am. Chem. SOC. 1993 115 12569. lo6 C.A. Willoughby and S. L. Buchwald J. Org. Chem. 1393 58 7627. N. J. Lawrence (60)96% 97% 8.8. with (61) 80%. 52% e.e.(S)with (62) 67% 9.8. with (s3) Scheme 16 introduced the concept of chiral poisoning as a new strategy for asymmetric cataiysis (Scheme 17b).'*' This is especially useful when the catalyst is expensive [such as chiraphos (6511 and the poison cheap. The principal is illustrated by the reduction of alkenes with the racemic chiraphos rhodium complex (66).Addition of the S isomer of the thiophosphinite (57) results in selective poisoning of the (S,S)-chiraphos species. Faller has also applied the same principle to the kinetic resolution of allylic alcohols by selectively reducing one alkene with a poisoned ruthenium catalyst.'" Cycloalkanones are reduced with impressive enantioselectivity ( >90% e.e.) by hydrogenation using iridium(1) BINAP catalysts in the presence of bis(o-N,N- dirnethy1aminophenyl)phenylphosphine. log The (R)-BICHEP-Ru(ir) complex (68)is also an excellent catalyst for the enantioselective hydrogenation of a-ketoamides (69) (Scheme IXa)."O Asymmetric hydrosilylation of ketones [(TO) + (7f)l is achieved with high enantioselectivity with the new chiral bipyridine Bipymox (72) (Scheme 18b),' and TADDOL-derived cyclic phosphonites and phosphites.' ' Reduction with complex hydride reagents is the subject of many reports.Carboxylic acids are conveniently reduced to aldehydes in a one-pot procedure with piperidine and sodium diethyldihydroaluminate. ' Singaram's newly reported lithium aluminium hydride equivalent lithium pyrrolidinoborohydride is highly regiospecific in a 1,2 sensein the reduction of a$-unsaturated ketones.' The same reagent reduces tertiary arnidesto the corresponding alcohol. * ' Reduction of esters' and acid chlorides' ' is lo' 1.W. Faller and J. Parr J. Am. Chem. Soc. 1993 115 804. lo8 J.W. FaIler and M. Tokunaga Tetrahedron Lett. I993,34 7359. lo9 X. Zhang T.Taketomi T. Yoshizumi H.Kumobayashi S.Akutagawa K. Mashima and H. Takaya J. Am. Chem. Soc. 1993 115 3318. 'lo T. Chiba A. Miyashita H. Nohira and H. Takaya Tetrahedron Lett. 1993 34 2351. 'I1 H. Nishiyama S. Yarnaguchi S.-B. Park and K. Itoh Tetrahedron Asymmetry 1993 4 143. 'I2 J.-i. Sakaki W.B. Schweizer and D. Seebach Helv. Chim.Acta 1993 76 2654. N.M. Yoon,K.I. Choi Y.S. Gyoung and W. S. Jun Synth. Commun. 1993 23 1775. .I.C. Fuller E. L. Stangeland C.T. Goralski and B. Singaram Tetrahedron Lett. 1993-34 257. 'I5 G. B. Fisher,3. C. Fuller J. Harrison C.T. Goralski and B. Singaram Tetrahedron Lett. 1993,34,1091. N. M. Yoon,J. H. Ghn D. K. An and Y.S. Shon 1.Org. Chem. 1993,58 1941. I" J.S. Cha and H.C. Brown J. Org.Chem. 1993,58,4732. Synthetic Methods t 1 79 % 95 % 8.8.(64) R = (R,R)-l,l'-biiaphth-2.2'-didate Scheme 17 achieved with sodium diethylpiperidinylafurninohydride and sodium tris-t-butoxyalurninohydride respectively. Esters carboxylic acids amides and nitriles are efficiently reduced with samarium diiodide in the presence of water."* Secondary amides are reductively deoxygenated by Scbwartz's reagent (Cp,ZrHCi) to the corresponding imine.' l9 Alcohols are reduced to alkanes12' by the action of sodium borohydride and the phosphonium anhydride reagent (Ph3P+)20(CF,S0,12. a-Amino acids are conveniently reduced without racernization to the corresponding amino alcoholby sodium borohydride and iodine.' ' Miscellaneous reagents fur the reduction of ketones include copper(1r)- exchanged-cation resin-NaBH and lithium trisf( 3-t-but yl-3-pentyl)oxy] aluminium hydride.l2'9' 118 Y.Kamochi and T. Kudo Chem. Lett. 1993 1495. D. J. A. SchedIer A. G. Godfrey and 3. Ganem Tetrahedron Lett. 1993 115 5035. J. B. Hendrickson M. Singer and M. S. Hussoin J. Org. Chem. 1993 58,6913. M.J. McKennon A.I. Meyers K.Drauz and M. Schwarm J. Org. Chem. 1993 58 3568. 122 A. Sarkar B.R.Rao,and 8. Ram Synth. Commun. 1993 23 291. G. Boireau A. Weberly and R.Toneva SYNLETT 1993 585. N.J.Lawrence 0 Scheme 18 4 Oxidation Oxidation is the subject of issue 164 of Topics in Current Chen~istry;’’~ peroxygen reagents,lZ4’ di~xiranes,”~~ and catalytic oxidation enantioselective ep~xidation,’~~~ with peroxide reagents’ 24d are reviewed. Sharpless and coworkers continue their pioneering studies of asymmetric dihydroxylation of alkenes.The osmium-catalysed asymmetric dihydroxylation of terminal alkenes is efficiently achieved by use of the pyrirnidine-Iinked ligand (DHQD),-PYR (73),’ 25 or (DHQD),-PHAL (74);’26for this type of aIkene the new ligands are superior to the previously described phthalazine catalysts whose preparation has been recently described. ”The asymmetric dihy- droxylation of tetrasubstituted double bonds occurs with low to very high enan- tioselectivity with both phthalazine and pyrimidine ligand classes. 12’ Among other substrates treated with AD-mixes are a-substituted styrenes and a-phenylacrylates,’ 29 a,P-unsaturated ketones,’ 30 a#-and &+unsaturated arnides,’” aryl ally1 allyldanes ’3371 34 and tertiary alIylic alcohols.‘35 The procedure has seen several uses lZ4 (a) H.Heaney Top.Curr. Chem. 1993,164 I ;(b)W. Adam and L. HadjiarapogIou,ibid. 1993,164,45; (c) E Hoft ibid. 1993 164 63; (d) R. Sheldon ibid. 1993 164 21. G.A. Crkpino K.-S.Jeong H. C. Koib Z.-M. Wang D. Xu and K. B. Sharpless,J. Org. Chem. 1993,58 3785. 126 M. P. Arrington Y.L. Bennani T. Gobel P. Walsh S.-H. Zhao and K. 8. Sharpless Tetrahedron Lerr. 1993,34 7375. W. Amberg Y.L. Bennani R. K. Chadha G.A. Crispino,W. 13.Davis J. Hartung.K.4. Jeong Y. Ogino T. Shibata and K. 8. Sharpless J. Org. Chem. t993 58 844. K. Morikawa J. Park P. G. Andersson T. Hashiyarna and K. B. Sharpless,J. Am. Chem.Suc. 1993,115 8463. Z.-M. Wang and K. B. Sharpless SYNLETT 1993 603. I3O P.J. Walsh and K.B. Sharpless SYNLETT 1993 605. 13’ Y.L. Bennani and K. B. Sharpless Tetrahedron Lett. 1993 34 2079. Z.-M. Wang X.-L. Zhang and K. B. Sharpless Tetrahedron Lett. 1993,34 2267. 13’ S. Okamoto K. Tani F. Sato K. 3.Sharpless and D. Zargarian Tetrahedron Lett. 1993 34 2509. ’34 J.A. Soderquist A.M. Rane and C. J. Lopez,Tetrahedron Lett. 1993 34 1893. 13’ Z.-M. Wang and K. B. Sharpless Tetrahedron Lett. 1993 34 8225. Synthetic Methods in natural product synthesis. 36-1 39 Not surprisingly asymmetric dihydroxylation may be used to resolve racemic oIefins kineticalIy;there being a 30-fold difference in the rate of reaction of each enantiomer with AD-mix a [containing (DHQ),-PHAL] and AD-mix #? [containing (DHQD),-PHAL] (Scheme l!J).'40Similarly secondary allylic acetates may be kinetically resolved using the teraphthalyl linked ligand (75).14' Corey's and Sharpless' groups have sought to explain the origin of the high enantioselectivity. Corey argues that the reaction proceeds via a p-0x0-bridged bisOsfvn~) species Q0,0s[O,]OsO,Q. 14' However the conclusion from the Sharp- less group is different; they believe that the two quinuclidine units do not act in concert tie. the active species is a 1:1 Os0,-phthalazine Iigand DHQD (R = Me} DHQD' (R = 'pentyl) Scheme 19 136 G.A. Cnspino and K.B. Sharpless SYNLETT 1993,47. 13' G. A. Crispino and K.B.Sharpless Synthesis 1993,777. 13' H.C.Kolb Y. L. Bennani and K. B. Sharpless Tetrahedron Asymmetry 1993 4 133. 139 Y.L. Bennani and K.B. Sharpless Tetrahedron Lecr. 1993,34 2083. M.S.VanNieuwenhze and K. B. Sharpless J. Ant. Chem. SOC. 1993,115 7864. 141 B. B. Lohray and V. Bhushan Tetrahedron Lett. 1993,34 3911. E. J. Corey M. C. Noe and S. Sarshar J. Am. Chem. Soc. 1993,115,3828; E. J. Carey and M. C. Noe J. Am. Chem. Soc. 1993 115 12579. H. C. Kolb P.G. Andersson Y. L. Bennani G.A. Crispino K.-S. Jeong H.-L. Kwong and K. B. SharpIess,J.Am. Chem.Soc. 1993,115,12 226;T. Giibel and K. B. Sharpless,Angew. Chem. Int. Ed. Engl. 1993 32 1329. N.J. Lawrence Hanessian et al. have used the readily available C symmetric 1,2-diamine (76) to control the enantioselectivity of osmium tetroxide mediated dihydroxylation of a wide range of alkenes (Scheme 2Oa). Although the enantioselectivities are impressive at present stoichiometric amounts of osmium and amine are required.'44 Henry and Weinreb report a useful method for the oxidative cleavage of alkenes C(77) -, (78)] with catalytic osmium tetroxide and excess Jones' reagent (Scheme 2Ub).145 Similarly alkenes are oxidatively cIeaved to aldehydes by the action of potassium permanganate supported on alumina -yields are good and the conditions mild."' Scheme 20 Many new reagents have been developed for the oxidation of alcohols.Allylic alcohols are selectively oxidized in the presence of primary alcohols with stoichiomet- ric palladium(I1) salts;147 this may prove more useful when a catalytic version is developed. Aerobic oxidation with metal catalysts is attractive for economic and environmental reasons.For example simple secondary alkyl alcohols are oxidized by molecular oxygen with a ruthium(r~~~obalt(~i) bimetallic catalyst. 148 Molecular oxygen has also been used in the Baeyer-Villiger oxidation of ketones to lactones in the presence of benzaldehyde with or without metal [CU(II)or Ni(~r)]catalysis.'49 Other reagents for the oxidation of alcohols include Mn0,-bentonite-microwave;' 50 trichloromelarnine;'51 hypochlorous acid in methanol (to yield esters directly from CrO (cat.F70% aq. B~t00H;~~~ primary alcohol~);'~~ chrornium-substituted aluminophosphate-5 zeolite-Bu'OOH; s4 and the complex HUF-CH,CN. 55 The S. Hanessian P.Meffre M. Girard S. Beaudoin J.-Y. Sanceau and Y.Bennani J. Org. Chem. 1993,58 1991. I*' J.R.Henry and S. M. Weinreb J. Org. Chem. 1993 58 4745. D.G. Lee T. Chen and Z. Wang J. Org.Chem. 1993 58 2918. V. Bellosta R. Benhaddou and S. Czernecki SYNLETT 1993 861. 14* S.-I. Murahashi T.Naota and N. Hirai J Org.Chem. 1993 58 7318. 149 C. Bolm G. Schlingloff and K. Weickhardt Tetrahedron Lett. 1993 34 3405. Is* L. A. Martinez 0.Garcia F. Delgadc C. AIvarez and R. Patiiio Tetrahedron Lett. 1993 34,5293. S. Kondo M. Ohira S. Kawasoe H. Kunisada and Y. Yuki,J. Org. Chem. 1993 58 5003. C. E. McDonald L. E. Nice A. W. Shaw and N. B. Nestor Tetrahedron Len.,1993 34 2741. J. Muzart and A. N'Ait Aijou Synthesis 1993 785. J.D. Chen J. Dakka E. Neeleman and R. A. Sheldon J. Chem. Soc. Chem. Commun. 1993 1379. S. Rozen Y. Bareket and M.Kol Tetrahedron 1993 49 8169. Synthetic Methods 287 Dess-Martin periodinane a useful reagent for the oxidation of alcohols has seen an improved and large-scale synthesis. Aromatic aldehydes are oxidized efficiently to the corresponding benzoic acid with hydrogen peroxide in formic Epoxidation continues to draw much attention. Iqbal and coworkers have found that the epoxidation of alkenes with molecular oxygen is achieved using the hydroperoxide(79),derived by in situ cobalt(I1)-catalysed autoxidation of (80)(Scheme 21a).158 Schwenkreis and Berkessel have used the manganese(Ir1) complex (81) of the dihydrosalen Iigand bearing a pendant imidazole group as a biomimetic catalyst for epoxidation of alkene~."~ Collman et al.160 have similarly used a threitoktrapped manganese porphyrin as an epoxidation catalyst; oxidation of 1,2-dihydronaphtha- lene (82) is highly enantioselective (88% e.e.).Katsuki and coworkers have used the dihydrosalen catalyst (83) bearing axially chiral binaphthyl groups to oxidize the same alkene (Scheme 21b).16' Komiya and coworkers also report the epoxidation of alkenes with molecular oxygen and catalytic copper(I1) salts; however the reaction is not stereospecific.'62 Other reagents for epoxidation include bis(ephedrine)cobalt~I~~~~;1",'54 clay-impregnated-wit h-Ni (11 b02 and is0 bu tyraldehyde;'6s and pol ymer-supported Mn(IIr)-salen compfexes and iodosylbenzene. Mukaiyarna et a/.have reported the use of propionaldehyde diethyl acetal as a reductant in the cobalt(i1)-catalysed aerobic epoxidation of afkenes.'67 The method is neutral and can be used to synthesize acid-sensitive epoxides.168 A different approach to catalytic epoxidation has been taken by Manoury et LZ~.;'~~ the tartrate-derived borate (84)catalyses oxygen transfer from t-bu tylhydroperoxide to prochiral alkenes with moderate enan tioselectivity (Scheme 22a).Chiral epoxides are obtained in moderate enantiomeric excess from racemates by chiral Lewis-acid catalysed ring-opening with diethylamine (Scheme 22b).170 Terminal epoxides are efficiently constructed in a two-step process from chiral trichloromethykarbinals (accessible by oxazaborolidine reduction of the ketone) by selective reduction and base-catalysed ring closure of the resulting chlorohydrin.17' Hindered alkenes are efficiently epoxidized with nitrogen dioxide.l" Epoxides are also synthesized by a modification of Corey's reaction of carbonyl compounds and sulfonium ylides by generation of the sulfoniurn ylide in situ from dimethyl sulfide methanol and sulfuric acid.' 73 Epoxides are converted directly into carboxylic acids 15' R. E. Ireland and L. Liu J. Org. Chem. 1993 58,2899. 157 R. H. Dodd and M. Le Hyaric Synthesis 1993 295. T. Punniyamurthy B. Bhatia and J. Iqbal Tetrahedron tert. 1993,34 4657. T. Schwenkreis and A. Berkesset Tetrahedron Lett. 1993 34 4785. J. P. Collman V.J. Lee X. Zhang J. A. Ibers and J.I. Brauman J. Am. Chem. Sor. 1993 115 3834. 16' H. Sasaki R. Irie and T. Katsuki S YNLETT 1993,300; for other compkxes see N.Hosoya R. Irie and T. Katsuki S YNLETT I993 261. S.4. Murahashi Y. Oda T. Naota and N. Korniya J. Chem. SOC. Chem. Commun. 1993 139. 163 I. Iqbal S. Bhatia and M.M. Reddy Synth. Commun. i993 23 2285. S. Bhatia T. Punniyamurthy B. Bhatia and J. Iqbal Tetrahedron 1993 49 6101. E. Bouhlel P. Laszlo M. Levart M.-T. Montaufier and G. P. Singh Tetrahedron Lett. I993,34,1123; P. Laszlo and M.Jxvart Tetrahedron Lett. 1993 34 1127. B. 3.De B. B. Lohray and P.K. Dhal Tetrahedron Lett. 1993 34 2371. 16' T. Mukaiyama K. Yorozu T. Takai and T. Yamada Chem. Lett. 1993,439. 168 K. Yorozu T. Takai T. Yamada and T. Mukaiyarna Chem. Lett. 1993 1579. 169 E. Manoury B. A. H. Mouloud and G.G.A. Balavoine Tetrahedron Asymmetry 1993 4 2339. 170 M. Brunner L. Mussmann and D.Vogt SYNLETT 1993 893. E. J. Corey and C.J. Helal Tetrahedron Lett. 1993 34 5227. 172 E. Bosch and J. K. Kochi J. Chem. Soc. Chem. Comrnun. 1993,667. 173 J. Forrester R. V. H.Jones P. N. Preston and E. S.C.Simpson J. Chem. Soc. Perkin Trans. 1,1993,1937. N.J. Lawrence (82) 72 % 64 % e.8. 7? % 86 % 8.8.. a. w2h (83)(2.5 d%) PhD pwine N -0-But-Scheme 21 by the action of bismuth(II1) mandelate; olefins and alcohoIs are tolerated by the reagent (Scheme 23).174 New methods for the asymmetric aziridination of alkenes continue to be developed. Jacobsen and coworkers report the use ofthe copper(1) complexes of the chiral Schiff base (85) to catalyse the aziridination of alkenes with the iodinane (85) (Scheme 24a);' 75 aziridination of chromene derivatives is particularly efficient.Katsuki and coworkers have also used the manganese-salen catalyst in a similar manner to achieve asymmetric aziridination with moderate selectivity in the best case.' 76 Similarly Evans et al. report the chiral aziridination of phenyl cinnamate with the copper complex of the bis(oxazo1ine)(87) (Scheme 24b).'77 N-hydroxy-N-pivaluylanilinehas also been used for the aziridination of a1kenes.l78 Sulfides are oxidized selectively to sulfoxides with the peracetoxyimidic acid T. Zevaco E. Duiiach and M. Postel Tetrahedron Lett. 1993 34,2601. Ii5 Z. Li K.R.Conser and E. N. Jacobsen J. Am. CAem. SOC.,1993,115 5326. K. Noda N. Hosoya R. Irie Y. Ito and T. Katsuki SYNLETT 1993,469. 177 D. A. Evans M. M.Fad M.T. Bilodeau B. A. Anderson and D. M. Barnes J. Am. Chem. Soc. 1993,115 5328. 17' M. M. Pereira P. P,U. Santos L.V. Reis A. M. Lobo and S. Prabhakar. J. Chem. Soc. Chem. Commun. 1993,38. Synthetic Methods 75 % 8.8. 52 % 0.8. Scheme 22 BII#l)+~mndeietef 10 mo! %) RCOZH DMSO 80 "C Scheme 23 .. 75% >98 % e.e. 61% 97 % 6.8. (87) Scheme 24 generatedin situ from acetonitriIe and hydrogen peroxide;'79 a similar transformation is affected by photolysis in the presence of tetranitromethane.18* Tetrapropylarnmon- ium perruthenate is an efficient catalyst for the oxidation of sulfides to sulfones.18' Sulfoxidesare kinetically resolved by titanium-binaph thol-mediated oxidation of one enantiomer to the sulfune. 82 P.C.Bulrnan Page A.E. Graham D. Bethell and K. B. Park Synth. Commvn. 1993,23,1507 D. Ramkumar and S. Sankarararnan Synthesis 1993 1057. 18' K. R. Guertin and A. S. Kende Tetrahedron Lett. 1993,34,5369. lBz N. Komatsu M. Hashizume T. Sugita and S. Uemura J. Org. Chem. 1993 58,7624. N.J. Lawrence 5 Protection Protecting group methodology has seen much study this year. The use of silyl ethers as protecting groups especially in conjunction with oxidation reactions has been reviewed.ls3 Primary and secondary alcohols are rapidly protected as their t- butyldiphenylsilyl ethers by the action of t-butyldiphenylsiiyl chloride and ammonium nitrate or perchlorate,' 84 and as their trimethylsilyt ethers with hexamethyldisilazane and zinc chloride.* 85 Lipshutz et a!.' 86 report the use of trimethylsilylfuorosulfonate (TMSOFS) as a cheap alternative to trimethylsiiyl triflate for the protection of sterically hindered alcohols. The TMSOFS is simply prepared in situ by protodesilyl- ation of allyltrimethylsilane with fiuorosulfonic acid. SeveraI methods fur the deprotection of allyl-protected amines and alcohols have appeared. AlIyl glycosides are deprotected by conversion into the 2-oxopropyl glycoside by Wacker oxidation [Pd(ri),Cu") O,] followed by photofysis.lS7 Ally1 and I-propenyl ethers are deprotected in a similar fashion [Pd(ri) CU~I), H,U,] but without recuurse to photolysis.ls8 AIiyI ethers and amines are deprotected by in situ generated dicyclopentadienyl zirconium (Cp,Zr);' 89 tetrahydropyranyl ethers diiso- propylidene acetals and esters (partially) are tolerated by this reagent.Allylamines are also rapidly deprotected by palIadium(o) allylic substitution with N,N'-dimethylbar- bituric acid.'" Propargylic ethers are selectively cleaved to the correspondingalcohol with low-valent titanium (TiCIJMg) in the presence of silyl benzyl and methyl ethers. 91 BenzyI-protected alcohols are seiectively deprotected in the presence of t-butyIdiphenylsily1 ethers by boron-trichloride-dimethyl-sulfide Tet-rahydropyranyl ethers are efficiently made from dihydropyran with catalytic [Ru(CH,CN),(triphos)30 [triphos = CH,C(CH2PPh,),].'93 Tetrahydro-pyranyl ethers are also formed by molybdenum(v1) acetyla~etonate,'~~ ceric am- monium nitrate,"' or H-Y zeolite'96 and 3,4-dihydro-2H-pyran.AIcohoIs are protected as their 2-tetrahydrofuranyl ethers by n-tetrabutyIammonium-peroxydisul-fate-mediated radical coupling with tetrahydr~furan.'~~ DimethoxytrityI-protected alcohols and thiols are selectively deprotected in the same molecule by 80% acetic acid (as.) and silver nitrate4ithioerythrito1 re~pectively.'~' Both 1,2 and 1,3-diols are rapidly and efficiently protected as their base-labile cyclic carbonates by reaction with triphosgene."' BOC-protected amides are selectively deprotected with catalytic J. Muzart Chem. Rev. I993,93 11. 18* S.A. Hatdinger and N. Wijaya Tetrahedron Lett. 1993 34 3821. H. Firouzabadi and B. Karimi Synth. Commun. 1993 23 1633. IB63.H. Lipshutz J. Burgess-Henry and G.P.Roth Tetrahedron Lett. 1993 34,995. I*' J. Liinning U. Moller N. Debski and P.Welzel Tetrahedron Letr. 1993 34 5871. IB8H. 3. Mereyala and S. Guntha Tetrahedron Lett. 1993,34 6929. €I. Ito T. Taguchi and Y.Hanzawa J. Org. Chem. 1993,58 774. 190 F. Garro-Helion A. Merzouk and F. Guibk J. Org. Chem. 1993 58,6109. 19' S.K. Nayak S.M. Kadam and A. Banerji SYNLETT 1993 581. 19' M.S. Congreve E.C. Davison M.A. M. Fuhry A. B. Holmes A. N. Payne R.A. Robinson and S. E. Ward SYNLETT 1993 663. 193 S. Ma and L. M. Venanzi Tetrahedron Lett. 1993,34 5269. 194 M. L. Kantarn and P. L. Santhi Synth. Comun. 1993 23 2225. 195 G. Maity and S.C. Roy Sy~th.Commun. 1993 23 1667. 196 P. Kumar C. U. Dinesh R.S. Reddy and B. Pandey Synthesis 1993 1069. J.C. Jung H.C.Choi and Y. H. Kim Terrahedron Lerr. 1993 34,3581. 198 Z. Huang and S. A. Benner SYNLETT 1993,83. 199 R. M. Burk and M. B. Roof Tetrahedron Lett. 1993 34 395. Synthetic Methods 29 1 rnagnesium(1r) perchlorate in acetonitrile even in the presence of BOC-protected amines.’ O0 Esters are often used to protect alcohols and several new methods for their synthesis and hydrolysis’” have been described. Vedejs eta!.report the use of tributylphosphine as a remarkable catalyst for the acetylation and benzoylation of alcohols.202 In the latter case tributyiphosphine is a more efficient catalyst than the well-documented acylation catalyst DMAP. The use of bulky amines (PriEtN or 1,2,2,6,6-pentamethyI- piperidine) with acetyl chloride (-78 “C r.t.) results in the selective acylation of primary alcohofs in the presence of secondary alcohols (>99.6 :0.4).203Folmer and Weinreb204 report a potentially useful and mild one-pot method for ester synthesis involving activation of carboxyk acids with AppeI’s salt (88)to acyl- 1,2,3-dithiazoles (89) (Scheme 25).Formate esters are efficiently made from alcohols with thionyi Scheme 25 chioride-DMF-lithium iodide; when potassium iodide is used the corresponding alkyl iodide is i~olated.”~ Another simple procedure for the formylation of alcohols and amines by reaction with cyanomethylformate is described.206 The deprotection of acetate and pivaloy1 esters is achieved rapidly (in just a few minutes) by microwave promoted hydrolysis on Similarly t-butyldimethyisityl ethers,208 benzal- dehyde diacetate~,~” acetates,’ lo and benzyl ethers’ are deprotected by microwave promoted hydrolysis on alumina.The procedures involve no reaction solvent and minimal work up. Several new methods for the removal of acetal protecting groups have been reported. Thioacetals and thioketals are deprotected photochemically (2 > 350 nm) in the presence of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ);alternatively the same transformation is achieved thermally by heating in acetonitrile under reflux.’’2 Node ‘O0 J. A. Stafford M. F. Brackeen D.S. Karanewsky and N. L. Valvano Tetrahedron Lerr. 1993,34,7873. ’O‘ C. J. Salomon E.G. Mata and 0.A. Mascaretti Tetrahedron 1993 49. 3691. ’02 E. Vedejs and S.T. Diver 3. Am. Chem.SOC.,1993 115,3358; E. Vedejs N. S. Bennet. L. M. Conn S.T. Diver M. Gingras S. Lin P. A. Oliver and M.J. Peterson J. Org. Chem. 1993 58 7286. ’03 K. Ishihara H. Kurihara and W. Yamamoto J. Ory. Chem. 1993 58 3791. ”* J.J. Folrner and S. M. Weinreb Terruhedron Lett. 1993 34 2737. ’05 I. Fernandez B. Garcia S. Muiioz J. R. Pedro and R.de la Salud SYNLBTT. 1993. 489. lo6 J. Deutsch and H.-3. Niclas Synth. Commun. 1993 23 1561. ’07 S.V.Ley and D.M. Mynett. SYNLETT 1993 793. ’08 R.S. Varma J. B. Lamture and M. Varma Tetrahedron Left. 1993 34 3029. ’09 R.S. Varma A. K. Chatterjee and M. Varma Tetrahedron Lett. 1993,34 3207. ”* R.S.Varrna M. Varma and A. K. Chatterjee J. Chem. Soc. Perkin Trans. 1 1993 999. ’” R.S. Varma A. K. Chatterjee and M. Varma Tetrahedron Lerr.1993 34 4603. ”’L. Mathew and S. Sankararaman J. Or$.Chem..1993 58 7576. N.J. Lawrence et 01.'~~have developed a reagent system (silver nitrate-iodine) for the rapid and mild deprotection of both dithioacetal and monothioacetal groups. Dithioacetals are efficiently hydrolysed by the electrophilic fluorinating reagent N-fluoro-2,4,6-trimethylpyridiniurn triflate in aqueous TNF.214Roskamp and Ford report an improvement for the deprotection of acetals with ti@) chloride; the rate of hydrolysis is greatly increased by simply adding catalytic naphthalene or remarkably C,,.21 On occasions in a synthesis it is necessary to change protecting groups to circumvent incompatibilityproblems. Efficient one-pot procedures are desirable for this purpose.To this end benzyl-protected alcohols are efficiently converted into their correspond- ing acetates by the action of catalytic tin@) bromide and acetyl bromide.216 Similarly amine protecting groups may be changed; N"-fluorenyirnethoxycarbonyl(Fmoc) groups are converted into an Nu-benzyloxycarbonyl (Z) group by potassium fluoride and N-benzyloxycarbonyl-5-norbornene-2,3-di~arboximide (BCN).'17 6 Miscellaneous Preparations Chiral acylations are normally best carried out by the use ofenzymes. However many workers are developing reagents and catalysts to effect this process. Evans and coworkers2" have used the imide (90)as a chiral acyhting agent to resolve secondary alcohols kinetically (Scheme 26a). Kinetic selectivity of 213-30:1 for the R enantiomer of the magnesium alkoxide is observed.Katsuki and co-workersZfg have used the chiral benzirnidazole (91) for the chiral acylation of lithium amide-enolates (Scheme 26b). Scheme 26 213 K. Nishide K. Yokota D. Nakarnnra T. Sumiya M. Node M. Ueda and K. Fuji Tetrahedron Len. 1993,34,3425. A.S. Kiselyov L. Strekowski and V.V. Semenov Tetrahedron Lett. 1993 49 215i. 'IS K.L. Ford and E.J. Roskamp J. Org. Chem. 1993,58,4142. T. Oriyama M.Kimura M. Oda and G. Koga SYNLETT 1993,437. ''' W.-R. Ei 3. Jiang and M. M. Jouilik SYNLETT 1993 362. 218 D.A. Evans J.C. Anderson and M. K. Taylor Terrahedron Lett. 1993,34 5543. 'I9 M. Ogata T. Yoshimura H. Fujii Y. Ito and T. Katsuki SYNLETT 1993 728. Synthetic Methods Several reports describe the development of reagents that are chira1 proton equivalents for the protonation of prochiral nudeophiles.Amines have rarely been used as the source of chiral protons for the enantioselective protonation of prochiral enolates [(94) -+ (9511 (Scheme27). However,the groups of Fuji"" and KogaZ2l have reported the use of the piperazine (92)and the triamine (93)respectively as reagents fur the stereoselective protonation of lithium enolates. @ h. &7wa033Pm -&.,,t),,,j":,"c bh (W (95) (92) Scheme 27 Davies et al. have continued to illustrate the usefulness of the enantioselective conjugate addition of (a-methy1benzyl)benzylamineto t-butyl cinnarnate by applica-tion to the syntheses of or-methyl-~-phenylaianines,222 the taxol-side chain,223 and cis-pen tach224 Perhaps just as important as asymmetric synthetic methods are the methods for the exact determination of enantiomeric excess Accordingly Feringa and coworkers have developedthe phosphoric acid chloride (96)for the determination of the optical purity ofchiral akohols and amines by "P NMR spectroscopy.225An interesting account of the accurate determination of extremely high enantiomeric purity appears in a paper by Rautenstrauch et ~1.~'~ The principles are applied to the determination of the enantiomeric purity (> 99.5% e.e.) of several commercially available samples of camphor.The year has seen several reports of novel procedures for the hydroboration of alkenes. Evans et al. report the use of achiral lanthanoid complexes as catalysts fur the hydroboration of olefins with catech~lborane.~~' The Lewis acidity of the boron atom is thought to be dramatically increased by coordination of the lanthanide (s.9.samarium) to a catechol oxygen atom. The chiral rhodium complex (97) is also an excellent catalyst for the hydroboration of substituted styrenes t(98) -(99)] (Scheme 220 K. Fuji K. Tanaka and H. Miyamoto Tetrahedron Asymmetry 1993,4,247. "' T.Yasukata and K. Koga Tetrahedron:Asymmetry 1993,4,35. '" S.G.Davies N. M. Garrida 0.Ichihara and I. A. S. Walters J. Chem. Soc. Chem.Cornmun. 1993,1153. M.E.Bunnage S. G.Davies and C.J. Goodwin J. Chem. SOC.,Perkin Trans. 1 1993,1375. 224 S.G. Davies 0.Ichihara and 1.A. S. Watters S ?"LETT 1993,461. 225 R.Hulst R. W. f.Zijlstra B.L. Feringa,N.K.de Vries,W. ten Hoeve and H. Wynhrg Tetrahedron Lett. 1993,34 1339. 226 V. Rautenstrauch M. Lindstrom B. Bourdin J. Currie and E. Oiiveros Helv. Chim. Acto 1993,76,607. 227 D.A. Evans A. R. Muci and R. Stiirmer J. Org. Chem. 1993,58,5307. 2'3 N.J. Lawrence 28a).228A process that is equivalent to the hydroboration of alkenes involves selenoalkoxylation and subsequent removal of the seleno group. Deziel et ~1.'~'have introduced a chiral version of this procedure. The C symmetric phenyIseleny1 triflate (100) reacts with alkenes in the presence of an akohol to give anti seIenyl ethers (lUI) which can be reduced to give chiral protected alcohols (Scheme 28b). Alkenes are hydrated in an anti-Markovnikov fashion by titanium(1n) borohydride species or zinc b~rohydride;~~' the lack of both stereospecificity and need of oxidant seems to rule out a hydroboration rnechani~rn.~~ * The hydroboration-oxidation of enamines by Ipc,BH yields fi-amino alcohols with high enantioselectivity (e.e.50_86%).232 Microwave-mediated synthesis has received much attention this year (see also section 5). Amides are prepared simply by heating (5 min) an equimolar mixture of a secondary amine and carboxyiic acid in a microwave Conventional heating (160-180 "C) of a similar mixture requires somewhat longer reaction times.234 Similarly esters are formed from carboxylic acids alcohols and an acid catalyst under microwave irradiati~n.~~' Anhydrides are synthesized from carboxylic acids iso-propenyi acetate and an acid catalyst.236 fi-Aminoesters and /?-lactarns are aIso prepared by rnontmorillonite-catalysed coupling of silyl ketene acetals and imines by the action of microwave radiation.237 '" J.M. Brown D. I. Hulmes and T.P. Layzell J. Chem. SOC.,Chem. Commun. 1993,1673. 229 R. Deziel S.Goulet L. Grenier J. Bordekau and J. Bernier J. Urg. Chem. 1993 58 3619. 230 B.C. Ranu R. Chakraborty and M. Saha Tetrahedron LRft. 1993 34,4659. 23' K.S.Ravi Kurnar S. Baskaran and S. Chandrasekaran Tetrohedrun Lett. 1993,34,171. 232 G. 3. Fisher C.T. Goralski L. W. Nicholson and 3.Singaram Tetrahedron Lett. 1993,34 7693. 233 M. P.Vazquez-Tato SYNLETT 1993,506. 231 8.S. Jursic and 2. Zdravkovski Synth Commun. 1993,23,2761. 235 A. Loupy A. Petit M.Ramdani C.Yvanaeff M. Majdoub B. Labiad and D. Villernin Can. J. Chem. 1993,71 90. 236 D. Villemin B. Labiad and A. Loupy Synth. Commun. 1993,23,419. 237 F. Texier-Boullet R. Latouche and J. Hamelin Tetrahedron tett. 1993 34 2123. Synthetic Methods 295 Some interesting functional group transformations described this year include the conversion of aldehydes into nitriles by the one-pot reaction of the corresponding N,N-dimethyIhydrazone with magnesium rnonupero~yphthalate.~~~ Triphosgene in combination with triphenylphosphine provides a mild reagent for the conversion of primary and secondary alcohols into alkyl chlorides.239 Miller et al. report a convenient conversion of carboxylic acids into alk-1-enes of one less carbon atom by a paIladiurn-catalysed decarbonylatiowdehydration of the mixed-acid-acetic-acid an- h~dride.~~’ Hexamethylene tetraamine txibromide provides a new mild reagent for electrophilic bromination of aromatic compounds.241 The synthesis of chiral organofluorine is currently receiving con- siderable attention.Davis’ group has used the N-F camphorsultam (102)as a chiral electrophilic fluorinating agent to synthesize a-fluoroketones from sodium enolates C(103) + (104)3 (Scheme 29).243The new electrophilic fluorinating agent (105) has seen several uses this year including the fluoro-destannylation of vin~lstannanes,’~~ and the fluorination of alkenes arenes and car bani on^.^^^ The chiral quaternary ammonium fluoride (106)derived from quinine has been used to catalyse the aldol reaction of silyl enol ethers and aldehydes with high enantio~electivity.~~~ N,N,N-trimethyl-1 -adamantylamrnoniurn and proton-sponge fluoride248 provide completely anhydrous sources of fluoride ion.Scheme 29 2’8 R. Fernindez C. Gasch J.-M. Lassaletta J.-M. Llera and J. Vizquez. Tetrahedron Letf. 1993,34 141. 239 I. A. Rivero R.Somanathan and L. H. HelIberg Synth. Commun. 1993.23 71 1. 240 J. A. Miller J. A. Nelson and M.P. Byrne J. Org. Chem. 1993,58 18. 241 S.C. Bisarya and R. Rao Synth. Curnrnun. 1993,23,779. 242 G.Resnati Tetrahedron 1993 49 9385. 243 F.A. Davis P. Zhou and C.K. Murphy Tetrahedron tetr. 1993,34 3971. 244 D. P.Matthews S. C.Miller E.T. Jarvi J. S.Sabol,and J. R. McCarthy Terrahedron Lett. 1993,34,3057. 245 G.S.Lal J. Org.Chem. 1993 58 2791. 246 A. Ando T. Miura T.Tatematsu and T. Shioiri Tetrahedron Left.,1993,34 1507. 247 K.M.Harmon B.A. Southworth K. E. Wilson and P. K. Keefer 1.Ory. Chem. 1993,58 7294. 248 R.D. Chambers E. F. Holmes S. R. Korn and G. Sandford J. Chem. SOC.,Chem. Commun. 1993,855. N. J. Lawrence Amide bases continue to be the topic of many important papers. Collum and coworkers have found that the extremely hindered base lithium bis(2-adaman- ty1)amide (107)is an excellent reagent for the generation of E enolates from ketones (E:2 50 l)(c$ LDA E 2 B 2.5 l).249 Williard has published the X-ray structure of an LDA-THF complex.* The crystalline aggregate prepared from LDA (from diisopropylarnine Iithium metal and styrene in ether) and THF is a bis-solvated dimer.Such studies are undoubtedIy of help to those researchers designing homochiral lithium amide bases. Indeed the X-ray structure of the chiral Iithiurn amide (108) has recently been reported.25' Koga and coworkers have found that the chiral lithium amides (109) and (1lo) the latter containing a fluorinated atkyl group induce high enantioselectivity in kinetic deprotonation of 4-substituted cyclohexanones (Scheme 30).2s2They have also shown that in certain cases the amide bases can further control the alkylation of chiral en01ates.~~' Bunn and Sirnpkins report that the enantiosefectiv- ity of chiral-amide-base-mediateddeprotonation under external quench conditions is improved by the addition of lithium chloride; this now allows direct reaction of the chiral enolate with electrophiles other than silyl chlorides in high enantioselectiv- ity.254Milne and Murphy have used the dilithium salt of norephedrine to effect enantioselective deprotonation of prochiral epoxides thereby providing allylic akohols.' Li I 93% 78 % 8.8.wlh (109) (109) R=€t 74 % 87 % 8.8.with (110) (93% e.e.at -100 "C) (110) R = CHzCF Scheme 30 249 K.Sakuma J. H.Gilchrist F. E. Romesberg,C. E. Cajthami and D. B. Collum Tetrahedron Lert. 1993 34,5213. P.G.Williard and J. M.Salvino J. Org. Chem. 1993 58 1. "' A.J. Edwards S. Hockey F. S. Mair P.R. Raithby R. Snaith,and N. S.Simpkins,J. Org. Chem. 1993,58 6942. 252 K.Aoki H Noguchi K. Tomioka,and K. Koga Tetrahedron Lett. 1993,34 5105. 253 Y. Hasegawa H.Kawasaki and K. Koga Tetrahedron Lett. 1993,34,1963. *" B.J.Bunn and N.S. Simpkins J. Urg. Chem. 1993,58 533. 255 D.Miine and P. J. Murphy J. Chern. SOC.,Chem. Commun. 1993 884. Synthetic Methods Beak and DuZs6report the stereoselective alkylation and silylation [(lll) -+ (1 12)] of carbanions in the presence of (-)-sparteine (Scheme 31). This method for asymmetric carbonxarbon bond formation is unlike that involving chiral lithium amide bases since the chiral catalyst is introduced onIy after deprotonation has occurred. The selectivity is probably a result of interconversion of the dia- stereoisomeric substrate-sparteine complexes since the organoli thiurn is configur-ationally unstable. Scheme 31 Several reports have appeared describing efficient procedures for the resolution of the often-used auxiliary 1,l'-binaphthalene-Z,2'-diol via its N-[(S)-cc-methyben- zylarnine]thiopho~phoramidate~~~ and 0-(-)-menthy1 phosphate.258 Finally Fritz-Langhals2'' reports a useful way to separate diastereoisomers.Conventionally this is carried out by fractional recrystallization or chromatography but in this study the racemic acid (113) is resolved by fractional distillation of the chiraI amides (114)and (1151 using a spinning-band column (Scheme 32). The boiling points of the amides (114) and (115) differ by 7K which allows for efficient separation of optically pure rnateria1. It is highly Iikely that this technique will find many applications. %heme 32 256 P. Beak and H.Du,J. Am. Chem. SOC., 1993,Ii5 2515.257 D. Fabbri G. Delogu and 0.De Lucchi J. Org. Chern. 1993 58 1748. J.-M. Brunel and G. Buono 3. Org. CheM. 1993,58 7313. 259 E. Fritz-Langhals Angew. Chem. Int. Ed. Engl. 1993 32,753.

ISSN:0069-3030    

DOI:10.1039/OC9939000269

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

10 Enzyme Chemistry By A. G.SUTHERLAND School of Applied Chemistry University of North London London N7 $08,UK 1 Introduction As some biotransformation methods particularly the kinetic resolution of carboxylate esters by hydrolysis or condensation are increasingly thought of as a standard weapon in a synthetic chemist’s armoury there has been a marked tendency for specialists in the enzyme chemistry field to move on to new areas. Thus the past year has seen an increase in the investigation of areas such as amide and epoxide hydrolysis and the use of oxidoreductase systems in resoIution processes. Accordingly in line with the trend of last year,’ this report will deal in greater detail with these emerging methods rather than attempting to reflect the relative volume of papers published on each of the topics below.The rate of publication on enzymes in synthesis has now made the publication of a full review of the subject a virtual impossibility but a Iarge symposium-in-print goes much of the way to delineating the state of the art.’ A review of the use of enzymes in the synthesis ofchiral drugs provides a different ~iewpoint.~ Two doyens of the field have written perspectives on their recent work thus Jones has discussed his seminal research on the prediction and control of enzyme ~pecificity,~ while Wong has summarized his syntheses of aza sugars using several enzyme systems.’ 2 Hydrolysis and Condensation Reactions Alcohols Carboxylic Acids and Esters-The resolution of racemic typically second- ary alcohols (or their esters) by acylation (or by hydrolysis or transesterification) forms the bulk of the current literature on biotransformations and as a relatively routine technique will only be covered briefly here.The transesterification methods have been reviewed6 and compared with similar chemical methods.’ Secondary alcohol resolutions are at their most powerful when used to resolve small highly functionalized and readily available starting materials such as the buten01 ’ A.G. Sutherland Ann. Rep. Prog. Chem. Sect. 3,Org. Chem. 1992 89 281. Tetruhedron:Asymmetry 1993,4 757-1396. A. L. Margolin Enzyme Microb. Technol.,1993 15 266. J. B. Jones Can. J. Chem. 1993 71 1273. G.C. Look C.H.Fotsch and C.-H. Wong Acc. Chem. Res. 1993,24 182. E.Santaniello P. Ferraboschi and P. Grisenti Enzyme Micrab. Technol. 1993 15 367. ’ .I.Otera Chem. Reo. 1993 93 f449. 299 A. G. Sutherland 0 0 (1) 32% 98%e.e. 40%,98% e.e. (2) > 95% e.e. > 95% e.e. (40% conversion) (60% conversion) Reagents i Pseudomonas sp. lipase toluene H,O; ii Pseuodomonas puorescens lipase vinyl acetate Scheme 1 derivative or the lactone (2)9 (Scheme 11 the last of which has been used to synthesize the anti-HIV carbocyclic nucleoside precursor carbovirg and also the key hydroxy-lactone moiety of the HMG CoA reductase inhibitors based on compactin." Other notable and extremely efficient resolutions include that of a general inositol precursor' and the chiral auxiIiary trans-2-(cc-cumyl )cyclohexanoI.' * Dasrhadi and O'Hagan have explored the resolution of diarylmethanols and found that the extent of discrimination between relatively similar rings @.g.2,5-difluorophenyI versus phenyl) can be surprisingly high.I3 The past year has seen more examples of successful resolutions of tertiary alcohols coming to light. Thus hydrolysis at the more hindered carbonyl of the oxalate (3) gave the resulting norbornanol in good enantiomeric excess (Scheme 2),14 while the enantiomers of bridgehead alcohols in a seriesof c4.1.O]heptanes have been resolved by hydrolysis of the corresponding chloroacetates.' OH 0 0 42%,90% e.e. 338 88% e.e. (3) Reagents i porcine pancreatic lipase Bu'OH H,O Scheme 2 8 M. Bazinger G.J. Griffiths and J. F. McGarrity Tetrahedron Asymmetry 1993,4 723.9 R. A. MacKeith R. McCague H.F. Olivo C. F. Palmer and S. M. Roberts J. Chem. Soc. Perkin Trans. 1 1993,313. 10 R. McCague H. F. Olivo and S. M. Roberts Tetrahedron Lett. 1993,34 3785. I1 L. Ling and S. Ozaki Tetrahedron Lett. 1993 34 2501. 12 D. L. Cornins and J. M. Salvador Tetrahedron Lett. 1993,34 801. I3 L. Dasradhi and ID. O'Hagan Bioorg. Med. Chem. Lett. 1993,3 1655. I4 I. Brackenridge,R. McCague S. M. Roberts and N. J. Turner J. Chem.Soc. Perkin Trans. I 1993 1093. 15 J. P. Barnier L. Blanco G. Rousseau E. Guibe-Jampel and I. Fresse J. Urg. Chem. 1993 58 1570. Enzyme Chemistry 301 The desymmetrization of mew diols (the 'meso trick') by lipase-catalyzed acylation remains a popular approa~h.'~.~' This technique has been extended by Uguen and coworkers to a tetra01 (4) with two-fold meso symmetry.'* Acylation gave a mixture of C,-symmetrica1 and meso diacetates (Scheme 31 which after conversion into the corresponding bis(phenylsulfides) were separated to give the chiraI product (5)as one enantiomer.An elegant exploitation of the meso trick in combination with a kinetic resolution has been used to deracemize and dediastereoisomerize the mixture of isomers of hexan-2,4-diol (Scheme 3)'' It was shown that acylation of these substrates only occurs at the S alcohol positions so that Mitsonobu inversion of the crude mixture followed by hydrolysis gives only the S,S enantiomer. 78% combined (5) 73% 8% t iii,vi v JJY OH OH > 98%e.e. > 98%d.e.66%,> 98%e.e. > 72% d.e. Reagents i Pseudomonas fluorescens lipase vinyl acetate; ii PhSSPh PBu, CH,CI,; iii Pseudomonas sp. lipase vinyl acetate Bu'OMe; iv DEAD p-nitrobenzoic acid PPh,; v LiOH; vi separation Scheme 3 l6 S. Takano M. Moriya Y. Higashi and K. Ogasawara,J. Chem. Soc. Chem. Commun. 1993 177. " N. Toyooka A. Nishino and T. Mornose Tetrahedron Lett. 1993,34 4539. P. BreuiIles T. Schmittberger and D. Uguen TetrahedronLett.,1993 34,4205. '' M.-J. Kim and I.S. Lee SYNLETT 1993 767. A. G. Sutherlaand Over recent years lipases have become popular as catalysts for regioselective ester hydrolysis (or condensation) and further examples of this use in the carbohydrate2’.*’ and phosph~lipid~’*~~ fields continue to be reported.This methodology has now been extended to poIyhydroxybenz~pyran,~~ and other aromaticz6 ben~opyranone,~~ systems with considerable success. The kinetic resolution of racemic carboxylic acids largely by hydrolysisof a simple alkyI ester also maintains its popularity -notably in the resolution of non-natural amino a~ids.’~.~’ A particularIy topical resolution is the transesterification of methyf trans-8-phenylglycidate under Mucor miehei lipase catalysis. Both enantiornerically pure products can be converted enantioconvergently into the taxol C-13 side chain (6) (Scheme 4).29 Reagents i Mucor miehei lipase Bu’OH hexane Scheme 4 A striking example of the use of the meso trick in the context of complex carboxylic acids has been provided by the direct enantioselective synthesis of the calcium antagonist (7) (Scheme 5).30 Pig liver esterase has been shown to perform diastereoselective hydrolyses of arylidene and dialkylidene malonate diester~.~’~~’ In the examples studied reaction tended to occur at the 2 position ester with moderate selectivity e.g.(8) (R’ = n-2a G. B. Oguntimein H. Erdrnann and R.D. Schmid Biotechnol. Lett. 1993 IS,175. 2* R. Lopez C. Perez A. Fernandez-Mayoralas and S. Conde J. Carbobydr. Chem. 1993 12 165. 22 G. Lin F.-C. Wu and S.-H. Liu Tetrahedron Lett. 1993 34 1959. 23 T. Morimoto N. Murakami A. Nagatsu and 3. Sakakibara Tetrahedron Lett. 1993,34 2487. 24 D. Lambusta G. Nicolosi A. Patti and M. Piattelli Synthesis 1993 1155. ” V. S. Parmar A. K. Prasad N.K. Sharma A.Vardhan H. N. Pati S. K. Sharma and K.S Bisht J. Chem. SOC.,Chem. Commun. 1993,27. 26 G. NicoIosi M. Piattelli and C. Sanfilippo Tetrahedron 1993 49 3143. 27 B. NieIsen H. Fisker B. Bjarke U. Madsen D. R. Curtis P. Krogsgaard-Larsen and J. J. Hansen Bioorg. Med. Chem. Lett. 1993 3 107. B. Imperiali T.J. Prins and S. L. Fisher 1. Org. Chern. 1993 58 1613. 29 Gou,Y.-C. Liu and C. S. Chen. J. Org. Chem. 1993 58 1287. D.-M. 30 T. Adachi M. Ishii Y. Ohta T. Ota T. Ogawa and K. Hanada Tetrahedron Asymmetry 1993,4,2041. 31 T. Schirmeister and H.-H. Otto J. Org. Chem. 1993 58 4819. 32 T. Schirmeister and H.-H. Otto Angew. Chem. fnt. Ed. Engl. 1993,32 572. Enzyme Chemistry ('7) 7745,> 99% e.e. Reagents i Aspergillus metieus protease 3-nitrooxypropan- 1-01 H,O Scheme 5 C,H 1 R2= CH3) 35% de,31to complete selectivity e.g.(8) (R'= Ph R2= H) and (9).3t,32 Amines Amides and Lactams.-The past year has seen a considerable upsurge in interest in the enzyme-catalysed hydrolysis and condensation reactions of amides. An example of this which could prove to be of some significance is the report by Sih and coworkersof the lipase-catalysed rnethanolysis of the /3-lactam (10)(Scheme6),which provides direct access to the C-13 side chain of taxol (6).33 0 Ad* ,I Ph A*. ,mo ii,K,H 0 (*I0pyL.p;Ka OMe Ph40H Ph OH (10) 42% > 99.5% e.e. (61 Reagents i Pseudomonos sp. lipase Bu'OMe MeOH; it NaOH(aq.) Scheme 6 33 R. Brieva J.Z. Crich and C.J. Sih 1.Org. Chem. 1993 58 1068.A. G.Sutherland The penicillin acylase from Escherichia coli has emerged in the important new application of the kinetic resolution of racemic amines via the hydrolysis of the corresponding phenylacetamides. This protocol has been used to synthesize both fl-34 and y-amino acids35 in high enantiomeric purity. The refinement of using p-hydroxyphenylacetamides in these reactions which often provides an increase in enantiosefectivity,also looks promising.36 In the opposite reaction direction Sheldon and coworkers have demonstrated that Iipases can catalyse the conversion of carboxylic esters into the corresponding primary amides (in the presence of and have further observed that this process can display a higher enantioselectivity than the analogous aqueous hydrdysis (Scheme 7).37Gotor and coIIeagues have shown that this type of procedure can be extended to more functionalized amine systems,38 while it has also been demonstrated that the protease 'alcalase' can catalyse the conversion of a peptide C-terminal ester into the analogous primary amide in a similar process.39 Proteases have seen further use in the incorporation of (protected) amino acid 96%e.e.Reagents i Candida antartica lipase Bu'OH NH Scheme 7 residues into peptides4' (and also peptide iso~feres~~) where the use of C-terminal oxazolones as acyl donors has proved to be effective as the enzyme only utilizes the 'naturaI' L enantiomer or diastereoisomer of the interconverting Epoxides.-The use of epoxide hydrolases to provide enantiomerically pure epoxides or vicinal diols has always seemed attractive.This approach has been limited by the fact that the well-characterized enzymes in this class usually from mammalian sources,are available in only very small quantities (although elegant uses of these systems are still appearing in the literat~re).~~.~~ However this situation is now likely to change as a 34 V. A. Soloshonok Y. K.Svedas V. P. Kukhar A.G. Kirilenko A. V. Rybakova V. A. SoIdenko N. A. Fokina,O. V,Kogut,I. Yu.Galaev,E. V. Kozlova,I. P.Shishkina,andS. V.Galushko,S YNLETT,1993,339. 35 A. L. Margolin Tetrahedron Lett. 1993 34 1239. 36 A. Guy A Dumant and P.Sziraky Bioorg. Med. Chem. Lett. 1993 3 1041. 37 M.C. de Zoete A. C. Kock-van Dalen F. van Rantwijk and R. A. Sheldon J.Chern.SOC.,Cbem. Commun. 1993 1831. 38 S. Puertas R. Brieva F. Rebolledo and Y. Gotor Tetrahedron 1993 49 4007. 39 S.-T.Chen M.-K. Jang and K.-T. Wang Synthesis 1993,858. S.-T. Chen C.-C. Tu and K.-T. Wang Bioorg. Med. Chem. Lert. 1993 3 539. 41 M. Schuster B. Munoz W. Yuan and C.-H. Wong Tetrahedron Lett. 1993,34 1247. 42 B.K. Hwang Q.-M. Gu and C.J. Sih J. Am. Chern. SOC. 1993 115 7912. 43 3.Borhan J. Nourooz-Zadeh,T. Uemetsu €3. D. Hammock,and M.J. Kurth Tetrahedron I993,49,2601. ''P. Barili G. Berti and E. Mastrorilli Tetrahedron 1993,49 6263. Enzyme Chemistry 305 number of microbial sources ofthese enzymes have come to light in the past year. While some of these systems such as those from Saccharomyces cereuisiae4’ and Rhodococcus SP.,~‘have yet to be shown to have potential in enantioselective reactions others from Aspergillus niger4’ and Beauusria sulfurescens,48 have considerabIe promise in this context.The reaction of the last two systems with racemic styrene oxide is of particular interest (Scheme 8).48 Thus A. niger hydrolyses the R epoxide seIectively to give the R diol while in contrast B. sulfurescens hydrolyses the S epoxide but with inversion of configuration at the benzylic position again to give the R diol. Therefore when this sequence is taken to its logical conclusion and the racernic epoxide is treated with a mixture of the two organisms both epoxide enantiomers ate converted into the R diol in high yield and enantioselectivity (Scheme 8). 23%,96%e.e. 54% 51% e.e.Pb/+A+ PhLo. PI3 19%,98% e.e. 47% 83% e.e. 92% 89%e.e. Reagents i Aspergillus niger; ii Beauvaria sulfllrescens Scheme 8 3 Oxidation Reactions Boyd at a!. have studied the cis dihydroxylation of benzo-fused unsaturated heterocycles by the dioxygenase of Pseudornonas putida (in whole cell form).49 A clear pattern emerged (Scheme 9) where non-aromatic heterocyclic aIkenes such as the chromene (ll) were oxidized to give an S-configuration alcohol at the benzylic position while heteroarenes e.g. benzothiophene were oxidized to give an R configuration. Other products were obtained from the heteroarenes through mutarota- tion and through oxidation of the benzenoid ring. The products of this type of dihydroxylation reaction have seen many applications in asymmetric synthesis in recent years and this trend continues for example in the Hudlicky group’s versatile synthesis of a range of biologically active aza sugars.50 ’’ G.Fauche R. M. Horak and 0.Meth-Cohn J. Chem. Soc. Chem. Cornmun. 1993 119. *‘ P. Hechtberger,G.Wirnberger M. Mischitz N. Kiempier and K. Faber Terrahedron Asymmetry 1993,4 1161. ‘’ X.-J. Chen A. Archelas and R. Furstoss J. Org. Chem. 1993 58 5528. 48 S. Pedragosa-Moreau A. Archelas and R. Furstoss J. Org. Chem. 1993 58 5533. 49 D. R. Boyd N. D. Sharma R. Boyle B.T. McMurray T.A. Evans J. F. Malone H. Dalton 3. Chima and G.N. Sheldrake J. Chem. Soc. Chem. Commtm. 1993,49. so T. Hudlicky J. Rouden and H. Luna J. Org. Chem. 1993,58 985. A. G. Sutherland OH 15% > 98%e-e.158 > 98% e.e. 98 > 98% e.e. Reagents i Pseudomonas putida UV4 Scheme 9 The enzymatic Baeyer-Villiger reaction is an attractive way to introduce both extra functionality and optical activity into a molecule. To date attempts to use the requisite monooxygenase obtained from Acinetobacter calcoaceticus in isolated form have been hindered by the difficulty in recycling the cofactor required NADPH. However Roberts and coworkers have obtained a new monooxygenase from fseudomonas putida that requires the easily recyclable NADH cofactor and have demonstrated that 60% e.e. > 95% e-e. Reagents i Pseudomonos putida NCIMB 10007 monooxygenase air NADH formate Condido boidinnii formate dehydrogenase Scheme 10 this enzyme is of considerable potential in these oxidations (Scheme The commercially availabIe enzyme Caldariomyces fumago chloroperoxidase has been shown to catalyse the epoxidation of alkenes by hydrogen peroxide.Although the reaction is generally restricted to the oxidation of cis-disubstituted alkenes the high enantiomeric excesses available make this a very promising discovery (Scheme 11 An interesting deveIopment in the past year has been the use of enzyme systems in ‘enantiosekctive destruction’ processes in which one enantiomer of a racemate is removed by oxidation to an achiral product. Using such a procedure a number of mphenylalanine analogues have been prepared by conversion of the L enantiomer into the keto acid using an L-amino acid oxida~e.’~ Similarly,a number ofenantiomerically G.Grogan S. M. Roberts and A. J. Willetts J. Chem. SOC.,Chem. Commun. 1993 699. 52 E.3. Atlain L.P. Hager L. Deng and E. N. Jacobsen J. Am. Chem. Soc. 1993 115,4415. 53 M.C. Pirrung and N. Krishnamurthy J. Org. Chem. 1993 58,957. Enzyme Chemistry -‘w I. .. 0 78% 96%e.e. Reagents i chloroperoxidase H,O (added slowly) pH 5 acetone Scheme I1 pure 1-arylethanols have been prepared by oxidation of the other enantiomer using a range of whole-cell systems which have included bakers’ yeast (Saccharornyces cere~isiae),~~ although other microorganisms have proved more efficient (Scheme 12).55 OH OH 0 100% e.e. OH 100% e.e. Reagents i Bacillus stearothermophilus; ii Acinetobacter calcoaceticus Scheme I2 4 Reduction Reactions The area of enzyme-mediated reductions continues to be dominated by whole cell transformations of 8-ketoesters.Bakers’ yeast has enduring popularity in this area and continues to prove highly effective for providing either simple chi run^,^^ or more sophisticated targets (Scheme l?).57 75-80% > 99% d,e. >93%e.e. Reagents i Saccharomyces cerevisiae sucrose 30“C Scheme 13 Fuganti et al. have looked at the reduction of B-ketoesters with a range of microorganisms as a potentia1 route to the /I-Iactam antibiotic precursor (12). While 54 G.Fantin M. Fogagnolo,A. Medici P. Pedrini S. Poii,and M. Sinigaglia Tetrahedron Lett. 1993,34,883. 55 G. Fantin,M. Fogagnolo A. Medici P. Pedrini S. PoIi and F. Gardini.Tetrahedron:Asymmetry 1993,4 1607. 56 H. Akita R. Todoroki H. Endo Y. Ikari and T. Oishi Synthesis 1993 513. ” D. W. Knight N. Lewis A.C. Share and D. Haigh Tetrahedron Asymmetry 1993 4 525. A. G. Sutherland the obvious precursor (13) failed to give useful diastereoselectivity the use of the sulfide-substituted analogue (14)gave the required intermediate (after desulfurization) as a single diastereoisomer (Scheme 14).58 00 Reagents i Candida guilfiermondii,gIucose; ii Raney nickel EtOH Scheme 14 Aside from /I-ketoesters remarkable selectivity has been reported in the reduction of a benzophenone where the only differentiation between the two aromatic rings is at the para position and hence remote from the ketone (Scheme 15).59 hi-/d'o \ \ \ \ CI a -50% 100% e.e.Reagents i Debaryomyces marama 30°C Scheme 15 Considerable attention continues to be paid to the reaction conditions of bakers' yeast reductions with the intention of optimizing not only yield and enantioselectivity but also ease of operation. It is now well estabiished that immobilizing yeast in or on a solid support (e.g. calcium alginate beads) a relatively simple procedure has considerable benefits with respect to the latter objective. Bhalerao et at. have now shown that using such immobilized systems exquisite and concomitant control of enantioselectivity and yield can be obtained by careful and continuous control of the reaction pH (Scheme 161,a factor largely ignored by others.60 In a remarkably different approach to the same end it has been shown that ethyl acetoacetate can be reduced '' C.Fuganti S. Lanati S. Servi A. Tagliani A. Bedeschi and G. Francheschi,J. Chem. SOC.,Perkin Trans.I 1993,2247. 59 G. Spassov V. Pramatorova R. Vlahov and G. Snatzke Tetrahedron:Asymmetry 1993,4,301. '* U.T. Bhalerao Y. Chandraprakash R. L. Babu and N. W. Fadnavis Synth. Commun. 1993,23 1201. Enzyme Chemistry pH product % e.e. 3 82 4.5 99 6 80 8 35 Reagents i Sacchmomyces cereuisiae Scheme 16 with high enantioselectivity and in good yield by the simple expedient of stirring the substrate with commercial freeze dried yeast in wet light petrole~rn.~' Adam et a!. have reported an unusual reductive kinetic resolution. Treatment of racemic hydroperoxides with horseradish peroxidase in the presence of an oxidation substrate leads to enantioselective reduction of the R hydroperoxide (Scheme I 7).62 > 99% e.e.> 99% e.e. Reagents i Horseradish peroxidase 2-methoxyphenol Scheme 17 5 Carbon-Carbon Bond-forming and Cleaving Reactions Although there is interest in the use of many different carbon-carbon bond-forming enzymes such as ~xynitrilase,~~ and pyruvate decarb~xylase,~~ tran~ketolase,~~ this area is dominated in the literature by reports of aidolase-catalysed reactions. Aldolase research seems evenly divided between the discovery and characterization of new enzymes (usually from a microorganism) as typified by Wong's study of the 3-deoxy-~-manno-2-octulosonic and acid aldolase from Aureobacterium b~rkerei,~~ the detailed investigation of the extremes of substrate specificity of more well-characterized catalysts such as rabbit muscle aldola~e.~~ Whitesides and coworkers have found that N-acetyl neuraminic acid aldolase accepts N-carboxybenzyl mannosamine (15)as a substrate (Scheme 18).This allows a subsequent simple nitrogen deprotection providing ultimately access to the glycoside 61 L.Y.Jayasinghe A. J. Smallridge and M. A. TrewhelIa TetrahedronLett. 1993,34,3949. '* W.Adam U. Hoch C.R.Saba-MolIer and P. Schreier Angew. Chem. int. Ed. EngL 1993,32 1737. 63 M. North SYNLETT 1993,807. '* G.R.Hobbs M. D. LilIy N. J. Turner J. M. Ward A. J. Willetts and J. M. Woodley J. Chem. Soc. Perkin Trans.I 1993 165. 65 V. Kren D.H.G. Crout H. Dalton D. W. Hutchinson W. Konig M. M. Turner G. Dean and N. Thomson J. Chem. Soc. Chem. Commun. 1993 341. 66 T.Sugai G.J. Shen Y.Ichikawa and C.-H. Wong J. Am. Chem. Soc. 1993,115,413. '' W.J. Lees and G. M. Whitesides J. Org. Chem. 1993,58,1887. A. G. Sutheriand Reagents i NeuAc aldolase sodium pyruvate Scheme 18 (16) which is a general precursor to a range of N-acyl neuraminic acid analogues of potential as inhibitors of virus-cell adhesion.68 Herbert et al. have discovered a 8-hydroxy-a-aminoacid aldolase in Streptomyces amakusaensis that is highly selective for the cleavage of the 2S 3R enantiomer (and diastereoisorner) and hence could have considerable potentia1 in the synthesis of the 2R 3s systems by selective degradation of the racemate.69 '' M.A.Sparks,K.W. Williams C. Lukacs A. Schrell G. Priebe A Spakenstein and C.M.Whitesides Tetrahedron 1993,49 1 69 R. B. Herbert B. Wilkinson G.J. Ellames and E. K. Kunec J. Chem. Soe. Chem. Comun. 1993 205.

ISSN:0069-3030    

DOI:10.1039/OC9939000299

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

I1 Biosynthesis By R.A. HILL Department of Chemistry University of Glasgow Glasgow GI2 8QQ.UK I Introduction The previous Report' on the biosynthetic studies of secondary metabolites and related work covered the period 1989-91. This report covers the period 1992-93. The study of biosynthetic pathways continues to be a highly active area This report is a personal view of some of the highlights in the area of biosynthesis. The production of new microbial metabolites using unnatural precursors a technique known as precursor-directed biosynthesis,2 the use of plant cell culture^,^ and the biosynthesis of marine natural products4*' and isocyanides and cyanides6 have been reviewed. 2 Fatty Acid and Polyketide Biosynthesis Reviews have appeared on the biosynthesis of fatty acid and polyketide rnetabolite~~*~ and the angucucline antibiotics.' Deuterium labelling studies were used to show that theconversion ofpalmitic acid (1) into the sex pheromone (2) of the moth Mamestra brassicue occurs by a formal syn elimination of the 1 1-(pro-R)- and 1 Z(pro-R)-hydrogenatoms.lo This result indicates that the insect A'' desaturase is similar to the A9 desaturase found in mammals,plants and bacteria. Labelling studies have shown that pahitic acid (1) is converted into diabolic acid (3)by Butyrivibrio~brisolvenswithout the loss of label from either C-14 or C-16 ofpalrnitic acid (I)-" This rules out the possibility of the intermediacy of At'-or Al5-pa1mitic acids in the biosynthesis of diabolic acid (3). The degradation of the keto acid (4) to produce &decalone (5) in Sporubulumycesodorus involves inversion of the stereochemistry.This has been shown to be due to the intermediacy ofa ketone which is later reduced to give the opposite stereochemistry.' * Degradation of a-linolenic and ' R.A. Hill Annu. Rep. Prog. Chem. Sect. B,1991,&8 283. R. Thiericke and J. Rohr Nat. Prod. Rep. 1993 10 265. J-P. Kutriey Acc. Chem. Res. 1993 26 559. 'M.J. Garson Chem. Rev. 1993,93 1699. G. Cimino and G. Sodan Topics Current Chem. 1993,167 77. 'P.J. Scheuer Ace. Chem. Rex 1992 25,433. ' D. O'Hagan Nat. Prod. Rep. 1992 9,447. * D. O'Hagan Nat. Prod. Rep. 1993 10 593. J. Rohr and R. Thiericke Nat. Prod. Rep. 1992,9,103. lo W. Boland C. Frossl M. Schlottler,and M.Toth J-Chem. SOC. Chem. Commun. 1993 1155. It W. Fitz and D. Arigoni J. Chem. SOC. Chem. Commun. 1992 1533. *' W. Albrecht M.Schwarz 1. Heidlas and R. Tress] J. Org. Chem. 1992 57 1954. 31 I 312 R. A. Hill linoleic acids in green leaves produces a 'green odour'. This has been characterized as a mixture ofC aldehydes and alcohols. The biogeneration ofthe 'green odour' has been reviewed. Marine brown algae (Phaeophyceae) produce pheromones by metabolism of unsaturated icosanoic acids to give a series of C,,H, hydrocarbons. Deuterium labelling studies have been used to investigate their bio~ynthesis.'~ For example it has been shown that all-cis-icosapenta-5,8,11,14,17-eno~c acid (6) is metabolized to giffordene (7) by Gifordia mitchellae.The 1abeIling studies are consistent with a thermally-allowed antarafacial f l,7) hydrogen shift during the biosynthesis (Scheme 1 ). COOH OH Scheme 1 l3 A. Hatanaka Phyfochemistry 1993 34,1201. '* K. Stratrnann W. BoIand and D.G. Muller Termhedron 1993 49 3755. Biosynthesis 313 Studies with single and double-labelled 13C acetates have shown that thiarubine A (8) from Ambrosia artemisiifoh is formed from seven acetate units with the terminal acetate being ~1eaved.I~ All the carbons of oncorhyncolide (9) from the marine bacterial isolate MK157 have been shown to be derived from acetate." The methyl branches arise from C-2 of acetate. This type of branching has only been observed in a few biosyntbetic pathways. 4 H& s-s HOH2C ob 0 (10) 0 (9) Extensive labelling studies have shown that decarestricine €3 (10) from PenicilIiurn simplicissimum is a pentaketide.The epoxide oxygenis derived from molecular oxygen and the hydroxyl oxygen is derived from the medium. The biosynthetic relationships between the various members of the decarestricine family have been presented." There is more evidence for the processive mode of polyketide biosynthesis. The evidence has been extended to the polyether antibiotics with the incorporation of the N-acetylcystearnyl thioester of 5-oxo-2,4-dimethylhexanoic acid (I I) labelled with deuterium into rnonensin A (12) in Streptornyces cinnamonensis.18During this study it was found that the presence of 2,6-0-dimethyl-~-cyclodextrin and a P-oxidation l5 M.L. Gornez-Barrios,F.J. Parodi D. Vargas L. Quijano M. A. Hjortso,H. E. Flores and N. H. Fischer Phytochemistry 1992 31 2703. J. Needham R. J. Andersen and M.T. Kelly J. Chem. SOC.,Chem. Commun. 1992 1367. l7 M. Mayer and R. Thiericke J. Chem. SOC. Perkin Trans. I 1993,495. '' HAPatzelt and J. A. Robinson J. Chem. SOC.,Chem. Commun. 1993 1258. 3 14 R. A. Hill inhibitor during the fermentation was essential for successful incorporation. Further compelling evidence for the processive mode has also been provided with studies on methymycin (13)from Srreptomyces uenezueiue” and nargenicin (14) from Streptomy-ces aureus.20In the latter study the proposed (4+2) cycloaddition to form the octalin ring of nargenicin (14) is also supported.(13) (14) Incorporation of labelled acetate propionate butyrate and glucose into elaiophylin (15) from a Streptomyes species has established the biosynthesis of this rnacrolide. A detailed analysis of the fermentation time course of Streptouerticiliium baldacii subsp. netropse that produces the desertomycin family of macrolide antibiotics has provided details of the relationships between the various members of the family.*l Extensive labelling studies have established the polyketide origin of the [7.7]paracyclophanes ll-mga OH 0 OH 0 \\ sugar4 I 1 1 1 (15) such as nostocyclophane D (16)from the cyanobacteria Nostoc linckiu and Cylindros-permurnlicheniforrne.2 The experiments indicate that these [7.7]paracyclophanes arise by dimerization of nonaketide intermediates.The fungus Artropsis ~runcataproduces a range of interesting metabolites. Incorporation studies on one of these metabolites arthropsadiol A (17) have indicated that one of the terminal methyl groups (C-12) arises from the methyl group of rnethi~nine.’~ Methylation of a hexaketide intermedi- ate is proposed to explain the results. Labelled acetate and methionine were used to establish that spiciferone A (18) and spiciferin (19) from Cochliobolus spicifer are derived from a hexaketide with two C units.24 They probably both arise by oxidative cleavage of a bicyclic system (Scheme 2). l9 D. E. Cane R. H. Lambalot P.C. Prabhakaran and W. R. Ott 6. Am. Chem. Soc. 1993,115 522. D.E. Cane W. Tan and W. R. Ott J. Am.Chem. Soc. 1993,115 527. M. Mayer and R. Thiericke J. Cfiem. Sac. Perkin Trans. I 1993 2525. 22 S.C. Bobzin and R.E. Moore Tetrahedron,1993 49 7615. 23 W.A. Ayer and P. A. Craw Can.1.Chem. 1992,70 1348. 24 H.Nakajima R. Matsumoto Y. Kimura and T. Hamasaki J. Chem.Soc. Chern. Cornmun. 1992,1654; H. Nakajirna H. Fujirnoto R. Matsumoto and T. Hamasaki J. Org. Chem. 1993,58,4525. Biosynthesis 315 Scheme 2 Similar studies were used to establish the biosynthetic origin of zaragozic acid A (20) a squalene synthase inhibitor from an unidentified fungus (MF5443)." The remaining carbons arise from benzoic acid and succinic acid. Chirally labelied malonyl CoA has been incorporated into orsellinic acid using orsellinic acid synthase from Penicilliurn cyclopium.26 The results are similar to those obtained earlier for 6-methylsalicyclic acid.' The hydrogen atoms removed from the two methylene groups at the 2-and 4-positions of the putative polyketide intermediate have opposite stereochemistry. Doubly labelled acetate was used to show that melkin and 2,4-dihydroxyacetophenone are biosynthesized in the ant Rhytidoponera chalybaea in the same way as in fungi.27 Detaiied labelling studies using I3C 'H and "0 labelled acetates and "0,gas on LL-D253or (211 a metaboliteof Phoma pigmentiuora have shown that the metabolite is derived from two preformed polyketide chains.28 The label observed in the hydroxy- 25 K.M. Bryne B H. Arison M. Nallin-Ornstead and L. Kaplan J. Org. Chem. 1993 58 1019.26 J. B. Spencer and P.M. Jordan J Chem. Sac. Chem. Commun. 1992 645. '' C.-M.Sun and R. F. Toia J. Nut. Prod. 1993,56 953. 28 I. M. Chandler C. R. McIntyre and T.J. Sirnpson 1.Chem. SOC., Perkin Trans. 1 1992,2285. 316 R. A. Hill methyl side chain is randomized. This is explained by the involvement of a spirocyclopropyl intermediate. OH OH 0 OH HOPMeOmo* (21) (22) [1,2-' 3C,]Acetate feeding results have defined the chain folding of torosachrysone (22) from Dermatocybe rnushro~rns.~~ Incorporation experiments with simple and advanced precursors labeiled with I3C,'H and have shown that tajixanthone (23) is derived through cleavage of an octaketide-derived anthraquinone with the introduction of two dimethylallyl moieties. 30 Purpactin A (24) from Penicilliurn purpuragenurn has also been shown to be derived by oxidative cleavage of an octaketide-derived anthraquin~ne.~' Xanthoquinodin A (25) from Humicola sp.FO-88 has been shown to be produced from two octaketide chains one having been oxidatively ~leaved.~ A similar biosynthesis has been shown for Cercospora beticola toxin (CBT) (26).33 HO 29 M. Gill A. Gimenez and R. Watling 1.Nat. Prod. 1992,55 372. 30 S.A. Ahrned E. Bardshin C. R.McIntyre and T. J. Simpson Aust. J. Chem. 1992 45 249. 31 H. Nishida H. Tomoda S. Okuda and S. Omura 1. Org. Chem. 1993,57,1271. 32 H. Tabata H. Tomoda K. Matsuzaki and S. Ornura J. Am. Chem. Soc. 1993,115 8558. 33 A. Amone G. Nasini L. Merlini E. Ragg and G. Assante J. Chem. Soc. Perkin Trans.I 1993 145. Biosy nthesis 317 A useful folding code using E/Z terminology has been devised for the comparison of multicyclic polyketides and this has been used to compare their biosynthetic origins.34 The genetic understanding of polyketide synthesis continues to improve. This is aptly demonstrated by a study in which genes from the polyketide synthase (PKS)from Streptornyces roseufuluus,which produces both frenolicin B (27) and nanaomycin A (28) were expressed in Streptomyces colelicolor A3 with components of the actinor- hodin (29) gene cluster. The primary products of the recombinant strain are the new metabolites RM18 (30) RM18b (31) and the anthraquinone (32).35Analysis of the results confirms earlier conclusions regarding the protein determinants of chain length keto reduction and cyclization specificities.The biosynthetic model in which keto reduction occurs only after the complete poiyketide chain has been synthesized is supported. && \ 0 CO2H \ 0 CO2H (27) (28) Theangucyclin group ofantibiotics continues to provide interesting results. Blocked mutants of Streptomycesfiadias have produced five new products. Their relevance to postulated biosynthetic pathways is disc~ssed.~' The origins of the oxygen atoms in aquamycin (33) from Streptomyces fiadi~e~~ and antibiotic PD 116198 (34)38 from 34 J. Rohr J. Urg. Chem. 1992 57 5217. '' R. McDaniel S.Ebert-Khosta D. A. Hopwood and C. Khosla J. Am. Chem. SOC. 1993 115 11671. 36 J. Rohr M. Schonewolf,G. Udvarnoki K.Eckardt,G.Schumann C. Wagner J. M. Beale and S. D.Sorey J. Org. Chem. 1993 58 2541. 37 G. Udvarnoki T. Henkel R. Machinek and J. Rohr J. Org. Chem. 1992 57 1274. 38 S.J. Gould and X.-C. Cheng Tetrahedron 1993 48,11 135. 318 R. A. Hill Streptornyces phaeochrogenes WP 3588 have been studied (Scheme 3). Most of the angucyclins appear to be derived from a decaketide intermediate folding into an angular conformation; however labelling studies on antibiotic PD 115198 (34) are consistent with rearrangement of an initially-formed linear tetracyclic intermediate. Feeding experiments using Streptomyces murayamensis that produces dehyd-roabelomycin (35) and tetrangulol (36) indicate that deoxygenation occurs at a prearomatic ~tage.~ *OH HO HO (34) Scheme 3 Early intermediates on the biosynthetic pathway of tetracenomycin C from Streptomyces gluucescens have been identified in blocked mutants4' Labelling studies on esperamicin A from Actinornadura uerrucososporuhave indicated that the enediyne core (37)is derived from an octaketide intermediate with loss of the terminal carboxyl group.4l RO OH OR OH 0 R 0 (35) R= OH (36) R= H (37) 3 Terpenoids Reviews have appeared on HMG CoA reductase inhibitors:' the folding of ~qualene,~~sterol metabolism in the biosynthesis of marine sterol~,4~,~~ and 39 S.J. Gould X.-C. Cheng. and K.A. Halley J. Am. CAem. SOC. 1992,114,10066. 40 B.Shen H. Nakayarna and C. R. Hutchinson J. Nat. Prod. 1993 56 1288. 41 K.S. Lam J. A. Veitch J.Golik B. Krishnan S. E. KIohr K. J. Volk S. Forenza and T.W. Doyle J. Am. Chem. SOL 1993,115 12340. 42 A. Endo and K. Hasurni NQC.Prod. Rep. 1993,10 541. '' R. Bohlmann Angew. Chern. Int. Ed. Engl. 1992,31 582. 44 N. Ikekawa M. Morisaki and Y. Fujimoto Ace. Chem. Res. 1993,26 139. 4s B.J. Baker and R. G. Russel Topics Current Chem. 1993 147 1. 46 J.-L. Giner Chem. Rev. 1993,93,1735. 3iosy nthesis 319 the bacterioh~panoids.~’*~~ A new pathway for the biosynthesis of isopentenyl diphosphate in bacteria has been identified.49 Geranyl diphosphate synthase has been used to study the stereochemistry of the formation of geranyl diphosphate from dimethylallyl diphosphate and isopentenyl diph~sphate.~’ Detailed Iabelling studies have been conducted to investigate the biosynthesis of limonene (38) from geranyl dipho~phate.~ Deuterium labelled geranyl diphosphate has been used in biosynthetic studies of monoterpenes from Saluia of~cinalis.~~ These results cast doubt on the use of natural abundance deuterium NMR for biosynthetic studies.A OGlc Deoxyloganic acid (39)has been efficiently converted into oleoside methyl ester (40) using Fraxinus excelsior and Syringa j~sikaea.’~ Analysis of the results of feeding deuteriated rnevalonates to Perilla frutescens callus revealed that the biosynthesis of a-curcumene (41) involves a 1,2-hydride shift and the biosynthesis of cuparene (42) involves a 1,3-hydride shift.54 Deuteriated farnesols were incorporated into dehyd- rogeosmin (43) using flower heads of the cactus Rebutia m~rsoneri.~~ The results are consistent with dehydrogeosmin (43) being formed by loss of the three-carbon side chain of a eudesmane intermediate.Q$Q=Q+-(41) +% (42) Competitive feeding experiments indicated that isotrichodiol(44) and isotrichotriol ” G.Ourison and M. Rahmer Acc. Chem. Res. 1992,25 403. 48 M. Rohrner Pure Appl. Chem. 1993,65 1293. M. Rohrner M. Knani P. Simonin B. Sutter and H. Sahm Biochem. J. 1993 295 517. T. Endo and T. Suga Phytochemistry 1992,31 1565. H.-3. Pyun,R.M. Coates K. C. Wagschat P.McGeady and R. B. Croteau J. Org. Chem. 1993,58,3998. 52 D. Arigoni D. E. Cane J. H.Shim R. Croteau and K. Wagschal Phytochernistry 1993,32 623. ’’ S. Damtoft H. Franzyk and S. R. Jensen Phytochemistry 1993 34 1291.54 K. NabeIa K. Kawakita Y. Yada and H. Okuyama Biosci. Biotech. Biochem. 1992 57 792. 5s Z. Feng U.Huber,and W. Boland Hell. Chim. Acta 1993 76 2547. 320 R. A. Hill (45) rather than trichodiol(46) and trichotriol(47) are intermediates in trichothecene bio~ynthesis.~~ Labelled velutinal(48) is incorporated into the Iactaranes vellerol(49) and velleral (50) by bruised fruiting bodies of the mushroom Lactmius elle ere us.^^ [14C]Arteannuic acid (51) has been incorporated into both arteannuin €3 (52) and artemisinin (qinghaosu) (53) using Artemisia annua,suggesting that arteannuic acid (51)might be a common intermediate in the biosynthesis of (52) and (53).58 (44) R = H (46) R = H (45) R=OH (47) R=OH (49) R=CHzOH (50) R=CHO 0 0 (53) (52) The biosynthesis of ether lipids such as di-0-phytanylglycerol(54)has been studied in Ar~haebacteria.~~~~' The results indicate that there is a cornrnun pathway for the biosynthesis of these lipids in both methanogenic and halophilic bacteria and that di-0-phytanylglycerol (54) is formed in two distinct steps from glycerol and geranyl- geranyl diphosphate in Methanobacterium thermoautotrophicum.Feeding experiments with [l,2-13C,facetate and [2-' 'C,'H,facetate in Amsonia ellipticahave provided details of the biosynthesis of the side chains of campesterol(55) and dihydrobrassicasterol (56)?' The results are consistent with the biosynthesis 56 A. R Hesketh B. W.Bycroft P. M. Dewick and J. Gilbert Phytochemistry 1993,32 105.57 T.Hansson Z.Pang and 0.Sterner Acfa Chem. Scad. 1993,47,403. 58 R.S.Sangwan K. Aganval R. Luthra R. S. Thakur and N. Singh-Sangwan Phytochernistry 1993,34 1301. 59 D.Zhang and C. D. Ponlter J. Org. Chem. 1993,58 3919. 60 D.Zhang and C. D. Poulter J. Am. Chem. Soc. 1993,115 1270. 61 S.Seo A. Uomori Y. Yoshimura K. Takeda H.Noguchi Y. Ebizuka U. Sankawa and H. Seto,3. Cfiem. Suc. Perkin Trans. I 1992 569. Biosynthesis 321 involving regiofacial specific reduction of a C-24 double bond which is formed by double bond isomerization of a A24‘28’-sterol (Scheme 4). Detailed studies on the biosynthesis of estrogens by human microsomal placental arornatase have shown that / \ Scheme 4 the biosynthesis proceeds through several different pathway^.^',^^ Incorporation of 13C-labelled acetate and formate into citreohybridone 3 (57) by a hybrid strain derived from Penicilliurn citreo-uiride indicated that citreohybridone B (57) is formed by a meroterpenoid pathway similar to that for terret~nin.~~ 4 Shikimate and Related Metabolites Reviews have appeared on the biosynthesis of shikirnate metabolite^,^^,^^ phenyl-62 E.Caspi H.R.W.Dharmaratne E. Roitman and C.Shackleton J. Chem. Soc. Perkin Truns. I 1993,1191. 63 H. R. W. Dharrnaratne,J. L. Kitgore E. Roitman C. Shackleton and E. Caspi,J.Chem.Soc. Perkin Trans. 1 1993 1529. 64 S. Kosernura H. Miyata K. Matsunaga and S. Yamamura Tetrahedron Lett. 1992 33 3882. 65 P.Dewick Nat. Prod. Rep. 1992 9 153. 322 R. A. Hill propanoids and isoflavonoids in alfaifa,67 isoflavone and pterocarpan phytoaIexins,68 and phenylpr~panoids.~~ The enzymes of the shikimate pathway have continued to cume under extensive scrutiny and have been re~iewed.~' The dehydration of 3-dehydroquinate (58) to 3-dehydroshikimate (59) is catalysed by 3-dehydroquinase.There are two distinct classes of 3-dehydroquinase which are quite different in physical and biochemical propertie~.~' The active site Iysine that is known to form a Schiffs base with the ketone carbonyl of 3-dehydroquinate (58) is found in Type I enzymes but not in Type I1 enzymes. The properties of isochorismate hydroxymutase which catalyses the interconversion of chorismic acid (60) and isochorisrnic acid (61) have been described.'2,73 OH (59) C02H C02H t [l-3C]PhenyIaIanine was incorporated into the phenylpropanoid (62) without 66 P.Dewick Not. Prod. Rep. 1993 10 233. 67 R. A. Dixon A. D. Choudhary K. Dalkin R. Edwards T. Fahrendorf G. Gowri M.J. Harrison C.J. Lamb G. L. Loake C. A. Maxwell J. Orr and N. L. Paiva Recent Adu. Phyrochern. 1992,26,81. 68 W. Barz and R. Welle Recent Adv. Phytochem. 1992,26 139. 69 C.J. Douglas M. Ellard K. D. Hauffe E. Molitor M. Moniz de Sa S. Reinold R. Subramaniam and F. Williams Recent Adv. Phytochem. 1992 26 63. 70 B.K. Singh D. L. Siehl and J. A. Connelly Oxford Suro. Plant Mol. Cell Bid. 1991 7 i43. 71 C. Kleanthous R. Deka K. Davis S. M. Kelty A. Cooper S.E. Harding N. C. Price A. R. Hawkins and J.R. Coggins Biochem. J. 1992 232 687.72 P.M.M.Schaaf,L. E. Heide E. W. Leistner Y. Tani M. Karas and R. Deutzmann J. Not. Prod. 1993,56 1294. 73 P. M. M. Schaaf L. E. Heide E. W. Leistner Y. Tani and M. M.El-Olemy J. Nut. Prod. 1993,56 1304. Biosynthesis 323 rearrangement of the side chain.74 Labelled l-j4-methoxyphenyl)prop-I-ene (63) was incorporated into epoxypseudoisoeugenol 2-methylbutyrate (64)in tissue cultures of Pimpinella anisum;the labelling of the metabolite indicated that an NIH shift of the side chain had occurred during the introduction of the aromatic hydroxyl group.75 A similar migration is probably involved in the biosynthesis of the tyrosine kinsse inhibitor erbstatin (65) from a Streptomyces species as iabeiled shikimic acid phenylalanine and tyrosine are incorporated efficiently into erbstatin (65).'5 Biosyn-thetic studies on axenornycin D (66) show that the aromatic moiety is derived from a metabolite of the shikimate pathway and that the biosynthesis is different to that of the menaq~inones.~~ I OMe (43) OH I I The role of salicyclic acid as a pIant hormone has been reviewed.78 The biosynthetic pathway ofsaIicycIic acid from cinnamic acid is nut clear at present.Levels ofsalicyck acid in plants appear to be controlled by conjugation with Sporopellenin from Curcurbita maxima is a biopolymer that is resistant to chemical physical and biological degradation. Although its structure is not known [U-'4C]-phenylalanine has been shown to be efficiently incorporated into sporopollenin.80-82 Labelling studies using [W-'3C]glucose [3-I3Cfphenylalanine and [1,2-'3C J-phenylacetic acid (67)into thiotropocin (68)from Pseudomonas CB-104 are consistent with a shikimate origin involving symmetrical phenylpyruvate and phenylacetate 74 K.H. Horz and J. Reichling Phytochemistry 1993 33 349. 75 R. Martin and J. Reichling Phytochemistry 1992 31 51 1. '' Y. Tabata M. Imoto and K. Umezawa J. Antibiot. 1992 45 1382. " V. Firese A. Boos H.-J. Banch and E. Leistner Phytochemistry 1993,32 613. '' I. Raskin Annu. Rev. Plant Physiol. Plant Mol. Biol. 1992 43 439. 79 N. Yalpani N. E. Blake and M. Schultz Plant Physioi. 1992 100 11 14. 8o S. Gubatz and R. Wiermann Bot. Acta 1992 105,407. 81 S. Gubatz and R. Wiermann Z. Naturforsch. C Biosci. f993,48 10.S. Wilmesmeier S. Steuernagel and R. Wiermann 2.Nnturforsch. C Biosci. 1993 48,697. 324 R. A. Hill 5 intermediate^.^^ PhenyIacetic acid (57) presumably undergoes oxidative ring expan-sion followed by further oxidation and incorporation of sulfur. The biosynthesisof ansatrieneA (59)from Streptumyces cullinus has been extensively studied.868 The results indicate that the cyclohexanecarboxylic acid portion is derived from shikimate. Full details of the biosyntheticstudies on rotenone (70) and amorphigenin (71) by Arnorpha jkuticosa seedlings have been published.8s-g0 A mechanism involving a spirodienoneintermediate has been proposed fur the migration of the phenyl group in the biosynthesis of isoflavon~ids.~ 0 OMe 1 HoY 0 (49)(49) (70)(70)RR == HH (71)(71) R=OHR=OH The biosynthesis of the aromatic side chains of taxol (74) has been studied.92The results indicate that phenylalanine is incorporated via B-phenylalanine (72) and phenylisoserine (73).The benzoyI moieties are also derived from 8-phenylalanine(72) either directly or via phenylisoserine (73) (Scheme 5). 83 D.E. Cane 2. Wu and J. E. Van Epp J. Am. Chem. Soc. 1992 I14,8479. 84 K. A. Reynoids P. Wang K. M. Fox and H. G. Floss J. Antibiot. 1992 45,411. 85 K.A. Reynolds J. Nut. Prod. 1993 56 175. 86 K. A. Reynolds N. Seaton K.M. Fox K. Warner and P. Wang J. Nut. Prod. 1993,545 825. 87 3.S. Moore H. Cho R. Casati E. Kenedy K. A. Reynolds U. Mocek J. M. kale and H. G. Floss,J.Am. Chem. Soc. 1993 115 5254. 88 P.Bhandari L.Crombie P. Daniels 1. Holden N. Van BrUggEn and D.A. Whiting J. Chem.Soc. Perkin Trans. 1 1992 839. 89 P.Bbandari L. Crombie G.W. Kilbee S.J. Pegg G. Proudfoot J. Rossiter M. Sanders and D.A. Whiting 1.Chem. Soc. Perkin Trans. I 1992 851. 90 P.Bhandari L. Crombie M. F. Harper J. Rossiter M. Sanders and D. A. Whiting J. Chem. Soc. Perkin Trans. 1 1992 1685. 91 L. Crornbie and D. A. Whiting Tetrahedron Lett. 1992 33 3663. 91 P.E. Flemming U. Mocek and H. G. Floss J. Am. Chem. Soc. 1993,115 805. Biosynthesis 325 Scheme 5 5 Alkaloids and Other Amino-acid-derived Metabolites Reviews have appeared on the biosynthesis of plant alkaloids and nitrogenous micro bid metabolites. 3,94 Labelled serine is a better precursor than alanine for the carbons and nitrogen of the dehydroalanyl portion of valanimycin (75) from Streptomyces uiridifaciens.Iso-butylamine and isobutylhydroxylamine are incorporated into the remaining carbons and nitrogen the latter very efficiently (Scheme 6).95It is not known how the N-N bond is formed in valanimycin (75). Labelling studies have established that ornithine is the precursor of avicin (76)from Streptomyces auiceusg6and that domoic acid (77)from Nitzscia pungens is derived from a geranyl precursor and a metabolite of the citric acid pathway.97 The hydroxycyclopentenone portion of reductiomycin (78) from Srrepto-myces xanthochromogenus has been shown to be derived from 5-arninolevuIinic acid 93 R.B. Herbert Nar. Prod. Rep. 1992 9 507. 94 R.B.Herbert Nut. Prod. Rep. 1993 LO 575. 95 R.J. Parry Y.Li and F.-L. Lii J. Am.Chem. Soc. 1992 114 10062. 96 S.J. Godd and S. Ju J. Am.Chem. Soc. 1992 114 10 166. 97 D.J. DougIas U.P.Ramsey J. A. Walker and J. L.C. Wright J. Chem. Soc. Chem. Comun. 1992 714. 326 R. A. Hill whereas the right-hand portion is derived by ring cleavage of a symmetrical product of the shikimic acid pathway.98 ,OH Several groups have been involved in biosynthetic studies of the tropane alkaloids. [l-13C]Acetate has been efficiently incorporated into ttopane alkaloids using hairy root cultures of Hywcyamus alb~s.'~ Intermediate trapping and competitive feeding experiments have established that phenyllactic acid (79)is a precursor of the tropic acid moiety of hyoscyamine and scopolamine (hyoscine) (81) from Dams str~rnoniurn.'~~-~~~ Transformed root cultures of a Datum hybrid were used to demonstrate that the 5a and 7cr hydrogens of hyoscyamine (80) are retained in the formation of scopolamine (81).Io3 OH (79) Transformed root cultures of Nicotiuna rustica have been used to convert the unnatural precursor N-ethylputrescine (82) into (S)-N-ethylnornicotine (831 with an 98 H.Cho,b.M.Beale,C.Graff U.Mocek A. Nakagawa S.Urnura,and H. G.Floss,J. Am. Chem.Suc. 1993 115 12296. 99 M. Sauerwein K. Shimomura and M. Wink Phytochemistry 1993,32,905. loo M. Ansarin and J. G. Wooley Phytochemistry 1993 32 1183. lo' M,Ansarin and J.G. Wooley J. Not. Prod. 1993 56 1211. lo' Y.Kitamura S. Nishima H. Miura and T.Kinoshita Phytochemistry 1993,34 425. lo' A. B. Watson I. K.A. Freer D.J. Robins and N. J. Walton J. Nut. Prod. i993,56 1234. Biusynthesis 327 H2N H-NEtI -+ N (82) (83) efficiency similar to that of the natural system which uses N-rnethylputre~cine.'~~ Detailed labelling experiments using benzoicacid benzaldehyde l-phenylpropane- 1,Zdione (84),and cathinone (85) to investigate the biosynthesis of the Ephedra alkaloids such as ephedrine (86) have been reported.'05 The results indicated that benzoic acid rather than benzaldehyde is involved in the biosynthetic pathway and that two carbons are added from pyruvate to produce l-phenylpropane-l,2-dione (84) and hence by transamination into cathinone (85) (Scheme 7). I Scheme 7 The stereochemistry of imidazoleglycerol phosphate dehydratase was studied using deuterium labelled precursors.lo' The study concluded that the reaction (Scheme 8) proceeded with inversion of configurationat C-3 of imidazole glycerol phosphate (87) and that the hydrogen added to C-2 comes from the medium. Scheme 8 Anatoxin a(s) (88) is a potent antichohesterase produced by Anabaena flosaquae. Feeding experiments using 'C-IabeHed precursors demonstrated that the carbon lo4 H. D. Boswell A. B. Watson N.J. Walton and D. J. Robins Phytochemistry 1993,34 153. '05 G.Grue-Ssrensen and I. D. Spenser J. Am. Chem. Soc. 1993 115 2052. lo' J. A. Moore A. R. Parker V. 1.Davisson and J. M. Schwab J. Am. Chem. Soc. 1993,115 3338 328 R. A. Hill atoms of the main skeleton are derived from arginine and the three methyl groups come from the C The labelled thiol(89) is incorporated into biotin (90)without loss of label; this finding gives sume insight into the introduction of sulfur into biotin.''' Full details of the biosynthetic studies on obafluorin (91) from Pseudomonas fluorexens have been published.'0g-' lo The labelling studies indicated that 4-aminophenylalanine 2,3-dihydroxybenzoic acid and giycine (which supplies carbons 1 and 2) are precursors... "K" +NH2 '",P/oMe+o -0' Labelling studies have shown that the quinolizidine (92) is an effective precursor of vertine (93) and lythrine (94) in Decodon uerticillaatus.' Labelled lysine was incorporated into ring A of these alkaloids and the results indicate that a symmetrical intermediate is involved.Full details of the biosynthetic studies on anosmine (95)from Dendrobium anosltturn have appeared. A detailed study on the biosynthesis of streptazolin (96)from a Streptomyces species has revealed that it has a polyketide origin with the carbonyl carbon being derived from the C pool.' The hydroxyl oxygen comes from molecular oxygen which suggests an epoxide intermediate. Feeding experiments using [1,2-'3C,]acetate to Lycopodiurn tristachyum indicated that the acetate derived C units of Jycopodine (97) are formed ID7 B. S. Moore 1. Uhtani C. 3.de Konig R. E. Moore and W. W. Carmichael Tetrahedron Lett. 1992.33 6595. *** A. Marguet F. Frappier G. Guillerm M. Azaulay D. Florentin and J.-C.Tabet,J. Am.Chern. SOC.,1993 115,2139. *09 R. B. Herbert and A. R. Knaggs J. Chem. Soc. Perkin Trans. I 1992 103. *lo R. 3. Herbert and A. R. Knaggs J. Chem. SOC.,Perkin Trans. I 1992 109. 'I1 S.H. Hedges R. B. Herbert,and P.C. Wormald J. Nar. Prod. 1993,56 1259. 'I2 T. Hemscheidt and 1.D. Spencer J. Nat. Prod. 1993 56 1281. M. Mayer and R. Thiericke J. Org. Chem. 1993 58 3486. Biosynthessis 329 though a symmetrical intermediate.' The phenazine antibiotic saphenamycine (98) from Streptomyces antibioticus has been shown to be derived from metabolites of the shikirnic pathway.'" 0 6Me (95) (93) R = aH (94) R= BH Oxazolomycin (99) has been shown to have a very interesting biosynthesis."6 Glycine is incorporated as the starter unit of two separate polyketide chains.Propionate is not incorporated; all the methy1 groups including the gsm-dirnethyl groups,are derived from methionine. The biosynthetic origin of the remaining carbons is still to be established. *Methionhe H3C-C02H 'I4 T. Hemscheidt and I.D. Spencer J. Am. Chem. Soc. 1993,115 3020. 'lS C. W.Van't Land U. Mocek and H. G. Floss J. Urg. Chem. 1993 58 6576. U. Grafe H. Kluge and R. Thiericke Leibigs Ann. Chem. 1992 429. 330 R. A. Hill Further details of the incorporation of glycerol into the rn-C,N unit of asukarnycin (100) from Streptomyces nodosus ssp. asukaensis have been published.' Biosynthetic studies on the aporphine and protoberberine alkaloids pruduced by cell cultures of Peumus boidus and Berberis stolorrijiera indicate dernethylation and remethylation occur readily via the C pooI.' l8 The biosynthesis of the cularine alkaloids in Corydalis claviculata and Sarcapnos crassifoh plants has been studied using 13C and I8O-labelled intermediates.l Precursor-directed biosynthesis of unnatural ergot alkaloids in Ciauiceps purpurea has been reported.Me I The biosynthetic pathways of a range of diketopiperazine alkaloids have been studied. N-Methylalbonoursin (101)from a Streptornyces species has been shown to be derived from leucine and phenylalanine."' Labelling studies using acetate and tyrosine have shown that all nine carbons of tyrosine are incorporated into sirodesmins A (1021 B (1031 and C (104)in Sirodemiurn diuersum.'22 The studies indicate that Claisen-type rearrangement of an 0-(3,3-dimethylallyl )tyrosine derivative is involved in the biosynthesis.[2,4,5,6,7-'H,]Tryptophan was incorporated into roquefurtine (105)by Penicilliurn roqueforti and into aszonalenin (106) by Aspergillus zonatus with retention in each case of all five deuterium atoms.123 The Sa-hydrogen of both metabolites is retained; this precludes the involvement of any 2-substituted indole intermediates in the biosynthesis. Incorporation studies using labelled acetate and rnevalonoIactones have established that the C-22 methyl groups become scrambled during the biosynthesis of fumitremorgin B (107) and verruculogen (108) by Penicilliurn uerrucutoswn.'24 It is proposed that the scrambling of the methyl groups occurs during H. Cho 1.Sattlet J. M. Beale A. Zeech and H.G. Floss J. Org. Chem. 1993 58 7925. ' B. Schneider and M. H. Zenk Phytochernisrry 1993 32 897. 119 M.J. Muelfer and M. H. Zenk Leibigs Ann. Chem. 1993 557. N. C. Perellino J. Malyszko M. Ballabio B. Gioia and A. Minghetti J. Nat. Prod. 1992 55 424. K. A. Gurney and P.G. Mantle J. Nut. Prod. 1993 56,1194. J. D. Bu'Lock and L. E. Clough Aust. J. Chem. 1992,45 39. 123 B. Bhat D.M. Harrison and H. M. Lamont Tetrahedron 1993 49 10663. "* R. Veggaar R. M. Horak and V. J. Maharaj J. Chem. SOC.,Chem. Commun. i993 274. Biosy nthesis 33 1 the formation of ring c. Evidence from feeding studies indicated that brevianamide A (109)irom Penicilliumbreoicompacfurnis probably nut formed via an indole derivative by a (4 + 2) cycloaddition.'2'~'z6 (102) n=2 (103) n=3 (104) n=4 (108) (1W The biosyntheses of the modified peptides thiostreptin from Streptornyces uzureus and Streptomyces luurentii,' nosiheptide from Streptornyces c~ctuosus and the destruxins from Metarhizurn anisopliae' 29 have been investigated.125 J. F. Sanz-Cervera T. Gliaka and R. M. Williams J. Am.Chem. Soc. 1993 115 347. 126 J. F. Sam-Cervera,T. Gliaka and R. M. Witliams Tetrahedron 1993,49 8471. 127 U. Mocek,Z. Zeng D. O'Hagan P. Zhou,L.-D.G. Fan J. M. Beale and H.G. Floss J. Am. Chem. Soc. 1993 115 7992. 128 U.Mocek,A. R. Knaggs R. Tsuchuja T. Nguyen J. M. Beale and H.G. Floss J. Am. Chem. SOC.,1993 115,7557. I29 A. Jegorov P. Sedmera and V. Matha Phytochemistry 1993 33 1403.332 R. A. Hill More results have been published in the area of B-lactam antibiotic biosynthesis. Full details of the studies using labelled valine in the formation of the ACV tripeptide by ACV synthase have been rep~rted.'~~-'~' The incorporation of '*O from both molecular oxygen and water into #l-Iactams using deacetoxy and deacetylcephalos- porin C synthase is interpreted as the first example of water exchange of intermediates in a non-haem iron a-ketoglutarate dependent di0xygena~e.I~~ Illuminating studies on the biosynthesis of clavulanic acid (10) in Streptornycas clavuligerus have been reported.'331135 The pathway has been elucidated and is shown in Scheme 9. The enzyme that catalyses the conversion of proclavaminic acid (I 11)into HO-..fJ H 0$YOk02H Scheme 9 130 J.E. Baldwin R.M. Adlington J.W. Bird R.A. Field N.M.O'Callaghan and C.J. Schofield Tetrahedron. 1992,48 1099. 131 J.E. Baldwin M. F.Byford R. A. Field C.-Y. Shiau W. J. Sobey,and C.J. Schofield Tetrahedron.,1993 49 322 1. 132 J. E. Baldwin R. M. Adlington N. P. Crouch I. A. C. Pereira,R. T. Aplin and C. Robinson J. Chem. Suc. Chem. Commun. 1993 i05. 133 B. P. Valentine C.R.BaiIey A. Doherty J. Moms S.W. Ebon K. H. Baggaky and N. H. Nicholson J. Chem. SOC.,Chem. Commun. 1993 1210. 134 S. W. Elson,K.H. Baggaley M. Fulston,N. H. NichoIson J. W. Tyler J. Edwards,H. Holms 1. Hamilton and D. MousdaIe J. Chem. Soc. Chern. Comun. 1993 121 t. 135 S. W. Elson K. H. Baggaley M. Davison M. Fulston N. H. Nicholson G.D.Risbridger and J. W. Tyler J. Chern. Soc. Chem. Commun. 1993 1212. Biosynthesis 333 clavaminic acid (112) has been well st~died.'~~-'~' Unnatural precursors have been used to probe the mechanism of this enzyme. 6 Porphyrins A book covering the biosynthesis of both linear and cyclic tetrapyrroles has been p~blished.'~' Phycobilins are open-chain tetrapyrroles that function as chromophores of light-harvesting chromoproteins in some photosynthetic organisms. The biosyn- thesis of these phycobilins has been re~iewed.'~' Genetic studies have had a great impact on studies of the biosynthesis of the tetrapyrr01es.l~~ Further evidence for the involvement of a spiro intermediate in the formation of uroporphyrinogen 111 from a linear hydroxyrnethylbilane has been presented.144 A synthetic spirolactam related to the proposed spiro intermediate was shown to be an inhibitor of cosynthetase (uroporphyrinogen I11 synthase). The studies of the biosynthesis of vitamin BI have been progressing and the pathway is now very well understood (Scheme The fate of the oxygen atoms in precorin-2 (112) when it is converted enzymatically into cobyrinic acid has been The results indicated that the carboxyl group of the C-2 acetategroup (*) in precorrin-2 (113) loses one labelled oxygen atom. This is consistent with the involvement of this carboxyl group in lactone formation. The structure of precorrin-3A (114) has been ~0nfirrned.l~~ Precorrin-3A (114) is converted into the hydroxy y-lactone precorrin-3B (3x) (115) by the enzyme encoded by gene CobG from Pseudornonas denitrificans.1487149 This enzyme contains iron and incorporates molecu-lar oxygen into precorrin-3B (115).150The ring contraction of precorrin-3B (1 15) is catalysed by the enzyme corresponding to gene CobJ. The product of this transform- ation was identified as precorrin-4 (116)' 51 Other workers identified factor IV the 35 J. E. Baldwin R. M. Adlington J. S. Bryans M. D. Lloyd T. J. Sewell,C. J. Schofield,K. H. Baggaley and R.Cassels J. Chem. Soc. Chem. Commun. 1992,877. 137 J. E. Baldwin K. D. Merritt C.J. Schofield S. W. Elson and K. H. Baggaley J. Chem. SOC. Chem. Commun. 1993 1301. 13' D. B. McElwaini and C. A. Townsend 1.Chem SOC.,Chem. Commun. 1993,1346. 139 D. Iwata-Reuyl A.Basak L. S. Silverman C.A. Engle,and C. A. Townsend,J. Nat. Prod. 1993,56,1373. 14* J.E. Baldwin V. Lee M. D. Lloyd,C. J. Schofield,S. W. Elson and K. H. BaggaIey,J.Chem. SOC.,Chem. Cornmun. 1993 1694. 14' 'Biosynthesis of Tetrapyrroies' ed. P.M. Jordan Elsevier Amsterdam 1991. S.I. Beak Chem. Rev. 1993,93,785. A.I. Scott Tetrahedron. 1992,48 2559. loo W.M. Stark C.J. Hawker G.J. Hart A. PhiIippides P. M. Petersen J. D. Lewis F. J. Leaper and A. R. Battersby .I.Chem. Soc. Perkin Trans. 1 1993,2875. 14' A.R. Battersby Acc. Chem. Res. 1993,26 15. 146 R. A. Vishwakarma S. Balachandran A. I. D. Alanine N. f.J. Stamford F. Kiuchi F. J. Leeper and A. R. Battersby J. Chem. SOC.,Perkin Trans. 1 1993,2893. 147 M. J. Warren C. A. Roessner S.-I. Ozaki N. J. Stolowich P.J.Santander and A. I. Scott Biochemistry 1992 31 603. A. I. Scott C. A. Roessner N. J. StoIowich J. B. Spencer C. Min and S.-I. Ozaki FE5S Lett. 1993,331 105. L.Debussche,D. Thibaut M. Danzer F. Debu D. Frkchet F. Herman F. Blanchqand M. VuiIhorgne,l. Chem. SOC.,Chem. Commun. 1993,1100. 150 J. B. Spencer N. J. Stolowich C.A. Roessner C. Min and A. 1.Scott J.Am. Chem. Soc. 1993,115,11610. A. I. Scott C. A. Roessner N. J. Stolowich J. B. Spencer C. Min and S.-I. Ozaki FEBS Lett. 1993,331 105. 14' 334 R. A. Hill IR' (115) R=H (114) R=CH3 Scheme 10 Biosynthesis 335 R' = CH,CH,CO,H; R2 = CH2C0,H Scheme 10 oxidation product of pre~orrin-4.'~~*'~~ The next step in the biosynthetic pathway is the addition of a methyl to C-11 of precorrin-4 (116) to produce precorrin-5 (117).'54 The acetyl group of precorrin-5 (117) is replaced by a methyl group to produce precorrindA (fix) (1 18).i55Precorrin-6A (6x)reducta~e'~~*'~~ (encoded by the gene 1S2 D.Thibaut L. Debussche D. Frechet F. Herman M. Vuilhorgne and F. Blanche J. Chem. SOC. Chem. Commun. 1993 513. 153 L. Debussche D. Thibaut M. Danzer F. Debu D. Frechet F. Herman and M. Vuilhorgne J. Chem.SOC. Chem. COmmUR. 1993 1100. 154 C. Min,B.P. Atshaves,C. A. Roessner N.J. StoIonwich J. B. Spencer,and A. I. Sc0tt.J. Am. Chem. Soc. 1993 115 10380. 155 F. Blanche M. Kodera M. Couder F.J. Leper D. Thibaut and A. R. Battersby J. Chem. Soc. Chem. Commun. 1992 i38. 156 F. Kiuchi D. Thibaut L. Debussche F.J. Leeper F. Blanche and A. R. Battersby J. Chem. Soc. Chem. Commun. 1992 306. 157 K. Ichinose M. Kodera F.J. Leeper and A. R. Battersby J. Chem. Soc. Chem. Commm. 1993 515. 336 R. A. Hill CO~K'~~) catalyses the reduction of precorrin-6A (118) to form precorrin-63 (6y) (119).lS9The enzyme that is encoded by CobLi6' catalyses the introduction of methyl groups at C-5 and C-15 of precorrin-6B and decarboxylation of the acetate side chain on C-12 to produce precorrin-8x (120).'61The transformation of precorrin-8x (120) into hydrogenobyrinic acid (121)is cataIysed by the enzyme encoded by CU~H'~~ and involves the migration of the methyl group at C-11to C-12 in a [1,5]-sigmatropic shift. The pathway to vitamin B, in anaerobic bacteria such as Salmonellatyphimuriurn is parallel but n0nidentica1.l~~ The methyl group of methionine has been shown to be the source of the methy1 groups at C-2 and C-7 of the porphyrin of cytochrome c3 in the anaerobic bacterium Desurovibrio vutgaris.164 7 Miscellaneous Metabolites Reviews on the biosynthesis of bacterial cell wall peptidogly~an'~' and the use of chiral methyl groups in biosynthetic studies'66 have been published.Further details of the biosynthesis of fosfumycin (122)from Streptomycesfiadiue have been p~bIished.'~~~~~~ The C-3 deoxygenation of pentopyranine C (123) from Streptornyces griseoch-romogenes has been studied. 69 Labelling studies using Streptomyces subrutilus which produces I-deoxynojirimycin (124) and I-deoxyrnannonojirimycin (125) have shown that the biosynthetic pathway involves the isomerism of glucose to fructose followed by oxidation of C-6 to an aldehyde transamination and cyclization.70 OH (124) R= aOH (125) R = f3OH F. Blanche D. Thibaut A. Famechon L. Debussche B. Cameron and J. Crouzet J.Bucteriol. 1992,174 1036. 159 F. Blanche F. Kuichi L. Debussche F.J. Leeper F. BIanche and A. R. Battersby J. Chem. SOC. Chem. Commun. 1992 139. F. Blanche A. Famechon D. Thibaut L. Debussche B. Cameron,and J. Crouzet,J. Bacreriot. 1992,174 1050. 16' D. Thibaut F. Kiuchi L.Debussche F. Blanche M. Kodera F. 3. Leeper and A. R. Battersby J. Chem. SOC.,Chem. Commun.,1992 982. 162 D. Thibaut M. Couder A. Famechon L. Debussche B. Cameron J. Crouzet and F. Bianche J. Bacteriol.1992 174 1050. 163 J. R. Roth J. G. Lawrence M. Rubenfield,S. Kieffer-Higgins and G.M. Church J.Bacreriol. 1993,175 3303. H. Akutsu J.4. Park and S. Sano J. Am. Chem. Soc. 1993 115 I2 185. 16' T.D.H. Bugg and C.T. Walsh Not. Prod. Rep. 1992 9 199. H. G. Floss and S. Lee Acc. Chem. Res. 1993,26 116. IC7 F. Hammerschmidt Leibigs Ann. Chem. 1992 553. ''* F. Hammerschmidt and H. Kahlig Leibigs Ann. Chem. 1992 1201. S.J. Gould and J. Guo J. Am. Chem. SOC. 1992 114 10 176. "* D. J. Hardick D. W. Hutchinson S. J. Trew and E. M.H. WelIington Tetrahedron 1992 48 6258.

ISSN:0069-3030    

DOI:10.1039/OC9939000311

出版商:RSC    

年代:1993

数据来源: RSC

摘要:

Aase K. 194 Abboud K.A. 145 Abd-El-Adz A.S. 264 Abdourazak A.H. 169 Abell C. 29 Aboutayab K. 86 Achiwa K. 252 Adachi T. 160 302 Adam W. 122 156 158 182 284 309 Adarns J. 27 Adger B.J. 181 Adlington R.M. 186 332 333 Aebersold R.,29 Afridi A.S. 160 Agarwal K. 320 Aganval R. 148 171 Agati V. 141 Agawa A. 219 Agbossou F. 248 Ager D.J. 106 Agrios K.A. 235 Aguilar M.A. 60 Ahlberg P.,148 Ahmed G. 263 Ahmed H.A. 256 Ahmed S.A. 316 Ahn J.H. 282 Ahuja J.R.,107 Aihara J. 148 Aimar M.L. 162 Airoldi M. 254 Akabori S. 266 Akermark B. 198 249 Akhrem I. 159 Aki S. 158 Akinyele E.T. 162 Akita H. 307 Akutagawa S. 282 Akutsu H. 336 Atagona G. 58 AIarni M.167 232 233,235 Alanine A.I.D. 333 Alberts I.L. 80 Albini A. 107 168 Albizati K.F. 112 Albrecht M. 107 Albrecht P.,159 Albrecht W. 311 Alcaide B. 186 Author Index Alcon M. 132 Alexander I.J. 257 Ali S.A. 197 Aliev A.E. 19 Allain E.J. 121 306 Allemand P.M. 25 Allen J.V.,271 AlIen M.H. 29 Alier E. 196 Allinson G. 148 Allison C.E.,24 Allmaier G. 27 Almena J. 128 Almlof J. 57 Almstead N.G. 108 Alonso-Perarnau D. 75 Atpegiani M. 185 Alper H. 129 AIt C. 248 AIvarez C. 286 AIves R.B. 138 Aly A.A. 176 Amat M. 108 235 Amberg W. 284 Amburgey J. 115 276 Amos R.D. 53 56 57 Amurrio D. 265 An D.K. 282 Anaya J. 183 Andernichael Y.W.93 Andersen R.J. 313 Andersh B. 85 Anderson B.A. 123 138 150 181 288 Anderson H.L. 105 141 Anderson J.C. 292 Anderson S. 25 105 Anderson W.K. 159 Andersson C.-M. 227 Anderson P.G. 119 122 235 247 249 284 285 Ando A. 295 Ando C. 224 Ando M. 128 Ando Y. 26 Andres C. 271 Andrus M.B. 105 Andzelm J. 54 Angell R.,277 Angle S.R.,206 208 Anglister J. 6 7 Anguyan J.G. 60 Annan US.,31 Annby U. 234 Annunziata R. 147 Ansarin M. 326 Ansink H.R.W. 162 Anthony J. 174 Anzini M. 210 Aoki K.,296 Aoki Y. 186 Aoyagi K. 243,244 Aoyama T. 202 ApIin R.T. 31 332 Appella E.,31 Aqvist J. 58 Arai I. 30 Arai K. 233 Arai S. 128 273 Araki M.,278 Arcadi A.226 233 237 Archelas A. 305 Archer D.B. 31 An€ A.M. 141 248 Arigoni D. 311 319 Arison B.H., 315 Armentrout P.B. 27 Arnold D.R. 168 Arnold M. 259 Arnone A, 316 Arnswald M. 159 Arredondo Y. 199 Arrington M.P. 284 Arseniyadis S. 138 Arts H.J. 204 Arumugam S. 18 Asano H. 266 Asano K. 172 Asao N. 106 132 Asao T. 257 Asayama M. 235 Asensio G. 182 Asfari Z. 105 Ashby E.C. 162 Ashby G.A. 29 Ashe A.J. 111 259 Ashimori A. 243 Ashton P.R.,147 Assante G. 316 Astruc D. 265 337 Ateeq H.S. 74 263 Atshaves B.P. 335 Attardo G. 202 Atta-ur-Rahman 151 Audier HE 22 24 Audouin M. 223 Aumann R. 151 Aurrecoechea J.M. 138 Austin S.J. 148 Ay M.154,219 235 Ayer S.W. 30 Ayer W.A. 314 Azaulay M. 328 Aznar F. 141 Azurna R. 102 150 Baba M.S. 26 Babin P. 235 Babu R.L. 308 Bach T. 108 Bachi M.D. I00 Bachrach S. 79 Baciocchi E. 95 193 Badone D. 108 BLckvall J.-E. 134 247 249 Baer C.D. 264 265 Baer T. 27 Baerends E.J. 64 Bagatti M. 75 BaggaIey K.H. 332 333 Bahktiar R. 27 Bahr U. 28 Bailey C.R. 332 Baker B.J. 318 Baker R.W. 267 Baker T.M. 267 Balachandran S. 333 Balasubramanian R. 26 Balasubramanian S.,257 Balavoine G.G.A. 287 Baldenius K.U. 149 Baldoli C. 262 263 Baldridge K.K. 146,149 Baldwin J.E. 186 276 332 333 Baldwin K.P. 233 Ball R.G. 125 Ballabto M. 330 BalIestri M. 82 129 280 Baltisberger J.H.16 Bando T.,I19 Banerjee A.K, 141 Banerji A. 290 Banfi L. 106 Banister J.A. 217 Banyai I. 4 Bao J. 138 150 278 Barbey S. 200 Bardone D. 227 Bardshiri E. 316 Bareket Y.,286 Barford R.A. 59 BariIi P. 304 Barlow S.J. 159 Barluenga J. 141 158 Barnes C.I. 29 Barnes D.M. 123 181 288 Barnier J.P. 300 BarraIl G.A. 16 Barras I.-P. 257 Barrett A.G.M. 167 244 Barrett C 181 Barton D.H.R. 94 183 Bartsch R.A. 266 Ban W. 322 Basak A. 333 Bashiardes G. 267 Basilevsky M.V. 60 Baskaran S. 294 Bastock T.W. 159 Bates R.W. 224 Bathnagar S. 79 Bats J.W. 108 Batsanov A.S. 266 Batta G. 4 7 Battersby A.R. 214 216 333 335 336 Bau R.57 Bauch H.-J. 323 Banerrneister M. 257 Bax A. 6 7 9 11 Bax B.M. 151,222 Bazinger M. 300 Beak P. 108 166 188 297 Beale J.M.. 317 324 326 330 331 Beale S.I. 333 Beaucage S.L.,106 Beaudet I. 240 3eaudoin S. 121 286 Beck W. 29 Becke A.D. 52 57 Becker D.P. 220 Becker H. 108 Beckett M.A. 266 Beckett R.P.,267 Beckham S. 149 Beckhaus H.D. 78 Beckwith A.L.J. 89 106 Bedeschi A. 237 308 Beer P.D. 266 3ehar V. 210 Behnen W. 271 Beholz L.G. 159 Beifuss U. 107 Belenlkii L.I. 160 Beley M.,230 Belfoure V.,160 Bell P.T.,256 Bellina F. 235 Bellosta V. 286 Bellur N.S. 107 Beltrane P. 76 Belyk K. 113 Benareb A. 206 Ben-David Y. 224 227 Benhaddou R.286 Author lndex Benincori T, 196 Bennani Y.L. 119 121 284 285 286 Benneche T.,200,250 265 Benner S.A. 290 Bennet N.S., 291 Bennetau B. 106 I58 235 Benniston A.C. 266 Bent B.F. 167 Bentley J.M. 77 Benyan L. 266 Berces A. 54 57 Bergander K. 4 8 Bergdahl M. 112 Berger E. 270 Berger S. 4 8 Berinstain A.B. 148 Berk S.C.. 220 Berk S.E. 138 Berkessel A, 287 Berkowitz J. 23 25 BerrneI W. 11 ljernard J.M. 252 Bernardi A+ 66 Bernardi F. 66 67 75 145 Bernardinelli G. 263 265 Bernardini C.B. 182 Bernier J. 119 294 Bernstein M.A. 160 Bernstein M.P. 108 Berrios-Pefia N.G. 249 Berson J.A. 148 Bertha F. 185 Berthomieu D. 24 Berti G. 304 Bertinato P.105 231 269 Bertrand G. I87 Beruben D. 135 Berven H.M. 138 Besanpn J. 264 Beslim P. 78 Bethell D. 289 Beveridge D.L. 58 Bhalerao U.T. 308 Bhandari P.,324 Bhat B. 330 Bhatia B. 287 Bhatia S. 287 Bhatt M.V.,156 Bhatt R.K. 112 Bhattacharya S. 166 240 Bhushan V. 285 Bicchierini N. 155 Bichard C.J.F. 191 3ickelhaupt F.M. 66 176 Biemann K.,31 Biesemans M. 3 Biggs T.N. 155 Bigler P. 8 Bilkis I.I. 168 Billups W.E. 145 Bilodeau M.T. 123 181 288 Bird J.W- 332 Birkett M.A. 193 Author Index Bisarya S.C. 158 295 Bisht K.S. 302 Bissinger P. 256 Bissolino P. 185 Bitsch F. 30 Bjarke B.,302 Bjork P.,229 Black M, 86 Blaser D. 145 259 Blagg J.244 Blake J.K. 71 Blake N.E. 323 Blanche F. 333 335 336 Blanco L. 300 Blank S. 188 Blart E. 252 Blau N. 31 Blechert S. 117 138 219 Bley J. 107 Blomberg M.,249 Blosser P.W. 254 Bobbitt K.L. 128 Bobzin S.C. 314 Bodenhausen G. 10 15 Bodwell G.J. 267 Boere B.B. I71 Boernsen K.O. 23 Boese R. 145,259 266 Bohlmann R. 318 Bohrn S. 79 Bohme D.K. 22 Boireau G. 283 Boland W. 311 3I2 319 Bolin G. 227 Bolrn C. 106 130,280,286 Bolton G.L. 140 Bonjoch J. 102 Bonner M.P.,79 80 Bonnert R.,208 Booker-Milburn K.I.,92 Boos A. 323 Booze,J.A. 27 Bordeleau J. 119 294 Borden W.T.,146 Borghi D. 185 Borgis D. 57 Borhan B. 304 Bornmann W.G. 230 Borzilleri R.M.,192 Bosch E.100,287 Bosch J. 102 108 235 Boswell H.D., 327 Bottoni A. 75 Bouchoux G. 24 Bouhlel E.,287 Bourdin B. 293 Bouzide A. 138 Bovens M.,253 Bovonsornbat P. I58 Bowen R.D.,21 24 25 Bowie J.H. 24 Boyd D.R. 148,305 Boyd R.J. 57 Boyde D.R. 171 Boylan M.J.,192 Boyle R.,232 305 Boyle T.J.,I2 Bracken M.F. 291 Brackenridge I. 300 Braddock D.C. 141 Bradshaw J.D. 233 Bradshaw J.S.,105 214 Brakta M.,228 Braley T.L. 171 BrambIe F.Q. Jr. 30 Brands M.,253 Brandvold. T.A. 138 150 Brauman J.I. 287 Braun M. 111 Bra A.V. 57 Breen A.P. 103 104 Breitenbacher J.G. 206 Brenna E. 196 Brennan J. 181 BreuilIes P. 301 Brezova V. 168 Brieva R.303 304 Brimbie M.A. 153 Brintzinger H.H. 138 236 Brisset H. 131 Brodbelt J. 22 Broene R,D. 131 281 Bronnimann C.E. 13 Brook A.G. 74 Brook M.A. 23 Brookhart M.,255 Brophy J. 74 Brossier P. 254 Brown D. 191 Brown D.A. 256 Brown G.R. 147 Brown H.C. 214,282 Brown J.M. 106 131 141 294 Brown R.F.C. 107 146 171 Brown S. 237 Bruche L. 213 Briickner R. 1 I I 150,233 Brurnmond K.M.,140 Brurnweli J.E. 84 138 Brunel J.-M. 297 Brunner H. 267 270 Brunner M. 287 Brussee J. 271 Bryans J.S. 333 3ryce M.R.,266 Bssaibis M. 77 Bubenitschek P.,171 Buchanan R. 30 Buchwald S.L. 131 138,220 244,281 Bugg T.D.H., 336 Buiman Page P.C. 289 Bu’Lock J.D. 330 Bunn B.J.295 Bunnage M.E. 293 Bunt R.C. 249 Bum U.H.F. 136,241 Buono G. 297 Bupp J.E. 171 Burcbat A.F. 128 Ilurdeniuk J. 224 Burdisso M. 75 Bures E.J. 29 Burgers P.C. 21 22 23 Burgess V.A. 267 Burgess-Henry J. 290 Burk M.J. 131 Burk R.M.,290 Burlingame A.L. 30 Burt S.K.,57 Burton D.J. 232 Burton,N.A. 59 60 Busacca C.A. 166,225 Buser H.R. 30 Bushby R.J. 148 Busia K. 156 Butenschon H.,263 Buttery C.D. 188 Bycroft B.W. 320 Byford M.F. 332 Byme K.M. 315 Byme M.P. 295 Cabaj J. 273 Cabiddu S. 165 Cabri W. 237 Cacchi S.,222 226 233 237 Caddick S. 86 97 Cadogan J.I.G. 86 Cadoni E. 76 CaiTyn A.J.M. 245 Cai D. 280 Cai 2.-W. 227 Cajthami C.E. 125 296 Caldwell K.A.25 Calkins T.L.,93 138 149 Callahan J.H. 25 CaIter M.A. 126 Cameron B. 335 Campbell E.E.B. 26 Campbell M.M. I07 Campbell S.J. 21 I Campora J. 244 Campus P.J. 158 Candiani I. 237 Cane D.E. 314 319 324 Cao Y.,264 CappeIli A. 210 Caputo R. 164 Car R.,56 Carless H.A.J. 156 Carling R.W. 190 Carlsen P.H.J. 194 Carlson H.A. 58 Camichael D.,208 Carmichael W.W. 328 Carofiglio T. 244 Carpenter B.K. 78 Carpenter K. 155 Carpita A, 235 Carreiio M.C. 271 340 Carter D.S. 165 Carter I.T. 57 Cartmell E. 21 1 Cartwright G.A. 86 Carty A.J. 14 Carvalho W.A. 106 Carver J.A. 258 Casarini D. 147 Casati R. 324 Case-Green S.C. 267 Casida K.C.57 Casida ME 57 Caspi E. 321 Cassels R. 333 Cassoschi A. 72 Castedo L. 138 205 CasteIijns A.M. 204 Castellino S. 108 Cavazza M. 155 Cerfontain H. 162 Cha J.S. 282 Chadha R.K. 284 Chakrabarti P. 263 Chakraborty R. 294 Chakraborty T.K.,105 231 269 Challener C.A. 138 150 Challoner R. 14 Chamberlain S. 151 222 Chamberh R. 162 Chambers R.D. 295 Chan C.-S. 230 Chan J.B. 81 Chan K.S. 230 Chandler I.M. 315 Chandraprakash Y. 308 Chandrasekaran S. 294 Chang C.J. 29 Chang K. 256 Chang S. 122 255 Chang S.-F. 108 226 Chang V.K. 219 Chapman J.R. 28 Charette A.B. 271 Charles N.R. 74 263 Chary K.V.R. 3 Chatani N. 153,218 Chatgilialoglu C.82 129 280 Chattejee A.K. 291 Chatterton W.J. 74 Chaudret B. 265 Chauret D.C. 277 ChBvez I. 266 Cheetham A.K. 12 Chelain E. 223 Chem B.-L. 158 Chemla F. 245 Chen C. 84 Chen C.-M. 138 Chen C.S. 302 Chen C.Z. 73 Chen H. 57 Chen J. 255 Chen J.D. 286 Chen L.Z. 25 Chen Q+-Y.,95 169 Chen S. 30 Chen S.-T. 304 Chen T. 286 Chen X.-J. 305 Chen Y. 23 155 Chen Y.-J. 138 Chen Y.T. 57 Chen Z. 266 Cheng C.-H. 236 Cheng K.,158 Cheng W,-J. 254 Cheng X. 24 Cheng X.-C. 317,318 Cheng Y.K.,58 Cheng Z.-Y. 266 Chiacchio U. 150 Chiarelli R.,57 Chiba T. 282 Chien C.J. 258 Chignell C.F. 168 Chirna J. 305 Chingas G.C. 16 Chiu R.-T. 138 Cho B.P.171 Cho H. 324 326 330 Cho I. 140 Cho S.J. 75 Cho W.J. 262 Chodorowski S. 230 Choi H.C. 290 Choi K.I. 282 Chong D.P. 57 Chong J.M. 128,277 C~OU, C.-M. 169 Chou T.S. 1i3 Choudhary AD. 322 Choueiry D. 244 Chowdhury C. 234 Chowdhury R. 265 Chowdhury S.K. 25 Christe K.O. 57 Christensen A.M. 18 Christian J.F. 25 Christova N.R 75 Chuang L.-W. 255 Chudinov G.E. 60 Chung D.S. 66 Chung J. 11 Chung T.M. 264 Chung Y.K.,220 221 246 264 265 Church G.M. 336 Cid P. 75 Cirnino G. 311 Cinquini M. 147 Cioslowski J. 65 72 Cladingboel D.E. 93 Clairet F. 22 Clark J.H. 159 Clark J.S. 203 Clark T. 41 Clark W.M. 155 Author Index Clarkson S. 237 Clasby M.C.141 Classon B. 252 Clausen F.P. 200 Clayden J. 121 Clayton S.C. 197 224 CIive D.L.J. 138 142 CIore G.M. 1I CIongh L.E. 330 Coates R.M. 319 Cobes A. 205 Cochennac C. 201 Coggins J.R. 322 Cohen LA. 234 Cohen T. 133 Colburn A.W. 25 Collett A. 182 Collin J.-P. 230 Collington E.W. 121 Collins D.J. 148 Collins J.J. 74 Collins P.W.,106 Collins S. 254 Collman J.P. 287 Collum D.B. 108 125 296 Colton R. 28 Colwell S.M. 57 Cornins D.L. 300 Compton R.N. 26 Conqepcion A.B, 132 Concha M.C. 57 Conde S. 302 Congreve M.S. 290 Conn L.M. 291 Connell R.D. 198 Conneily J.A. 322 Connoily C.B. 247 Conser K.R. 123 288 Constantin E. 28 Cooks R.G.22,29 Cooper A. 322 Coote S.J. il4 163 198 253 271 Corey EJ.,101 119 121 i36 141 271 279 285 287 Cornelis A. 159 Cornelisse I. 171 Cornforth J.W.,269 Corrigan J.F. 14 254 Corriu R.J.P. 227 Cortez C. 171 Cossi P. 235 Cossio F.P. 65 75 Cossy J. 138 Costa A.L. 270 Costello J.F. 267 Couder M. 335 336 Coughlan S.M., 248 Courtemanche G. 138 Couture A. 205 Covey T.C. 29 Cox A.L. 31 Cox D.B. 28 Cox D.M. 25 Author Index Coxon J.M. 108 Cozzi F. 147 Cozzi P.G. 244 Crabtree G.R. 105 Craig D. 141 182 Craig G.A. 27 Cramer C.J. 57 Crampton M.R. 162 Craw P.A. 314 Cremer D. 148 Crich D. 84 89 Crich J.Z. 303 Crimrnins M.T.,106 137 269 Crisp G.T.232 Crispino G.A. 119 284 285 Crist D.F. 162 Crombie L. 324 Cross G.G. 105 Croteau R.B. 161 319 Crouch N.P. 332 Crousse B. 232 Crout D.H.G. i05,309 Crouzet J. 336 Crow G.R. 269 Crurnrine D.S. 72 Cucciolito M.E. 249 Cuevas C. 75 Cuisiat S.V. 74 Cullen S.R. 159 Cunningham D. 255,264 Curci R. 132 Curran D.P. 84 86 88 93,97 99 106 129 Currie J. 293 Curtis D.R. 302 Curtis J.M. 28 Czech R.P. 266 Czernecki S. 286 D’Accolti L. 132 Daban F. 187 265 Dai W.M., I49 Dakka J. 286 Dakternieks D. 28 d’Alessandro N. 168 Daley S.T.A.K. 266 DaMn K. 322 Dalton D.M. 248 Dalton H. 305 309 Dalvi P.V. 142 Darnbacher G. 108 Damrn W. 97,98,99 129 Damtoft S.,319 Dance 1-43.,27 Daniell GJ.9 DanieIs P. 324 Danil de Namour A.F. 105 Danis P.O. 28 Danishefsky S.J. 105 108 210 227 230,269 Danzer M. 333,335 Daran J.-C. 223 Dasgupta S.K. 232 Da Silveira E,F. 28 Dasradhi L. 300 Dass C.H. 24 Date T.,108 141 273 Dauelsberg C. 280 Daves G.D. Jr. 228 Davies H.M.L. 107 Davies I.W. 247 Davies S.G. 106 168 267 293 Davis F.A. 295 Davis K. 322 Davis M.F. 13 Davis W.D. 284 Davison E.C. 290 Davison M. 332 Davisson V.J. 327 Davister M. I59 Dawson G.J. 114 163 198 253 271 De B.B.,287 Deacon G.B. 271 Dean G. 309 De Benedetto L. 246 Deberly A, 283 Dekrnardinis S. 237 Debrauwer L. 24 Debski N. 290 Debu F.333 335 Debussche L. 333 335 136 Dec S.F. 13 Decamp A.E. 1t1,232 De Clerq E. 228 de Denus C.R. 264 de Dios A. 232 de Gala S. 230 Deganello G. 254 Deka R. 322 de Koning C.B. 328 Dekoning L.J. 66 de la Salud R. 291 Del Buttero P. 242 253 Delgado F. 286 Delgado M. 271 Del Grosso M. 108 Dell K.A. 155 Dell’Erba C. 163 Deiogu G. 297 del Rjo Portilla F. 10 DeIuca M. 208 De Lucchi O. 297 Delvalle F.J.O. 60 Delville M.-H. 266 de March P. 75 de Meijere A. 178 Demura T. 162 Deng t.,121 306 Dengler A. 107 Deniau E. 205 DeNisco M. f64 Denisov V. 117 244 Denmark S.E. 108 115 276 Denney B. 152 Denney D.Z. 162 Deppe A. 28 341 de Rossi R.H. 162 Derrick P.J.24 25 27 28 30 Deschenaux R. 266 Desimoni G. 72 78 Deslongchamps P.,72 Desponds O. 106 Destabel C. 90 Detomaso A. 132 Deutsch J. 291 Deutzrnann R. 322 de Vargas E.B. 162 de Vries E.F.J. 271 de Vries N.K. 293 de Vroom E. 182 Dewey MA. 248 Dewick P.M. 320 321 de Wolf W.H. 176 Dkziel R. 119 294 de Zoete M.C. 304 Dhal P.K. 287 Dharmaratne H.R.W. 321 DiCapua F.M. 58 Dickhaut J. 98 129 Dickson R.M. 57 Diederich F. 174 Dietz A, I07 DiIlet V. 60 DiMichele L. 232 Dimitroff M. 141 Dinesh C.U. 290 Ding D. 26 Ding S. 227 249 Disch R.L. I46 Diver S.T. 291 Dixon D.A. 57 Dixon R.A. 322 Djakovitch L. 266 Djuric S.W. 106 Ro,J.Y. 90 Dobson C.M.12 Dodd R.H. 287 DSrner W. 138 Diitz K.H. 223 Doherty A, 79 332 Doherty S. 14 Doi T. 150 DoI P.P.M. 73 DoIbier W.R. Jr. 78 Dolling U.-H. 111 232 Dominguez D. 138 Dornling A. 199 Donaldson W.A. 256 257 Donchi K.F. 24 Donogues J. 158 Donohoe T.J. 106 168 Donovan T.A. Jr. 22 168 Dorado M. 138 Dorsey B.D. 125 Doty M.J. 222 Doucet J.P., 69 Douglas A.W. 280 Douglas C.J. 322 Douglas D.J. 325 Dove Y.,156 342 Dowd P. 90 106,211 279 Doyle M.P.,135 Doyle T.W. 318 Doyon J. 138 Drader J.J. 27 Dragovich P.S.,149 Drauz K. 283 Drew M.G.B. 266 Drewello T. 23 Drewes S.E. 203 Drummond M.H, 29 Du H. 297 Dual C. 56 DuBay W.J. 190 Duchamp J.C.148 Duchenne A. 240 Diirner G. 108 259 Duffy P. 57 Duggan P.J. 89 Duhamei L. 117 277 Duhamel P. 11 7 277 Dulcere J.-P. 119 141 Dumant A. 304 Dumas J. 238 Dufiach E. 288 Dunbar R.C. 22 Duncan S. Jr. 160 Dunn M.J. 235 Dunn W.J. 58 Dunogues J. 106,235 Durant G.J. 58 Dutto G. 246 Dvortsak P. 12 Dwight W.J. 108 Dwyer T.J. 8 Dyker G. 171 Dykstra R.R. I28 Eades R.A. 54 57 Eady R.R.,29 East M.B. 106 Eastman M.A. 16 Eastwood F.W. 107 146 171 Eaton P.E. 132 Eberbach W. 214 Eberlein T.H. 193 Eberlin M.,22 Ebert G.W. 158 Ebert-Khosla S. 317 Ebizuka Y. 320 Eckardt K. 317 Eckert H. 25 Edge S.J. 179 Edwards A.J. 125 267 276 296 Edwards I.332 Edwards J.P. 153 241 Edwards R. 322 Effenberger F. 193 Egan M. 138 149 Eggenberger U. 8 Eggers A. 11 1,233 Eggleston D.S. 199 Eguchi H. 158 Eichele K. I4 Einaga H. 57 Eisenberg C. 113 Ekeberg D. 27 Eksterowicz J.E. 71 98 107 Elgendy S.M.A. 155 El Hafa H. 246 Elid E. 270 Ellames G.J. 310 EIIard M. 322 Ellinger Y.,57 Ellis D. 235 Ellis W. 254 Ellstead K.E. 140 El Mouatassim R,264 El-Olemy M.M. 322 Elson S.W. 332 333 Emokpae T.A. 162 Emsley L. 8 16 Emslie N.D. 203 Enders D. 141 254 271 Endo A. 318 Endo H.,307 Endo T. 319 Engbexsen J.F.G. 190 Engel G.T. 192 Engelhard V.B.,31 Engle C.A. 333 Enkelmann V. 136 241 Eppers O. 4 Erdrnann H.302 Eriksson A. 234 Eriksson LA. 57 Eriksson M. 112 Erker G. 107 Eshghi H. 159 Especl P.H . I59 Essex J.W. 58 59 Etinger A. 24 Evans B.,108.227 Evans D.A. 106 108 123 126 130 181 278,281 288 292 293 Evans D.H. 106 Evans G.R. 141 Evans S. 30 Evans T.A. 305 Evans W.J. 12 Evanseck J.D. 65 Everberg K.A. 137 Ezcurra J.E. 153 Fabbri D. 297 Faber K.,305 Fabre A. 88 138 Fabrizi G. 233 Fache F. 281 Fadnavis N.W. 308 Fahrendorf T. 322 Fairfax D.J. 150 Faita G. 72 78 Falck J.R. 112 Author Index Falck-Pedersen M.L. 250 Faller J.W.,132 254 282 Fallis A.G. 141 Famechon A. 336 Fan L.-D.G. 331 Fan W.-Q. 160 Fang D. 74 Fang J. 30 Fang Z.164 Fantin G. 307 Farata T. 158 Farina V. 167 232 Farrant R.D., 11 12 Farrell J. Jr. 21 Farthing C.N. 276 Fates B. 258 Fattuoni C. 165 FauI M.M. 123 181,288 FauIkner D.J. 106 Faure R. 141 Faust R. 146 Fava A. 107 Feaster J.E. 131 Ftaux de Lacroix S. 15 FederseI H.-J. 269 Fehr C. 125 Feibelmann S. 140,220 Feigelson G.B. 184 Feistner G.J. 30 Felder M. 130 280 Feldman K.S. 123 138 Feltman T.L. 160 Feng T. 271 Feng Z. 319 Fend R.W. 241 Fenn J.B. 28 Fensterbank L. 165 Ferguson M.D. 74 263 Feringa B.L. 293 Fernindez I. 291 Fernindez R. 295 Fernandez-Acebes A. 138 Fernandez-Baeza J. 265 Fernandez-Mayoralas A. 302 Ferraboscbi P. 299 Ferreri C.82 129 280 Fern F. 167 233 Ferrier R.J. 138 Fetter J. 185 Feuilleaubois E. 69 Fevig J.M. 208 Fidalgo J. 138 Fiedler A. 27 Field J.S. 203 Field R.A. 332 Fields S.C. 273 Fields T.L. 101 Figatere F. 107 Figuerdo M. 75 Filipkowski M.A. 77 137 Filipp N. 74 Filippini L.. 227 Fillaut J.-L. 266 Finch H. 108,227,258 Author Index Fink D.M. 164 Finkam M. 254 Firouzabadi H. 290 Fischer. B. 187 Fischer J.E. 25 Fischer N.H. 313 Fischer W. 200 Fishbein K.W. 19 Fisher E.R.,27 Fisher G.B. 282 294 Fisher H. 124 Fisher S.L.,302 Fisker H. 302 Fitz W. 311 Fitzgerald G. 53 57 Fitzgerald J.J. 13 Fitzpatrick N.J. 256 Fleet G.W.J. 191 Fleming I.122 Flemming P.E. 324 Fleukiger P. 57 Flippin L.A. 165 Florentin D. 328 Flores H.E.,313 FIoriani C. 244 Floris B. 95 Floris C. 76 165 Floss H.G. 108 324 326 329 330,331 334 Flynn B.L. 232 Flynn D.L. 220 Fogagnolo M. 307 Fokina N.A. 304 Fokkens R.H. 24 Folga E. 54 57 Folkers P.J.M. 4 Folmer J.J. 291 Folmer R.H.A. 4 Foltin M. 27 Font J. 75 Fontain E. 107 Ford K.L. 292 Forenza S. 318 Formica M. 249 Fornarhi S. I59 Forrester J. 287 Forster S.,267 Forsti E. 147 Fothergill M. 58 Fotsch C.H. 105 299 Foubelo F. 128 Foubister A.J. 147 Fouche G. 305 Fournier F. 24 Fournier R. 57 Fowler P.W.,148 Fox D.N.A. 127 Fox K.M. 324 Fox T.,4 61 Foxall P.J.D.12 Foxman B.M. 266 Francheschi G. 185 308 Franck B. 174 Franczyk H. 319 Frank-Neumann M. 256 Frappeir F. 328 Fraser-Reid B. 81 Freccero M. 168 Frbhet D. 333,335 Freeman R. 10 Freer I.K.A. 326 Frenzen G. 73 Fresse I. 300 Fried C.A. 249 Friese V, 323 Fnm R. 178 Frish M.,61 Fritch P.C. 193 Fritz-Langhals E. 297 Frossl C. 311 Frost C.G. 114 153 198 253 27 1 Frost J.W. 155 Fry A.J. 278 Frydman L. 16 Fu,D.-K. 244 Fu G.C. 106 117 Fu,H.-W. 255 Fu P.P. 156 171 Fu S. 258 Fu X.,74 76 Fuchs P.L. 108 Fuest M. 235 Fugami K. 247,254 Fuganti C. 308 Fuhry M.A.M, 290 Fuji K. 106 116 132 276 292 293 Fujihara H. 153 Fujii H. 292 Fujimori T.252 Fujimoto H. 314 Fujimoto K.,122 235 Fujimoto Y. 318 Fujisaka S. 158 Fujisawa M. 138 Fujita M. 108 Fujiwara K. 150 Fukuhara T. 163 Fukurnoto K. 107 136 138 200 Fukurnoto Y. 153 218 Fukuno A. 188 Fukushima N. 57 Fukuyama Y.,232 FuIler D.J. 108 Fuller J.C. 130 282 Fulston M. 332 Funakoshi K. 138 Funk R. 140 271 Furstner A. I06 Furstoss R. 305 Furukawa N. I53 Furukawa S. 229 Furuta T. 30 Fusco C. I32 Futano M.,249 Fyles T.M. 105 Gabel C.J. 224 Gable K.P.,23 Gabrik A.H. 30 Gagne M.R.,130,281 Galaev I.Yu. 304 Galambos G. 232 Galindo J. 125 Gall C. 152 GaIlagher D.J. 108 166 Gallagher R.T.,28 Gallagher T. 247 Gaili C. 159 GaIlucci J.C.254 Galushko S.V. 304 Gambe A. 256 Gamez P. 281 Gandoifi R. 75. 256 Ganem B. 283 Ganesan A. 208 Ganesh P.,245 Ganesh S. 263 Ganeskpure P.A, 156 Ganghoff A.R. 198 Ganguly A.K. 201 Gann S.L. 16 Gao J.L. 58 62 Gao J.R. 22 Gao O. 141 Garanti L. 213 Garbow J.R. 18 Garbutt R. 27 Garcia A.E. 58 Garcia B. 291 Garcia E. 167 Garcia O. 286 Garcia-Granda,S. 141 Garcia-Martin M.A. 158 Garcia Ruano J.L. 271 Gardini F. 307 Gardner M. 66 Garner P. 206 Garrett B.C. 67 68 79 Garrett D.S.,11 Garrido N.M.,293 Garro-Helion F. 252 290 Garson M.J.,311 Gasch C. 295 Gasche J. 108 207 226 Gasparrini F. 147 197 Gasteiger J. 69 Gatti R. 247 252 Gauthier A.72 Gawley R.E. 128,201 Geib S.V. 99 Gelli G. 76 165 Gelling O.J. 218 Genet J.-P. 250 252 281 Geng B.,227 Gennari C. 66 Gennaro G. 254 Gentili P. I52 Geoffroy P. 255 George G.I. 183 George M.,22 Geppert T.,8 Geraci L.S. 127 270 Gere R. 256 Gero S.D.,183 Gerson F. 178 Gervasio G. 221 Ghanimi A. 171 277 Ghio C. 58 Ghosh A. 57 Ghosh R. 135 Giannis A. 105 Giblin D.E. 25 Gibou-Barbedette A. 256 Gielen M. 3 Giese B. 83 97 98 99 f29 Giese R.W. 156 Giesen V.,235 Giguere R.J. 141 Gilbert A.M. 138 157 236 Gilbert B.A. 118 Gilbert J. 80 320 Gilchrist J+H.,108 125 296 Gilchrist T.L. 235 Giles M. 208 Gill G.B.,77 Gill M.316 Gill P.M.W., 53 GiIlard J.W. 202 Gilimann T. 138 Gilmore R.J. 266 Gimenez A. 316 Girnisis T. 171 Gin D.Y. 128 Giner J.-L. 318 Gingras M. 291 Gioia B. 330 Giordano F. 249 GiovannoIi M. 197 Girard M. 121,286 Girijs K. 165 Girijavallabhan V.M. 201 Giuliano R.M.,72 Gladstone B.G. I52 Gladysz J.A. 248 GUnzer J. 223 Glaser J. 4 Glass W.K. 256 GlassI B. 201 Glatzhofer D.T. 265 Gleason M.M. 247 Gleiter R. 106 145 149 218 Glending E.D. 146 Gliaka T. 331 Glish G.L.,28 Gloaguen B. 266 Godard A. 201 229 Goddard R. 263 Godfrey A.G. 283 Godfrey C.R.A. 186 Gobel T.,284,285 Goghari M.H. 29 Gogoll A. 247 Goldberg D.R. 141 Goldberg I.B.,57 Goldschmidt Z.264 Goldstein S. 72 Golebiowski A. 107 Golik J. 318 Goliins D.W. 185 Golz T. 80 210 Gomez-Barrios M.L. 313 Gomibuchi T. 150 Gonon K. 162 Gonzalez J.M. 142 158 Gonzalez N.C. 141 Gonzalez-Lafont A. 68 Gonzalez-Nunez M.E. I82 Good A.C.G. 69 Goodman J.M. 66 Goodwin C.J. 293 Goodwin L. 57 Goralski C.T. 130 282 294 Gorrod J.W. 30 Goto Y.,254 Gotor Y.,304 Gottlieb H.E. 264 Gottschalk G. 156 GOU,D.-M., 302 Gould I.R. 60 Gould S.J. 317 318 325 336 Goulet R. 119 Goulet S.,294 Gourdel Y.,131 277 Govil G. 3 Gowri G. 322 Grace K.J.S. 235 GrBfe U. 329 Graf R. 138 Graff C. 326 Graham A.E. 289 Grainger D.S. 9 Granberg K.L. 247 Grandclaudon P.,205 Grande M.183 Grandinetti P.J.,16 Grandjean D. 111 Grant T.G. 156 Gras J.-L. 116 276 Gratti Comini S. 78 Gray J.L. 137 Green D.V.S. 59 50 Green H. 15 Green I.R. 153 Green J.R. 254 264 Greenspan P.D. 250 Greeves N. 193 220 Grenier L. 119 294 Grey A.G. 33 Grey C.P. 12 Gribble G.W. 147 200 Grier M.C. 270 Griesinger C. 8 Griffin D. 23 Griffin R.G. 19 Griffiths G.J. 300 Grifiths O. 157 Griffiths S.L. 248 Grigg R.,112 237 240 Author index Grill V. 27 Grisenti P.,299 Grissom J.W. 93 138 149 Grogan G. 306 Gronenborn A.M. I1 Gronert S. 66 108 Gronowitz S. 229 234 Gross M.L. 22 24 25 Grosshenny V. 233 Grossman R.B. 138 220 Grotemeyer J.29 Groth U. 125 Grubbs R.H. 117 Gruber B. 107 Grue-Sorensen G. 327 GruseHe M.,246 Grzesiek S. 6 7 Gschneider D. 141 Ga M. 24 Gu Q.-M. 304 Guan J.G. 57 Guan L. 247 Gubatz S. 323 Gudel H.U. 56 Guella G. 155 Giinther H.,4 8 Guertin K.R.,132 289 Gueugnot S. 234 Guibi F.,252 290 Guibe-Jampel E. 300 Guijarro A.G. 128 167 Guillaumet G. 206 GuilIenn G. 328 Guillon T. 18 Guindon Y.,97 129 Guiry P.,141 Guitian E. 205 Gulevich Y.V.,235 Guntha S. 290 Guo C. 1.18 Guo J. 336 Guo L. 135 GUO,Z.-X. 118 I79 Gupta V. 94 Gurevich A. 162 Gurney K.A. 330 Gurski A. 153 Gurthler S. 185 Gurunmurthy R. 162 Gusmeroli M. 227 Guy A. 304 Guy L. 182 Guzik H.201 Guzzi U. 108 227 Gyoung Y.S.,282 Haas G.W. 24 Hachiya I. 272 278 Haddix G.W. 13 Hadida S. 108 235 Hadjiarapoglou L. 284 Haeffner F. 249 Hafner K. 79 Author Index 345 Hagaman E.W. 13 Hagemeyer A, 16 Hagen K.S. 136 Hager L.P. 121 306 Hai A.K.M.A. I83 Hai Y. 73 Haigh D. 307 Hailes H.C. 202 Haines A.H. 179 Halcrow M.A. 265 Hales N.J. 257 Halevi E.A. 65 Haley M.M. 145 Hall G.G.,147 Hail S. 30 Hallberg A. 227 HaIler B.-U. 124 HaHey K.A. 318 Hamada Y. 230 Hamaguchi M. 187 Hamasaki T. 314 Hamelin J. 294 Hamilton I. 332 Hammerschmidt F. 336 Hamrnes S. 80 210 Hammock B.D. 304 Han S. 13 Hanada K. 302 Hanafusa T. 23 Hananki N.272 Hanano T. 119 Hanaoka M. 245 260 262 Handy N.C. 53 57 Hanessian S. 121 286 Haning H. 125 Hansen J.A. 141 Hansen J.J. 302 Hansson S. 249 Hansson T. 320 Hanzawa Y. 136 138 290 Hara R. 117,243 Harayama H. 119 247 Hardick D.J. 336 Harding S.E. 322 Hardinger S.A. 290 Harendza M. 280 Harkema S. 190 Harlow R.L. 131 Harrnan W.D. 142 Harmange J.-C. 107 Harmon K.M. 295 Harper M.F. 324 Harran P.G. 85 Harriman A, 266 Harris G.D. Jr. 239 Harris K.D.M. 18 19 Harris M.C.J.,244 Harrison A.G. 24 25 Harrison A.T. 108 Harrison C.T. 282 Harrison D.M. 330 Harrison M.J. 322 Harrity J.P.A. 223 Harrowven D.C. 94 194 Hart DJ. 81 Hart G.J. 216 333 Hartung J.83 284 Harusawa S. 215 Harvey D.F. 223 Harvey R.G. 171 Hasegawa E. 84 Hasegawa M. 94 159 279 Hasegawa Y. 125 296 Hashimoto T.,174 Hashimoto Y.,159 Hashiyama T. 284 Hashizurne M. 289 Haslego M.L. 196 Hassan A.A. 176 Hassner A, 187 Hasumi K. 318 Batanaka A, 312 Hattori T. 163 Haubold E.M. 149 Haner C.R. 31 Hauffe K.D. 322 Haufler R.E. 26 Hawker C.J. 216 333 Hawkins A.R. 322 Hawkins G.D. 57 Hayamizu K. 13 Hayashi A. 138 Hayashi E. 276 Hayashi N. 26 Hayashi S. I3 Hayashr T. 128,242 252 Hayashi Y. 116 264 Hayashizaka N. 163 Hayward C.M. 105 269 He P. 183 Healy M.A.M. 235 Heaney H. 284 Heathcock C.H. 208 220 Heaton N. 267 Heaton S.B.264 271 Heber J. 222 Hechtberger P. 305 Hedgecock C.J.R.,267 Hedges S.H. 328 Heeg M.J.J. 74 Hefu G. 240 Hegedus L.S. 247 Heide L.E. 322 Heidias J. 31 1 Heimer N.E. 164 Heinemann D. 57 Hemrich N. 23 Heinze J. 178 Heizmann C.W. 31 HeIal C.J. 101 287 Helene C. 105 Hellberg L.H. 295 Hellendahl B.,219 HeImchen G. 253 271 Helmick J.S. 155 Helquist P.,198 Hemming K. 76 Hemscheidt T. 328 329 Henderson E. 13 Henderson G.L. 254 Henderson R.A. 31 Hendrickson J.B. 283 Henkel T. 317 Henning K. 203 Henriquez R. 169 Henry J.R. 286 Henshilwood J.A. 74 263 Herberg C. 78 Herbert R.B. 310 325 328 Herdewijn P.A. 228 Herges R. 107 Herman F. 333 335 Herman Z.27 Herndon J.W. 223 Herr R.J. 239 Herrrnann W. 106 Hertel I.V. 26 Hervai B.H. 238 HerzfeId J. 19 Heshmati P. 246 Hesketh A.R. 320 Hetzenegger J. 65 72 Hezroni-Langerman D. 264 Hickey E.R. 138 Hidai E. 116 276 Hidrts M.S. 77 Hiemstra H. 254 Hierstetter T. 65 72 Higaki C. 224 Higashi Y. 301 Higasbihara T. 266 Higuchi H. 172 174 Hilbers C.W., 4 Hill C.L. 84 Hill R.A. 3 11 HiIlenkamp F. 28 Hillers S. 242 Hillier I.H. 59 60 Hilvert D. 105 Hinkle R.J. 108 Hino T. 141 Hira Y. 150 Hirai N. 286 Hirako K. 250 Hirama M. 121 138 I50 Hiramatsu K. 235 Hirao T. 252 Hirashima T. 156 Hirata K. I59 Hirayama N. 132 Hirohara Y.,136 Hiroi K.77 Hirose Y.,271 Hirsch A, 25 I07 Hirst J. 162 Hirvela L. 154 Hiyama T. 111. 241 Hjortso M.A. 313 Ho J. 264 Ho W.B. 206 Hobbs G.R. 309 Hobson A.D. 179 Hoch U. 309 Hockey S. 125,296 Haft E. 284 HSmfeldt A.-B. 229 HoRman A. 30 Hoffman R.W. 235 Hofhann H.M.R. 134,248 Hofmann M.,I2 Hogan J.D. 28 Hohenberg P.,51 Hoioki J. 172 Hojo M. 136 Hoke S.H. IT 29 Holden I. 324 Holkar A.G. 158 Holladay J.E. 141 Holland H.L. 270 Hollander J. 259 Holle A. 28 Holliman C.L., 22 Hollis W.G. 137 Hotmes A.B. 290 HoImes E.F. 295 Holmes J.L. 22 Holms H. 332 Holoboski M.A. 102 Holwerda R.A. 266 Hommann K.,181 Hong C.Y.,225 Hong Y.P.,149 Honig B.57 Hoogsteen K. 72 136 219 Hoorn J.A. 135 Hopwood D.A. 317 Horak R.M. 305,330 Hare P.I. 9 Hormi O.E.O.,154 Horz K.H. 323 Hosaka T. 141 Hoshino M. 132 Hosokawa M. 152 Hosokawa T.,119 Hosomi A. 136 Hosono K. 246 Hosoya N. 287 288 Hotta H. 163 Houk K.N. 63,65 66 71 77 98 107 108 Houpis I.N. 232 Hovestreydt E.R.,271 Hoveyda A.H. 106 Howard J.A.K. 264 Howard K.J. 205 Howard K.P.,11 Howdle S.M.,217 Howell J.A.S. 264 Hoye T.R. 221 Hrusak J. 22 21 Hu L. 255 Huang D.F. 197 Huang S.F.,22 Huang T.-Y., 126 Huang W. 137 Huang X. 237 Huang Y.,93 Huang Z. 77,290 Huang Z.-T. 163 Huber P.,10 Huber R.S.,264 Huber U. 319 Hudecek M.220 Budlicky T. 305 Hudson C.E. 22 Huff S.,29 Hughes,D.J. 191 Hughes D.L.,195 Hugo V.I. 153 Huhn M.M. 57 Huhn T. I25 Huisgen R. 65 Hulmes D.I. 131 294 Hulst R.,293 Hummel C.W. 149 Humphreys V.M.,267 Hung S.M., 73 Hunt A.R. 108 166,224 Hunt D.F. 31 Hunziker P. 31 Hur C.U. 100 Hurd R.E. f 1 Hussoin M.S., 283 Hutchens W.T. 29 Hutchinson C.R. 318 Hutchinson D.W. 309 335 Huttedoch M.E. 138 236 Huval C.C. 94 Hvistendahl G. 27 Hwang B.K.,304 Hwu J.R.,118 Hynes J.T. 66 Ibata T. 162 Ikrs J.A. 287 Ichihara O.,293 Ichikawa H. 74 Ichikawa Y.,309 Ichinose K. 335 Ida T. 141 153 Idrees K. 256 Ihara M.,107 136 200 Ihle N.C. 220 Iida H. 213 Iida K.,121 Ikari Y.,307 Ikeda H.78 Ikeda I. 252 Ikeda M. 83 183 Ikeda S.,228 Ikekawa N.,318 Ikenaga K. 235 Imada Y,,250,254 Imai R. 95 Imamoto T.,277 Imi K. 136 Imoto M. 323 Imperiali B. 302 Imrie C, 266 Author Index Inada K.,281 Inagaki A. 156 Inami H. 251 Indolese A.F. 136 Ingemann S. 24 Ino Y. 172 Inoue H.,127 130,270 Inoue Y.,177 Invernizzi A.G. 72 Iqbal J. 287 Ireland RE.,287 Irie H. 132 Irie R. 287,288 Iseki K.,125 Ishibashi H.,83 183 Ishida M. 108 Ishihara K.,141 272 279 291 Ishii M.,188 302 Ishili T. 175 Ishitani H. 278 Ishiyama T. 235 Isobe M. 246 Isobe S.,249 Isoe S. 141 Ito H.. 136 138 290 rto K.,74,279 Ito N.250 Ito S. 169,257 Ito T. 202 251 Ito Y.,122 235 288 292 Itoh K. 158 160 235 244 282 Ztoh N. 108 128 273 Itoh T.,167 244 Iwamoto S. 266 Iwao M.,229 Iwaoka T. 74 Iwasawa N. 220 Iwata C. 255 Iwata-Reuyl D. 333 Iyer R.P. 106 Iyer V.S. 273 Iyoda M. 95 Izatt R.M.,105 214 Jackson G. 142 Jackson R.F.W. 128 235 245 Jacob LA. 158 Jacobs P.A. 159,245 Jacokn E.N.,121 122 123 288 306 Jacobson D.B. 27 Jaeger E. 41 Jain M. 162 Jakobsen H.J. 13 Jandu K.D. 180 Jang M.-K., 304 Janson M.,252 Janssens B. 159 Jaouen G. 246 lardine D.R. 47 Jardine I. 48 Jarvi E.T. 295 Jayaraman H.C. 214 Author index Jayasinghe L.Y. 309 Jaynes B.S. 84 Jean T.-S.138 Jedicka 3.,243 266 Jeenes D.J. 31 JefTery T. 108,230 Jegorov A. 331 Jenneskens L.W. I71 Jennings K.R. 35 46,47 Jensen M.S. 135 Jensen N.J. 24 Jensen P. 57 Jensen S.R. 319 Jeong K.-S. 119 284 285 Jeong N. 140,220 22i 246 Jerome K.S. 217 Jeschke T. 234 Jevnaker B,,265 Ji J. 240 Jia X.Q. 162 Jiaang W.-T., 86 Jiang B.,229 Jiang J. 74 292 Jiang S. 248 Jiang Y. 73 Jimbo M. 175 Jin F. 137 229 Jin M.-J. 256 Jin Z. 108 255 Jing N. 78 Joe G.H. 90 John B.K. I1 Johner M. 185 Johnson B.G. 53 Johnson C.D. 107 Johnson C.S. 5 Johnson D.D. 105,269 Johnson G. 208 Johnson J.V. 48 Johnson RE. 166 225 Johnson R.S. 34 Johnston M.V. 23,4I Jones D.K.280 Jones D.W. 78 Jones G.B. 264 271 Jones G.C. 42 Jones J.A. 9 Jones J.B. 105 299 JORCS, J.L. 46 Jones M.Z. 35 Jones P.G. 171 Jones R.C.F. 205 Jones R.G. 188 Jones R.O. 56 Jones R.V.H. 287 Jones W.M. 145 Jordan AD. 72 Jordan P.M. 315 Jorgensen K.A. 80 Jorgensen W.L. 58 71 Joshi S.K. 158 JOU D.-C. 236 JoulIie M.M. 292 Ju S. 325 Jubert C. 113 Juhl-Christensen J. 200 Jumnah R. 250 Jun J.-G. 206 Jun W.S.,282 Jung D.K. 137,230 hng G. 29 Jung J.C. 290 Jung M.E.,90,141 154 Jung S.-H. 133 Junga H. 117 138 Junggebauer J. 280 Juntunen S.K. 134 Jurczak J. 107 Jursic B.S. 294 Jutand A. 244 Kabuto C. 136 Kacan M. 155 Kacun M.193 Kadam S.M. 290 Kado N. 226 Kahlig. H. 336 Kaercher G.R. 28 Kagan H.B. 266 Kagechika K. 243 Kageyama M. 117 243 Kagoshima H. 159 Kahn M. 105 Kahne D. 94 Kajbaf M. 30 Kajita S. 249 Kajtar-Peredy M. 185 Kakindii O. 184 Kakiuchi K. 175 i78 Kambe,N. 101 128 Kambuchi A. 141 Kameoka C. 183 Kameyama Y.,128 Kamigata N. 95 Kamochi Y.,283 Kampf J.W. 128 171 259 Kanai G. 153 Kanai M. 46 Kaneda T. 23 Kaneko C. 74 Kane-Maguire L.A.P. 258 Kanemasa S. 126 Kann N. 116,215 Kannagara G.S.K. 235 Kannan K.R.,25 Kant J- 183 Kantam M.L. 290 Kaplan L. 315 Kapoor I.P.S. 162 Karanewsky D.S. 291 Karas M. 28 37 40,42 322 Karcher T. 65 72 Kardos N. 250 Karikomi M.,213 Karimi B.290 Karp G.M. 187 Karr D.E. 28 Karthikeyan M. 165 Kasar R.A. I41 Kassel D.B. 39 Kassir J.M. 150 Kasumov T.M.,158 Kasuya Y. 30 Kataoka O. 245 Katritzky A.R. 160 165 191 Katsoulos G. 165 Katsuki T..279 287 288 292 Katz T.J. 138 236 Kaufmann R. 41 Kawabata T. 132 188 Kawada A. I59 Kawaguchi M. 178 Kawajiri S. 65 72 Kawakami T. 184 Kawakita K.,319 Kawarnura T. 235,240 Kawarmine K. 132 Kawasaki H. 125 296 Kawasaki I. 188 Kawasoe S. 286 Kawecki R.,102 Kay L.E. 7 Kayganich K.A. 36 Kayser F. 3 157 Keck G.E. 127 133 270 Keefe L.J. 42 Keefer P.K.,295 Keglevich G. 200 Keim W.,220 Keiderman E. 190 Keller M. 214 Kelley J.A.37 Kelly M.T. 313 Kelly S.C A48 Kelly S.M. 322 Kelly T.R. 201 Kemp T.J. 27 Kende AS. 132 289 Kenedy E. 324 Kennewell P.D. 76 237 Kenny P.T.M. 33,46 Kent K.D. 45 Kent S.B.H. 39 Kenttamaa H.I. 21 22 23 Keough T. 37 42 Kerns M.L.,155 Kerr M.A. 235 Kerr W.J. 223 Kerrick S.T.,108 166 Kerrigan J.E. 141 Rerssebaum R, 1I Kesselheirn C. 83 Kessler B. 106 Kesura G.M. 185 Khan MA. 253 265 khan S. 97 Khan S.I. 57 141 Khemani K.C. 25 Khosla C. 317 Khrushchova N. 266 Kido M.,252 Kieffer-Higgins S. 336 Kihara N. 159 Kiho T. 35 Kikuchi N. 119 Kikuchs I. 172 Kilbee G.W. 324 Kilburn J.D. 90 Kilby G.W. 32 Kilgore J.L. 321 Kim B.H. 76 106 Kim C.K.66 Kim C.S. 208 Kim B.J. 66 Kim I.J. 250 262 Kim J. 135 Kim J.N. 160 Kim J.S. 135 266 Kim K. 141 Kim K.D. 149 Kim K.S. 76 Kim M. 171 Kim M.-J. 301 Kim S. 89,90 135 Kim S.H. 206 Kim S.W. 247 Kim S.Y. 100 Kim Y.,155 193 Kim Y.C. 135 Kim Y.H. 290 Kim Y.S. 247 Kirnarathasan R. 74 Kiminkinen L.K.M. 22 Kimowski A. 164 Kimnra M. 247 292 Kimura T. 171 236 Kimura Y. 314 Kin H. 273 Kinder J.D. 233 King F.L. 46 King G. 59 King P.M. 58 King R.M., 11 158 Kingsmill C.A. 21 Kingston J. 266 Kinny D. 27 Kinoshita T. 326 Kinsel G.R. 29 Kiplinger J.P. 34 Kirilenko A.G. 304 Kiriyama Y. 232 Kirpekar F. 37 Kirsch D. 41 Kirschner S.80 Kiryu T. 132 KiseIyov AS. 292 Kishi Y. 244 Kitagawa H. 159 Kitagawa T. 145 Kitamori Y. 172 Kitamura Y.,325 Kitigawa O. 119 Kiuchi F. 333 335 Klamer F.-G. 80 210 Klamt A. 61 KIatt M. 271 Kfeanthous C. 322 Ktein D.P.,248 Kleintop B.L. 49 Klempier N. 305 Kline D.N. 77 Klohr S.E. 318 Klots C.E. 26 Kluge H. 329 Kiunder A.J.H. 73 Knackmuss HA. 156 Knaggs A.R. 328 331 Knani M. 319 Knapp R. 266 Kriauer M. 107 Kniaz K. 25 Knight D.W. 188 193 307 Knight J. 90 Knight S.D. 208 269 Knobler C.B. 174 Knochel P. 106 113 f38 238 245 262,271 Knolker H.-J. 138 222 257 Kobatake Y.,242 Kobayashi H. 264 266 Kobayashi R. 57 Kobayashi S. 159 271 272 273,278 Kobayashi Y.,125 Kobbing S.136 Koch A. 25 Kochi J.K. 237 Kochling H.J. 42 Kock-van Dalen A.C. 304 Kobvsky P. 250 272 Kodama K. 183 Kodama M. 232 Kodera M. 335 336 Koertvelyesi T. 78 Kovtr K.E. 7 Koga C. 292 Koga K. 125 157 252 293 296 Koga N. 67 Kogai ?. 158 Kogut O.V. 304 KohIpaintner C.W.,106 Kohn W. 51 Kohnke F.H. 171 Koike N. 163 Koja K. LM,125 Kol M.,161 284 Kolb H.C. 119 284 285 Kolter T. 105 Komatsu K. 177 Komatsu N. 277 289 Komatsu Y. 95 Komiya N. 287 Kondakov D.Y. 117,243 Kondo K. 243 Kondo S. 286 Kondo T. 254 Kondo Y. 108,225 226 228 235 264 Author Index Konig B. 178 Konig W. 309 Konings R.N.H. 4 Konkoli Z.I48 Kono M. 30 Konopelski J.P.,141 Konovalov V.V. 168 Konshi Y.,45 Koot W.J. 254 Koprowski M. 225 Koreeda M.,80 171 Korn S.R. 295 Kornberg B.E. 79 Korning J. 171 Korsmeyer K.K. 42 Kosemura S. 321 Koskinen A.M.P. 276 Koskinen P.M. 276 Koster C. 43 44 Kostov G.K. 75 Kosugi M. 236 Kovacik V. 35 Kowakwski T. 18 Koyama K. 160 Koyuncu D. 155 193 Kozlova E.V. 304 Kounin A.S. 158 Kraebel C.M. 123 Krafft M.E. 140 220 Kraka E. 148 Krakowiak K.E. 105 214 Krasowski M. 57 Kratky C. 243 266 Kratz D. 106 149 Kraus G.A. 86 Krayushkin M.M. 160 Kren V. 309 Kress M.H. 244 Kreutzberg J. 259 Krishna A. 165 Krishnarnurthy D. 270 Krishnamurthy N.306 Krishnamurthy R. 81 Krishnamurthy V. 88 138 Krishnan B. 167 232 318 Kristainsen K. 37 Krogsgaard-Larsen P. 302 Krohn K. 141 Krow G.R. 107 Krowiak S.A. 203 Krstenansky J.L. 33 Krueger A.C. 74 213 Kriiger C. 107 262 Kruse C.G. 163,271 Krysan D.J. 153 241 Kubota H. 252 Kucera D.J. 239 Kuck D. 23 Kudaka I. 32 Kudo T. 283 Kuehne M.E. 208 Kiimmerlen J. 18 Kiindig E.P. 263 265 Kuhn N. 259 Author Index Kuichi F. 336 Kukhar V.P. 304 Kukolich S.G. 254 Kulik W. 23 Kulkarni D.G. 107 Kulkarni G.U. 25 Kulkami S.J. 159 Kumar B.S.A. 17 Kumar P. 290 Kurnashiro K.K. 148 Kumbhar P.S. I59 Kurnobayashi H. 282 Kundu N.G. 232,234 237 Kunec E.K. 310 Kunisada €I., 286 Kuno H.281 Kunz H.,106 Kuo,D.L. 251 Kurihara A. 94 279 Kurihara H. 291 Kurihara T. 215 Kurita J. 188 209 Kuroda C. 142 Kuroda T. 199 Kurono M. 46 Kurosawa H. 252 Kurth M.J. 304 Kurumatani S. 244 Kustanovich I. 14 Kusumoto N. I28 Kuthan J. 79 Kutney J.P. 311 Kuwajima I. 128 Kux U. 171 Kuzmicrkiewicz W. 160 Kuznikowski M. 225 KvarnstrGm I. 252 Kvasnicka V. 69 75 Kvita V. 200 Kwan T.K. 36 Kwast A. 204 Kwong H.-L. 119 285 Laasonen K. 56 Labiad B. 294 Labroue D. 265 Lacey M.P. 37,42 Ladd P. 69 Lage M. 174 Lai C. 169 Lai G. 159 Lai J.-S. 171 LaGIling K. 47 Laine R.A. 35 36 Lal G.S. 295 Lallemand J.Y. 79 Lallemant M.162 Lam K.S. 318 Lamb C.J- 322 Lamb J.H. 3a Lambalot R.H. 314 Lambert N. 31 Lambusta D. 302 Laming G.J. 57 Lammert S.A. 47 Lamont H.M. 330 Lamont R.B.,121 Lamothe S. 72 Lampard C. 82 Lampe E.-M. 259 Lamture J.B. 291 Last X. 165 191 Lanati S. 72 308 Landry C.J.T. 14 Landuyt L. 79 Lang H. 165 Lange C. 31 Langer F. 245 Lantos I. 199 Lappenbusch W.C. 137 Larcheveque M. 232 Larhed M. 227 Larock R.C. 222 227 237 249 Larsen B.S.,24 Laschat S. 262 Lassaletta J.-M. 295 Laswell W.L. 183 Laszlo P.,159 287 Latajka Z. 57 Latouche R. 294 Lattman E.E. 42 Laude D.A. Jr. 28 43 44,45 Laumann C. 105 Lautens M. 106 Lawrence J.G. 336 Lawrence N.115 277 Lawson A.M. 34 Lay J.O.,Jr. 37 Laycock M.V.,30 Layzeil T.P. 131 294 Leadbetter M.G. 29 Leary J.A. 34 Lebeau E. 202 Leblanc D. 22 Leblanc Y.,160 Lebrilla C.B. 35 Lecea B. 65 75 Leclaire M. 79 Le Corre M. 131 277 Lectka T. 278 Lee AS. 278 Lee B.S. 66 Lee B.Y. 220 221 246 Lee C. 52 57 86 169 190 Lee C.T. 53 Lee C.Y.,56 Lee D.C. 286 Lee E. 86 100 169 190 Lee G.-H. 254 256 Lee H. 171 Lee H.-C. 126 Lee I. 66 Lee IS. 301 Lee I.-S. 265 Lee N.H. 122 Lee P.H. 135 Lee,P.W.,30 Lee S. 108 336 Lee S.-G. 246 Lee S.-H. 140 Lee S.J. 221 Lee S.M. 246 Lee,S.S. 265 Lee S.W. 108 Lee Y.,333 Lee V.J. 287 Lee W.K. 188 Lee Y.K.,16 16 Leeper F.J.216 333 335 336 Lees W.J. 309 Leeson P.D. 190 LeFloch P. 208 Lehmann R. 106 L.e Hyaric M. 287 Leibfritz D. 11 Leigh D.A. 152 Leimbacher W.,31 Leistner E.W. 322 323 Lellouche J.-P., 256 Lemaire M. 281 Lemaire-Audoire S. 252 Lemal D.M. 78 LeMeillour S. 46 Lemeune S. 252 Lemmerz R. 176 Lemoine J. 35 Lempot K. 185 Lentz R.,138 Leong W. 249 Leresche J. 263 Lerman O. 158 Lerner R.A. 105 180 Lessmann K. 280 Levart M. 287 Levin J.I. 227 Levine B.H. 1 11 238 Lewis J.D. 216 333 Lewis N. 82 155 193 307 Lewis S. 42 Ley S.V. 188 235 291 Li C.-J. 106 250 Li C.M. 29 38 Li C.-S. 236 Li K.S. 86 169 Li L. 32 42 246 Li W. 156 Li W.-R.292 Li x. 24 Li X.H. 29 Li X.-Y. 160 Li Y. 44,63 71 Ilk 232 325 Li Z. 123 288 Li Z.-T. 95 169 Liang Y. 265 Liao C.L. 23 Liao Y.-H. 266 Liao Y.-L. 254 Licandro E. 263 Liebeskind L.S. 136 153 229 241 254 Light-Wahl K.J. 38 350 Lii F.-L. 325 Lilly M.D. 309 Lim D. 7f Lim J.A. 243 Lim K.M. 89 Lim S. 128,243 Limbach P.A. 44 Lin F.-T. 133 Lin G. 302 Lin H.Y., 28 Lin S. 291 Lin S.-H. 254 Lin W.-Y. 138 Lindbeck A.C. 128 Lindell S.D. 188 235 Linden A. 254 Lindh P. 35 Lindner H.J. 79 83 Lindner J. 29 Lindon J.C. 11 12 Lindstrom M. 293 Ling L. 300 Linnane P. 162 Linnert H.V. 146 Linstrumelle G. 167 232 233 234 Liotard D.A.57 Liotta D.C. 280 Liou C.C. 47 Lipniunas P.,35 Lippard S.J. 37 Lipshutz B.K 167,232 235 290 Liso F.-L. 236 Litrico A. 150 Liu D.H. 79 Liu HJ- 73 Liu L. 287 Liu Q.-Y. 108 Liu R.-S. 254 256 Liu S.-H. 302 Liu Y. 248 Liu Y.-C.,162 302 Liu Y.P.,67,68 79 Livinghouse T.,124 Llenes C.F. 29 Llera J.-M. 295 Lloyd M.D. 333 LO H.-C. 126 Loake G.L. 322 Lobo A.M. 180,288 Locke J.S.,74 Lofstrom C. 134 Lohray B.B.,285 287 Londry F.A. 48 Long T.E. 14 Longvialle P.,24 Loo J.A. 38 39 45 Look G.C. 105 299 Lbpez C.J. 284 Lopez R. 302 Lopez X.,65 Lorenzo MA. 196 Lothian A.P. 158 Loubser C. 266 Louey J.P. 243 Loupy A. 294 Lovey R.G.201 Lowe G. 31 Lowen G.T. 141 Lowis D.R. 58 Lu,D.H. 67,68 Lu,R. 57 Lu X. 118 220 237 240 Lu Y.-F. 141 Lubman D.M. 47 Lucas-Lokhorst G. 36 Lunning J. 290 Lugtenburg 171 Luheshi A.B.N. 76 Luibrand R.T. 108 Lukacs C.,310 Lumb K.J. 31 Luna E. 171 Luna H. 305 Lunazzi L. 147 LunelI S. 57 Luo C.W. 37 Luo w. 79 Luteyn J.N. 163 Luthra R. 320 Lutjens H.,113 Lutz G. 278 Luu B. 36 Lykke K.R. 26 Lynch G.C.,57,67 Lynch J.E. 183 Lynch S.V.,135 Lyngh G.C. 79 Lytle F.W. 26 Ma S. 76 220 237 290 Ma W. 30 Maas P.J.,204 McAdoo D.J. 22 McArdle P. 256 264 McCabe R.W. 266 McCague R.,300 McCallum J.S. 253 McCarIey T.D. 22 McCamck MA. 63 McCarthy J.R.295 McCauley J.P. 25 Macciantelli D. 147 McClain R.D. 32 McCloskey J.A. 37 McClure. K.F. 108,227 McCombie,S.W. i06 McCormack A.L. 47 McDaniel K.F. 259 McDaniel R.,317 McDonald C.E. 286 Macdonald C.J. 29 Macdonald F. 30 McRonaid F.E. 247 McDougaI P.G.. 141 McElvany S.W. 25 Author Index McEwen C.N. 26 McGarrity J.F. 300 McGarry P.F. 80 McGeady P. 319 McGibbon G.A. 21 23 McGlinchey M.J. 246 McGrane P.L. 124 McGrath K.J.,19 McGready P.,161 McGuigan P. 181 Machiguchi T. 65 72 Machinek R. 150 317 Maciel G.E. 13 McIlwaini D.B. 333 McIntosh A. 49 McIntyre C.R. 315 316 McIntyre L. 10 McIver R.T:,Jr. 44 McKay R.G. 26 MacKeith R.A. 300 McKennon M.J.157 283 McKervey M.A. 181 McKie J.A. 281 McKillop A. 155 163 193 McLafferty F.W. 45 McLaren L. 155 193 McLean D.B. 35 McLuckey S.A. 28 37 47,48 49 McMahon K. 168 McMillen H.A. 93 149 McMurray B.T. 305 McNab H. 86 211 McNally J.J. 79 80 McNeill AM. 127 McNelis E. 158 MacPherson A.D. 86 McQuire L. 208 McWherter C.A. 18 Macy T.S.,259 Madsen U. 302 Maeda K. 251 Maerk T.D. 27 Maes R.A.A. 38 Maestro M.C. 271 Maeta H. 117 Magnin D.R. 2% Magnus P. 208 Magriotis PA. 149 Mahajan J.R. 124 Maharaj V.J. 330 Mahr N. 24.4 Maier M.E. 124 Maier W.,214 Maiorana S. 262 263 Mair F.S. 125 296 Maisa W. 73 Maity G. 290 Majdoub M.,294 Majetich G.160 Majurndar A. 11 Majumdar T.K. 22 Mak C.C. 230 Makin H.L.J. 36 Author Index Makino T. 138 Makita K. 136 Mako M. 254 Makosza M. 164,206 Malbuk T.E. 169 Malenfant E. 271 Malik S.S. 156 MaIlart S. 250 Mallet M. 201 MaIm J. 229 Malone J.F. 305 MaIyszko J. 330 Mambu L. 232 Mamos P. 228 Manako K. I08 Mandelbaum A. 26 Mangeney P. 281 Manning H.W., 138 Mano S. 131 Manolache N.,151 Manoury E. 287 Manriquez J.M .,266 ManteIl S.J. 191 Mantle P.G. 330 Marcaccini S. 187 March R.E. 48 Marclti M. 237 Marcinow Z. 169 Marcos CF, 248 Marcos E.S. 60 Marcuzzi A. 254 Marder M. 162 Marek I. 135 138 245 Maresca L. 197 Margolin A.L.299 304 Marguet A. 328 Marinelli F. 226 233 237 Marko I.E. 141 Marko L. 221 Marlow G.E.,58 Marques C.A. 198 Marquis R.W., Jr. 208 Marr J.C. 30 Marrs C.M. 252 Marsais F. 201 229 Marsh A. 141 Marshall A.G. 43,44 Marshall D.R. 167 232 Marshall J.A. 190 Marson C.M. 179 Martens J, 271 280 Martin A, 141 Martin A.R. 232 Martin C.J. 114 253 271 Martin D. i92 Martin E. 141 Martin N. 183 Martin P. 200 Martin R. 323 Martin S.A. 32 Martin T. 38 Martin Cabrejas L.M. 271 Martin-Cantelejo Y. 186 Martinez J.P. 141 Martinez LA. 286 Martoreli G. 108 Martynow J. 141 Maruoka E. 196 Maruoka K.,132,278 Maruyama A. 266 Maruyama K. 270 Maruyama T,,250 MaryanotT C.A.75 196 Mascaretti O.A. 107 291 Mashirna K. 282 Masson S. 165 Masters J.I. 230 247 Mastrorilli E. 304 Masuda H. 57 Masuda K. 244 Mata E.G. 107 291 Mataka S. 177 Matha V. 331 Mathew L. 291 Mathews C.K. 26 Mathews D.P. 295 Mathey F.,208 Mathis J.R. 66 Mathre D.J. 280 Matsui S. 165 Matsukawa S. 77,I27 Matsuki K. 130 Matsumoto J.-I. 175 Matsumoto K. 128 186 Matsumoto R. 314 Matsumoto S. 235 Matsumura S. 149 Matsunaga K. 321 Matsunaga S. 277 Matsuo T. 39 220 Matsushita H. 281 Matsuura T. 243 Matsuzaki K. 316 Matthias C. 23 Mattson M.,134 Matusik J.E, 29 Maxwell C.A. 322 May M.A. 43 Maye J.P. 243 Mayer F. 28 Mayer H.K. 35 Mayer M.313 314 328 Mayo J.E.,21 I Mayr H. 257 Mazzieri M.R.. 254 Mebane R.C. 193 Medebielle H.,163 Medici A. 307 Meerholz K. 178 Meffre P.,286 Mehler T. 271 Mehta G. 170 Meinhardt K,P. 79 Melikyan G.G. I06 MeIis S. 165 Mella M. 168 Mello R.,182 Mellon C. 271 351 Mellon F.A. 30 Melnyk P. 108 207 226 Mendez N.Q. 248 Mereyala H.B. 290 Medic C.A. 152 Merlini L. 316 Merritt A. 208 Merritt K.D.,333 Merz K.M.,58 145 Merzouk A. 252,290 Meske M. 137 Messmer R.P.,145 Meth-Cohn O. 204 305 Metzenthin T. 57 Metzger J.W. 29 Metzler MA. 267 Meyer C. 138 Meyer S.D. 105 269 Meyers A.I. 156 157 167 188 283 Mi A.Q. 73 Michael J.P. 106 108 226 Michael S.M.47 Michel H. 31 Michoud C. 141 230 Middlemiss D. 223 Middleton S. 138 Mieglo A. 75 Miehlich B. 52 Miertus S. 59 Migita T. 236 Mihn B.J. 76 Mijoule C. 57 Mikami K. 77 127 128 Milan S. 75 Miller J.A. 295 Miller J.M. 25 Miller S.C. 295 Miller S.J. 278 Miller W.H. 244 Milliet A. 22 Milne D. 125 296 Miiot G. 188 Milstein D. 224 227 Milzer J. 270 Min C. 333 335 Minabe M. 171 Minami T. 11I 241 Minami Y. 102 I50 Minamikawa J.-I. 158 Minato T. 65 72 Minghetti A. 330 Mink J. 57 Min-Min G. 138,236 Minowa N. 105 231,259 Mirza U.A. 39 Mirzaei Y.R.,188 Mischitz M. 305 Mishina F. 171 Misiti D. 147 197 Mitamura S. 159 Mitarai A. 169 Mitcheil M.B.193 Mitchell R.H. 273 352 Mitsudo T.-a. 254 Miura. H. 326 Miura M. 158,235 Miura T. 295 Miyamoto H. 293 Miyano S. 163 Miyashi T. 78 Miyashita A. 282 Miyashita M.,132 Miyata H. 321 Miyaura M. 235 Miyaura N. 141 153,232 Miyazawa A. 175 Mizuno K. 168 Mizuno Y.,149 Mocek U. 324 326 329,331 Moller U. 290 Moffre P. 121 Mohan V. 58 Mohr B.J. 238 Moise C. 254 MoIander G.A. 128 281 Molenaar-Langeveld,T.A. 24 MoIina A. 232 Molina P. 196 206 MoIitor K.D. 322 Moiler M. 174 Mornose T. 301 Monderhack D. 182 Mongomery D. 134 Moniz de Sa M. 322 Monnig C.A. 42 Mons El.-E. 4 8 Monstel R.F. 141 Montagnani R. 61 Montanan F. 198 Montanan S.162 Montaufier M.-T. 287 Moore A.J. 266 Moore B.S. 324 328 Moore H.W. 153 Moore 3.A. 327 Moore J.S. 108 Moore R.E. 314 328 Moorlag M. 167 Morand K.L. 47,48,49 Moreau J.J.E. 227 Moreno-Manas M. 199 Moret E. 106 Moret M. 254 262 Morey J. 156 Morgan J. 47 Mori M. 243 Mori T. 126 158 Mori Y. 145 Moriarty R.M. 135 Moriguchi S. 224 Moriguchi T. 177 Morikawa K. 284 Morimoto T.,252,302 Morinaga Y.,95 Morisaki M. 318 Morita N. 257 Moritani M. 141 Moriya M.,301 Morizur J.P. 24 Moman R.J. 78 Morodome M. 127 270 Morokuma K.,67 M~rris,J. 332 Morns K.F. 5 Morris K.G.,151 222 Morrow G.W. 155 Morrow J.C. 23 Morton T.H. 22 24 Morwick T.138 Morzherin Y.,190 Mosandl T. 146 Mosher M.D. 247 Moskowitz N. 81 Mosleh A. 244 Moss J.R. 266 Motallebi S. 264 Motoki K. 138 Motoki Y. 138 Motoyama I. 266 Moulines F. 266 Mouloud H.A.H. 287 Mourad A.-F.E. 176 Mousdale D. 332 Mowbray C.E. 92 Mowrey C.D. 41 Mowrey R.C. 25 Moyake R. 264 Moyano A. 132 Muchowski J.M. 165 Muci A.R. 130 281 293 Mueller C. 8 Muller D.G. 312 Muller K.-H. 257 Mueller L. 7 Mueller M.D. 30 MueUer M.J. 330 Miiller P. 264 Miiller U. 246 MueHer-Westerhoff,U.T. 273 Muenster B. 39 Muhammad F. 115,277 Mukai C. 245 260 262 Mukaiyama T. 159 287 Mukata T.,250 Mulder P.P.J. 171 MuIheim C. 31 Munasinghe V.R.N. 182 Munoz B.304 Muiioz S. 291 Munson M.S.B. 28 Muraglia E. 95 193 Murahashi S.-i. 119 250,254 286,287 Murai S. 128 153 218 250 Murakami M. 122 235 Murakami N. 302 Murakami Y. 224 Murase N. 132 278 Murashima T. 158 Author Index Murata K. 32 Murayama K. 106 Murphree S.S. 77 Murphy C.K. 295 Murphy J.A. 82 103 104 Murphy M.M.,238 Murphy P.J. 125 296 Murphy R.C. 36 Murray C.W. 53 57 Murray J.S. 57 Musco A. 249 MusseIman B.D. 34 39 Musser S.M. 37 Mussmann L. 287 Mutter M.,42 Muzart J. 107,286,290 Myers A.G. 128 149 Mynett D.M. 291 Nabela K. 319 Nadelman N.S. 162 Naemura K. 175 178 Nagai K. 35 Nagai T. 187 Nagata T. 42 Nagatsu A. 302 Nagra D.S.32 Nagy P.I. 58 Naidu B.N. 204 N’Ait Adou A. 286 Naito M. 128 Nakada M. 149 Nakadaira Y. 254 Nakafuku K. 172 174 Nakagawa A. 326 Nakagawa M. 141 Nakai T.,127 Nakajima H. 314 Nakajima M. 252 Nakamura D. 292 Nakamura H. 122 235 Nakamura K. 108 Nakamura N. 83 Nakamura T. 128 149 Nakanishi J. 250 Nakanishi K. I68 Nakanishi Y.,281 Nakashima H. 266 Nakata M. 149 Nakatani H. 83 Nakatani K. 141 233 Nakayama H. 318 Nakayama K. 264 Nakazawa M.,66 Nallin-Omstead M. 315 Namchuk M. 29 Nandi M. 263 Naota T. 286 287 Napolov D.V. 60 Narasaka K. 116 276 Narasimhan T.S.L. 26 Narayana M. 13 Narto S. 46 Author Index Naruta Y. 106 270 Nasaka N.235 Nash J.J. 146 Nasini G. 314 Natale N.R. 188 Natile G. 197 Nayak S.K.,290 Naylor A. 277 Naylor S. 30 Ndibwami A. 72 Nedelec J.Y. 167 235 Needham J. 313 Neeleman E. 286 Negishi E.-i. 117 154 219 235 243 244 Negri J.T. 138 Neidlein R. I71 Neil D.A. 223 Neiid G.H. 12 Nelson C.C. 37 38 Nelson J.A. 295 Nelson R.W. 29 37 40 Nelson S.G. 130 281 Nelson T.P. 167 Nestler B. 122 Nestor N.B. 284 Neto C.C. 265 Neuheiser F. 31 Neumann W.P. 159,280 Neunhoeffer H. 201 Ng C.Y.,23 57 Nguyen B.V. 232 Nguyen J.T. 254 Nguyen M.T. 24 79 Nguyen S.T. 117 Nguyen T. 58 331 Nguyen V. 24 Ni Z. I37 Nibbering N.M.M. 24,66 Nice L.E. 286 Nicholas J.B. 57 Nicholas K.M.245 253 Nichols M.A. 108 Nicholson J.K. 12 Nicholson L.W. 294 Nicholson N.H. 332 Nickel S. 271 Nickisch K. 112 Niclas H.-J. 291 Nicolaides A. 146 NicoIaou K.C. 105 149 231 Nicolosi G. 302 Nieder M. 30 Nteger M. 176 Nielsen B. 302 Niessen W.M.A. 35 36 Nigawara Y. 251 Nijssen W.P.M. 69 Nikolski M. 246 Nilsson B. 35 Nilsson M. I12 Nilsson Y.I.M. 249 Nishida A. 158 Nishida H. 316 Nishide K. 292 Nishigaichi Y. 106 270 Nishiguchi H. 160 Nishiguchi I. 156 Nishijima K.-i. 235 Nishikawa Y. I38 Nishima S. 326 Nishimura A. 11 1 238 Nishimura H. 242 Nishimura K. 172 Nishimura R. 171 Nishino A. 301 Nishino E. 251 Nishio K. 271 273 Nishiyama H.282 Nitta M. 172 Niyazymbetov M.E. 106 Njamela O.L. 203 NobeI D. 143 Noda K. 288 Noda Y. 235 Node M.,292 Noe M.C. 119 121,285 Noe R. 262 Noguchi H. 295 320 Nohira H. 282 Nohmi T. 28 Nomura M. 158,235 Nonhebel D.C. 169 Nordhaus P. 237 NordhotT E. 37,42 Normant J.-F. 135 138 245 Norrby P.-O. 249 Norris D.J. 254 North M. 271 309 Nourbakhsh S. 23 Nourooz-Zadeh J. 304 Nourse 3.D. 49 Novak M. 155 Novi M. 163 Noyori R. 270 Nozaki K. 131 Nuber B. 218 267 Nucci L. 155 Nugent H.M. 266 Nugent W.A. 131 Nukui S. 113 243 Nusair M. 53 Nuss J.M. 111 238 Nuyken O. 168 Oak O.Z. 156 Oba S. 254 Oberlies N. 155 Obora Y.,235 240 O’CaIlaghan N.M.332 O’Connor S.J. 239 Oda H. 235 Oda M. 292 Oda Y.,287 Odagaki Y. 141 OeIckers B. 266 O’FerralI R.A.M. 148 Ogasawara K. 213 301 Ogata M. 292 Ogawa A. 94 101 128 Ogawa S. 251 Ogawa T. 302 Ugbu C.O.,74 Ogden M. 266 Ogino Y. 284 Ogoshi S. 250 Oguntimein G.B. 302 Ogura K. 108 O’Hagan D. 300 311,331 O’Hara K. 30 Ohara Y. 111 241 Ohashi A. 149 Ohe K. 250 Oh-e T. 232 Ohga Y.,132 Ohira M. 285 Ohira S. 141 Ohkita H. 244 Ohkohchi M. 26 Ohnishi M. 136 Ohnishi Y. 142 Ohno T. 156 Ohno Y. 271 Ohsaku M. 67 Ohshima T. 243 Ohsuka A. 252 Ohta H. 209 Ohta K. 149 Ohta S. I88 Obta Y. 116 276 302 Ohtani I. 328 Ohtsuka A. 149 Ohuchi K.215 Oishi M. 132 196 Oishi S. 125 Oishi T. 121 307 Ojima J. 172 174 Okarnoto A. 158 Okarnoto S. 118 284 Okamura K. 108 141 273 Okazaki M. 83 Okuda S. 316 Okumoto H. 111 183 238 Okuyama H. 319 Olah G.A. 107 160 Oliver P.A. 291 Oliveros E. 293 Olivo H.F. 300 Olivucci M. 66 67 75 145 Olson E.R. 147 Olsson T. I12 O’Malley R.M., 29 Omura A. 158 Ornura S. 316 326 Ong C.W. 258 Ono N. 118 Opdenbusch K. 111 Opella S.J.,17 Oppolzer W. 249 Ori A. 75 Oriyama T. 292 Orlando R. 46,47 OrIinkov A. I59 Orozco M.,58 Orr J. 322 Osaki H. 215 Osamura Y.,108 Osella D. 246 Oshima K. 186 Oshio A. 128 Osman R. 62 108 Osterhout M.H. 130 Ostrowski S.164 Ostwald R.,I13 Ota T. 302 Otani T. 102 150 Otera J. 299 Otsuji V. 168 Ott W.R. 314 Otte A.R. 134 248 Otto C. 278 Otto H.-H. 185 302 Ottow E. 270 Oturan MA. 163 Ourison G. 319 Overberg A. 42 Overman L.E. 208 226 239 243 269 Owen D.A. 258 Owen T.I. 33 Ozaki M, 156 Ozaki S. 300 333 Ozawa F. 242 Ozlu Y. 93 Pace P. 226 Padwa A. 77 137 150 Paillaud J.L. 148 Pairaudeau G. 208 Pais M. 31 Paiva N.L. 322 Pal M. 234 237 Palacios S.M., 162 Pale P. 111 Paley R.S. 232 Palin M.G. 264 Palmer C.F. 300 Palmer I.J. 57 145 Palmer K.W. 78 Palmer R.T. 263 Palmieri G. 197 Palomo C. 65 75 Palovich M.,86 Palurnbo G. 164 Pan Y.,40 Panaye A.69 Pandey B. 142 290 Pandey G. 165 Panetta C.A. 164 Pang Z. 320 Pannecouke X.,36 Pannek J.B. 257 Papagni A. 263 Papai I. 57 Papayannopoulos €. 34 Papousek D. 57 Pappalardo R.R.,60,61 75 Paquette LA. 138 Paradisi C. 47 48 162 Paraudeau G. 269 Parchment O.G. 59 Pardo L. 62 108 Paris A. 24 Paris M.F. 171 Park C.M. 190 Park J. 284 Park J.-S. 336 Park K,B. 289 Park M.A. 28 Park S.-B. 128 282 Park W.M. 76 Park Y.C. 100 Parkanji L. 185 Parker A.R. 327 Parker C.E. 30 Parker D.H. 26 Parkinson J.A. 12 ParIier A. 223 Parmar V.S. 302 Parodi F.J. 313 Pam G.R. 42 Parr J. 282 Parr R.G.,51 52 Parrain J.-L. 240 Parrinello M. 56 Parry D.E.266 Parry R.J. 325 Parsons E.J. 217 Parsans P.J. 93 277 Parvez M. 123 Pascualahuir J.L. 60 Pasto D.J. 74 Pastor A. 206 Fatel U.R.,21 1 Paterson I. 66 180 276 Pati H.N. 302 Patil V. 275 Patiiio R. 286 Pattenden G. 90,92 106,230 Patti A. 302 Patzelt. H. 313 Pauson P.L. 220 Pavlova S.D. 75 Payne A.N. 290 Payne G. 48 Pearson A.J. 106,256,257 Pearson W.H. 128 Pedder R.E. 48 Pedersen M.J. 38 Pedragosa-Moreau S. 305 Pedrini P. 307 Pedro J.R. 291 Pedrosa R.,271 Peeran M. 72 Peersen O.B. 14 Pegg N.A. 108 227 Pegg S.J. 324 Author Index Pellissier H. 138 Pellon P. 131 277 Pelter A. 155 Peltier J.M., 35 Penco S, 237 Peng S.-M. 254 256 Peng T.-S.248 Peng Z. 58 Percas M.A. 132 Pereira I.A.C. 332 Pereira M.M. 180 288 Perellino N.C. 330 Perez A.J. 162 Perez C. 302 Pirez-Encabo A. 263 Pergola F. 155 Periasarny M. 155 Perichon J. 167 235 Perkins J.R. 30 Perrio S.,78 263 Perrone E. 185 Peschke M.,47 Petasis N.A. 244 Petersen P.M.,216 333 Petersen T.H.,78 Peterson M.J.,273 291 Peterson P.E. 264 Petit A. 294 Petitou M. 105 Petrillo G. 163 Petrusiewicz K.M., 225 Pettitt B.M. 58 Pews R.G. 158 Pfaltz A. 106 114 198 253 271 272 Heifer K.H. 145 Pfenning D.R. 168 Masterer G. 218 Pflug T. 237 Phan L.T. 219 Phan T.N. 23 Philippides A. 2I6 333 Phythian S.J. 153 Piattelli M. 302 Piazza M.G.270 Pickering J. 179 Piers E. 11I Pietra F. 155 Pietruszka J. 235 Pindur U. 278 Pine S.H. 117 269 Pinel. C. 281 Fines A. 16 Pinkston J.D. 49 Pinson J. 163 Pipeng Y.,146 Pirrung M.C. 306 Piscopio A.D. 105,231 269 Pitsinos E.N. 149 Plant D. 11 Plaquevent J.-C. 117 277 Plater M.J. 170 Platzer I?. 135 Plaziak A.S. 37 Authar Index Ple N. 200 201 Pleasance S. 30 Pleixats R. 199 Plummer B.F. 171 PIzak K.J. 125 Poch M. 132 Pochapsky S. 11 Poirot P. 206 Poitier P. 138 Poli S. 307 Poliakoff M. 217 Politzer P. 57 Pommier A. 107 Ponec R. 71 Pons J.-M. 107 Pontellini R. 249 Pook L.M. 81 POOR D.J. 243 Pople J.A. 53 Portnoy M.224 227 Pospical J. 69 75 Postel M. 288 Postema M.H.D. 142 Poufter C.D. 320 Poulter G.T. 108 Powers R. 11 Powers T.S. 73 Prabhakar S. 180 288 Prabhakaran P.C. 314 Pradeep T. 25 Prakash G.K.S. 160 Prakash S. 160 Pramanik B.N. 39 Pramatorova V. 308 Prasad A.K. 302 Prein M. 158 Prescott M.C. 36 Press J.B. 79 80 Prestegard J.H. 11 Preston P.N. 287 Preuss H. 52 Price K.R. 30 Price N.C. 322 Prieba G. 310 Prime J.C. 267 Prins T.J. 302 Proudfoot G. 324 Proudfoot J.R. 21 1 Prout K. 267 Prusiner S.B. 31 Puertas S. 304 Punniyamurthy T, 287 Puranik D.B. 259 Purdon M. 42 PYUR, H.-J. 319 Quallich G.J. 130 280 Queguiner G. 200 201 229 Quijano L.313 Quilliam M.A. 30 Quinkert G. 108 Quinn J.P. 45 Quintard J.P. 240 Raabe G. 136 271 Rabideau P.W. 169 Rabinovitz M. 156 Rabinowitz J. 108 Rabinowitz J.R. 62 Radanovich L.J. 263 Rader J. 241 Radford S.E. 31 Ragazos IN. 66 67 145 Ragg E. 316 Rahman N.A. I86 Raithby P.R. 125 246 296 Rajapohal D. 113 Ram B. 283 Rama M. 256 Ramaiah P. 160 Ramamoorthy P.S. 97 Rama Rao A.V. 159 Ramdani M. 294 Ramesar N. 203 Ramkumar D. 289 Ramon D.J. 167 Ramsden C.A. 158 Ramsey M.J. 48 Ramsey U.P. 325 Rancourt J. 97 129 Rane A.M. 120 191 284 Rangappa K.S. 155 Ranu B.C. 294 Rao B.R. 283 Rao C.N.R. 25 Rao D. 24 Rao P.R.V. 26 Rao R. 158 295 Rao S.N.148 Raphael R.A. 202 Rappe C. 30 Rapta P. 168 Rashid M.A. 111 238 Raskin I. 323 Rassat A. 57 Rastelli A. 75 Rastogi V.K.,3 Ratanunga T.D. 23 Rathke E. 35 RatoveIomanana V.,167,235 Ratoveiomanana-Vidal V.,281 Rau D. 257 Rauchschwalbe G. 106 Rauhut G. 51 Rautenstrauch V.,293 Rauth T. 27 Ravikumar K. 170 Ravi Kumar K.S. 294 Ravinovitz M. 178 Rawai V.H. 88 91 138 141 230 Raymo F.M., 171 Reagan A.C. 224 Reamer R.A. 183 280 Reau R. 187 Rebiere F. 266 Rebolledo F. 304 Reddy G.S. 30 Reddy J.P. 130 Reddy M.M.,287 Reddy R.S. 290 Redhouse A.D. 75 Reese W.G. 171 Reetz M.T. 106 125 127 Reeves W.P. 158 Regan A.C. 197 Reguero M. 61 75 Rehahn M.266 Reich H.J. 107 128 141 269 Reich I.L. 141 Reichling J. 323 Reimann C.T. 41. Reimes U. 73 Rein T. 116 275 Reinhold T.L. 106 Reinhoudt D.N. 105 190 Reinold S. 322 Reis L.V. 180 288 Reisch J. 237 Reiser O. 178 242 253 Reissig H.-U. 18I Reitsam K. 107 Reitz O. 106 Rempel D.L. 22,43 Ren H. 7 Rennels R.A. 111,238 Resck I.S. 124 Resnati G. 107 295 Restituyo J.A. 183 Reszka KJ. 168 Rettie AX 128 Reusch W. 36 Rexroth A. 8 Reynolds C.A. 58 59 69 Reynolds J.H. 148 Reynolds K. 134 324 Rhw H. 261 Rhee Y.H. 100 Rheingold A.L. 138 150 269278 Riant 0.. 266 Ricard L. 208 266 Ricca D.J. 239 Ricca T.L. 44 Rice J.E. 227 Richards W.G. 58 59 69 Richter N.125 Riddell F.G. 18 Riddoch A. 46 Ridge D.P. 28 Ridiehuber R.W. 162 Riedel M. 242 Rieger D.L. 111 232 Rielly M.D. 79 Riera A. 132 Riesinger S.W. 229 Rigby J.H. 74 106 213 263 Righetti P.P. 72 78 Riley T.A. 37 Rinaldi D. 60 Rink H.,42 Ripoll J.-L. 107 Risbridger G.D. 332 Ritter K. 106 167 Riva R. 227 Rivail J.L. 60 Rivero I.A. 295 Riveros J.M. 146 Robb M.A. 61 66,67 75 145 Robert A. 77 Roberts S.M. 105 300 306 Roberts W.M. 152 Robins DJ. 326 327 Robinson C. 332 Robinson J.A. 313 Robinson R.A. 290 Robison T.W. 266 Rocca P. 201 229 Rockwood A.L. 28 39 Rodewald U. 174 Rodriguez J. 119 Rodriguez R. 271 Rodriguez-Lopez J.186 Roehrig MA. 254 Roell B.C. Jr. 259 Roepstorff O. 27 37 Roessner C.A. 333 335 Rogers D.H. I28 Rogerson M. 18 Rohmer M. 319 Rohr J. 311 317 Roitman E. 321 Rolfe J. 44 Roman,E. 266 Romanens P. 263 Romanow W.J. 25 Romberger M.L. 133 Romero R.H. 220 Romero S.H. 140 Romesberg F.E. 125 296 Romo D. 105 Romo L.K. 34 Rornon D. 269 Roof M.B. 290 Roper,T.D. 219 Rosankiewicz J.R. 34 Rosch N. 51 Rosen A. 57 Rosenberg F.E. 108 Rosenberg R. 35 Rosenblum M. 266 Roskamp E.J. 183 292 Ross C.W. 111 44 Ross M.M. 25 Ross P.L. 23 Rossi R.A. 162 235 Rossiter J. 324 Rost B.,70 Roth C.P. 167 232 290 Roth J.R. 336 Roth K.-D. 246 Rouden J. 305 Rouillard L.27f Rousseau G. 300 Rouvray D.H. 69 Row,T.N. 25 Roxburgh C.J. 144 209 Roy S.C. 290 Royer A.C. 193 Rozema M.J. I f 3 245 Rozen S. 158 161 286 Rubetlo A. 148 Rubenfield M. 336 Rubino F.M. 29 Rubio A. I18 Rudewicz P. 46 Rudler H. 223 Ruechardt C. 78 Riick K. 106 Ruel R. 244 Ruf S. 185 Ruiz-Lopez M.F. 60 Ruiz-Montes J. 249 Runsink J. 141 Ruscic B. 23 25 Russel R.G. 318 Russell A.T. 276 Ryan W.J. 264 Rybakova A.V. 304 Ryu E.K. 160 Ryu I. 94 101 128 129 279 Ryu S.I.,45 Rzepa H.S. 61 75 Saa J.M. 108 156 Sabat M. 142 Saberi S.P. 151 222 266 Sabol J.S. 295 Sacki M. 150 Sadakane M. 183 Sadler I.H. 12 211 Saeki M. 102 Saeki N. 247 Saha M.156 294 Saha-Moller C.R. 309 Sahrn H. 319 Saigo K. 159 Saiki S. 175 Saimoto H. 149 Sainsbury M. 107 Saint-Clair J.-F. I65 Saito K. 74 Saito T.,128 Saito Y. 26 Sakaguchi K. 31 Sakai H. 266 Sakai K. 106 138 Sakai N. 131 Sakaki J.-i. 282 Sakakibara J. 302 Sakamoto T. 108 225 226 228 235 Sakamoto Y. 66 215 Saksena A.K. 201 Sakuda S.-i. 128 Sakuma K. 125,296 Sakurai T. 39 Saiahub D.R. 57 Salrnan S.R. 11 Author Index Salomon C.J. 107 291 Salter M. 151 Salter M.M. 248 Salter M.W. 222 Salvador J.M. 300 Salvino J.M. 296 Saizner U. 108 Samuel O.,266 Sarnuelsson RE. 46 252 Sanckau J.-Y. 12i 286 Sandanayaka V.P. 263 Sander C. 70 Sanders J.C.P.57 Sanders M. 324 Sanderson P.N. 11 Sandford G. 295 Sanfilippo C. 302 Sangwan R.S. 320 Sankararaman S. 289 291 Sankawa U. 320 Sannicolo F. 194 Sano H. 266 Sano S. 336 Santander P.J. 333 SantanieUo E. 299 Santelli M. 138 Santelli-Rouvier C. 249 Santhakumar V. 240 Santhi P.L. 290 Santiago J. 266 Santos P.P.O. 180 288 Sanz-Cervera J.F. 331 Sappa E. 221 Saquat M. 165 Sarakinos G. 279 Sarkar A. 263 283 Sarrazin L. 246 Sarshar S. 119 285 Sasai H. 108 114 128,243 273 Sasaki H. 287 Sasaki K. 169 Sathe K.M. 263 Sato F. 118,251,284 Sato FI. 26 Sato K. 108 Sato M. 162 266 Sato T. 83 183 Satoh J.Y. I42 Satoh S. 153 Satoh T. 158 235 Sattlet I.330 Sauer J. 65 12 Sauerwein M. 326 Saulnier M.G. 200 Saunders A.C.G. 69 Saunders J.K. f41 Saunders J.K.M. 105 Sauvage J.-P.,230 Saveant J.-M. 163 Savignac M. 252 Savin A. 52 Sawada M. 23 Scaiano J.C. 80 148 Author Index Schaaf P.M.M. 322 Schack CJ. 57 Schaefer H.F. 111 80 Schaefer J. 18 Schafer M. 244 SchaeKer M.J. 118 Schaer M. 42 Schaller T. 14 Schelder D.J.A. 283 Scherer H.J. 141 Scheuer P.J.,311 Scheuplein S.W. 111 150 233 Schieitz D. 37 Schimpf R.,210 226 Schimpff D.G. 254 Schink H.E. 252 Schioett B.,80 Schirmeister T. 302 Schleyer P.von R. 108 Schlingloff,G. 286 Schlogl K.,266 Schlosser M. 106 115 165 275 Schmalz H.-G.259 Schmid R.D. 302 Schmidt A. 18 Schmidt I. 23 Schmidt T. 252 Schmidt W. 157 Schmittberger T. 301 Schmittel M. 73 Schnatter W.F.K. 151 Schneider B. 330 Schneider C. 70 Schneier A. 29 Schnell A. 28 Schoellkopf K. 270 Schoenewolf M. 317 Schoenmakers P.J. 69 Schijttler M. 311 Schofield C.J. 332 333 SchoIs H.A. 35 36 Schteier P. 309 Schrell A. 310 Schreurs J. 33 Schrieber SL. 105 269 Schrimpf M.R. 273 SchrobiIgen G.J. 57 Schroeder D. 22 27 Schuchardt U. 106 Schulman J.M. 146 Schultz A.G. I02 Schultz M. 323 Schultz P.A. 146 Schultz P.G. 105 Schulz D.J. 90 Schumann G. 317 Schuster M.,304 Schuurmann G. 61 Schwab J.M. 327 Schwalbe H. 8 Schwarm M.283 Schwartz B.L.,32 Schwartz H. 107 Schwartz J.C. 48 Schwarz H. 22 23 27 Schwarz M. 31I Schwarzhans K.E. 27 Schweikert E.A. 28 Schweikhard L. 43 Schweizer W.B. 282 Scbwenkreis T. 287 Schwiebert K.E. 248 Scopes,D.I.C. 247 Scorrano G. 162 Scott A.I. 107 214 333 335 Scott I.L. 140 220 Scott L.T. 145 196 Scrocco E. 59 Searle P.A. 107 Seaton N. 324 Sebald A. 14 18 Sebek P. 79 Sedmera P. 79 331 Seebach D. 188,282 Seely F.L. 81 Sehata M. 138 Sehra M. 198 Seibt W. 41 Seitz G. 73 Sekiguchi S. 162 Selig H. 25 Selivanov B.A. 168 Selzle H.L. 23 Sernenov V.V. 292 Serninario J.M. 57 Semmelhack M.F. 261 262 Semones,M.A. 1% Sengupta S. 166 240 Senko M.W.45 Seo S. 320 Seres P. 141 Servi S. 308 Seto H. 320 Setti E.L. 162 Seviiir N. 31 Sewell T.J. 333 Seyler J.W. 248 Shabanowitz J. 31 Shackieton C. 321 ShackIeton C.H.L. 30 Shalaby M.L. 30 Shan C.-K., 138 Shaozu W. 266 Share A.C. 307 Sharghi H. 159 Sharma N.D. 305 Sharma N.K. 302 Sharma P.K. 171 Sharma S. 252 Sharma S.K. 302 Sharp K. 57 Sharpless K.B. 119 284 285 Shaw A.W. 286 Sheil M.M. 32 Sheldon R.A. 286 284 304 Sheldrake G.N. 305 Shen B. 318 Shen C.-Y. 138 Shen G.J. 309 Shen T.Y. 197 Shen W. 88,93 Shenggang Y. 240 Sherbine J.P.,133 Sheu B.-A, 255 Shedin C.G. I80 Shi Y.,138 219 238 Shi Y.-J. 280 Shiau C.-Y. 332 Shibasaki H.30 Shibasaki M. 108 113 114 128 168 243 273 281 Shibata O. 250 254 Shibata T. 284 Shibayama K. 149 Shida Y. 30 Shidori K.,224 Shieh WX. 121 Shiel M.M. 46 Shigekuni M. 175 Shigiwara A, 74 Shihua W. 240 Shim J.H. 319 Shimizu I. 250 Shirnomura K. 326 Shin H.S. 206 Shin W. 265 Shindo M. 157 Shinhama K. 158 Shinkai I. 183 280 Shinkai S. 105 Shinohara H. 26 Shioiri T. 106 230 295 Shiraki T. 150 Shiratori S. 209 Shiro M. 264 Shirori T. 202 Shishkina I.P. 304 Shizuma M. 23 Shon Y S. 282 Shook C.A. 133 Short K.M.,74 263 Shreeve J.L. 12 Shtah S.R. 170 Shteingarts V.D. 168 Shui X. 199 Shushan B. 29 Siangouri-Feulner I. 71 Sibille S.167 235 Sicking W. 65 Sidduri A. 245 Sieburth S.McN. I65 Siedem C.S. 154 Siegbahn K. 41 Siegel J.S. 146 147 149 Siegel M.G. 215 Siegmann K. 147 Siegmund E. 49 Siehl D.L. 322 Sierra M.A. 184 Siesei D.A. 232 Sieskind O. 159 Sih C.J. 303 304 358 Author index Silla E.,60 Silverman L.S. 333 Simard M.,108 Simion C. 205 Sirnrns J.R. 49 Simon V. 69 S~ORE~, J. 171 Simonin I?. 319 Sirnonsen S.H. 135 Simpkins N.S. 84 125 138 Simpson E.S.C. 287 Simpson T.J. 315 316 Singaram B. 130 282 294 Singer M. 283 Singer R.D. 106,271 Singh B.K. 322 Singh G. 162 287 Singh-Sangwan N. 320 Singleton D.A. 94 141 Singleton T. 262 Sinigaglia M. 307 Sirisoma U.N. 278 Sirois M.22 Sirani A. 254 Sivaraman N. 26 Sjogren M.P.T. 249 Skabara P.J. 266 Skelton 3.W. 271 Skibsted J. 13 Sklenak S. 69.75 Slawin A.M.Z. 151,248 253 Smaill J.B. 180 276 Smalley R.K.,76 Smallridge A.J. 309 Smith A.B. ll1 25 Smith A.L. 149 Smith B.J. 54 Smith D.A. 58 65 Smith D.M.,77 Smith D.R. 147 Smith L.M. 42 Smith R.D. 37 38 39 45 Smith R.W. 35 Smith S.O. 14 Smits J.R.M. 69 Smyth M.S. 102 Snaith R. 125 296 Snatzke G. 308 Sneden A.T. 105 Snijrnan P.W.,153 SO S.-S.,69 Soai K.,128,271 Sobey W.J. 332 Sobukawa M.,125 Sodano G. 311 Sodeoka M. 113 114 168,243 Soderquist J.A. 120 191,284 Sokolov V. 266 Soldenko V.A. 304 Sole D. 102 Solladie G. 118 Soloshonok V.A. 304 Somanathan R.,295 Somogyi A, 47 Son J.C.191 Sonada K. 128 Sonawane H.R.,I07 Sonderholm L. 26 Sonoda,N. 94 101,279 Sorey S.D. 317 Sorgi K.L. 79 80 196 Soria A, 75 Sorokin V.D. 158 Sosa C. 54 57 Sotiriou-Leventis C. 156 Souay P. 72 Souizi A. 77 Southworth B.A. 295 Spaltmstein A. 310 Sparks M.A. 310 Spassov C. 308 Speckamp W.N. 254 Speir J.P. 41 Spencer D.M. 105 Spencer ID. 328 327 329 Spencer J.B. 315 333 335 Spencer N. 147 Spencer P. 266 Spengler B. 41 Sphon J.A. 29 SpieImann H.P. 8 Spiess H.W. 16 Spinace E.V. 106 Spraul M. 12 Sprinz J. 253 271 Squires R.R. 146 Srdanov G. 25 Srebnik M. 235 Sridharan V. 112 237 240 Snnivas R. 22 Srinivasan K. 257 Srinivasan T.G. 26 Stacel S.J.13% Stadtmiiller H. 138 238 Staempfli A. 34 Stafford J.A. 291 Stageland EL. 130 Stahl B. 42 Stahl D.C. 30 Stahl N. 31 Staley S.W, 232 Stallman J.B. 140 Stamford N.P.J. 333 Standing K.G. 40 Stang P.I. 108 141 158 Stangeland EL. 282 Stara I.G. 250 272 Stark W.M. 216 333 Stary I. 250 272 Stasko A. 168 Staunton J. 202 Stave M.S. 57 Stec D. 158 Steding A. 37 Steffen L.K. 171 Stein N. 107 Steiner V. 42 Steinke T. 61 Stempf I. 125 Stenstroem Y.,27 Stephan C. 218 Stephenson G.R.,257 258 Stepowska H. 267 Sterbenz J.T. 253 Sterin S. 182 Sterner O. 320 Steurnagel S. 323 Stevenson P. 134 Stewart I.J.P.,51 Stewart S.K. 108 166 224 Stille J.R. 159 Stiller L. 58 Stinson S.C.269 Stirk K.G. 22 Stoddart J.F. 147 Stoll H. 52 Stolowich N.J. 333 335 Stone G.B. 118 Stout R.L. 38 Strange J.H. 18 Stratmann K. 312 Street L.J.,203 Streitwieser A. 146 Strekowski L, 292 Strife R.J.,49 Stringer M.B.,24 Strnad M. 71 Strongin R.M., 25 Stryker J.M. 248 Stiidemann T. 13% Stuerga D. 162 Stunner R. 293 Sturnpf R. 124 Stupczewski,J.T. 164 Subba Rao Y.V. 159 Subrahmanyam M. 159 Subramaniam R. 322 Subramanian R. 72 Suchen S.D. 168 Suemune H. 106 Suffert J. 111 150 233 Suga T. 319 Sugai T. 309 Sugathapala P.M. 263 Sugihara T. 154 219 Suginome M. 122 235 Sugita T.,277,289 Sugiura Y.,132 I50 Sulsky R. 250 Sumiya T. 292 Sun B.Q. 15 Sun C.-M. 315 Sun S.99 129 Sun Y. 14,254 Sundaresan,I. 201 Sundermeyer J. 106 Sundqvist B.U.R. 41 Suriano J.A. 221 Susfalk R.B.,235 Sustmann R. 65,71 Sutherland A.G. 299 Author Index Sutter B. 319 Suziki Y.,165 Suzuki A. 141 153,232,235 Suzuki F. 199 Suzuki H. 107 158 Suzuki I. 213 Suzuki K. 117 159 Suzuki N. 117,243 244 Suzuki T. 25 108 128 162 163 273 Svedas Y.K. 304 Svensson P. 148 Svensson S.C.T. 252 Svoboda I. 83 Swafford A.M. I93 Swanson S.,258 Swarbick T.M. 141 Sweeley C.C. 36 Sweigart D.A. 264,265 Swenton J.S.,155 Swestock J. 166 225 Sygula A. 169 Sygula R. 159 Szalontai G. 7 Sdntay C. 232 Szarek W.A. 35 Szczecinski P. 263 Sziraky P.,304 Szymoniak J. 264 Tabata H.316 Tabata Y.,323 Taber D.F. 138 243 Tabet J.-C. 22 24 46,328 Tacconi G. 78 Tachdijian C. 183 Tachiro M. 177 Tada T. 188 Tadano K.,251 Tadokoro T. 111 238 Tae J.S. 86 169 190 Taga T. 116 276 Tagliani A. 308 Tagliavini E. 270 Taguchi T. 119 125 135 138 290 Takada K. 141 Takagi €. 251 Takagi K. 167 Takahashi K.,74 11 1,241 281 Takahashi T. 66 117 150 243 244 Takahashi Y.,78 Takahori T. 272 Takai. M.,215 Takai T. 287 Takai Y.,23 I72 Takano M. 136 Takano S. 213 301 Takao K. 251 Takasaki T. 78 Takase K.,172 Takashima M. 224 Takaya H. 131.282 Takayarna M. 26 Takazawa N.,108,235 Takeda K.,138 320 Takeda M. 130 Takehara H. 229 Takemoto S. 114 Takemoto T. 243 Takemoto Y.,255 Takemura S.215 Taketomi T. 282 Takeuchi H. 150 Takeuchi J. 255 Takeuchi K.,132 177 Takigiku It. 42 Takuwa A. 106,270 Tarnaru Y.,247 254 Tamis J. 185 232 Tamura J. 34 39 Tamura Y.,t19 Tan C.-W. 126 Tan W. 314 Tanabe K.,I41 Tanahashi A. 252 Tanaka A+,254 Tanaka H. 150 183 Tanaka K. 108 116 165 184 273,276 293 Tanaka S.,246 247,250 Tang K. 42 Tang S.C. 13 Tani K. 118,284 Tani Y.,322 Taniguchi N.,136 Taniguchi T. 136 Tanino K. 128 Taniseki Y.,254 Tanya M.J. 171 Tao C. 257 Tarbet K.H. 127 270 Tarbit B. 181 Tashiro M.,175 Tasuaka M. 129 Tatematsu T. 295 Tatsukawa A. 126 Tatsumi A. 158 Tatsuta K.,154 Tau S.-I. 255 Tauwa A. 106 Tavani C. 163 Taylor D.L. 204 Taylor M.K.292 Taylor N.J. 254 Taylor P.J. 59 Taylor R.J.K.,118 155 179 193,203 Teasdale A.J. 237 Tebbe M.,198 Teesch L.M. 27 Tejeda J. 187 ten Hoeve W. 163. 293 Teplow D.B. 31 Terada M. 127 Terashima S.,233 Terlouw J.K.,21 22 23 Terrett N.K.,84 138 Tessier C.A. 233 Tester R.W. 193 Tews H. 280 Texier-Boullet F. 294 Thakur R.S. 320 Thal C. 108,207 226 Theurig M.,235 Thibault P.,30 Thibaut D. 333 335,336 Thiecke J.R.G. 153 Thiel W.,266 Thiericke R.,311 313 314 328 329 Thorn S.M. 230 Thomas B.E. IV,65.77 Thomas E.J. 127 Thornas G.,99 Thomas PJ,,158 Thomas R. 37 Thomas S.E.,151 222 248 263 Thomas-dit-Dumond L. 201 Thompson,C.F. 264 Thompson D.F. 92 Thompson J.R. 76 Thomson N.309 Thorat T.S. 159 Thorimbert S.,250 Thorneley R.N.F.,29 Thuong N.T.. 105 Thurman EM.,38 Tietze L.F. 107,210,226 Tillyer R.D., 180 Timofeeva L.M. 60 Tinachoe S.W. 90 Titman J.J- 16 Tius T.A. 235 Tkaczyk M. 25,48 Tobe Y.,175 178 Toda F. 106 184 Toda T. 213 Todd J.F.J. 47 48 Todoroki R. 307 Todres Z.V. 263 Togni A. 253 Toia R.F. 315 Tokuda M. 150 Tokunaga M. 132,282 Totman J.R. 11 Tornasi J. 59 61 Tomaszewski M.J. 81 280 Tom Dieck H. 218 Tomer K.B. 30 Tornioka K. I57,296 Tomita K.,136 Tomoda H. 316 Toneva R. 283 Tonnies S.D. 133 Topol I.A. 57 Torchio M. 263 Torii S. 11I 183 238 Torisawa Y. 141 Torode J.S. 193 220 Toromanoff E. 138 Torroba T.,187 Tortajorda J.,24 Toru T.,100 129 Toshima K.,149 Tbth M.,311 Toupet t.,138 TOUZ~, A.-M.250 Towne T.B. 247 Townsend C.A. 333 Toyooka N. 301 Toyota M. 138 Trafford D.J.H. 36 Traldi P.,47,48 Tran V.D. 239 Treiber K.D. 247 Tress] R.,311 Trew S.J. 336 Trewhella M.A. 309 Trombini C. 270 Trost B.M. 136 138,218 219 238 249 250 252 Truhlar D.G. 57 57 68 79 Truong T.N. 67 79 Tsai Y.-M. 86 Tsarbopoulos A. 39 Tsay S.C. 149 Tschaen D.M. 183,280 Tschudin R.,11 Tseng W.-H. 138 TSO,H.-W. 118 Tsubota M. 171 Tsuchiya T. 188 209 Tsuchuja R. 331 Tsuda N. 132 Tsuge A. 177 Tsuji K. 39 Tsuji R. 177 Tsuji Y. 235 240 249 250 Tsukiyama T.,246 Tsunoi S. 94 279 Tsusaka M. 100 Tsvetkov V.D.168 Tsyganov D.V. 160 Tu,C.-C. 249 304 Tubul A. 138 Tucker C.E. 138 238 Tully 3..171 Tunde P. 198 Tunon I. 60 Turchi I.J. 75,79 80 Turck A. 200 201 Turecek F.,24 Turner I. 205 Turner M.M. 309 Turner N.J. 300 309 Turner R.M.,188 235 Turos E. 248 Tyler A.N. 34 TyIer J.W. 332 Tyrrell E. 246 Uchida S. 247 Uchiyama M. 226 Udvarnoki G., 317 Ueda M. 292 Ueda R. 183 Ueda Y. 85 Uejima A. 165 Uemetsu T. 304 Uemura J. 85 Uemura M. 242 264 Uemura N.,83 Uemura S.,277 289 Ueno K. 169 Ueno Y.,100 129 Ugalde J.M. 65 Uggerud E. 27 ugi I. 107 199 Uguen D. 301 Uhrin D. 7 Ukai S. 35 Ulmer C.W. 65 Ulmer G. 26 Urnani-Ronchi A. 270 Umemura M. 77 Umezawa K.,323 Underwood DJ.24 Undheim K. 200,250,265 Uneyama K.,85 Uno H. 107 Unverzagt C. 105 Uornori A. 320 Uozumi Y.,128 252 Urabe H. 251 Urbanos F. 265 Urry D.W. 107 Urushibara S. 171 Utimoto K. IS6 Uwakwe P.U. 162 Vadecord J. 117,277 VailIancaurt V. 112 Vainiotalo P. 21 Vaissermann J. 223,246 Valdes C. 141 Valentine B.P. 332 Vallee Y. 107 Valvano N.L. 291 Van Aerschot A.A. 228 Van Berkel G.J. 28 37 van Boeckel C.A.A. 105 Van Bramer S.E. 23 Van Bruggen N.,324 van den Berg K.J. 193 Vanderbilt D. 56 57 van der Gen A. 271 Van der Greef J.. 35 36 Van der Hoeven R.A.M. 35 36 van der Kerk-van Hoof A. 35 van der Made A.W. 160 van der Made R.H. 160 VanDerveer D. 141. Van Dongen W.D. 33 Van Dorsselaer A, 36 Van Dyke G.171 Author fndex van Eck E.R.H. 16 Van Epp J.E. 324 Van Es D.S. I76 Vanest Q.C. 69 van HurnrneI G.I. 190 van Leeuwen M. 163 van Leusen A.M. 193 van Lier J.E. 232 Van Nieuwenhze M.S.,285 Van Pelt C.E. 140 220 Vanquickenborne L.G. 79 van Rantwijk F. 304 Van Rooyen P.H. 266 Van Seggern H. 73 Van’t Land C.W. 329 Vardhan A. 302 Vargas D. 313 Varma M. 291 Varma R.S.,105 291 Vath J.E. 32 Vaugeois J. 108 Vaughan G.B. 25 Vaughan J.G. 186 Vaughan W.S. 259 Vaupel A. 138,238 Vazquez J. 295 Vazquez-Tato MY.,294 Vedejs E.,273 291 Veeman W.S. 16 Veggaar R. 330 Veitch J.A. 318 Venanzi L.M. 253 290 Venkateswara Rao B. 81 Venturni A. 75 Vera W.J. 141 Verbroom W. 190 Verentchikov A.40 Verhoeven T.R. 280 Verweij J. 182 Vessitres A. 246 Vestal M.L. 39 Vettori U. 47 Vey A. 31 Vicens J. 105 Vicker N. 208 Vidal J. 182 Vijn R.J.,204 Vilaplanu M.J. 206 Villani C.,147 Viliemin D. 294 Vincent MA. 59 Viola A. 74 Virgili A. 75 Vishwakarma R.A. 333 Vitagliano A, 249 Vlahov R.,308 Vogel P. 148 Vogel R.,168 Vogt D. 287 Vogtle F. 176 Volante R.P. 183 Volk K.J. 318 Vollhardt K.P.C. 146 Volpin M.,159 Author Index Vomera S. 210 von Matt P. 114 198 253 271 Von Philipsborn W. 254 Voragen A.G.J. 35 36 Vosko S.H. 53 Vouros P. 30 Vuilhorgne M. 333 335 Vuister G.W. 9 11 Vulpetti A. 66 Waas J. 245 Wada Y.,39 Wadsworth H.J. 77 Wagner C. 317 Wagner P.J.I58 Wagschal K.C. 319 Waht J.H. 45 Waizumi K. 57 Walker A.J. 179 Walker J.A. 325 Walkup R.D. 247 Wallace D.W. 254 Wallace E.M. 167 244 Walls F.C. 30 Wally H. 266 Walsh C.T. 336 Walsh E.J. 192 Walsh K.A. 34 Walsh P. 284 Walter C.J. 141 Walters I.A.S. 293 Walther B.W. 57 Walton N.J. 326 327 Wandless T.J. 105 Wang A.C. 9 Wang A.P.L. 32 42 Wang J. 136 241 Wang J.T. 57 Wang K.-T. 304 Wang K.K. 93 Wang M. 77 Wang P. 324 Wang Q. 160 Wang S. 159 Wang S.-L.,236 254 Wang W.-B. 183 Wang Y. 138 248 Wang Z. 286 Wang Z.E. 141 Wang Z.-M. 284 Wang Z.-X. 266 Ward J.M. 309 Ward M.F. 151 222 Ward S.E. 290 Warkentin J. 81 280 Warner K. 324 Warren M.J. 333 Warren S.I21 Warshel A. 58 Wartenberg F.-H. 138 219 WasyIishen R.E. 13 14 Watanabe H. 85 Watanabe M.,229 266 Watanabe Y. 100 129,254 Watling R. 316 Watrelot S. 240 Watson A.B. 326 327 Watson C.H.,28 Watson J.T. 33 36 Watson R.J. 155 I93 Watterson S.H. I37 Wazeer M.I.M. I97 Webb H.M. 25 Webb T.H. 105 Weber J. 56 57 Weber M. 49 Weickhardt K. 286 Weinhold F. 146 Weinreb P.H. 138 Weinreb S.M. 239 286 291 Weinstein H. 62 108 Weiss E. 108 Weiss J. 105 Weiss R.G. 19 Weissensteiner W. 243 266 Weitz IS. 156 Welch J.T. 102 Weilauer T. f 78 Welle R. 322 Weflington E.M.H. 336 WeIpy J.K. 39 WeIzeI P. 290 Wemmer D.E. 8 Wender PA.,149 Wensbo D. 234 Wentrup C. 146 Werner H. 244 Wessel T.174 West F.G. 193 204 West G.M.J. 69 West R. 86 Westemann J. 112 Westmann A. 41 Westwood R. 76 Wetterich F. 97 98 99 129 Wey H.G. 263 Weyns N.J. 228 Whang H.S. 86 169 Whang Z. 271 Wheatley J.R. 191 Whitby R.J. 244 White A.H. 271 White J.D. 135 White P.S. 255 Whitehouse C.M. 40 Whitesides G.M. 309 310 Whiting A. 108 166 224 Whiting D.A. 324 Whittaker M.,267 Whitten W.B. 48 Wider G. I1 Widhalm M. 243 266 Wiegelmann J.E.C. 241 Wier M.R. 48 Wiermann R. 323 Wierschke S.U. 146 Wiersum U.E. 171 351 Wierzchleyski AT. 263 Wijaya N. 290 Wijsman G.W. 176 WiIcox C.S. 105 Wilde A. 134 248 Wilen S.H. 270 Wilk L. 53 Wilkins C.L. 40 42 43 44 Wiikinson B. 310 Willard P.G. 108 WiIlem R.3 Willets A.J. 306 309 Willey K.F. 47 Williams A.C. 250 Williams D.J. 147 151 248 263 Williams D.R. 130 Williams E.R. 42 Williams F. 57 322 Williams I.H. 62 Williams J.D. 48 Williams J.M.J. 114 163 198 250 253 271 Williams K.W. 310 Williams P. 37 Williams R.M. 331 Wiliiamson B.L. 141 Williard P.G. 264 296 WilIis C.L. 77 Willker W. 11 Willoughby C.A. 281 Wilrnesmeier S. 323 Wilson C. 108 226 Wilson I.D. 12 Wilson K.E. 295 Wilson S.R. 107 259 Wilson W.W. 57 Wilt J.W. 72 Winchester W.R. 135 Winger B.E. 38 Wink M. 326 Winkler J.D. 215 Winter S.B.D.,122 Wipf P. 106 128 155 193 243 Wirnsberger G. 305 Wishart N. 235 245 Wison P.D. 138 Wittekind M. 7 Wnuk S.F. 106 Wojcicki A.254 Woleben C.M. 137 Wolf J. 244 Wolf R.E. 107 Wolfe J.J. 69 WoIfsberger M. 65 Wolkaw C. 42 Wollowitz S. 107 269 Wong C.-H. 105 299 304 309 Wong N.R.,171 Wong T. I1 1 Woo S.H. 153 Wood J.M. 29 Wood T.D. 43 Woodall T.M. 130 280 Woodcock S. 59 Woodley J.M. 309 Woods A. 42 Wooley J.G. 326 Wookey N.F. 263 Wormald P.C. 328 Wrede P. 70 Wrigglesworth R.,179 Wright AD. 21 46 47 Wright B. 45 Wright J.D. 69 Wright J.L.C. 325 Wrinn M.,57 Wrobel Z. 206 WU F.-C. 302 Wu G. 13 14 Wu H.F. 48 Wu J. 12 Wu K.J. 37 Wu X.,13 14 WU,X.-M. 138 Wu Y. 13 108 WU Y.-C. 138 Wu Y.D. 63 WU Y.-J. 136 WU Y.-S. 171 WU,Z. 25 324 Wu Z.J. 183 Wndl F. 25 Wuest J.D. 108 Wuethrich K.1 I WulfF W.D. 73 138 150 151 222,278 Wurster J.A. 192 Wurthner F. 193 Wurz P. 26 Wyler H. 207 Wynberg H. 163,293 Wysocki V.H. 46,47 Wythes M.J. 235 245 Xavier L. I1 1 232 Xhang X. 44 Xi M. 157 Xia X.F. 58 Xiao M. 133 Xie L. 160 Xinquan H. 240 Xu,D. 152,284 Xu F. 208 Xu L.H. 263 Xu S.L. 150 XU w., 201 Xu Y. 137 229 XU Y.-C. 150 202 Xu,Z. 108 Yak M. 153 Yada Y.,319 Yadav G.D. I59 Yajima T. 254 Yakubov A.P.,160 Yalpani N. 323 Yamabe S. 65 72 Yamada H. 23 150 Yarnada N. 250 Yamada T. 287 Yamaguchi H. 26 Yamaguchi K. 138 Yamaguchi M.,138 Yamaguchi S. 282 Yamaguchi Y. 80 Yamamoto A. 250 Yamamoto G. 172 174 Yamarnoto H. 127 132 141 196 270 272 278 291 Yamarnoto Y.106 128 132 273 Yarnamura S. 321 Yamanaka H. 108,225,226 228,235 Yamashita M. 188 Yamato M. 141 Yamato T. 175 Yamazaki A. 252 Yarnazaki H. 101 Yamazaki Y.,264 266 Yamori S. 213 Yan T.-H., 126 Yanagisawa A. 127,270 Yanai M. 136 219 Yang AS. 57 Yang C. I71 Yang D.-L. 162 Yang G.K. 248 Yang H. 23,253 Yang T.K. 73 Yang W. 51 52 53 Yang Y . 232 Yang Z.-Y. 232 Yao Q. 89 Yashunsky D.V. 138 Yasuda N. 11I 232 Yasuhara A. 228 Yasui K. 254 Yasuike S. 188 209 Yasukata T. 293 Yasunami M. 172 Yau P.Y. 41 Ye J. 112 Yeh M.-C.P. 255 Yelm K.E. 141. Yeske P.E. 77 Yeung B. 30 Yeung E.S. 41 Yeung K.-S. 276 Yin H.M., 23 Yin J. 145 Yip T.T. 29 38 40,42 Yip Y.C.132 Yohannes D. 105,269 Yokokawa F. 230 Yokota K. 292 Yokoyama Y. 224 Yoneda N. 163 Author Index Yoneda R.,215 Yoo R.K. 25 Yoo,S.-e. 140 Yoon E. 35 Yoon N.M. 282 Yoon T.-S. 265 Yorozu K. 287 Yoshida I. 35 Yoshida K. 46 102 150 Yoshida M. 95 Yoshida N. 138 Yoshida W. 250 Yoshihara K. I32 Yoshii E. 138 Yoshikawa A.. 183 Yoshirnura T. 292 Yoshimura Y.,320 Yoshizumi T. ,282 Yost R.A. 48,49 You Z. 80 Young P. 60 Young R.J. 171 Youngs W.J., 233 Yu H. 34 Yu,M.S. 136 241 Yu,R.H. 135 Yu S.J. 22 Yu W. 32 Yu Y. 255 Yuan W. 304 Yuki Y. 286 Yulan Z. 266 Yum E.K. 249 Yus M. 128 147 Yvanaeff C. 294 Zachara J. 263 Zaia J. 31 Zair T. 249 ZaltsgendIer I.160 Zamojski A. 267 Zare R.N. 42 Zargarian D. 284 Zdravkovski Z. 294 Zecca L. 29 Zecchi G. 213 262 Zeech A. 330 Zefirov N.S. 158 Zeitz H.-G. 97 Zeller L. 21 Zeltz H.-G. 129 Zelvelder E. 162 Zeng Z. 331 Zenglu L. 266 Zenk M.H. 330 Zercher C.K. 149 Zettlmeier W. 270 Zevaco T. 288 Zband S.-W. 254 Zhang B. 133 Zhang D. 320 Zhang H.-C. 228 Zhang I.Y. 32 Author Index Zhang Q. 128,201 Zhang W. 90,106,279 Zhang W.-Y. 199 Zhang X. 282 287 Zhang X.-L. 284 Zhang X.-M. 162 Zhang X.-P. 115,275 Zhang Y . 160 Zhang Z. 191 Zhao S.-H. 284 Zhao W.-Y. 163 Zhdankin V.V. 158 Zheng L. 19 Zheng Q-,232 Zheng W. 245 Zheng Z.B. 211 Zhoa H. 32 Zhong H.M. 91 Zhou J. 40 Zhou M.273 Zhou f.,295 331 Zhou Q.-L. 114 272 Zhou T. 254 Zhou Y. 248 Zhou z.,34 Zhu G. 9 220 Zhu J. 94 Zhuo J.-C. 207 Ziegler C.B. Jr. 101 Ziegler F.E. 85 ZiegIer T. 54 57 66 Ziessel R. 233 Zijlstra R.W.J. 293 Ziller J.W. I2 Zilm K.W. 13 14 148 Zimrner R. 107 181 Zirnmerman C.N. 141 Zink T.,79 Zora. M. 223 Zou X. 162 Zuiderweg E.R.P. 11 Zurnbulyadis N. 14 Zupan J. 69 Zwannenberg B. 73 Zych K.,171

ISSN:0069-3030    

DOI:10.1039/OC9939000337

出版商:RSC    

年代:1993

数据来源: RSC