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8 OrganometalIic Chemistry The Transition Elements By G. R. STEPHENSON School of Chemical Sciences University of East Anglia Norwich NR4 7TJ UK 1 Introduction Surveying the work related to organic chemistry from the main organotransition metal research groups in 1992 gives the overall impression that this has been a year for consolidation and application of earlier discoveries. This is part of the normal cycle of scientific research synchronized by a loss in confidence and drive by the funding agencies at the onset of recession at the start of the decade. This report will mostly point out the successful applications rather than emphasize new discoveries. Perhaps the best headway has been made in the application of organometallic 7c-complexes in organic synthesis.Here while the overall impression is of the skilful application of established reaction types there are still new reactions being described and new methods for the utilization of bond forming processes. The Annual Report this year will start with a few examples not necessarily selecting reactions that are totally new but rather those where the outcome of attempts to utilize the process is far from predictable at the present time. This is where the excitement lies in the future development of this subject. Rearrangement reactions driven by metal cation complexes show promise applying a ‘classical’ metal complex [FeCp(CO),,Fp] in new ways. Professor Bly’s group at South Carolina report full details of their work mapping the reactions of vinylidene iron complexes.’ An iron acyl complex is the familiar starting point for this reaction sequence.Conversion into the cationic carbene intermediate is followed by loss of triflic acid to form the vinylidene complex (1). Rearrangement of (1) depends on ring size. Intermediates with small rings are converted into the q2-alkene complexes (2) whereas larger rings (able to incorporate a triple bond) can accommodate the ring-expanded alkyne complexes (3). Product (2) has gained two additional hydrogens. Use of deuterated solvent showed that one originates from diethyl ether the other presumably arising from acidic species in the reaction. Reactivity switching of a different type is seen in the chemistry of palladium complexes derived from familiar allylic acetate displacement (discussed in detail in Section 2) employing an allenic acetate as the substrate.An unusual q3 1,2-diene complex (4) produced in this way can interconvert with a a-bound 1,3-diene intermediate (5) which is intercepted by suitable nucleophiles. Padwa’s group at Emory University Atlanta has applied this reaction to sulfur-substituted allenes with R. S. Bly M. Raja and R. K. Bly Organometallics 1992 11 1220. 207 G.R. Stephenson 0 OTf Scheme 1 substituents at the carbon bearing the acetate leaving group. Efficient conversion into intermediate (5) is indicated by access to highly substituted 1,3-diene products such as (02 X OAc X=H CO,R Scheme 2 Cumulated double bonds figure in the work of Thomas' group at Imperial College where the chemistry of vinylketene n-complexes is under exploration.Insertion of alkynes into these compounds has now been described leading to synthetically valuable metallocyclic n-ally1 complexes such as (7).3Use of a more unusual alkyne was rewarded by a more unusual product the Fe(CO) compound (8). Z. Ni and A. Padwa SYNLETT 1992 869. K.G. Morris S. P. Saberi A. M.Z. Slawin S. E. Thomas and D. J. Williams J. Chern. SOC. Chem. Commun. 1992 1788. Organometallic Chemistry -The Transition Elements \ C02Me EtzN-Me (7) -& NEt2 Scheme 3 These examples show the versatile reactivity of transition metal n-complexes; a great variety of bond forming processes are possible. It is the use of highly reactive starting materials or intermediates that provides the unifying feature bringing together the chemistry described in Schemes 1-3.Combining processes of this type with more familiar reactions later in synthetic sequences offers an exciting prospect for the future. 2 Transition Metal Alkene and Arene n-Complexes q*-Complexes-The use of palladium catalysis to activate alkenes and alkynes for nucleophile addition has a long history but heteroatom nucleophiles offer new developments in 1992. Baig Jenck and Kalck have used morpholine and 2,3- dihydrofuran to demonstrate the first example of a palladium catalysed condensation of an amine with an alkene leading to the isolation of the product (9).4 Addition of thiophenol to an alkyne has also been described.In this case the nucleophile adds to the internal carbon atom to form (lo)? Sulfur is used in a different way in an example of terminal addition to an v2-alkene complex containing a thioalkylether side-chain providing an internal directing influence by chelation to the metal. The bulky nucleophile leading to the malonate derivative (1 1) gave the best result.6 The disconnections marked in Scheme 4 show the power of these reactions in providing controlled bond formation in situations where this would not normally be easy. (9) T. Baig J. Jenck and P. Kalck J. Chem. SOC.,Chem. Commun. 1992 1552. H. Kuniyasu A. Ogawa K.-I. Sato I. Ryu N. Kambe and N. Sonoda J.Am. Chem.SOC. 1992,114,5902. ' Y.-Z. Zhang X.-X. Shi and L.-X. Dai Huaxue Xuebao 1992 50 726. G.R.Stephenson Conjugate addition would normally allow one bond to be formed at the terminus of an a,S-unsaturated ester. By use of Wacker oxidation conditions in methanol (typical conditions for direct acetal formation) the heterocyclization product (12) has been obtained.' A second example of direct acetal formation leading to (13) is of note because the Wacker conditions have left the allylic acetate intact despite the normal role of allylic acetates as precursors to $-ally1 intermediates.' In a synthesis of optically active substituted dihydrofurans and dihydropyrroles intramolecular heteroatorn addition to an q2-alkene complex has been proposed. In this system too an allylic leaving group was present.' Scheme 5 With dienes as substrates Backvall's group at Uppsala have used 'Wacker-type' addition to gain access to n-ally1 intermediates.In an example directed towards the pyrrolizidine and indolizidine alkaloids cyclizations of amide-substituted dienes lead directly to 1,4-difunctionalized bicyclic products such as (14)." Other examples of stereocontrolled 1,4-difunctionalization of cyclic 1,3-dienes have also been described.' Depending on conditions either cis or trans relative stereochemistry can be achieved. Me Me I -$ 0 L,Pd 0 (14) 85% Scheme 6 Work from the Gladysz group still dominates the field of rhenium q2 chemistry. ' S. X. Auclair M. Morris and M. A. Sturgess Tetrahedron Lett. 1992 33 7139. * T. Hosokawa S. Aoki and S.-I. Murahashi Synthesis 1992 558.S. Saito T. Hara N. Takahashi M. Hirai and T. Moriwake SYNLETT 1992 237. lo P.G. Anderson and J.-E. Backvall J. Am. Chem. SOC.,1992 114 8696. " J.-E. Backvall and P.G. Anderson J. Am. Chem. SOC. 1992 114 6374. Organometallic Chemistry -The Transition Elements 21 1 End-on and side-on aldehyde complexes,' '*' and allene cornplexe~'~ are featured this year. Related use of rhenium nitrosyl complexes as chiral Lewis acids is underpinned by detailed kinetic studies' indicating that o isomers are more reactive towards nucleophiles (in this case cyanide) than the z isomers. Asymmetric induction under kinetic control should thus be rationalized on the basis of n to o interconversions followed by nucleophile addition to the more reactive intermediates.Kinetic work on alkene and carbene rhenium complexes has also been reported.16 Both alkene and alkyne Fp complexes are popular as stoichiometric intermediates. Considerable progress has been made in the Rosenblum group towards the application in asymmetric synthesis of induced asymmetry in q2 iron complexes. Chiral diols are used as auxiliaries. A multi-step reaction sequence leads to the transfer of chirality in two new carbon-carbon bond formations employing first cuprate and then Grignard reagents. The prochiral starting material (15) is taken through to the o-bound product (16) from which metal-removal by oxidation replaces Fp by C0,Me.l' Heteroatom nucleophile addition to an alkyne complex gives the cr product (17) or the carbonyl insertion product (18).' Me Me0 OMe i HOfl,OH A i Me-EtMgBr *Ar 0 ii.LiCuMe2 -xMe I /-0 FP FP+ iv.iii MeOC&&H20HHBF4 FP+ Ar (15) (16) 52% Ph Ph-Ph -Fpgph + E::Fe2ph \/ FP+ Ph NR2 (17) (18) Scheme 7 q3-Complexes.-The chemistry of allyl complexes offers valuable catalytic procedures employing palladium. Nice applications have employed 1,4-disubstituted alkenes as starting materials. The route taken by the Trost group to carbovir and aristeromycin exemplify these procedures. The dibenzoate (19)is taken through to (20),and hence by allylic acetate displacement to (21) in the carbovir synthesis. Use of adenine as the nucleophile with (20) gave access to aristerornycin.'' The sodium salt (22) has been used with a palladium allyl complex to afford (23) in 72% yield.20 I.Saura-Llamas D. M. Dalton A. M. Arif and J. A. Gladysz Organometallics 1992 11 683. l3 F. Agbossou,J. A. Ramsden,Y.-H. Huang A. M. Arif and J. A. Gladysz,J. Am. Chem. SOC.,1992,114,693. l4 J. Pu T.-S. Peng A.M. Arif and J. A. Gladysz Organometallics 1992 11 3232. l5 D.P. Klein and J.A. Gladysz J. Am. Chem. SOC. 1992 114 8710. C. Roger T.3. Peng and J. A. Gladysz J. Organornet. Chem. 1992,439 163. K.-H. Chu W. Zhen X.-Y.Zhu and M. Rosenblurn Tetrahedron Lett. 1992 33 1173. M. Akita S. Kakuta S. Sugimoto M.Terada and Y. Moro-oka J. Chem.SOC..Chem. Commun. 1992,451. l9 B. M. Trost L. Li and S.D. Guile J. Am. Chem. SOC. 1992 114 8745. F. Liotta C. R. Unelius J. Kozak and T. Norin Actu Chem. Scund. 1992 46 686.G.R. Stephenson c1 Scheme 8 A variety of nucleophiles including Meldrum's acid,2 phenols,22 and ph~sphites,~~ have been examined. The later case provides another instance of a transition metal version of the Michaelis-Arbuzov reaction to form allylic phosphonates. Allylic phosphine oxides are also accessible using palladium catalysis this time employing an allylic transposition in the presence of a pre-formed phosphine oxide moiety.24 Another allylic transformation employs an imidate as the leaving group. With (24) nitrogen-carbon bond formation results in structures of type (25).25An allylic oxygen in a cyclic carbonate can also be exchanged for nitrogen. This reaction uses an isocyanate as the precursor for the N-R unit in (26).26Allylic carbonates also undergo rearrangement combined with carbonylati~n.~~ A more unusual transformation (also performed under a carbon monoxide atmosphere) forms a carbon-carbon bond in (27) starting in this case from a cyclic carbonate.28 Allylic displacement reactions have been employed in steroid systems,29 with vinyl cyclopropane~,~~ and with fluoroalkene starting material^.^ q3-Dienyl intermediates have been taken through to precursors for intramolecular Diels-Alder reaction^.^' When ally1 displacement is used for deprotection it is the leaving group not the substrate that carries the feature of importance.Deprotection of allylic carbonates has now been performed in the presence of trimethylsilylamines to form silyl ester products.33 21 E.Bernocchi S. Cacchi E. Morera and G. Ortar SYNLETT 1992 161. 22 C. Goux P. Lhoste and D. Sinou SYNLETT 1992 725. " R. Malet M. Moreno-Mafias and R. Pleixats Synth. Commun. 1992 22 2219. 24 J. Clayden E. W. Collington and S. Warren Tetrahedron Lett. 1992 33 7039. 25 P. Metz C. Mues and A. Schoop Tetrahedron 1992 48 1071. 26 Y. Tamaru T. Bando Y. Kawamura K. Okamura Z.4. Yoshida and M. Shiro J. Chem. Soc. Chem. Commun. 1992 1498. '' S.-Z. Wang K. Yamamoto H. Yamada and T. Takahashi Tetrahedron 1992 48,2333. 28 T. Bando S. Tanaka K. Fugami Z.I. Yoshida and Y. Tamaru Bull. Chem. SOC.Jpn. 1992 65 97. 29 V. K. Datcheva and B.A. Marples J. Chem. Res. (S) 1992 238. 30 A. Stolle J. Ollivier P. P. Piras J. Salaun and A. de Meijere J. Am. Chem. Soc. 1992 114 4051.31 P. V. Fish S. P. Reddy C. H. Lee and W. S. Johnson Tetrahedron Lett. 1992 33 8001. 32 P.C. Bulman Page and D.C. Jennens J. Chem. Soc.. Perkin Trans. I 1992 2587. 33 A. Merzouk G. Guibe and A. Loffet Tetrahedron Lett. 1992 33 477. Organometallic Chemistry -The Transition Elements Et Et (24) (25) 68% Scheme 9 With trimethylenemethane complexes palladium can promote cycloaddition. Examples from Trost include both interm~lecular~~ and intramolecular cases.3s A diacetate has been used in place of the normal acetoxymethylallylsilane precursor.36 In a more unusual case an allylzinc reagent is used with a ~ilylalkyne.~~ Me Me3Si0 Scheme 10 Induction of asymmetry in palladium catalysed allylic displacement reactions is still a major growth area.Increasingly elaborate ligands such as (28)38,39and (29)40are now employed. Enantiomeric excess is typically in the range 88-95%. When chirality is present in substrates the transition metal can give exceptionally efficient chirality transfer. Cyclic carbonates derived from acylic viscinal diols are useful substates in these reaction^.^' 1,4-DifunctionaIized alkenes are also of interest since asymmetry can be induced before the palladium catalysed allylic displacement. This has been achieved by using acetylcholene esterase to yield a product that was taken on through 34 B. M. Trost and M. C. Matelich Synthesis 1992 151. 3s B. M. Trost and T.A. Grese J. Orq. Chrm. 1992 57. 686. 36 D. Gravel S. Benoit S. Kumanovic and H. Sivaramakrishnan Tetruhedron Lett.1992,33 1403; rhid. 33 1407. 37 J. van der Louw J. L. van der Baan F. J. J. de Kanter F. Bickelhaupt and G. W. Klumpp. Trrruhedron 1992 48 6087. 38 B. M. Trost and D. L. Van Vranken. Anyew. Chem.. Int. Ed. Enyl.. 1992 31 228. 39 B. M. Trost D. L. Van Vranken and C. Bingel. J. Am. Chem. Soc.. 1992. 114. 9327. 40 U. Leutenegger G. Umbricht C. Fahrni P. von Matt and A. Pfaltz. Tetrahedron 1992 48. 2143. 41 S.-K. Kang. S.-G. Kim and J.3. Lee Trtruhedron:Asymmerry 1992. 3 1139. G.R. Stephenson allylic displacement to produce substituted allylic alcohols suited for further elab~ration.~~ An unusual rearrangement of a silyl substituted vinyl epoxide has also been evaluated for prospects for chirality transfer.Reaction of (30) with a palladium catalyst afforded aldehydes of type (31).43 PdL (31) R=H,Me Scheme 11 Anti-substitution on palladium allyl complexes is normally disfavoured. The groups of Akermark and Vitagliano have joined forces to devise ligands which will promote the anti-stere~chemistry.~~ An objective of the KoEovsky group has been to promote initial syn displacement of the allylic leaving group. They have employed an intramolecular interaction with a phosphine ligand in the ~ubstrate.~~ Another syn oxidative addition has been described in the addition of allylic halides to alkene c~mplexes.~~ With palladium catalysts nucleophile addition generally takes place at an end of the allyl complex but recently with other metals central attack has been described.Now Hoffmann Otte and Wilde report47 internal attack with a palladium complex using a stoichiometric bis-n-ally1 palladium chloride dimer as the precursor. When the ends of the allyl ligand carry different substituents regiocontrol in the nucleophile addition step is an important issue. Differently substituted aryl substitu- ents have been employed by Prat Ribas and M~reno-Maiias.~~ Detailed studies of the isomerization of palladium allyl complexes using the classic methoxycarbonylcyc- lohexenyl ligand,49 and investigations of the electronic structure of palladium complexes by photoelectron spectros~opy,~~ have also appeared this year. In stoichiometric systems there has been renewed interest in cationic tetracarbonyliron complexes.Reactions with functionalized organocopper reagent? and silylenol ethers,52 have been described. In the latter case a terminal trimethylsilyl group directs nucleophiles to the far end of the metal-bound n-system in (32). The cationic rhenium pentalmethylcyclopentodienyl(Cp*) q3-propargyl complex (33)53undergoes reactions with nucleophiles at the central carbon atom. Metal removal from an allyl complex usually promotes interesting chemistry since the allyl ligand will participate in further 42 H.E. Schink and J.-E. Backvall J. Org. Chem. 1992 57 1588. 43 F. Gilloir and M. Malacria Tetrahedron Lett. 1992 33 3859. 44 M. Sjogren S. Hansson P.-0. Norrby B. Akermark M. E. Cucciolito and A. Vitagliano Organometallics 1992 11 3954. 45 I.Stary J. ZajiEek and P. KoEovsky Tetrahedron 1992 48 7229. 46 H. Kurosawa H. Kajimara S. Ogoshi H. Yoneda K. Miki N. Kasai S. Murai and I. Ikeda J. Am. Chem. SOC. 1992 114 8417. 4’ H. M. R. Hoffmann A. R. Otte and A. Wilde Angew. Chem. Int. Ed. Engl. 1992 31 234. M. Prat J. Ribas and M. Moreno-Mafias Tetrahedron 1992 48 1695. 49 K. L. Granberg and J.-E. Backvall J. Am. Chem. SOC. 1992 114 6858. 50 F. Bokman A. Gogoll L. G. M. Pettersson 0.Bohman and H. 0.G.Siegbahn Organornetallics 1992,11 1784. 51 M.-C.P. Yeh and S.-I Tau J. Chem. SOC. Chem. Commun. 1992 13. 52 C. Gajda and J. R. Green SYNLETT 1992 973. ’’ C.P. Casey and C.S. YI J. Am. Chem. SOC. 1992 114 6597. Organometallic Chemistry -The Transition Elements reaction once free from the metal.The use of CpMo(C0)NO complexes (eg. 34) in multi-step synthetic routes oia (35) has been brought to an attractive conclusion with an unusual nitrosyl insertion occurring upon metal removal. An alkenyl isoxazole (36) was produced.54 Scheme 12 0 4di Me Me/' steps - - NOBF4 10 eq. CpMoCo~ Ph (34) \-/ Scheme 13 q4-Complexes.-Reactions of cationic q4-complexes with nucleophiles have been combined with electrophile addition to vinyl-substituted neutral q3 precursors. A sequence of stereocontrolled bond formations are possible in this way. Formation of (37) provides a typical example.55 Similar reactions with differently configured starting materials allow the formation and utilization of cationic q4 trimethylenemethane complexe~.~~ Neutral trimethylenemethane complexes of the tricarbonyliron unit also undergo reactions with n~cleophiles.~ A more unusual example of nucleophile addition has been promoted by provision of a nucleophilic side-chain in the cyclopentadienyl ligand.The use of trimethylamine-oxide however is required to effect the metal-nitrogen bond-formation leading to (38).58 tris-Pyrazolylborate used in place of the normal cyclopentadienyl ligand has provided novel q4 complexes which have been employed in reactions with nucle~philes.~~.~~ been employed in neutral cobalt diene complexes.6 ' 1,2-Azaborolyl ligands have Progress with the chemistry of q4-enone complexes has been considerable. Direct nucleophile addition and nucleophile addition/carbonyl insertion pathways have been explored with a$-unsaturated acylsilanes.62 Chiral sulfoxide substituents on 54 S.-H.Lin S.-M. Peng and R.-S. Liu J. Chem. Soc. Chem. Commun. 1992 615. 55 M.-H. Cheng Y.-H. Ho S.-L. Wang,C.-Y. Cheng S.-M. Peng G.-H. Lee and R.6. Liu,J. Chem. SOC.. Chem. Commun. 1992 45. 56 G.-M. Yang G.-M. Su and R.-S. Liu Organometallics 1992 11 3444. 57 W. A. Donaldson and M. A. Hossain Tetrahedron Lett. 1992 33 4107. 58 T.-F. Wang and Y.-S. Wen J. Organomet. Chem. 1992 439 155. 59 J. Ipaktschi and W. Sulzbach J. Organomet. Chem. 1992 434 287. 6o J. Ipaktschi A. Hartmann and R.Boese J. Organomet. Chem. 1992 434 303; see also 287. 61 G. Schmid and M. Schutz Organometallics 1992 11 1789. S. E. Thomas G. J. Tustin and A. Ibbotson Tetrahedron 1992 48 7629.G.R. Stephenson CpMoCO NMe I m3c+ Me3NO ,Mo-yMez OCOMoYO oc I b Scheme 14 enone ligands have been exploited in diastereoselective c~mplexation,~~ and Wit- tig-Horner elaboration of vinylketene complexes afforded q4-vinylallene products of type (39) which lactonize upon removal of the Tris enone complexes of molybdenum and tungsten have been reported.65 Neomenthyldiphenylphosphine has been used as a metal-bound chiral auxiliary for the resolution of enone n-complexes.66 The circular dichroism spectra of optically active chiral enone complexes have been examined in Azadiene complexes have been employed as versatile transfer reagents,68 serving as a useful source of the tricarbonyliron group. Reaction adjacent to a neutral tricarbonyliron diene complex provides the Gree group with access to allenyl-substituted diene complexes and ultimately to the free 2,4,6,7-tetraene.Acetylide addition to a formyl substituent on the tricarbonyliron complex gives access to a propargyl alcohol derivative at the start of this reaction sequence. Rearrangement in the normal fashion built the allene. This reaction showed good diastereocontrol between the planar chirality of the metal n-complex and the axial element of chirality in the allene within structure (40).69Donaldson has examined the alkylation of enolates 63 A. Ibbotson A. C. Reduto dos Reis S. P. Saber] A.M. Z. Slawin S. E. Thomas G.J. Tustin and D. J. Williams J. Chem. Soc. Perkin Trans. I 1992 1251. 64 S. P. Saberi and S.E. Thomas J. Chem. Soc. Perkin Trans. 1 1992 259. 65 T. Schmidt and S. Neis J. Organomet. Chem. 1992 430 C5. 66 A. Marcuzzi A. Linden D. Rentsch and W. von Philipsborn J. Organomet. Chem. 1992 429 87. 67 B. R. Bender M. Koller A. Linden A. Marcuzzi and W. von Philipsborn Organometallics 1992,11,4268. " H. J. Knolker and P. Gonser SYNLETT. 1992 517. 69 K. Nunn P. Mosset R. Gree R. W. Saalfranck K. Peters and H. G. von Schnering Anqew. Chem. Int. Ed. Engl. 1992 31 224. Organometallic Chemistry -The Transition Elements formed adjacent to acyclic q4-diene complexes. Deprotonation of (41) followed by reaction with methyl iodide led to the formation of (42) in 93% d.e. and 97% yield." )--Et (39) Ph Scheme 15 Tricarbonyl(q3-cycloheptatrieny1)ironanions give access to acylcycloheptatriene complexes.The rearrangement pathways of these structures have now been explored in detail.7 Stereoselective functionalization within the ring has also been examined. Tropone complexes undergo stereoselective reduction and osmylation. Hydride delivery and osmium-mediated 1,2-dioxygenation both proceed on the face of the ligand opposite to that bearing the q5-Complexes.-The use of heterocyclic bases as nucleophiles as seen already in the discussion of q3 chemistry has also received attention in the q5 case. With tricarbonyliron complexes this type of addition is precedented but a new form has been examined by Potter McCague and Jarman who use 2'-deoxyguanosine to promote reactivity at N-2. Removal of the metal afforded (43) in 60% yield.73 An elaborate alkenylcopper nucleophile has been used with a 2-alkoxy-substituted dienyl complex in an iron-mediated synthesis of tamandron (44).74 In a route towards dihydroscorine the dienyl complex (45) carries a functionalized side-chain.The prochiral 6-methoxy-substituted dienyl complex (46) has been employed with a copper-modified dianion nucleophile in a model study for a route to hippeastrine. The methoxy group served as a leaving group to regain access to the q5 cation form of the metal complex during the lactonization procedure affording (47).76 The Pearson group has taken up the chemistry of tricarbonyliron derivatives of biologically derived cyclohexadiene- 1,2-diol complexes. The regiocontrol advantages of the trifluoro- methyl substituent in these compounds (described in the Annual Reports last year) has been confirmed in this study which also proves by X-ray crystallography the all-cis stereochemistry of the metal complex.77 The Knolker group has described details of 'O W.A.Donaldson R. Craig and S. Spanton Tetrahedron Lett. 1992 33 3967. l1 G. M. Williams and M. J. Pino Organometallics 1992 11 345. 72 A. J. Pearson and K. Srinivasan J. Org. Chem. 1992 57 3965. 73 G.A. Potter R. McCague and M. Jarman J. Chem. Soc. Chem. Commun. 1992 637. 74 G.A. Potter and R. McCague J. Chem. Soc. Chem. Commun. 1992 635. 75 G. R. Stephenson R. D. Thomas and F. Cassidy SYNLETT 1992 247. 76 S.T. Astley and G. R. Stephenson SYNLETT 1992 507. 11 A. J. Pearson A. M.Gelormini and A. Pinkerton Oryanometallics 1992 11 936. G.R. Stephenson reactions of tricarbonyliron cation complexes and donor-substituted arylamines. 78 Charge stabilization by aromatic substituents during acid-catalysed demethoxylation routes to cationic dienyl complexes has been studied79 and X-ray crystallography and high field NMR have been employed to elucidate details of the stereochemistry of wring steroidal cyclohexadienyl complexes.80 An acyclic complex carrying a trimethylsilyl directing group at C-2 has been prepared in Donaldson's laboratory. Reaction with malonate or triphenylphoshine traps the complex in the cis form (49)' but in methanol the trans-product (48) was produced.81 Pearson's group made considerable progress in seven-membered ring complexes.The pattern of electrophile addition followed by nucleophile addition (compare this with the r14 example above) leads to the formation cis-disubstituted product. This reaction sequence has been described in both the phosphine (L = PPh3)82 and the phosphite [L = P(OPh),]83 series. Work directed towards the immunosuppressant compound FK-506 used an em-substituted dienyl complex in stereocontrolled C-0 0 0 Me i.?Po-""' Br BuLi/Cu(Me*S)Br ii W12 HzO,EtOH ROJ@ -+F~(co)~ " H. J. Knolker M. Bauermeister and J.-B. Pannek Chem. Ber. 1992 125 2783. 79 G. R. Stephenson D. A. Owen H. Finch and S. Swanson Aust. J. Chem. 1992,45 121. 'O R. E. Perrier C. S. Frampton and M J. McGlinchey J. Organomet. Chem. 1992 435 357. " W.A. Donaldson P. T. Bell and M.-J. Jin J. Organomet. Chem. 1992 441 449. " A. J. Pearson and K. Srinivasan Tetrahedron Lett. 1992 33 7295. 83 A. J. Pearson and K. Srinivasan SYNLETT 1992 983. Organometallic Chemistry -The Transition Elements 2 19 50% (*)-(47) 70% Scheme 16 bond formation.84 Kinetics of 4-cyanopyridine addition to both cyclohexa- and cyclohepta-dienyl iron complexes have been described.8 SiEt SiEt I OMe HpF6 AQO ___) (48) 89% SiEt OH Me 23% -<co2Me\ C02Me C02Me (49) 71% Scheme 17 Low temperature h rdride addition to the inden 3 complex (50) affords the unusual metal hydride product (51). The ruthenium complex (SO) undergoes ligand exchange with cyclopentadiene to afford (51) which reacts by hydride transfer to reform a trimethylbutadiene ligand in the product (S2).86In another unusual reaction of a 84 A.J. Pearson Y.-S. Lai and K. Srinivasan Aust. J. Chem. 1992 45 109. T.I. Odiaka and R. van Eldik J. Organomet. Chem. 1992 425 89. 86 D.N. Cox T. Lumini and R. Roulet J. Organomet. Chem. 1992 438 195. G.R. Stephenson cyclopentadienyl structure (in this case pentamethylcyclopentadienyl bound to Mo(CO),) ring opening to form a oxacyclohexadienyl cation is promoted by oxidation in air.87 As with diene complexes oxygen replacement in dienyl structures also opens up new territory. Examples of ruthenium complexes of this type have been described.88 The stereodynamics of 6-exo-phenylcyclohexadienylcomplexes of man- ganese and rhenium have been examined in collaboration between the groups of Sweigart and B~shweller.~~ Cone angles for substituted cyclopentadienyl complexes have been determined,” and conformational studies of a-carbonyl complexes of manganese and rhenium have been described.’ Cyclopentadienyl molybdenum complexes have been connected together to form co-polymers with Mo and Fe subunits arrayed along the polymer ba~k-bone.~ $ Ru’ Ru’ Gutd‘cNBut (50) (51) 75% (52) 80% Scheme 18 q6-Complexes.-Developments in the organometallic chemistry of heterocyclic ligands give new illustrations of the utility of the transition metal complexes.Widdowson’s group has described a synthesis of ( +)-chuangxinmycin methyl ester employing regioselective metalation of an q6 indole complex followed by transmetallation using trimethyltin chloride.After decomplexation tin is replaced by iodine for use in palladium catalysed coupling to form a thi~ether.~~ Anion addition to indole complexes (e.g. 53) provides an alternative for functionalization at the same position on the indole ring requiring only oxidation of the chromium anion intermediate with iodine to complete the construction of products such as (54).94 Metalation of a chromium benzothiophene complex has been used to provide a nucleophile for reaction with q6 tricarbonylmanganese arene c~mplexes.~~ Comparison of the Widdowson [complex (55)] and Beck [complex (56)]metallation products indicates the possibilities for regioselection available with these compounds.Reduction of ” F. Bottornley and J. Chen Organometallics 1992 11 3404. W. Trakarnpruk A. M. Arif and R. D. Ernst Organometallics 1992 11 1686. 89 R. D. Pike T. J. Alavosus W. H. Hallows N. S. Lennhoff W. J. Ryan D.A. Sweigart C. H. Bushweller C. M. DiMeglio and J. H. Brown Organometallics 1992 11 2841. 90 N. J. Coville M. S. Loonat D. White and L. Carlton Organometallics 1992 11 1082. 91 E.S. Shubina A. N. Krylov T. V. Tirnofeeva Y.T. Struchkov A.G. Ginzburg N. M. Loirn and L. M. Epstein J. Organomet. Chem. 1992 434 329. 92 S. C. Tenhaeff and D. R. Tyler Organometallics 1992 121 1466. 93 M. J. Dickens T. J. Mowlern D. A. Widdowson A. M. Z. Slawin and D. J. Williams J. Chem. Soc. Perkin Trans. 1 1992 323. 94 C. W. Holzapfel and F. W. H. Kruger Aust.J. Chem. 1992 45 99. 95 J. Breimair M. Wieser and W. Beck J. Organomet. Chem. 1992 441 429. Organometallic Chemistry -The Transition Elements 22 1 cationic cyclopentadienylruthenium complexes of benzo[b]thiophene with triethyl- borohydride effects nucleophile addition at the metal-bound ring adjacent to the sulfur. Again the regiochemistry leading to (57) is different to that responsible for the formation of (54). Related reduction of an iridium dication complex (58) was per formed in two stages first using borohydride and then using an aluminium hydride reagent.96 Similar chemistry of q5-tricarbonylchromium complexes of thi~phene~~ and q7-tricarbonylmolybdenum complexes of a boracycloheptatrienyl ligand98 was reported. PhSJ Q-d- ii.iInhfi-12; iii HzO (CO),Cr I I 'Boc 'Boc (53) (54) 62% Li Scheme 19 Activation for nucleophile addition to aromatic rings is a typical use of chromium arene complexes. Addition of anions derived from carboxylic and phosphoric arnide~,~~ anionic carboranes,' O0 and amino esters and nitriles. 'O1 provide examples of nucleophile addition/leaving group displacement from q6 haloarene complexes. This reaction offers an alternative to the use of palladium coupling to functionalize chromium-bound haloarene systems. lo2 When no leaving group is present on the metal-bound ring nucleophile addition can be followed by trapping with an alkyl halide under a carbon monoxide atmosphere to effect acyl transfer. 96 J. Chen Y. Su R.A. Jacobson and R.J.Angelici. 1.Orgunomrt. Chem.. 1992. 428 415. 97 M.S. Loft D.A. Widdowson and T.J. Mowlem. SYNLETT. 1992 135. 98 A. J. Ashe 111 J. W. Kampf Y. Nakadaira and J. M. Pace Angew. Chem.. Int. Ed. EngI 1992. 31 1255. Y9 C. Baldoli P. Del Buttero and S. Maiorana Tetruhedrnn Lrtr.. 1992. 33 4049. 1 no T. J. Henly C. B. Knobler and M. F. Hawthorne. Organometal/ic.s 1992 11 2313. 101 F. Rose-Munch K. Annis E. Rose and J. Vaisserman J. Orgunornet. Chern. 1992 415. 223. 102 J. F. Carpentier. Y. Castanet J. Brocard. A. Mortreux and F. Petit. Tt,truhedron Lerr. 1992. 33 2001. G.R. Stephenson Nucleophile addition to benzaldehyde complexes can also give efficient stereocon- trol. Typical systems employ ortho-substituted aryl aldehydes. The reaction has been extended in a cycloaddition route to produce an enantiopure halostachine analogue (60).'03 An interesting isonitrile-derived anion (59) is used in this reaction.After removal of the metal hydride reduction detaches the sulfur group. Lewis acid catalysed trimethylsilylketene 0,s-acetal addition afforded stereocontrolled aldol products such as (61).'04 Even conjugate addition can be placed under the stereocontrol of the chromium arene unit. By using an enantio-defined organocopper nucleophile with Lewis acid catalysis the product (63) was obtained efficiently with greater than 99% diastereoselectivity. With the enantiomer of (62)as the starting material however only a 66:34 ratio of stereoisomers could be obtained. This is an example of double stereodifferentiation with (63) arising from the matched combination of stereo isomer^.'^^ Wittig and Reformatskylo6 and lithium/titanium tri~hloride"~ coupling reactions were performed with q6-tricarbonylchromium acylarene complexes.Anions can also be developed adjacent to a tricarbonylchromium arene complex. Bases used include LiMEt,,"* b~tyllithium/TMEDA,'~~ t-butyllithium,' lo and Me / ii hv; iii LiAIh Scheme 20 103 A. Solladie-Cavallo S. Quazzotti S. Colonna A. Manfredi J. Fischer and A. DeCian Tetrahedron Asymmetry 1992 3 287. I04 C. Mukai M. Miyakawa A. Mihira and M. Hanaoka J. Org. Chern. 1992,57 2034. 105 M. Uemura H. Oda T. Minami M. Shiro and Y. Hayashi Organornetallics 1992 11 3705. 106 T. E. Bitterwolf and X. Dai J. Organornet.Chem. 1992,440 103. 107 J. Besaqon J. Szymoniak and C. Moise J. Organornet. Chem. 1992 426 325. 108 V. N. Kalinin I. A. Cherepanov and S. K. Moiseev J. Chem. SOC. Mendeleev Commun. 1992 113. 109 M. Persson and U. Hacksell J. Chem. SOC.,Perkin Trans. 1 1992 131. 110 S.G. Davies C. L. Goodfellow and K. H. Sutton Tetrahedron Asymmetry 1992 3 1303. Organometallic Chemistry -The Transition Elements potassium t-butoxide.' '' The first two cases illustrate the switching of regiocontrol by the placement of alkoxy and silyloxy substituents in q6 tetralin complexes. Enolates developed from transition metal complexes of ortho-substituted arylmethylketones give reasonable (9 1) diastereoselectivity in aldol reactions.' l2 Metalation of the metal-bound arene is also an important process.Asymmetric modification of this reaction using a chiral acetal substituent has been examined.' l3 Related chiral aminals are used to induce asymmetry during the complexation reaction.' l4 The physical properties of tricarbonylchromium complexes have been studied in detail. Scalar 13C-19F spin-spin coupling has been used in conformational studies.' Fluorinated biaryl complexes have also been examined.' l6 Slowed rotation of tricarbonylchromium groups in benzyl cation systems has been studied by I3C NMR and EHMO investigations.' ' Highly functionalized arene complexes also exhibit rotational barriers.' ' Interactions between the metal and side-chain alkynes in phenylacetylene complexes have been investigated.' l9 A series of papers describe the interactions of donor and acceptor groups as substituents on chromium arene complexes.Comparison' 2o of crystal structures have led to the conclusion that donor substituents bend away from the chromium arene unit while acceptor substituents are bent down towards the metal. 1,4-Disubstitution influences the electron density of the aromatic ring. When several substituents are present the effects are not directly additive.' 21 Organosilicon' 22 and organometallic' 23 substituents have been examined on chromium arene units. As with organic substituents the organometallic donor unit (FeC0,Cp) in (64) is bent away from the metal distorting the planarity of the aromatic ring. The bimetallic complex (64) was obtained by displacement of fluoride from the fluorobenzene tricarbonylchromium complex with Fp- .In other studies bimetallic products arise from reaction of a metal halide with the lithiated arene complex (65). Titanium-dicyclopentadienylchloride and gold-tristriphenylphosphine,'24 and pen- tacarbonylmangane~e'~~ have been introduced in this way. Another route to bimetallics employs a substituent on the organometallic arene complex as a ligand. Addition of sodium cyclopentadienide to the cationic benzene complex (66) provides a suitable case. Reformation of the cyclopentadienyl anion followed by addition of a metal halide has given access to a variety of bimetallic compounds.'26 Mechanistic studies of reactions of tricarbonylchromium complexes have now appeared.' 27 M.-C.Senechal-Tocquer D. Senechal J.-Y. Le Bihan D. Centric B. Caro M. Gruselle and G. Jaouen J. Organornet. Chem. 1992 433 261. M. Uemura T. Minami M. Shiro and Y. Hayashi J. Organornet. Chem. 1992 57 5590. 'I3 J. Aube J.A. Heppert M. L. Milligan M. J. Smith and P. Zenk J. Org. Chem. 1992 57 3563. A. Alexakis P. Mangeney I. Marek F. Rose-Munch E. Rose A. Semra,and F. Robert J. Am. Chem.SOC. 1992 114 8288. P. Szczecinski J. Organornet. Chem. 1992 423 23. 'I6 P. Szczecinski and K. Wisniewski J. Organomet. Chem. 1992 423 C13. 'I7 P.A. Downton B.G. Sayer and M. J. McClinchey Organaometallics 1992 11 3281. 'I8 K.V. Kilway and S. Siegel Organometallics 1992 11 1426. J. Szewczyk and A. Gryff-Keller J. Organomet. Chem. 1992 424 41. A. D. Hunter L. Shilliday W. S.Furey and M. J. Zaworotko Organometallics 1992 11 1550. ''' A. D. Hunter V. Mozol and S. D. Tsai Organometallics 1992 11 2251. 12' M. Moran I. Cuadrado M. C. Pascual C. M. Casado and J. Losada Organometallics 1992 11 1210. lZ3 J. Li A. D. Hunter R. McDonald B. D. Santarsiero S. G. Bott and J. L. Atwood Organometallics 1992 11 3050. lZ4 P. H. van Rooyen M. Schindehutte and S. Lotz Organometallics 1992 11 1104. S. Lotz M. Schindehutte and P. H. van Rooyen Organometallics 1992 11 629. T.-M. Chung and Y. K. Chung Organometallics 1992 11 2822. 12' R. D. Rieke K. P. Daruwala D. Schulte and S. M. Pankas Organometallics 1992 11 284. G.R. Stephenson i NaCp ii Bu"Li (66) Scheme 21 Like the neutral tricarbonylchromium complexes cationic arene complexes of haloarenes are highly effective at promoting nucleophile addition/leaving group displacement.Chlorobenzene derivatives are typical substrates. Examples include the formation of t-butyl-N-(ary1oxy)carbamates' 28 and reactions with imidazole and triazole anions'29 and with malononitriles.' 30 With two halogen substituents on the aromatic ring a sequence of two leaving group displacements can be performed. l,4-Dichlorobenzene'3' and 1 ,3-dichlorobenzene1 32 complexes have also been em- ployed as substrates. In the latter case Pearson has developed a highly efficient route to diether complexes. Direct nucleophile addition can be performed without the presence of a leaving group. The directing effect of t-b~tyl'~~ substituents on a manganese arene complex has been determined in this reaction.A tricarbonylmanganese complex of 2,6-dimethoxyethylbenzene was used as a precursor in a synthetic route to antibiotic stilbenes in which the metal complex promotes nucleophile addition by Grignard reagents derived from bromostyrenes.' 34 When bases are employed instead of nucleophiles deprotonation of alkyl substituents adjacent to tricarbonylmanganese arene complexes can be achieved.' The combination of nucleophile addition/leaving group displacement with substituent-directed nucleophile addition and oxidative re-aromatization provides alternative access to 1,3-disubstituted arene~.'~~ Selective activation of carbon-chlorine bonds has employed a ruthenium complex.' 37 Quinones have also been complexed to ruthenium but the products contained hydroquinone structures.' 38 Highly substituted aromatic rings can be obtained employing the products from deprotonation reactions.Tentacled aromatic iron sandwich complexes are available in this way. Compounds such as (67) can be elaborated by hydroboration or hydrozir- M. S. Holden and K. A. Cole Synth. Commun. 1992 22 2579. lZ9 R. M.G. Roberts J. Organomet. Chem. 1992 430 327. 13' A.S. Abd-El Aziz and C.R. de Denus Synrh. Commun. 1992. 22. 581. 131 R. C. Cambie S.J. Janssen P.S. Rutledge and P. D. Woodgate J. Organomet. Chem. 1992 434 97. A. J. Pearson J.G. Park and P.Y. Zhu J. Org. Chem. 1992 57,3583. 133 E. Jeong and Y.K. Chung J. Orgunomet. Chem. 1992 434 225. 134 G. R. Krow W. H. Miles P. M. Smiley W.S.Lester and Y. J. Kim J. Org. Chem. 1992 57,4040. 135 J.W. Hull Jr. K. J. Roesselet and W. L. Gladfelter Orgunometallics 1992. 11 3630. 136 A. J. Pearson and H. Shin Tetrahedron 1992 48 1527. 137 D. Rondon X.-D. He and B. Chaudret J. Orgunomet. Chem. 1992,433 CIS. 13* Y.4. Huang. S. Sabo-Etienne X.-D. He and B. Chaudret Orgunomrtullics 1992 11 3031. Organometallic Chemistry -The Transition Elements or ~onation,'~~ by repeated deprotonation and attachment of a further alkyl ~ide-chain.'~' Ruthenium complexes of aromatic steroids (68) have also been prepared .I4' 7 ' 42 Rucp* Tricarbonylchromium complexes have also been used to form some unusual chiral auxiliaries. A chromium arene complex with a chiral a-aminoether substituent effects highly efficient reaction between diethylzinc and benzaldehydes affording products in up to 99% e.e.' 43 Asymmetric palladium- and nickel-catalysed cross coupling reactions between Grignard and zinc reagents and vinyl halides employed another organometallic auxiliary inducing asymmetry to the extent of 68% e.e.' 44 3 Alkyne Complexes Electrophilicity Adjacent to the A1kyne.-The Nicholas reaction involves nucleophile addition at a cation stabilized at a position adjacent to a hexacarbonyldicobalt alkyne complex.These cationic intermediates are not as stereochemically straight-forward as they may appear. A detailed study from the Nicholas group has identified the stereochemical issues in isomerization processes available to the cations. The normal drawing (69) conceals some of the key issues.'45 Thioalkyne complexes have been obtained by propargyl alcohol displacement via hexacarbonyldicobalt stabilized ~ati0ns.I~~ Enamines have also proved useful nuc- leophile~,'~~ and work continues employing silylenol ether derivatives as nucleophilic species; reactions using cyclic silylketene acetals have been described.I4* In this case a propargyl aldehyde served as the substrate with a Lewis acid promoting electrophilic- ity enhanced by the stabilization provided by the two cobalt atoms.Propargyl cations I39 F. Moulines L. Djakovitch J.-L. Fillaut and D. Astruc. SYNLETT. 1992 57. 140 F. Moulines B. Gloaguen and D. Astruc Angew. Chem.. Int. Ed. Engl.'. 1992 31. 458. 141 D. Vichard M. Gruselle H. E.Amouri G. Jaouen. and J. Vaissermann Orqanometallirs 1992. 11. 976. 142 Idem. Organornetalirs 1992 11 2952. 143 S. 9. Heaton and G. B. Jones Tetrahedron Lett. 1992 33 1693. I44 M. Uemura. R. Miyake H. Nishimura Y. Matsumoto and T. Hayashi Tetrahedron Asymmetry 1992,3. 213. 145 D. H. Bradley M. A. Khan and K. M. Nicholas Orqanometullics 1992 11 2598. 146 S.C. Bennett A. Gelling and M. J. Went .I.Organomet. Chem. 1992 439 189. 147 K.-D. Roth SYNLETT 1992 435. 148 C. Mukai K. Suzuki K. Nagami M. Hanaoka J. Chem. Soc.. Perkin Trans. 1 1992 141. G.R. Stephenson Scheme 23 of type (69) are typically formed by the displacement of propargyl leaving groups in acid. When two leaving groups are present (one at each end of the alkyne) a sequence of two nucleophile addition reactions can be performed.Allylsilanes allylstannanes and silylenol ethers have been used in this process.149 Diasteroisomeric alkynes with chirality centres at the ends of the triple bond are hard to separate. It has been found that formation of hexacarbonyldicobalt complexes at the alkyne can ease separation. This has been interpreted as a relay of a chiral interaction between the two ends of the molecule. 'O Manganese acetate promoted radical addition to vinyl substituted hexacarbonyldicobalt alkyne complexes. An unusual cyclization can be effected in this way affording (70) after oxidative removal of the ~obalt.''~ Mey s' Me (70) 40% Scheme 24 Cyclization to Form Cyc1opentenones.-The Pauson-Khand reaction (the cyclization of an alkyne an alkene and carbon monoxide to form a cyclopentenone) has now become a well established synthetic step.Hexacarbonyldicobalt alkyne complexes are '49 S. Takano T. Sugihara and K. Ogasawara SYNLETT 1992 70. C. Alayrac C. Mioskowski J.P. Salaun and F. Durst SYNLETT 1992 73. Is' G. G. Melikyan 0.Vostrowsky W. Bauer and Y.J. Bestmann J. Organomet. Chem. 1992 423 C24. Organometallic Chemistry -The Transition Elements used as precursors with reactions performed by heating or carbonyl group removal. A typical example of this reaction has been reported by Rowley and Shore adding to the now extensive range of applications of this reaction in synthetic routes to triquinane natural products.' 52 Coordinating ligands adjacent to the alkyne component have been found to accelerate the Pauson-Khand reaction.53 Enantioselective modifica- tion of the Pauson-Khand reaction is also becoming important. Attachment of chiral auxiliaries to both the alkyne and alkene in an intramolecular version of the reaction has been examined.154 Diastereoselectivity as high as 94 :6 was observed. Variants on the Pauson-Khand reaction are now becoming common. The 1-alkynylcyclopropano1(71) for example can serve as a starting material. Complexa- tion with dicobaltoctacarbonyl followed by heating at reflux afforded the cyclopen- tenone (72) in 71% yield.155A combination of the Pauson-Khand cyclization with other cobalt mediated bond-forming reactions is an important strategy. An attractive possibility starts with a vinylalkyne dicobalt complex which can be elaborated first by electrophile addition (using an acylium cation) followed by nucleophile addition before the Pauson-Khand step removes the metal to build the cyclopentenone.At present typical nucleophiles are alcohols which can either be employed to introduce the ally1 ether building blocks needed for the cyclization or can produce other (72) 71% 0 Me i MeCO+ -0 ii -OH iii Siq (73) i. do I ii. MeOH 7s iii Siq (CO)3C0-Co(CO) Scheme 25 E.G. Rowley and N.E. Shore J. Org. Chem. 1992,57 6853. M. E. Krafft I. L. Scott and R.H. Romero Tetrahedron Lett. 1992 33 3829. X. Verdaguer A. Moyano M. A. Pericas A. Riera A. E. Greene J. F. Piniella and A.Alvarez-Larena J. Organomet. Chem. 1992 433 305. N. Iwasawa Chem. Lett 1992 473. 228 G. R. Stephenson functionality when the vinyl substituent is introduced to the acylium cation. Reaction sequences leading to (73) and (74) illustrate these possibilities.' 56 Molybdenum and tungsten complexes have also been used in Pauson-Khand steps,' and further examples of titanium-mediated cyclopentenone formation have been described. ' Structurally related indenones have been obtained by alkyne insertion under palladium catalysis. In this case an ortho-metalated aromatic aldehyde was used as the starting material and carbonylation was not involved.'59 When two alkynes are combined with carbon monoxide a cyclopentadienone is formed.Iron carbonyls have been examined independently by the groups of Pearson16' and Knolker161 for this purpose. Intramolecular versions of the reaction give efficient access to the tricar- bonyliron complexes of type (75). Intermolecular reactions with trimethylsilylalkynes are also efficient and regioselective. Intermediate q4-diene complexes are produced and these can be demetalated to afford cycloaddition adducts of type (76). Another bis-alkyne (77) affords a mixture of (78) and (79) using a mixed rhodium/cobalt catalyst. With tetrarhodiumdodecacarbonyl however the same substrate affords only (79) in 81YOyield. Bis-N-allylpropargylamines have also been treated with a rhodium catalyst in the presence of a silane. In this case however cyclization occurred without carbon monoxide insertion.'62 Both the dot^'^^ and M~retO'~~ groups have examined cobalt-mediated Pauson-Khand cyclizations in the presence of tungsten aminocarbene complexes.Again allylamine derivatives are involved in the cyclizations. While cyclopentenone products can be obtained,' 63 first trimetallic and ultimately bimetallic cobalt complexes are also formed from the silylalkynes following reaction sequences which begin by interaction of the alkene within the allylamine unit at the carbene complex.164 Cyclization to Form Arenes.-When three alkynes cyclize aromatic rings are formed. This is the well known cobalt-catalysed Vollhard cyclization. A stannylalkyne variant reported by McNichols and Stang provides an improved synthesis of rocketene (80).'65Nickel catalysis has been used with propargyl alcohols to produce tricyclic products through lactonization following the cyclotrimerization step.' 66 The lactone (81)is a typical product and is formed at room temperature under these conditions.Palladium catalysts under acidic conditions have also been used for alkyne cyclo- trirneri~ati0n.l~~ The terminal alkyne in the starting material (82)can be replaced by a 2-bromoalkene. With this substrate under conditions that employ triethylamine in place of acetic acid the yield for the cyclotrimerization is improved to 85%. Two 15' A. S. Gybin W. A. Smit R. Caple A. L. Veretenov A. S. Shaskov L.G. Vorontsova M. G. Kurella V.S. Chertkov A.A. Carapetyan A.Y. Kosnikov. M.S. Alexanyan S.V. Lindeman V.N.Panov A.V. Maleev Y.T. Struchkov and S. M. Sharpe J. Am. Chem. SOC.,1992 114 5555. Is' C. Mukai M. Uchiyama and M. Hanaoka J. Chem. SOC.,Chem. Commun. 1992 1014. Is* R. B. Grossman and S. L. Buchwald J. Org. Chern. 1992 57 5803. J. Vicente J.-A. Abad and J. Gil-Rubio J. Organomet. Chem. 1992 436 C9. ''O A. J. Pearson R. J. Shively Jr. and R. A. Dubbert Oryanometallics 1992 11 4096. 16' H.-J. Knolker J. Heber and C.H. Mahler SYNLETT 1992 1002. 16' I. Ojima R. J. Donovan and W. R. Shay J. Am. Chem. SOC. 1992 114 6580. K. H. Dotz and J. Christoffers J. Orgariomet. Chem. 1992 426 C58. 164 L. Jordi. J. M. Moreto S. Ricart M. Viiias M. Mejias and E. Molins Orgmometullics 1992 11 3507. A.T. McNichols and P. J. Stang SYNLETT 1992 971. P. Bhatarah and E.H.Smith J. Chem. SOC.,Perkin Trans. I 1992 2163. 167 E. Negishi L. S. Harring,Z. Owczarczyk M. M. Mohamud and M. Ay Tetrahedron Lett. 1992,33,3253. Organometallic Chemistry -The Transition Elements R (75) R = Ph 97% R = Me3Si,70% i Fe(C0)s. A D Me$i ii MqNO EgSiH -(BdNC)4RhCo(CO)4 CO A (79) Scheme 26 alkynes and an alkene can also be cyclized. Examples involving a variety of cobalt catalysts have now been reported.'68 Unusual Reactions for the Formation and Transformation of Alkyne Complexes.-The chemistry of propargyl cation complexes has been discussed in detail at the start of Section 3. Deprotonation to form a propargyl anion complex is a much more unusual type of reaction. With an iodotungsten carbonyl Tp' complex [Tp' = hydridotris(3,5-dimethylpyrazolyl)borate] the anion is intercepted by cleavage of the tungsten-iodine bond to form an $-propargyl complex.This will react with alkyl halides at the a-carbon atom.'69 Hydride reduction of a cationic alkyne complex has been used to form an q2-vinyl complex from diphenylethyne. With a methyl substituent on the alkyne in place of one of the phenyl groups an q3 product resulted from the same reducing conditions. ''O Carbonyl insertion into a carbene ligand formed an unusual 16x Z. Zhou M. Costa and G. P. Chiusoli J. Chem. SOL..,Perkin Trans. I 1992. 1399. 169 M.A. Collins S.G. Feng P.A. White and J.L. Templeton. J. Am. Chem. SOL...1992 114 3771. 170 S.G. Feng and J. L. Templeton Organometullics.1992 11 2168. G. R. Stephenson OSiMe cPcy2 -mosiMe3 BuLi 0 I[ 5nbu3 / SnBu3 50% (80)65% Et02c&Me et02c 67% Scheme 27 structure with the carbon monoxide bridging between metal and carbon of the carbene. Reaction with acid chlorides affords q2 alkyne complexes.' 71 Alkyne complexes in small rings have been formed by elimination of selenium and dinitrogen. The selenocycle (83) reacts with tetracarbonyldi(cyclopentadieny1)dimolybdenum to form an intermediate dimolybdenum complex which is taken through to the small-ring cycloalkyne complex (84).' 72 (84) 19% Scheme 28 4 Carbonylation Reactions Hydroformylation.-In hydroformylation reactions of unsymmetrical alkenes re- giocontrol is an important issue.An unusual zwitterionic rhodium catalyst for hydroformylation has been evaluated by Alper and Zh~u.'~~ Using (85) high "' K.A. Belsky M. F. Asaro S. Y. Chen and A. Mayr Organometallics 1992 11 1926. "* A. J. Mayr B. Carrasco-Flores L. Parkanyi and K. H. Pannell J. Am. Chem. SOC.,1992 114 5467. H. Alper and J.-Q. Zhou J. Org. Chem. 1992 57 3729. Organometallic Chemistry -The Transition Elements 23 1 selectivity for branched products was obtained in the hydroformylation of a,p-unsaturated esters. With more conventional rhodium catalysts the size of the phosphorous co-catalyst has been found to be a crucial factor in regioselectivity.' 74 Another strategy to obtain regiocontrol places a ligand site in the substrate for hydroformylation. In the case of (86) hydroformylation at the near end of the alkene was achieved.Complete control to form the cis stereoisomer was an added benefit of the method.' 75 Hydroformylation in the presence of a dialkylamine achieved chain extension and reductive amination in a single reaction step. Again rhodium catalysts were used. 1 -0ctene was converted into diethylnonylamine using diethylamine hydrogen and carbon monoxide. '76 Deformylation with Wilkinson's catalyst afforded an '8Flabelled sample of 3-fluoroanisole from 4-formyl-3-nitroanisole and radiolabel- led potassium fluoride. The speed of reaction was an important factor in the use of this short half-life radioisotope.' 77 0 Scheme 29 New Applications of Collman's Reagent.-l,4-Dicarbonyl compounds can be prepared from alkyl halides and enones using Collman's reagent in a conjugate addition manner.Carbonyl insertion introduces the new ketone functionality.' 78 Overman and Sharp have used Collman's reagent to open an aziridinium salt in order to complete a tricyclic cyclopentanone. '79 Double carbonyl insertion can produce 1,2-diketones. Modification of the normal Collman reagent system by adding CuCl leads to the production of symmetrical dicarbonyl products. '8o Other Routes to Ketones.-Triruthenium dodecacarbonyl has been used as a catalyst with pyridine and 1-alkenes to produce 2-acylpyridine.' 81 Iodoalkanes and vinyltin compounds serve in a similar manner to produce phenylvinylketones. '82 Tricar-bonyliron complexes are well known as starting materials for cyclic ketones using Lewis acid promoted carbonylated.New examples have been described in two papers from Frank-Neumann's group.' 83*184 174 A. Polo C. Claver S. Castillon A. Ruiz J. C. Bayon J. Real C. Mealli and D. Masi Organornetnllics 1992 11 3525. 17' W. R. Jackson M.R. Moffat and P. Perimutter Aust. J. Chem. 1992 45 823. I76 T. Baig and P. Kalck J. Chem. SOC. Chem. Commun. 1992. 1373. 177 A. Plenevaux C. Lemaire A. J. Palmer P. Damhaut and D. Comar Appl. Rndiat. Zsot. 1992,43 1035. 17' M. Yamashita H. Tashika and M. Uchida Bull. Chem. SOC.Jpn. 1992 65 1257. 17' L.E. Overman and M. J. Sharp J. Org. Chem. 1992 57 1035. A. Devasagayaraj and M. Periasamy Tetrahedron Lett. 1992 33 1227. ''I E. J. Moore W. R. Pretzer T. J. O'Connell J.Harris L. LaBounty L. Chou and S. S. Grimmer J. Am. Chem. SOC. 1992 114 5888. ''' T. Sakamoto A. Yasuhara Y. Kondo and H. Yamanaka Chem. Pharm. Bull. 1992,40 1137. M. Frank-Neumann E. L. Michelotti R. Simler and J. M. Vernier Tetrahedron Lett. 1992 33 7361. M. Frank-Neumann and J. M. Vernier Tetrahedron Lett. 1992 33 7365. G. R. Stephenson Carbonylation to Form Esters.-Hydroxycarbonylation of vinyl or allyl triflates produced the corresponding carboxylic acid under palladium catalysis.' 85 Alkynyl-silanes in ethanol were carbonylated to afford a,&unsaturated esters with the silicon atom at the 2 position of the product.'86 Arylfluorosulfonates are also useful starting materials.' 87 In both these cases palladium catalysis was used. Palladium catalysts also convert allyl bromides into the corresponding acyl fluorides using carbon monoxide and postassium fluoride.' 88 Functional alcohols can be employed in place of simple alcohol solvents.Two examples using phenols have been described recently. With phenylacetylene and 4-methylphenol carbonyl insertion catalysed by Pd(PPh,) afforded the 1-phenylacrylate (87).'89 Lactonization by Carbonyl Insertion.-The Ley lactonization precedure involving tricarbonyliron metallolactone complexes provides an important general method which is being exploited in natural product synthesis. An advantage is that starting materials are vinyl epoxides which often can be formed with good enantioselectivity .A simple example is provided by the construction of a C building block containing a Scheme 30 &lact~ne.'~~.'~~ This building block provides a key component in the synthesis of ro~tiennocin.'~~ A palladium catalysed lactonization has been used by Gracza and Jager in a synthesis of ( -)-goniofufurone.This process employs a modification of the Wacker oxidation conditions with three equivalents of cupric chloride allowing re-oxidation of the palladium catalyst at the completion of each cycle. In the Wacker oxidation water adds as a nucleophile to an electrophilic q2-complex (see Section 2). Modification allows intramolecular oxygen attack to be followed by carbonylation to S. Cacchi and A. Lupi Tetrahedron Lett. 1992 33 3939. 186 R. Takeuchi M. Sugiura N. Ishii and N. Sato J. Chern. SOC.,Chern.Cornmun. 1992 1358. In' G.P. Roth and J. A. Thomas Tetrahedron Lett. 1992 33 1959. T. Okano N. Harada and J. Kiji Bull. Chern. SOC.Jpn. 1992 65 1741. ln9 K. Itoh M. Miura and M. Nomura Tetrahedron Lett. 1992 33 5369. 190 N.R. Kotecha S.V. Ley. and S. Mantegani. SYNLETT 1992 395. D. Diez-Martin N. R. Kotecha S.V. Ley and J. C. Menendez SYNLETT 1992 399. 19' D. Diez-Martin N. R. Kotecha S. V. Ley. S. Mantegani J.C. Menendez H. M. Organ A. D. White and B. J. Banks Tetrahedron 1992 48 7899. Organometallic Chemistry -The Transition Elements form a lactone from the 3,4-dihydroxy-l-alkene (88). The bicyclic product (89) was formed in high yield.193 Oxidative addition to a vinyl-triflate can also provide the metal carbon a-bond needed for carbonylation.194 A combination of oxidative addition and alkene insertion followed by carbon monoxide insertion has been employed to combine aryl halides and norbornenes to form large cyclic lactone with acylnorborane units completing the ring system.195 Carbon dioxide insertion with allenyl ethers has also been used as a lactonization procedure under palladium catalysis 0 OH OH co HOAc (88) (89) 93% Scheme 31 Multiple Carbonyl Insertion.-Since carbonyl insertion produces a new carbon-metal a-bond in the metal acyl intermediate insertion of a second molecule of carbon monoxide can be anticipated. The furan product (90)arises in this way.19' A ziconium or hafnium-diene complex is the starting point for carbonyl insertion to form (91 ).' 98 Triple carbonyl insertion using propargyl alcohol as the substrate has also been reported.199 5 Palladium Coupling Reactions Simple Coupling Processes.-Asymmetric modification of palladium catalysed coup- ling is the new growth area in the subject. Two distinct strategies are available elaboration of a prochiral alkene by differentiation of the enantiofaces in the coupling process and the differentiation of two enantiotropic alkenes within a symmetrical diene. Examples of both types of reaction have appeared during the year.200-202 Elaboration of 2,3-dihydrofuran in coupling with an aryl-triflate has been performed in the presence of the BINAP ligand. An enantiomeric excess as high as 96% is possible in the products. A rearranged 2,3-dihydrofuran is shown as the product (92) but under other conditions 3,4-dihydrofuran products are formed.200-202 Reactions leading to enantiotropic group differentiation have also employed the BINAP ligand.A vinyl-halide attached by an alkyl spacer to the 3-position of a cyclohexa-1,4-diene allows differentiation of the two alkenes within the ring. Diastereoface selectivity in this T. Gracza and V. Jager. SYNLETT 1992 191. 19' G.T. Crisp and A. G. Meyer J. Org. Chem. 1992. 57 6972. IY5 E. Dalcanale Z. An L. P. Battaglia M. Catellani and G.P. Chiusoli J.Organomet. Chem. 1992.437.37s. 196 T. Tsuda T. Yamamoto and T. Saegusa J. Organornet. Chem.. 1992 429 C46. 197 K. Okuro M. Furuune M. Miura and M. Nomura J. Org. Chem. 1992 57 4754. 198 R. Beckhaus D. Wilbrandt S. Flatau and W.-H.Bohmer J. Organornet. Chem. 1992 423. 21 1. 199 B. Gabriele M. Costa. G. Salerno and G.P. Chiusoli J. Chem. Soc.. Chem. Commun. 1992 1007. F. Ozawa and T. Hayashi J. Organomet. Chem. 1992 428 267. *"I A. Ashimori and L. E. Overman. J. Org. Chem. 1992. 57 4571. 202 F. Ozawa A. Kubo and T. Hayashi Tetrahedron Lett.. 1992. 33. 1485. G. R. Stephenson 1' Scheme 32 reaction was complete to form the cis fused system (93) with excellent enantiomeric excess at 92%. The unusual base (Ag3P04/CaC0,) was used in this reaction.203 With the triflate substituent at the terminus of the alkene the same procedure forms an optically active decalin with similar enantiomeric excess.2o4 An unusual chiral auxiliary containing a disubstituted tricarbonylchromium-bound arene was used in an asymmetric induction that employs the coupling of stereochemically labile secondary alkylmagnesium and zinc reagents with vinyl bromides.Products had optical purities up to 61 %.20s In general BINAP seems to be the most popular ligand in asymmetric palladium cross coupling. Other examples of the use of BINAP are provided by Ozawa and Hayashi206 and Sakamoto Kondo and Yamanaka.'07 Pd(0Ac)z Ar-oTf (R)-BINAF' 0 OSiBu'Mez ?SiBu'M% PdCI2 + c (R)-BINAP AOTf (93) 35% Scheme 33 '03 Y. Sato T. Honda and M. Shibasaki Tetrahedron Lett. 1992 33 2593. '04 Y. Sato S. Watanabe and M. Shibasaki Tetrahedron Lett. 1992 33 2589. '05 M. Uemura R. Miyake H. Nishimura Y. Matsumoto and T. Hayashi Tetrahedron Asymmetry 1992,3 213.'06 F. Ozawa and T. Hayashi J. Organomet. Chem. 1992 428 267. '07 T. Sakamoto Y. Kondo and H. Yamanaka Tetrahedron Lett. 1992 33 6845. Organometallic Chemistry -The Transition Elements Palladium coupling reactions fall into two main categories. Those which employ alkene functionality which is regained after coupling through elimination (the Heck-type coupling) and those which combine two a-bound components (cross- coupling reactions). During the year there have been a great many new examples of both of these classes of coupling procedures. The reaction is capable of providing versatile new routes in heterocyclic chemistry. Cross-coupling of 3-chloropyridine with a phenylboronate to produce a phenyl-substituted pyridine offers a typical example.In this case [Pd(dppb)Cl,] was used as the catalyst but with chloroquinolines [Pd(PPh,),] was perferred.208 2-BromopyridinesZo9 couple with tin derivatives of thiophenol to form new carbon-sulfur bonds and an elaborated bicyclic 2-iodopyrrole derivative has been coupled with a functionalized chiral alkyne.2 lo The vinylthiophene derivative (94) was coupled by replacement of the carbon-silicon bond;211 in (95) coupling was achieved by replacement of the carbon-tin bond.212 Attachment of an alkyne at the site of iodine substitution in (96) has been described.,13 An example in bipyrridyl chemistry is provided by the iodide (97). In this case a vinylboronate ester was the coupling partner.214 The substrate (98)has two labile carbon-halogen bonds but these were easily differentiated.Replacement of the carbon-iodine bond with an aryltin reagent was performed first. The carbon-bromine bond was then replaced by coupling with an arylboronate. In this way a diary1 indole derivative was produced.” 2,5-Dibromothiophene has been coupled with a 4-stannylpyridine to produce a 2,5-disubstituted thiophine. Furan derivatives behave in the same fashion. The products have been taken on to provide new viologen~.~~~ One of the most popular applications of palladium catalysed cross-coupling is the formation of biaryls. A buttressed reagent (a 2,6-dimethoxyallyltriflate) has been N. M. Ah A. McKillop M. B. Mitchell R. A. Rebelo and P. J. Wallbank Tetrahedron 1992 48 8117. ’09 C. Jixiang and G.T.Crisp Synth. Cornmun. 1992 22 683. P. A. Jacobi and S. Rajeswari Tetrahedron Lett. 1992 33 6235. *I1 R. Rossi A. Carpita and T. Messeri Gazz. Chim. Ztal. 1992 122 65. M. Iyoda Y. Kuwatani N. Ueno and M. Oda J. Chem. SOC..Chem. Cornmun. 1992 158. M. Brakta and G.D. Daves Jr. J. Chem. Soc.. Perkin Trans. I 1992 1883. V. Kumar J.A. Dority E. R. Bacon B. Singh and G. Y. Lesher J. Orq. Chem. 1992 57 6995. Y. Yang and A. R. Martin Synth. Commun. 1992 22 1757. K. Takahashi and T. Nihira Bull. Chem. SOC.Jpn. 1992 65 1855. K. Takahashi T. Nihira K. Akiyarna Y. Ikegami and E. Fukuyo J. Chem. SOC. Chem. Commun. 1992 620. G.R. Stephenson Scheme 34 successfully employed in a biaryl synthesis.’ Highly functionalized compounds suited to natural product synthesis can also be employed.The combination of the trimethoxyarylboronate (99) with 4-bromo-l,2-methylenedioxybenzene afforded a pentasubstituted biaryl derivative. A by-product in the reaction however proved to be a biaryl lacking the methylenedioxy ring.’I9 Another unusual biaryl synthesis starts with 2-iodoanisole which by reaction with palladium diacetate forms a palladium metallocycle which produces cross-coupling products containing two biaryl units.’” Scheme 35 Alkynes are popular partners in coupling reactions. An unusual example employs a bromoalkyne with a vinyltin reagent.221 In another case an alkynyltin reagent is used with an aryl iodide.222 More typically simple terminal alkynes are used. Examples from Yamanaka’s group use the common copper iodide mediated conditions with aryl iodides.223 In another case an alkynyl-substituted amino acid building block was combined with aromatic and heteroaromatic halide and triflate reagents to form a variety of propargyl derivatives.224 The copper mediated conditions have been employed in syntheses of (+ )-and (-)-HETE using a chiral vinyliodide reagent.’25 Another example with a vinylhalide uses an alkylborane as a less conventional coupling partner.Because the vinyl bromide component carried an alkoxy or acetoxy substituents at the other end of the alkene the products were enol ethers and enol acetates.226 Iodine-substituted cyclopentenones make nice building blocks in similar coupling reactions. ’2 Radioisotope synthesis has been accomplished using palladium 218 J.M. Saa G. Martorell and A. Garcia-Raso J. Org. Chem. 1992 57 678. ’I9 D. F. O’Keefe M. C. Dannock and S. M. Marcuccio Tetrahedron Lett. 1992 33 6679. 220 G. Dyker Angew Chem. Int. Ed. Engl. 1992 31 1023. ’’I I. Beaudet J.-L. Parrain and J.-P. Quintard Tetrahedron Lett. 1992 33 3647. z22 T. Sakarnoto A. Yasuhara Y. Kondo and H. Yarnanaka SYNLETT 1992 502. 223 T. Sakamoto F. Shiga A. Yasuhara D. Uchiyama Y. Kondo and H. Yamanaka Synthesis 1992,746. 224 G.T. Crisp and T. A. Robertson Tetrahedron 1992 48 3239. 225 D. Chernin S. Gneugnot and G. Linstrurnelle Tetrahedron 1992 48 4369. 226 S. Abe N. Miyaura and A. Suzuki Bull. Chem. SOC.Jpn. 1992 65 2863. ”’ C. R. Johnson J. P. Adarns M. P. Braun C. B. W. Sananayake P. M. Workulich and M.R. Uskooric Tetrahedron Lett. 1992 33 917. Organometallic Chemistry -The Transition Elements 237 catalysis with a vinyl bromide. Radiolabelled “C cyanide from HCN was used to form acrylonitrile. Cinnamonitrile was prepared in a similar fashion.228 Vinyl nucleophiles can also be used. An example from Labaudiniere and Normant combines a vinylzinc reagent with an aryl iodide.229 Vinylzinc reagents can be combined with vinylhalides in the presence of a CF group in a convenient diene synthesis.230 Some examples using vinyltin also contained carbon- oxygen bonds at the carbon carrying the tin atom. A nice example forms the functionalized sugar derivative^.^^' Coupling a tin reagent with unprotected 2-bromobenzyl alcohol formed a product which cyclized on mild acid treatment (exposure to deutrochloroform) to form an a~etal.~,~ Vinyltriflates have been coupled with 4-alkynyl carboxylic acids to form a la~tone.~,~ The same substrate has also been used in coupling with sodium tetraphenylb~rate.~,~ The divinyltriflate (100)provides an interesting issue for regiocontrol.Coupling with alkynes under the copper iodide procedure has been selectively performed to form (101) which was taken on in a second coupling step to form (102) a building block for studies related to the synthesis of neocar~inostatin.~~’ In a different strategy the trimethylsilyalkyne was attached in the place of the protected propargyl unit in (101).Copper iodide mediated palladium coupling this time employing diethylamine as the base produced another intermediate for neocarzino~tatin.~~~ &f COTHP SiMe3 GTHP OTf yomp -5 OTf -SiMe3 D D pd(pm3)2cIZ pd(Pm3)2c12 cut CUI (100) (101) 47% (102) 77% Scheme 36 Finally some more unusual coupling reactions will be discussed.An asymmetric coupling with a silylketene acetal has been performed regioselectively to yield after hydrolysis chiral 2-ar~lalkanoates.~~’ A chloroformate reagent has been joined to chiral optically pure amino acid building and cross-coupling with vinyl- alkynyl- and aryl-tin reagents had been employed with an organometallic substrate with an iodine-substituted cyclopentadienyl ligand.239 Numerous examples of Heck-type coupling have been reported. Simple styrene^^^'^^^^ are typical substrates.Less conventional is the functionalization of an ’” G. Antoni and B. Langstrom Appl. Radiat. Isot. 1992 43 903. 229 L. Labaudiniere and J.-F. Normant Tetrahedron Lett. 1992. 33 6139. 230 B. Jiang and Y. Xu Tetrahedron Lett.. 1992 33 511. 23‘ E. Dubois and J.-M. Beau Curbohydr. Res. 1992 228 103. 232 D. A. Elsley D. MacLeod J. A. Miller P. Quayle and G. M. Davies Tetrahedron Lett. 1992 33. 409. 233 A. Arcadi A. Burini S. Cacchi M. Delmastro F. Marinelli and B. R. Pietroni,J. Org. Chem. 1992,57.976. 234 P.G. Ciattini E. Morera and G. Ortar Tetrahedron Lett. 1992 33 4815. 235 S. W. Scheuplein K. Harms R. Briickner and J. Suffert Chem. Ber. 1992 125 271. 236 K. Nakatani K. Arai N. Hirayama F. Matsuda and S. Terashima Tetrahedron. 1992 48 633.23’ R. Galarini A. Musco R. Pontellini and R. Santi J. Mol. Card.. 1992 72 L11. R. F. W. Jackson N. Wishart and M. J. Wythes J. Chem. Soc.. Chem. Commun. 1992 1587. 239 E. C. Brehm J. K. Stille and A. I. Meyers. Organometallics. 1992 11 938. 24” Y. Ben-David M. Portnoy M. GoLin. and D. Milstein Organomrta//ic.s. 1992 1I 1995. 241 P. Yi Z. Zhuangyu and H. Hongwen. Synth. Commun.. 1992. 22 2019. 238 G.R. Stephenson allylphosphonate.242 Use of cyclic allylamines (103)243 or the enamine derivative (104)244shows different regiochemical relationships between the nitrogen atom and the carbon- carbon double bond. Vinylethers have served in a similar fashion.245 Compare this with the vinylic carbon-oxygen bond in the p-lactone substrate (105) which couples with zinc modified arylmagnesium bromides under palladium catalysis to form ring-opened styrene derivative^.'^^ In the coupling of arylchlorides with styrene derivatives the effect of chelating phosphines has been examined in detail in the Milstein Benzylhalides coupling with acrylate double bonds have been More work with acrylates in this case using 3-iodoaniline has been reported by the Ginet An important feature is the use of homogeneous aqueous media made possible by a solubilizing ligand namely the sodium salt of an arylsulfonyl analogue of triphenylphosphine.Dienes can also be used as coupling partners. An example with aryliodides produces (E,E)-conjugated aromatic diene~.’~’ Other diene syntheses combine vinylhalides and alkenes derived from ally1 alcohols and silly1 ethers.250 (Compare the stereochemistry of this product with an anomalous stereochemistry reported in the final example of this section.) Another route to conjugated dienes coupled two 7c components (alkene and an alk~ne).~~’ This type of coupling process is mechanistically related to alkene and alkyne oligermization reactions discussed in Section 3.The Negeshi group has reported two seemingly unrelated reactions which are linked by a common mechanistic explanation. Pallad- ium catalysed cyclization of (106) afforded a cyclopropane viaan endo addition to the alkene. A related vinyl iodide has an exo cyclization available and produced the diene (107) with isomerization of the double bond stere~chemistry.~~’ Multi-Step Coupling Processes-Forming several carbon-carbon bonds in a single step can clearly be an attractive short-cut in synthetic chemistry.Palladium catalysed multi-step methods are easiest to understand when two coupling partners are brought together to a bifunctional unit or even a simple alkene. Examples include the coupling of cyanide and a vinyliodide with n~rbornene,’~~ and the related process employing an alkyne with the copper iodide conditions in place of the cyanide.254 A diiodonaphtha-lene has also been coupled to an alkene unit to form a five-membered ring.255 A more subtle example employed bromobenzaldehyde with acrylates. Two displacements can be effected replacing the formyl substituent. Dehydroformylation could account for the second step. One side-chain retained the alkene but the other did not.256 Many strategies for multiple bond-formation employ palladium first to activate an 242 N.N. Demik M. M. Kabachnik Z. S. Novikova and I. P. Beletskaya Bull. Acad. Sc. USSR 1992,41,380. 243 K. Nilsson and A. Hallberg J. Org. Chem. 1992 57 4015. 244 W. Cabri I. Candiani A. Bedeschi and R. Santi J. Org. Chem. 1992 57 3558. 245 W. Cabri I. Candiani A. Bedeschi and R. Santi SYNLETT 1992 871. 246 K. Itoh T. Harada and H. Nagashima Bull. Chem. Soc. Jpn. 1991 64 3746. 247 Y. Ben-David M. Portnoy M. Gozin and D. Milstein Organometallics 1992 11 1995. 248 J. P. Genet E. Blart and M. Savignac SYNLETT 1992 715. 249 T. Jeffery Tetrahedron Lett. 1992 33 1989. 250 J. L. Mascareiias A. M. Garcia L. Castedo and A.Mouriiio Tetrahedron Lett. 1992 33 4365. 25’ B. M. Trost and P.A. Hipskind Tetrahedron Lett. 1992 33 4541. 252 Z. Owczarczyk F. Lamaty E. J. Vawter and E. Negishi J. Am. Chem. Soc. 1992 114 10091. 253 S. Torii H. Okumoto H. Ozaki S. Nakayasu 0.Tadokoro and T. Kotani Tetrahedron Lett. 1992,33 3499. 254 S. Torii H. Okumoto T. Kotani S. Nakayasu and H. Ozaki Tetrahedron Lett. 1992 33 3503. 25s G. Dyker J. Org. Chem. 1993 58 234. S. K. Meegalla N. J. Taylor and R. Rodrigo J. Org. Chem. 1992 57 2422. Organometallic Chemistry -The Transition Elements alkene or alkyne for nucleophile addition and subsequently in a coupling step with typically an aryl iodide. Examples include the formation of disubstituted indolesZs7 and lactonization procedures.258~2s9 An other version used a second alkyne as a ligand on palladium.Intramolecular lactonization promoted by activation of the alkyne by the palladium is then followed by reductive elimination to produce an enyne.260 Intermolecular carboxycyclic acid addition to an alkene is used to differentiate two enantiotropic alkenes in a cis-1,2-divinylcyclohexane. After nucleophile addition the new carbon a-bond is picked up by coupling to the second alkene. Chiral carboxcyclic acids have been evaluated in this reaction.261 Allenes are also used as the electrophilic component. An example that combines intramolecular nitrogen addition with carbonyl insertion (related to examples discussed earlier) has been described.262 The cyclization of alkenylanilines has also been extended by adding a carbonyl insertion step.Instead of indoles quinoline products were obtained.263 Elegant sequences of coupling reactions can be conceived and executed in natural product synthesis. A vinyl halide an alkyne and an alkene have been combined to form (108)and (109) in a new strategy for the synthesis of vitamin D metabolites (1 Further examples have been developed into versatile 1,3-~yclohexadiene syntheses in which the diene takes the central position in a polycyclic unit.265 An intramolecular version of this reaction has also been described.266 A different natural product skeleton (1 11) has been obtained by cyclizing an allyliodide with two alkene~.'~~ Use of formate 257 A. Arcadi S. Cacchi and F. Marinelli Tetrahedron Lett.1992 33 3915. 258 A. Arcadi A. Burini S.Cacchi M. Delmastro F. Marinelli and B. R. Pietroni J.Org. Chem. 1992,57,976. 259 S. Cacchi M. Delmastro S. Ianelli and M. Nardelli Gazz. Chim. Ztal. 1992 122 11. 260 D. Bouyssi J. Gore and G.Balme Tetrahedron Lett. 1992 33 2814. 261 L. Tottie P. Baeckstrom C. Moberg J. Tegenfeldt and A. Heumann J. Org. Chem. 1992 57 6579. T. Gallagher I. W. Davies S. W. Jones D. Lathbury M. F. Mahon K.C. Molloy R. W. Shaw and P. Vernon J. Chem. SOC..Perkin Trans. 1 1992 433. 263 S. Torii L.H. Xu M. Sadakane and H. Okumoto SYNLETT 1992 513. 264 B.M. Trost J. Dumas and M. Villa J. Am. Chem. Soc. 1992 114 9836. F. E. Meyer J. Brandenburg P. J. Parsons and A. de Meijere J. Chem. SOC.,Chem. Commun. 1992,390. 266 B.M. Trost W. Pfrengle H.Urabe and J. Dumas J. Am. Chem. SOC.,1992 114 1923. 267 L. E. Overman M. M. Abelnian D.J. Kucera V. D. Tran and D. J. Ricca Pure Appl. Chem. 1992 64 1813. G.R. Stephenson can replace the metal by a hydrogen at the final step. Cyclization of (112)illustrates this point.26s Mildly reactive nucleophilic groups such as allylzinc reagents are also employed in this type of multiple bond formation under palladium catalysis.269 (110) 76% Me 0 (111) 80-90% (112) 60-70% Scheme 38 6 Coupling Using Other Transition Metals Stoichiometric arylmanganese reagents have been employed in a variety of coupling reactions. Photolysis with alkynes formed cyclization products.270 Oxidative and thermal procedures have been employed in similar coupling reactions using diter- penoid precursors to form steroid analogues,27 and with intermediates derived from podocarpic acid and other diterpenoid example^.^^'.^^^ 268 B.Burns R. Grigg V. Santhakumar V. Sridharan P. Stevenson and T. Worakun Tetrahedron 1992,48 7297. 269 J. van der Louw J. L. van der Ban C. M. D. Komen A. Knol F. J. J. de Kanter F. Bickelhaupt and G. W. Klumpp Tetrahedron 1992 48 6105. 270 W. J. Grigsby L. Mgin and B. K. Nicholson Organometallics 1993 12 397. 271 R. C. Cambie M. R. Metzler C. E. F. Rickard P.S. Rutledge and P. D. Woodgate J.Organomet. Chem. 1992 426 213. 272 R.C. Cambie M. R. Metzler P. S. Rutledge and P. D. Woodgate .I. Organomet. Chem. 1992 429 41. 273 Idem. J. Organornet. Chem. 1992 429 59. OrganometalIic Chemistry -The Transition Elements 241 Examples to illustrate metal-catalysed coupling reactions are drawn from the chemistry of ruthenium and nickel.Many of the features seen in the palladium chemistry discussed in Section 5 are also apparent in the ruthenium coupling reactions; diene synthesis combining vinylhalides with activated alkene~,~ 74 and oligomization of butadiene with acrylate~~~~ are typical cases. A more unusual example however is the combination of pyridine and a terminal alkene with carbon monoxide to produce With 2-a~ylpyridines.~~~ nickel chemistry too there are similarities with the palladium examples particularly in coupling reactions of aromatic halides to produce biaryl~.~~ Nickel catalysed opening of vinylethers however follows a different course producing a trisubstituted alkene with a hydroxyalkyl group as one of the substitu- ents.278.279 A further unusual step proceeds with nickel catalysis after an initial stoichiometric elaboration of an alkene with triethylaluminium.A metalocyclic compound in the presence of [Ni(acac),] and triphenylphosphine reacted to effect first P-elimination and then reductive elimination to put alkenyl and alky substituents in place of the two metal-bearing units.280 7 Hydrogenation Hydrosilation and Metal Catalysed Hydroboration Hydrogenation.-The utilization of asymmetric hydrogenation is the main priority in research in this field at present. Work directed to enantioselective synthesis of amino acids indicates a typical application.Details of the effects of the structures of chelating phosphines in these hydrogenation reactions have been examined.,” In some cases very large changes (even reversal of the favoured enantiomer) can be achieved with relatively small alterations to catalysts. An example involves the substitution of achiral phosphine centres attached to a chiral backbone.282 r,j-Unsaturated carboxcyclic acids have been evaluated as substrates.283 A variety of substituents including other ester groups are compatible with this type of rea~tion.~~~*,*~ In another study rhodium ruthenium cobalt and nickel catalysts have been compared.286 Car- bon-oxygen double bonds can also undergo asymmetric hydrogenation. Achiwa’s group has compared three chiral auxiliaries in the reduction of arylketones with alkylamine ~ide-chains.~~’ More typical are applications of ruthenium BINAP complexes in the selective reduction of P-ketoesters in work targeted to a synthesis of ’14 T.Mitsudo M. Takagi. S.-W. Zhang and Y. Watanabe J. Oryanomrt. Chem. 1992 423 405. ‘15 T. Mitsudo S.-W. Zhang T. Kondo and Y. Watanabe Trtruhedron Lett. 1992 33 341. 216 E. J. Moore W. R. Pretzer T. J. O’Connell J. Harris L. LaBounty. L. Chou and S. S. Grimmer J. Am. Chrm. Soc. 1992. 114 5888. 277 T. Yamamoto S. Wakabayashi and K. Osakada J. Orgunomet. Cheni. 1992 428. 223. ’” P.A. Ashworth N. J. Dixon. P.J. Kocienski and S.N. Wadman J. Cheni. Soc.. Prrkin Truns. I 1992 343 1. ’” P. J. Kocienski M. Pritchard. S. N. Wadman R. J. Whitby.and C. I. Yeates,J. Chem.Soc. Prrkin 7runs. I. 1992 3419. ’” U. M. Dzhemilev A. G. Ibragimov and A. P. Zolotarev J. Chem. Soc.. Mendelrev Commun. 1992. 28. 281 H. Krause and C. Sailer J. Organornet. Chrm.. 1992. 423. 271. “’ J.-J. Brunet H. Hajouji J.-C. Ndjanga and D. Neibecker J. Mol. Cutul.. 1992 72 L21. 2x3 J.-P. Ginet C. Pitel S. Mallart S. Juge N. Cailhot and J. A. Laffitte Trtruhedron Lett.. 1992,33 5343. 284 L. Shao K. Takeuchi M. Ikemoto,T. Kawai M. Ogasawara H. Takeuchi. H. Kawano.and M. Saburi. J. Oryanomet. Chem. 1992 435 133. ’”M. Saburi H. Takeuchi M. Ogasawara T. Tsukahara. Y. Ishii. T. Ikariya T. Takahashi and Y. Uchida. J. Orgunomet. Chem. 1992 428. 155. 286 A. Corma M. lglesias C. del Pino. and F. Sanchez. J. Orgunomer. Chrm. 1992 431 233.“’ S. Sakuraba N. Nakajima and K. Achiwa SYNLETT 1992 829. G.R. Stephenson ( -)-indolizidine 223AB."' Enones can also be selectively reduced at the carbonyl function. An example using iridium catalysts has been reported.289 Hydrosilation and Hydroboration.-Carbonyl groups are also typical substrates for metal catalysed asymmetric hydrosilation. Two papers this year provide an interesting intramolecular delivery of the silicon hydride unit. A comparison of DuPHOS CHIRAPHOS and BINAP has been made.290 With BINAP and a ruthenium catalyst an enantiomeric excess as high as 97% was achieved. Formation of (113) is a typical e~ample.~' Burgess Ohlmeyer and Whitmire have examined stereochemically matched and unmatched pairs using DIOP-DIPAMP hybrid ligand~.~~~ Acetophenone was used as a substrate for asymmetric induction.Two mechanistic studies of hydrosilation have been rep~rted.~~~.~~~ Models for asymmetric induction were advanced.294 Asymmetric hydrogenation of carbon-nitrogen double bonds is also of interest. An unusual example has employed rhodium with an aminophosphine chiral auxiliary to form (1 14).295 Stereocontrol in hydroboration has also been further examined.296 The matched ligands referred to earlier have also been evaluated in asymmetric hydr~boration.'~~ n h "'p-n \ Scheme 39 8 Carbene Complexes Rhodium Catalysis.-Rhodium catalysed insertion reactions of diazoketones continue to receive attention. Good selectivity is often obtained despite the availability of several possible sites for insertion to occur.Selective cyclization of (1 15)to form (1 16) 288 D. F. Taber P.D. Deker and L. J. Silverberg J. Org. Chern. 1992 57 5990. 289 K. Mashirna T. Akutagawa X. Zhang H. Takaya T. Taketorni H. Kumboyashi and S. Akutagawa J. Organomet. Chem. 1992 428 213. 290 M. K. Burk and J. E. Feaster Tetrahedron Lett. 1992 33 2099. 291 S.H. Bergens P. Noheda J. Whelan and B. Bosnich J. Am. Chem. SOC. 1992 114 2121. 292 K. Burgess M. J. Ohlrneyer and K. H. Whitrnire Organornetallics 1992 11 3588. 293 S. B. Duckett and R.N. Perutz Organometallics 1992 11 90. 294 S.H. Bergens P. Noheda J. Whelan and B. Bosnich J. Am. Chem. SOC. 1992 114 2128. 295 E. Yu. Zhorov V.A. Pavlov 0.A. Fedotova V. I. Shvedov E. A. Mistryukov D.N. Platonov L.S. Gorshkova and E.I. Klabunovskii Bull. Acad. Sci. USSR (EngI. Transl.) 1991 40,763. 296 D.A. Evans G.C. Fu and A.H. Hoveyda J. Am. Chem. SOC. 1992 114 6671. Organometallic Chemistry -The Transition Elements rather than (117) illustrates this point.297 The nature of the OR substituent had a significant effect on regiocontrol. Rhodium catalysed insertion employing a diazodi- ester provides a route to seven membered lac tone^.^^^ In other cases simple alkyl CH bonds provide the site for reaction. A study of selectivity between fused and spirocyclic products has been made.299 Insertion of an a-keto carbene complex derived from an o-alkoxyarylalkylketone provides a synthesis of chroma none^.^^^ + Scheme 40 Rhodium carbene complexes are frequently used to effect cyclopropanation.An intramolecular example has been rep~rted.~" Another intramolecular cyclization using a diene in place of the alkene constituted a key step in the synthesis of ( -)-PGE methyl ester.302 The vinyl group can be placed next to the carbene complex. Both these reactions form vinyl-cyclopropanes. Davies and Hu have demonstrated the ring expansion of these products with dimethylaluminium chloride to form stereochemi- cally controlled cy~lopentenes.~'~ Cyclopentene products can also be obtained directly from the carbene addition reaction.304 When carbene complexes add to alkynes cyclopropenes can be formed.305 An intramolecular version of this reaction has been examined and was found to follow a different path.A vinyl substituted indinone was obtained.306 Thiocyanates have also been used with rhodium carbene complexes to form 2-amino- 1,3-0xathiols.~~~ Chromium Molybdenum and Tungsten Complexes-Carbonylative cyclization of aryl- and vinyl-carbene complexes of chromium molybdenum and tungsten to form hydroquinone mono-ethers is the best known and most widely used application of these compounds in organic synthesis. New examples still appear.308 Typically the initial product is an q6 transition metal n-complex. Combining vinyl and aryl units together as a single substituent on the carbene complex Merlic's group has been able to 297 D.M. Spero and J. Adams Tetrahedron Lett. 1992 33 1143. 298 F. Kido A. B. Kazi K. Yamaji M. Kato and A. Yoshikoshi Heterocycles 1992 33 607 299 S.Hashimoto N. Watanabe and S. Ikegami Tetrahedron Lett. 1992 33 2709. 300 M.A. McKervey and T. Ye J. Chem. Soc.. Chem. Commun. 1992 824. 301 P. Ceccherelli M. Curini M. C. Marcotullio and 0.Rosati Tetrahedron 1992 48 9767. 302 D. F. Taber and R. S. Hoerrner J. Org. Chem. 1992 57 441. 303 H. M. L. Davies and B. Hu J. Org. Chem. 1992 57 3186. 304 H. M. L. Davies and B. Hu Tetrahedron Lett. 1992 33 453. 305 K. Paulini and H.-U. Reissig SYNLETT 1992 505. 306 A. Padwa K. E. Krumpe and J. M. Kassir J. Org. Chem. 1992 57 4940. 307 T. Ibata and H. Nakano Bull. Chem. Soc. Jpn. 1992 65 3088. 308 B. L. Balzer M. Cazanoue and M.G. Finn J. Am. Chem. Soc. 1992 114 8735. G.R. Stephenson promote a 1,Z-oxygenation pattern on the resulting arene after cyclization.Now by the use of isonitriles ether and amine substituents have been introduced.309 Alkynyl substituents attached by an ortho disubstituted arene to the carbene complex have been e~arnined.~"Heterocyclic (118) and carbocyclic (1 19) products are accessible from these reactions. Since conventional vinyl-substituted methoxycarbene complexes afford $-chromium arene products after cyclization these can be utilized in further bond formations before decomplexation allowing selectivity between the formation of (120) and the spirocyclic product (121).311 A priority currently is understanding the factors that select between different OMe OMe (118) 78% CN-B~ -OMe SPh OMe OMe Scheme 41 309 C. A. Medic E. E. Burns D. Xu and S.Y. Chen J. Am. Chem. SOC.,1992 114 8722. 310 K. H . D" otz T. Schafer F. Kroll and K. Harms Angew. Chem. Int. Ed. Engl. 1992 31 1236. 311 S. Chamberlain and W.D. Wulff J. Am. Chem. Soc. 1992 114 10667. Organometallic Chemistry -The Transition Elements 245 reaction pathways in carbene mediated bond formation. Aminocarbene complexes in reactions with alkynes give five-membered ring cyclization product^.^ '2,3 3,3 l4 Changing the nature of the substrate opens up new pathways. Chromium carbene complexes react with ketene acetals to form a selection of cyclization product^.^' The less common dicarbonylmanganese(methylcyclopentadieny1)moiety has been em- ployed with alkoxycarbenes and related titanium species in cyclizations with alkynes. Mixtures of quinones and acyclic 1,2-dicarbonyl compounds are f~rrned.~' Reaction of alkoxycarbene complexes with separate alkene and alkyne components also has considerable scope.Cyclopropane and cyclopentenone products are accessible from this ~hemistry.~' 7.31* Stereoselectivity in the formation of vinylcyclopropanes from 1,3-dienes using chromium carbene complexes has been e~amined.~ Cyclopropyl ' substituted carbene complexes give access to cyclopentenones. Yields are variable dependent on the substitution pattern on the alkyne; not surprisingly the trans-isomer predominated in the Anions can be stabilized adjacent to metal-carbene complexes. Reaction with an alkyl halide then provides a method for the elab~ration.~~' Deprotonation is typically effected with butyllithium.In related epoxide openings borontrifluride etherate was added before the epoxide substrate was introduced to the reaction mixture.322 Stabilization of negative charge adjacent to the carbene complex allowed conjugate addition by nucleophiles to vinyl carbene complexes. This reaction is related to aldol chemistry and shares similar stereochemical issues in terms of syn and anti product selectivity. Further cyclization is possible by alkoxide addition to the carbon bearing the metal atom. Thus enolate addition followed by cyclization combined with addition of the product alcohol to the carbene complex and demetalation can give stereocon- trolled access to unusual cyclization products.323 Selectivity in the conjugate addition step has beenexamined with chromium and tungsten complexes.324 In this study some alkynylcarbene complexes were used as substrates.Alkynylcarbene complexes also react with sillylenol ethers to form cyclization products.325 [2 + 21-Additions involving the carbene itself have been popular.326 Photochemical conditions are employed. Cyclization using cationic iron carbene complexes has been studied in detail. The stereochemistry and mechanism of the cyclopropane formation has been examined.32 312 E. Chelain R. Gournont L. Hamon A. Parlier M. Rudler. H. Rudler J.-C. Daran. and J. Vaisserrnann J. Am. Chem. Soc. 1992 114. 8088. 313 K M D.' . . otz A. Rau and K. Harms J. Organomet. Chem.. 1992 439 263. 314 D. B. Grotjahn F. E. K. Kroll T. Schafer K. Harms and K.H.Dotz Organometullics 1992 11 298. 315 S. L. B. Wang J. Su W. D. Wulff and K. Hoogsteen J. Am. Chem. Soc. 1992 114. 10665. 316 B.L. Balzer M. Cazanoue M. Sabat and M.G. Finn Organometallics 1992. 11 1759. 317 D. F. Harvey K. P. Lund. and D. A. Neil J. Am. Chem. Soc. 1992 114. 8424. 318 T.R. Hoye and J. A. Suriano Organometallics 1992. 11 2044. 319 D. F. Harvey and M. Brown. J. Org. Chem. 1992. 57 5559; M. Buchert and H.-U. Reissig. Chem. Ber.. 1992 125 2723. 320 S.U. Tumer J.W. Herndon and L.A. McMullen J. Am. Chem. Soc. 1992 114 8394. 321 D. W. Macomber and P. Madhukar J. Organomet. Chem.. 1992 433 279. 322 L. Lattuada E. Licandro S. Maiorana. A. Papagni A. Zanotti-Gerosa SYNLETT 1992 315. 323 S. Aoki. T. Fujirnura. and E. Nakarnura. J.Am. Chem. Soc. 1992 114 2985. 324 A. Llebaria J. M. Moreto. S.Ricart J. Ros J. M. Viiias and R. Yaiiez. J. Organomet. Chem.. 1992.440,79. 325 F. Camps L. Jordi M. Moreto S. Ricart A.M. Castaiio. and A.M. Echavarren J. Organomet. Chem. 1992 436 189. 326 C. Betschart and L. S. Hegedus J. Am. Chem. Soc. 1992 114 5010; D. K. Thompson N. Suzuki L. S. Hegedus and Y. Satoh J. Org. Chem. 1992. 57 1461. 327 C. P. Casey and J. Smith Vosejpka Organometallics 1992 11. 738. G. R. Stephenson Even combination of two cationic reagents can be achieved. An example is the cyclopropanation using a cationic carbene complex and an q2 cation formed by complexation of a 1,3-diene.328 Cyclic carbene complexes of iron and ruthenium have also attracted considerable attention.329 Similar studies involve manganese330 and molybdenum331 metal carbene complexes.The ubiquitous palladium catalysis has found a particularly attractive application in cyclopropanation. Also the remarkable and highly symmetrical product (122) was obtained in 40% yield by metal catalysed cyclopropanation using dia~omethane.~~~ Scheme 42 9 Ferrocene Chemistry There has recently been something of a resurgence of interest in ferrocene chemistry largely driven by the search for stable organometallic compounds with unusual chemical or physical properties. Non-linear optical effects have been measured in the ferrocenyl derivatives of styrenes such as ( 123).333 Redox active bis-ferrocene macrocyclic ethers such as (124) have also been a target for synthetic There are now many successful ligands based on ferrocenyl units.Mixed phosphinobipyridyl- ferrocene derivatives have been prepared.335 Complexes of type (123) have been the subject of a high resolution EPR study. Electronic communication between the nitro group (X) and the ferrocene unit was examined for ortho meta and para substitution patterns.336 Exchange of hydrogen using D+has also been examined.337 Polymetallic ferrocene derivatives are of interest particularly when charge stabilization is shared between the two metal units. The dimolybdenum species (125) provides a typical e~arnp1e.j~~ Other investigators have examined the placement of conjugated bridges between the rings of the ferrocene unit; (126) was characterized by X-ray crystallog- ra~hy.~~~ Similar structures with alkoxy donors on the bridge have also been 328 V.Guerchais S. Levsque A. Hornfeck C. Lapinte and S. Sinbanhit Organometallics 1992 11 3926. 329 R. L. Trace J. Sanchez J. Yang J. Yin and W. M. Jones Organometallics 1992 11 1440. 330 D. J. Crowther Z. Zhang G. J. Palenik and W. M. Jones Organometallics 1992 11 622. 331 J. D. Carter T. K. Schoch and L. McElwee-White Organometallics 1992 11 3571. 332 K. A. Lukin S. I. Kozhushkov A. A Andrievski B. I. Ugrak and N. S. Zefirov J. Chem. SOC.,Mendeleev Commun. 1992 51. 333 H. E. Bunting M. L. H. Green S. R. Marder M. E. Thompson D. Bloor P. V. Kolinsky and R. J. Jones Polyhedron 1992 11 1489. 3 34 P. D. Beer J. E. Nation M. E. Harman and M. B. Hursthouse J. Organomet.Chem. 1992 441 465. 335 J.R. Butler Polyhedron 1992 11 3117. 336 G. F. Pedulli and Z.V. Todres J. Organomet. Chem. 1992 439 C46. 337 Z. V. Todres and D. S. Ermekov J. Organomet. Chem. 1992 439 C28. 338 C. Cordier M. Gruselle J. Vaissermann L. L. Troitskaya V. I. Bakhmutov V. I. Sokolov and G. Jaouen Organometallics 1992 11 3825. 339 M. S. Erikson F. R. Fronczeck and M. L. McLaughlin Tetrahedron Lett. 1993 34 197. Organometallic Chemistry -The Transition Elements prepared.340 Silicon atoms have been used to attach the bridging units to the ferrocene rings.34’ Biphenyl provides an interesting bridge because it introduces an axis of chirality. The Scheme 43 product (127) was obtained by palladium catalysed cross-coupling between diiodobiphenyl and a double zinc chloride derivative obtained from dilithiofer- r~cene.~~~ This product was also characterized by X-ray diffraction.Bimetallic units have also been made to bridge the rings of ferr~cene.~~~ Even more exotic structures are obtained when functionalized ferrocenes are persuaded to serve as ligands at a central metal atom.344 The properties of ferrocene and its analogues are still under study. A chiral ferrocinium salt has been examined by circular dichroism spectros- copy.345 An azoferrocene serves as a redox-active species for the photo-activation of a cobalt p~rphyrin.~~~ Many practical applications are being found for ferrocene the earliest of the sandwich organometallics. Work of this type points the way for future general developments in organometallic chemistry.340 J. K. Pudelski and M. R. Callstrom Organornetallics 1992 11 2757. 341 W. Finckh B.-Z. Tang A. Lough and I. Manners Organometallics 1992 11 2904. 342 M. E. Huttenloch J. Diebold U. Rief H. H. Brintzinger A. M. Gilbert and T. J. Katz Organornetallics 1992 11 3600. 343 W. R. Cullen A. Talaba and S. J. Rettig Organometallics 1992 11 3152. 344 H. Gornitzka F.T. Edelmann and K. Jacob J. Organornet. Chern. 1992 436 325. 345 V. I. Sokolov I. A. Mamedyarova M. N. Nefedova and G. Snatzke J.Organornet. Chem. 1992,438,C26. 346 J. Zakrzewski and C. Giannotti J. Chern. Soc. Chern. Commun. 1992 662.

ISSN:0069-3030    

DOI:10.1039/OC9928900207

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

9 Synthetic Methods By N. LAWRENCE Department of Chemistry UMIST PO Box 88 Manchester M60 1QD UK 1 Introduction Despite the ever increasing sophistication of synthetic methods the need for better regio- chemo- stereo- and enantioselective transformations remains as pressing as ever. Considerations of cost and environmental impact make catalytic reagents very desirable -indeed the study of asymmetric catalysis is particularly prevalent. The year has seen many impressive total syntheses of natural products including Kishi’s synthesis of halichondrin B;’ the second ever reported synthesis of strychnine by Magnus;2 Nicolaou’s3 total synthesis of calicheamicin 7 ; Evans’4 and Barrett’s5 syntheses of calyculin and dephospho calyculin respectively. Some targets such as the headlining anti-tumour agent taxol remain unconquered despite phenomenal effort .6 Some general review articles that have appeared include Schreiber’s account of his use Me 0 MeSSS, OMe OH HO H ? HO OH Calicheamicin y T.D. Aicher K. R. Buszek F. G. Fang C. J. Forsyth S. H. Jung Y. Kishi M.C. Matelich P. M. Scola D. M. Spero and S. K. Yoon J. Am. Chem. Soc. 1992 114 3162. P. Magnus M. Giles R. Bonnert C. S. Kim. L. McQuire A. Merritt and N. Vicker J. Am. Chem. Soc. 1992 114 4403. K. C. Nicolaou C. W. Hummel. E. N. Pitsinos M. Nakada A. L. Smith K. Shibayama and H. Saimoto,J. Am. Chem. Soc. 1992 114 10082; A. L. Smith C.-K. Hwang E.N. Pitsinos G. R. Scarlato and K.C. Nicolaou J. Am. Chem. Soc. 1992,114,3134; K. C. Nicolaou and A.L. Smith Acc. Chem. Res. 1992,25 491. D. A. Evans J. R. Gage and J. L. Leighton J. Ory. Chem. 1992 57 1964. A. G. M. Barrett J. J. Edmunds J. A. Hendrix J. W. Malecha and C. J. Parkinson J. Chrm. Soc. Chem. Commun. 1992 1240 and preceding papers. For a review of synthetic strategies see C.S. Swindell Org. Prep. and Proc. 1991 465; Total and semi-synthetic approaches to taxol symposium-in-print Tetrahedron 1992 48 6953. 249 250 N. Lawrence of organic chemistry for solving biological problem^;^ a review of recent advances in the study of FK 506;8an interesting review article entitled ‘Chiral Drugs’ has appeared in the wake of the F.D.A.’s recently published guidelines for the marketing of such drugs.’ The synthesis of unnatural products also provides challenging tasks; c60 is proving especially fertile ground for organic chemists.’ O Specialist books that have been published this year include a new volume of Fieser;’ two volumes of ApSimon’s ‘Total Synthesis of Natural Products’;I2 and copies entitled ‘Tandem Organic Reactions’;’ ‘Modern Methodology in Organic Synthe~is’;’~ ‘Organic Synthesis in Japan’;’ ‘Sulphones in Organic Synthesis’;’ ‘Conjugate Addition Reactions in Organic Synthesis’;’ ‘Biocatalysts in Organic Synthesis’;’ ‘Organic Synthesis with Oxidative Enzymes’.’ 2 Carbon-Carbon Bond Formation Much attention has focused upon the development of asymmetric catalytic variants of well established organometallic protocols that involve the formation of carbon-carbon bonds.Seebach2’ has used his tartrate-derived catalyst (1) to make the Grignard reaction enantioselective.In the presence of (1) primary Grignard reagents add with high stereoselectivity to aryl vinyl and alkynyl ketones (Scheme 1). The selectivity is only slightly reduced when 25 mol% of (1)is used. The reaction shows a curious solvent effect; in diethyl ether the reaction between ethylmagnesium bromide and benzal- dehyde (not a particularly good substrate in this reaction) gives (S)-1 -phenylpropan- 1-01 (70% e.e.) whereas in tetrahydrofuran the (R)isomer (58% e.e.) is the major product. 00 i 3 eq. Pr’MgBr e Ph K “L ii. PhCOMe -100°C HOh*%OH iii. NH&l Ar Ar Ar Ar 84% > 98% e.e. Scheme 1 The asymmetric catalytic addition of organozinc reagents to carbonyl groups has proved promising of late and has recently been reviewed.21 A bewildering variety of 7 S.L. Schreiber Chem. Eng. News 1992 October 26 22. 8 M.K. Rosen and S. L. Schreiber Angew. Chem. lnt. Ed. Engl. 1992 31 384. 9 S. C. Stinson Chem. Eng. News 1992 September 28 46. 10 H. W. Kroto Angew. Chem..lnt. Ed. Engl. 1992,31 111; H. Schwarz Angew. Chem.,lnt. Ed. Engl. 1992 31 293. 11 M. Fieser ‘Reagents for Organic Synthesis’ Wiley New York 1992 Vol. 16. 12 ‘The Total Synthesis of Natural Products’ ed. J. ApSimon Wiley New York 1992 vols. 8 and 9. 13 T. L. Ho ‘Tandem Organic Reactions’ Wiley New York 1992. 14 ‘Modern Methodology in Organic Synthesis’ ed. T. Shono Kodansha Tokyo 1992. 15 ‘Organic Synthesis in Japan Past Present and Future’ fokyo Kagaku Dojin Tokyo 1992.16 N. S. Simpkins ‘Sulphones in Organic synthesis’ Pergamon Oxford 1992. 17 P. Perlmutter ‘Conjugate Addition Reactions in Organic Synthesis’ Pergamon Oxford 1992. 18 J. Halgas ‘Biocatalysts in Organic Synthesis’ Elsevier 1992. 19 H. H. Holland ‘Organic Synthesis with Oxidative Enzymes’ VCH 1992. 20 B. Weber and D. Seebach Angew. Chem. Int. Ed. Engl. 1992 31 84. 21 K. Soai and S. Niwa Chem. Rev. 1992,92 833. Synthetic Methods 25 1 amino alcohol catalysts (Scheme 2) have been studied this year such as the complex benzylglycine derivative (2);22 the anthracine derived (3);23 the norephedrine deriva- tives (4)24 and (5);25the proline derived (6);26 and the 2,2’-bipyridine (7).2’ The norephedrine-derived ligand (8) catalyses the addition of diethylzinc to chiral aldehydes.The (1R,2S) catalyst delivers diethylzinc to (9) with high selectivity (91% d. e.) to give the anti product and the (1S,2R) isomer gives the syn product with mismatched stereocontrol (78% d. e.) (Scheme 3).28 The studies of the Kn~chel~~ group have resulted in a general synthesis of dialkylzinc reagents that will significantly increase the scope of this organozinc methodology. They have made alkylethylzinc reagents from reaction of diethylzinc with the appropriate alkyl halide. Dispropor- tionation of the mixed alkylethylzinc under high vacuum (0.1 mmHg 40-50 “C) produces pure dialkylzinc reagent since the diethylzinc also produced is volatile. The procedure will tolerate esters nitriles alkyl chlorides and boronic esters.Oppolzer3* has also been able to use a variety of vinylzinc reagents which he makes by transmetallation of vinyl boranes with dimethylzinc. The vinyl moiety of resulting vinylmethylzinc reagent is selectively delivered to aldehydes in the presence of the camphor-derived amino alcohol (10) (Scheme 4). Ph (2) (31 (4) 0.05 eq. Et2Zn PhCHO 1.2 eq. Et2Zn PhCHO 0.05 eq. Et2Zn PhCHO 78% 91% e.e. (S) 78% 96% e.e. (S) 62% 81% e.e. (S) p ?OH +*H Butpq “H OH HO But I (5) (6) (7) 0.2 eq. Bu2Hg PhCHO 1 eq. BrZnCH2CN PhCHO 0.05 eq. Et2Zn PhCHO 82%. 90% e.e. (S) 76%. 93% e.e. (S) 97%. 92% e.e. (R) Scheme 2 22 A. Mori D. Yu and S. Inoue SYNLETT. 1992 427. 23 K.Kirnura E. Sugiyarna T. Ishizuka and T. Kunieda Tetrahedron Lett. 1992 33 3147. 24 K. Ito Y. Kirnura H. Oarnura and T. Katsuki SYNLETT. 1992 573. 25 M. J. Rozerna D. Rajagopal C.E. Tucker and P. Knochel J. Organornet. Chem. 1992,438 11. 26 K. Soai Y. Hirose and S. Sakata Tetrahedron Asymm. 1992 3 677. ” C. Bolrn G. Schlingloff and K. Harms Chem. Ber. 1992 125 1191. ’* K. Soai T. Hatanaka and T. Yarnashita J. Chem. SOC.,Chem. Commun. 1992 927. 29 M. J. Rozerna A. Sidduri and P. Knochel J. Org. Chem. 1992 57 1956. 30 W. Oppolzer and R.N. Radinov Helv. Chim. Acta 1992 75 170. 252 N. Lawrence (lS.2R)(8) -\/\/\ 43%,78%d.e. EtZn BnO OH BnO 0 Et2Zn -\/\f\ 4570,919bd.e. (9) (1R.W(8) BnO OH Scheme 3 0.1 eq. -* -9 me 011 81% 96%e.e.Scheme 4 Enantioselective conjugate addition reactions of organometallic reagents have recently been re~iewed.~' Among the many catalysts used to achieve reactions of this type is the proline-derived phosphine (1l) used by Tomioka to transfer a methyl group from dimethyllithiocuprate to chalcone with high stereoselectivity (Scheme 5).32 The amidocuprate (12) has also been used to deliver a butyl group in a Michael sense to cy~loheptenone.~~ Reetz has undertaken a comparison of the nucleophilic reaction of manganese(I1) reagents and organocerium reagents; the stereoselectivity of nucleophilic addition to conformationally restricted cyclic ketones is very sensitive to the nature of X in RMnX (best equatorial selectivity with X = OCOCMe3).34 The study has also shown that organocerium reagents selectively react with aldehydes when in the form RCe(OPr'),MgX.Similarly modified Grignard reagents RMgOTs exhibit high chemoselection between carbonyl compounds preferentially reacting with aldehydes in the presence of ketones.35 In general problems can often be encountered during the preparation of organocerium reagents. A solution has been provided by Greeves who has shown that the use of ultrasound can greatly aid the preparation of active cerium chloride. 31 B. E. Rossiter and N. M. Swingle Chem. ReE. 1992 92 771. 32 M. Kanai K. Koga and K. Tomioka Tetrahedron Lett. 1992 33 7193. 33 B. E. Rossiter G. Miao N. M. Swingle M. Eguchi A. E. Hernandez and R.G. Patterson Tetrahedron Asymm. 1992 3 231.34 M.T. Reetz H. Haning and S. Stanchev Tetrahedron Lett. 1992 33 6963. 35 M.T. Reetz N. Harmat and R. Mahrwald Angew. Chem. Int. Ed. Engl. 1992 31 342. 36 N. Greeves and L. Lyford Tetrahedron Lett. 1992 33 4759. Synthetic Methods v 79%,84% e.e. 0 0 54% 96% e.e. The asymmetric catalysis of the aldol reaction is a topic that is currently attracting much attention. Significant contributions in this area have been made by the Masamune and Corey groups (Scheme 6). Both have concentrated on variants of the Mukaiyama aldol reaction between silylenol ethers and aldehydes. Masamune has used the sulfonamide (13),37 whilst Corey used the (S)-tryptophan-derived borane complex ( 14).38 Corey has also used his C,-symmetric bis-sulfonamide (15)to catalyse the aldol reaction between bromoesters and aldehydes.The bromohydrins obtained in high selectivity were converted into [j-hydroxy-r-amino acids.39 Another example of the elegant use of chiral Lewis acid catalysis is the asymmetric Prins4' reaction between methyl glyoxalate and a prochiral diene 41 promoted by a binaphthalene titanium complex (Scheme 7a). This example of a so-called desymmet- rizing reaction provides efficient access to complex bis-allyic alcohol systems. Similarly Shibasaki has used an (R)-BINAP palladium complex to perform Heck reactions upon prochiral dienes to construct highly functionalized cis decalin and hydrindan systems (Scheme 7b).42 Group 4 organometallic compounds have seen continued attention; the use of chiral organosilicon compounds in organic synthesis has been reviewed.43 Allylstannanes have been shown to be highly Cram selective in their reaction with aldehydes in lithium perchlorateediethyl ether at room temperat~re;~~ previous examples of high stereocontrol in such reactions required much lower temperatures (Scheme 8).Stannyl cupration of ethyne provides cuprate (16) which adds conjugatively to enones thus 37 E.R. Parmee Y. Hong 0.Tempkin. and S. Masamune. Tcrruhedron Letr. 1992 33 1729. '' E. J. Corey. C. L. Cywin. and T. D. Roper. 7trrukedron Left.. 1992. 33. 6907. 34 E.J. Corey. D.-H. Lee and S. Choi Tetrahedron Lrrt.. 1992. 33 6735. 40 K. Mikama M. Terada S. Narisawa. and T. Nakai SYNLETT. 1992. 255. 4' K. Mikama S. Narisawa. M. Shimizu.and M. Terada J. Am. C'hrm. Sot,.. 1992. 114 6566. 42 Y. Sato S. Watanabe and M. Shibasaki Trtruhrdron Lett. 1992. 33 2589; Y. Sato T. Honda. and M. Shibasaki Trtruhedron Lett. 1992. 33 2593. J3 T. H. Chan and D. Wang Chem. Rrt.. 1992 92. 995. 44 K. J. Henry Jr.. P. A. Grieco and C. T. Jagoe. Trrrruhrdrori Lett. 1992. 33. 1817. 254 N. Lawrence COZH "SEt and Ph I -.. 80% e.e. 89% 94% e.e. Me3SiO 0.2eq. (14) -78°C.14 h. then H 3O' / Ph Ph \ H Bu 82%. 89% e.e. (14) 0 0 F3C Br CF3 (15) 1.05 eq. I Br 90%. 92% e.e.,anri:syn 98:2 Scheme 6 providing a synthetic equivalent for cis-1,2-ethene diani~n.~' Impressive 1,5 stereocon-trol is observed between allylstannanes (17) and aldehydes to give 1,5-diols and is explained by reaction of the allylically rearranged stannane in the transition state (18) (Scheme 9).46Hudrlik has used an intramolecular alkoxide displacement of silanes to generate benzyl or allyllithi~m.~~ Yus and his group also report an unconventional route to organolithium compounds that involves naphthalene-catalysed lithium reduction of mesylates (ally1 and ben~yl)~* and dialkyl sulfates.49 45 J.P.Marino M.V. M. Emonds P. J. Stengel A. R. M. Oliveira F. Simonelli and J.T.B. Ferreira Tetrahedron Lett. 1992 33 49. 46 A. H. McNeill and E. J. Thomas Tetrahedron Lett. 1992 33 1369. 47 P. F. Hudrlik Y. M. Abdallah and A. M. Hudrlik Tetrahedron Lett. 1992 33 6747. 48 D. Guijarro B. Mancheiio and M. Yus Tetrahedron 1992 48 4593. 49 D.Guijarro B. Mancheiio and M. Yus Tetrahedron Lett. 1992 33 5597. Synthetic Methods TiClz b0; 4A mol. sieves CH2C12 10 mo1% * WOMe O"C OHCCOzMe ThexMqSiO Thex MqS i0 0 2796 > 99% syrt > 99% e.e. [62%based on recovered starting material] /OTBDMS ,OTBDMS 0.1 eq.PdC12[(R)-BINAF'] Ag3P04,100 h -p OAc OAc 67%.87% e.e. Scheme 7 Bu$n CuLi OSiEt, b LJ (16) -gaU3 Et3SiCl 92% Scheme 8 The use of enzymes for carbonsarbon bond formation a developing subject has been reviewed this year.50 Cyc1oadditions.-The asymmetric catalysis of the Diels-Alder reaction continues to be a fruitful area of study and has been recently reviewed.51 Studies in this area include those of Yamamoto who has shown that the binaphthalene (19) and tartrate (20) H.Waldmann Nachr. Chem. Tech. Lab. 1991 39 1408. 51 H.B. Kagan and 0.Riant Chem. Rev. 1992 92 1007. 256 N. Lawrence (17) OBn 90% (< 4% other isomers) (18) R = PhCH2 or CH2CH=CH2 and 07 Si HO-SiHR i MeLi /\ /\ ii PhCHO R‘Ph 63% for R = PhCH2 Scheme 9 boron complexes will catalyse hetero Diels-Alder reactions between iminess2 or aldehydess3 and Danishefsky’s diene (Scheme 10).Corey has used the bis(oxazo1ine) complex (21) as an efficient cataly~t,’~ which is conformationally more rigid than his previous catalysts that lacked the yem-dimethyl group adjacent to the oxygen (Scheme 11). The nature of the Lewis acid is important; the complexes of (21)with ferric iodide OMe \/ R R R = H X = NBn 75%.82% e.c. with (19) It = Me X = 0 95%. 97% e.e. with (20) OMe Scheme 10 52 K. Hattori and H. Yamamoto. J. Org. Chem. 1992. 57 3264. 53 G. Gao T. Maruyama M. Mouri and H. Yamamoto J. Org. Chem. 1992 57 1951 54 E. J. Corey and K. Ishihara Terrahedron Lerr. 1992 33 6807. Synthetic Methods magnesium iodide or magnesium tetraphenylborate all give high selectivity between cyclopentadiene and acryloyloxazolidinone; the assembly (22) is proposed to explain the selectivity. Corey has also proposed a model to explain the selectivity of his previously reported Diels-Alder catalyst (23)? A detailed analysis of the X-ray crystal structure of (23) and NMR studies of its complex with acryloyloxazolidinone have led to (24) being proposed as the transition-state assembly (Scheme 11).Reports of substrate-controlled Diels-Alder reactions abound. A rare example of good dias- tereocontrol arising from a 2-substituted chiral diene (25) has been reported; the control possibly arises from hydrogen bonding between the hydroxyl and maleimide carbonyl groups.56 Holmes and Helmchen have studied the hetero Diels-Alder reaction of.the glyoximine (26) (Scheme 12); good selectivity is observed in the reaction with ~yclopentadiene.~ The Diels-Alder reactions of the camphor-derived auxiliary (27) have been studied.58 U 82% 90.6% e.e. 97%endo phhph CF30,SN ,NSOZCF 'Al Me (23) Scheme 11 Evans has used his bis(oxazo1ine) catalyst (28) to effect the asymmetric cyclo- propanation of alkenes with diazoacetates (Scheme 13a);59 the enantioselectivity is excellent but there is some loss of trans:cis selectivity.Kobayashi reports his endeavours to effect asymmetric Simmons-Smith type reactions between allylic alcohols and diiodomethane by the use of 1,2-disulfonamide (29) and diethyl zinc (Scheme 13b).60 Denmark61 and Fujisawa62 have also studied this type of approach. 55 E.J. Corey S. Sarshar and J. Bordner J. Am. Chem. Soc. 1992 114 7938. 56 S. Hatakeyama K. Sugawara and S. Takano J. Chem. Soc.. Chem. Commun. 1992. 953. 57 P. Hamley G. Helmchen A. B. Holmes D. R. Marshall J. W. M. MacKinnon D. F. Smith and J. W. Ziller J. Chem. Soc. Chem. Commun. 1992 786. 58 R. K. Boeckman Jr. S.G. Nelson and M. D. Gaul J. Am. Chem. Sor. 1992 114 2258.59 D. A. Evans K. A. Woerpel and M. J. Scott Angeu. Chem. Int. Ed. Enyl. 1992 31 430. 6o H. Takahashi M. Yoshioka M. Ohno. and S. Kobayashi Tetrahedron Lett. 1992 33. 2575. " S.E. Denmark and J. P. Edwards SYNLETT. 1992 229. 62 Y. Ukaji M. Nishimura and T. Fujisawa Chem. Lett. 1992 61. 258 N. Lawrence Activated zinc for Simmons-Smith reactions can be prepared very -simply by magnetically stirring zinc dust at 140-150 "C for several hours under argon.63 14%.76% d.e. 50-60% 16% d.e. (27) Scheme 12 (b) ~mso2k P h v O H (29) (0.12 eq.) Et2Zn (2eq.) CII21 (3 eq.) -NHso,Ar -ph'''qOH 82%.76%e.e. (29) Ar =p-02NC6H4 Scheme 13 The use of a tethering silyl group has proved a useful way of obtaining high stereocontrol in cycloadditions (Scheme 14).This strategy has been used in the [2 + 21 photochemical cyclization of a bisallyloxysilane to give exclusively the cyclobutane (30).64 Stork has similarly shown that the [4 + 21 addition of the silylether (31) produces solely the alcohol (32).65Yamamoto has shown that the [2 + 21 addition between silylketenes and aldehydes with the aluminium catalyst (33) proceeds with exceptional selectivity.66 63 Y. Stenstrom Synth. Commun. 1992 22 2801. 64 S. A. Fleming and S. C. Ward Tetrahedron Lett. 1992 33 1013. 6s G. Stork T.Y. Chan and G. A. Breault J. Am. Chem. Soc. 1992 114 7578. 66 K. Maruoka A.B. Concepcion and H. Yamamoto SYNLETT. 1992 31. Synthetic Methods 259 P h v 0 I hV - ii. ByNF Ph*0'TPh Ph Ph" OH (30) 95%.single diastereoisomer (3 1) (32) 65% (single isomer) Me3Si L.=O EtCHO * Me3siY0 Et BrGO'dO *Br With (33) cis:truns 1OO:O \ / But Bu' With BF3.Et20cis:truns70:30 (33) Scheme 14 Radical-based Methods.-The current interest in the enediyne class of antibiotics has stimulated a fresh look at the Bergman cyclization and 1,4-aryl diradicals in both a mechanistic and synthetic sense. Both Semrnelha~k~~ and Nicolaou6* have contem- poraneously shown that the reaction is decelerated if the alkene is part of an aromatic ring. Additionally they have shown that the cyclization is especially facile if the alkene is part of a quinone ring as for (34) + (35)(Scheme 15). The Bergman cyclization has (34) (35) 79% 210°C. phc"A // n-03 (36) 72% Scheme 15 '' M.F.Semmelhack T. Neu and F. Foubelo Tetrahedron Lett. 1992 33 3271. 68 K.C. Nicolaou A. Liu Z. Zeng and S. McComb J. Am. Chem. Soc. 1992 114 9279. 260 N. Lawrence been used advantageously to produce the naphthalene (36) via a tandem cyclization pr0cedu1-e.~~ Bergman himself has made naphthalene from (Z,Z)-deca-3,7-diene- 1,5,9-triyne.” Rebek and Curran have introduced the auxiliary (37)’derived from Kemp’s triacid to direct a variety of radical reactions (Scheme 16a).71 They find that the addition of alkyl radicals to the mixed fumarate derivative occurs with exceptional stereo- and regioselectivity. Giese has developed an equivalent of the Felkin-Ahn rule to explain the selectivity observed for addition of radicals to carbon-carbon double bonds flanked by a stereogenic centre.72 Addition of a tert-butyl radical to (38) occurs in a Felkin-Ahn fashion to give the anti product (39) via reaction in conformation (40) (Scheme 16b).70% 94% d.e. (37) (38) (39) 75% anti:syn85:15 (40) Scheme 16 Curran has developed a series of new radical allylating reagents; allyl groups can be added to alkyl halides using allyl tris(trimethylsi1yl)silyl sulfide; 2-bromoallyl groups using 3-phenylthio-2-bromopropene; and 2-stannylallyl groups using 2,3- bis(trimethylstanny1)propene.73 Radical cyclization is as popular as ever. Pattenden has made large ring systems by use of a novel 14-endo-trig macrocyclization in his synthesis of ( -)-zearalenone (Scheme 17a).74 Oppolzer’s auxiliary has been used in an elegant and concise synthesis of the cis-hydrindanone (41) (Scheme 17b).75 Curran has also used a tandem radical cyclization in an elegant synthesis of the antibiotic camptothecin (Scheme 17c).The radical (42) generated by radical addition to phenyl isocyanide adds to the alkyne. Further addition to the phenyl ring followed by oxidative re-aromatization completes the pro~ess.’~ The samarium iodide coupling of ketones and acyl chlorides has been improved by 69 J. W. Grissom and T. L. Calkins. Tetrahedron Lett.. 1992 33. 2315. 70 K. N. Bharucha R.M. Marsh R. E. Mint, and R.G. Bergman J. Am. Chern. Soc. 1992 114 3120. ” J.G. Stack D. P. Curran. S.V. Geib J. Rebek Jr. and P. Ballester J. Am. Chem. Soc. 1992 114 7007.’’ B. Geise W. Damrn M. Roth and M. Zehnder SYNLETT. 1992 441. 73 D. P. Curran and B. Yoo Tetrahedron Lett. 1992. 33 6931. 74 S.A. Hitchcock and G. Pattenden J. Chem. Soc.. Perkin Trans. I 1992 1323. 75 P.A. Zoretic X. Weng C. K. Biggers M. S. Biggers. M. L. Caspar and D.G. Davis Tetrahedron Lett. 1992 33 2637. 76 D. P. Curran and H. Liu J. Am. Chem. Soc. 1992 114 5863. Synthetic Methods 261 OMe 0 Me0 Me0 0 Br (-)Dimethoxyzearalenone (41) 66%. 50%d.e. Scheme 17 the use of acetonitrile; indeed it is recommended that the samarium iodide be prepared in a~etonitrile.~~ Samarium diiodide'* has also been used to generate %-nitrogen anions uia 1,5-hydrogen abstraction of iodobenzylamines (Scheme 18).79 71 S. M.Ruder Tetrahedron Lett. 1992 33 2621. 7n G. A. Molander Chem. Ret... 1992. 92 29. M. Murakarni M. Hayashi and Y. Ito. J. Ory. Chem.. 1992. 57. 793. 262 N. Lawrence 74% Scheme 18 Alkene Synthesis.-The controlled synthesis of exocyclic double bonds has seen much progress recently. To these methods Suzuki has added an elegant process that involves tandem hydroboration and vinyliodide-boronate-palladium coupling (43)+ (44) (Scheme 19).80 In this case the stereocontrol is derived unambiguously from the starting vinyliodide (43).Kauffmann has developed a McMurry-type coupling using a (43) (44) 60% Scheme 19 reagent presumed to be NbCl, derived from niobium pentachloride and methyl lithium or potassium.*' Reaction between NbCl,/MeLi and benzaldehyde gave (E)-stilbene quantitatively; the more reactive NbCl,/K gives tetraphenylethylene (78 %) from benzophenone.Motherwell reports an improvement to his zinc mediated carbonyl coupling method by the use of 1,2-bis(chlorodimethylsilyl)ethanein place of trimethylsilyl chloride.82 In this way the corresponding trans stilbene from p-methoxybenzaldehyde was obtained in 79% yield. Barrett has improved his Peterson based strategy to alkenes with an experimentally simple synthesis of trisubstituted alkenes (Scheme 20a). The 1,2-silylalcohols (45)required for the Peterson elimination were made by the highly stereoselective Felkin-Ahn-Cram addition of alkyllithium reagents to a-dimethylphenylsilyl ketones.83 Parsons has also put the Peterson N.Miyaura M. Ishikawa and A. Suzuki Tetrahedron Lett. 1992 33 2571. T. Kauffmann and H. Kallweit Chem. Ber. 1992 125 149. 82 C.A. M. Alfonso W. B. Motherwell D. M. O'Shea and L. R.Roberts Tetrahedron Lett. 1992,33,3899. 83 A.G. M. Barrett J. M. Hill and E. M. Wallace J. Org. Chem. 1992 57 386. Synthetic Met hods reaction -in vinylogous fashion -to good use in his diene synthesis. He assembled the necessary 1,4-silyl alcohols (46) by reaction of silylchromium reagents and aldehydes (Scheme 20b).84 I (45) C4H9 61%ZE955 0 OH Br VSiMeJ (b) CrClz(6eq.) -Ph NiCIz (0.1 eq.) quant. EIZ > 1O:l (46) 74% (3:l EIZ) Scheme 20 Among the many Wittig methods for alkene synthesis White has demonstrated that nucleophilic addition to butadienyl phosphonium salts generates an allyl phosphorane (47) which adds to aldehydes to give selectively (E,Z)-dienes (Scheme 21a).85 Hanessians6 and Denmarks7 report the use of chiral benzyl phosphonamides (48) and phosphonamidate (49) respectively to synthesize chiral alkenes from prochiral ketones with exceptionally high stereocontrol (Scheme 21 b).Honss has extended his curious Wittig reaction between stabilized ylides and ozonides to include those ozonides derived from acylic alkenes (Scheme 21c). The mechanism of the reaction is unclear although there is some evidence that the reaction proceeds via an aldehyde and not a carbonyl oxide as previously thought. The use of unusual organobarium complexes has been reported from both the Coreys9 and Yamamotogo groups.They describe the excellent a,af coupling of allyl barium derivatives and allyl halides; other Group I and I1 metals produce mixtures of a,af and a,$ coupling products (Scheme 22a). Another unusual metal complex for alkene synthesis has been used by Trost who reports the use of hexakis(tert-butylisonit-ri1e)molybdenum to effect the elimination of allyl pivalates to dienes. (Scheme 22b).91 3 Reduction The Corey oxazaborolidine (50) one of the most promising asymmetric reducing 84 R. Angel] P. J. Parsons A. Naylor and E. Tyrell SYNLETT. 1992 599. " J.D. White and M.S. Jensen Tetruhedron Lett. 1992 33 517. '6 S. Hanessian and S. Beaudoin Tetrahedron Lett. 1992 33 7655. 87 S.E. Denmark and C.-T. Chen J. Am. Chem. SOC. 1992 114 10674. " Y.3.Hon K.-P. Chu P.-C. Hong and L. Lu Synth. Commun. 1992 22 429. 89 E. J. Corey and W.-C. Sheih Tetrahedron Lett. 1992 33 6435. 90 A. Yanagisawa H. Hibino S. Habaue Y. Hisada and H. Yarnamoto J. Org. Chem. 1992 57 6386. 91 B. M. Trost and M. S. Rodriguez Tetruhedron Lett. 1992 33,4675. 264 N. Lawrence 62% E,Z:E,E 16:l i Bu‘Li -4 ii O e B u ‘ i. Bu’Li - iii P~~COSO~CF.J ii Bu‘ 2,6-lutidine A But 65% e.e. > 99% (49) 91% e.e. > 98% C02Me I C02Me 40% Scheme 21 6196 E,E MO(CNB& * @> (0.1 eq.) OCOCMe3 (-)-Ipsenol Scheme 22 Synthetic Methods agents of recent years has seen continued interestg2 with an improved synthesis93 and the solution of its X-ray structure as its borane complex supporting the proposed transition state assembly (51) (Scheme23).94Corey has illustrated the potential of (50) with an ingenious synthesis of cx-amino acids.95 Asymmetric catalytic reduction of or-trichloromethyl ketones (Scheme 24)96 proceeds as expected with high enan-tioselectivity.Treatment of the resulting trichloromethyl alcohols with base affords \Bu H Rs = Small group (50) (51) RL = Large group Scheme 23 96% 95% e.e. OH- N;1 bW2 RAC02H R*C02H 92% 91% L 'NS 1 90% (52) yields for R = PhCH2CH2 Scheme 24 1,I-dichlorooxiranes (52) which can be captured in situ with a variety of nucleophiles leading eventually to a-amino acids cx-aryloxy acids and a-hydroxy acids.97 Two routes to or-trichloromethyl ketones from alkylzinc reagents and acyl chlorides and from trichloromethylsodium and aldehydes followed by oxidation have been studied.98 Alcohols obtained by reduction of arylalkyl ketones with (50) have been 92 B.B. Lohray and V. Bhushan Angew. Chem. Int. Ed. Engl. 1992,31 729; J. Wang and X. Zhou Youji Huuxue 1992,12,241;Chem. Abs. 1992.117 110 906s; S. Wallbaum and J. Martens Tetrahedron Asymm.. 1992 3 1475. y3 E.J. Corey and J.O. Link Tetrahedron Lett. 1992. 33 4141. q4 E. J. Corey M. Azimioara and S. Sarshar Tetruhedron Lett. 1992. 33 3429. y5 E. J. Corey and J.O. Link J. Am. Chem. Soc. 1992 114. 1906. 96 E.J. Corey J.O. Link and R.K. Bakshi Tetrahedron Lett. 1992 33 7107. 97 E. J. Corey and J. 0. Link Tetrahedron Lett. 1992 33 3431. y8 E. J. Corey J.O.Link and Y. Shao Tetrahedron Lett.. 1992 33. 3435. 266 N. Lawrence used to make thiols sulfinic esters and sulfonic acids via Mitsonobu reaction with the appropriate sulfur nucleophile.'' The oxazaborolidine can also be used to induce axial chirality; the lactone (53)was reduced by (50)and borane to give the homochiral biaryl (54)with high selectivity (Scheme 25).'0° The success of (50)has stimulated interest in other oxazaborolidines such as the indoline"' derivative (55)and four-membered ring analogue (56),'02 both of which catalyse the reduction of ketones stereoselectively. Midland has also studied the nopol derived azaborane (57) which unlike the oxaza- borolidine catalysts only induces moderate stereoselectivity .'O3 Buono has found that substitution of the boron with phosphorus leads to a catalyst the oxazaphospholidine- borane (58) that retains the high selectivity of the parent oxazab~rolidine.'~~ BA3.THF.4 eq. c (50). 3 eq. THF. 30°C %O / Y (53) (54) 94%. 94% e.e. (55) (57) (58) Scheme 25 The titanocene (59) has been used to catalyse the reduction of ketimines to secondary amines.lo5 The reaction is thought to proceed via hydride delivery from a Ti"' hydride complex first formed by the reaction of (59) with the butyllithium and triphenylsilane. Similarly the stoichiometric reduction of ketimines with dialkoxyboranes such as (60) has been reported (Scheme 26).'06 Reports of other hydroborating agents and their uses include pinacol borane;' O7 1,4-thioxane:BH3;' O8 rhodium(1) and iridium (I) catalysed hydroboration with catechol borane."' 99 E.J. Corey and K. A. Cirnprich Tetrahedron Lett. 1992 33,4099. loo G. Bringmann and T. Hartung Angew. Chem. Int. Ed. Engl. 1992 31 761. lo' J. Martens C. Dauelsberg W. Behnen and S. Wallbaum Tetrahedron Asymm. 1992 3 347. lo' A. V. Rarna Rao M. K. Gurjar and V. Kaiwar Tetrahedron Asymm. 1992 3 859. M. M. Midland and A. Kuzubski J. Org. Chem. 1992 57 2953. lo4 J.-M. Brunel 0.Pardigan B. Faure and G. Buono J. Chem. SOC. Chem. Commun. 1992 287. lo' C. A. Willoughby and S.L. Buchwald J. Am. Chem. SOC. 1992 114 7562. T. Kawate M. Nakagawa T. Kakikawa and T. Hino Tetrahedron Asymm. 1992 3 227. lo' C. E. Tucker J. Davidson and P. Knochel J. Org. Chem. 1992,57 3482. H.C. Brown and A.K. Mandal J. Org. Chem. 1992 57 4970. lo9 D. A. Evans G.C. Fu. and A. H. Hoveyda J. Am. Chem. SOC.,1992 114 6671. Synthetic Met hods H NCH2Ph NCH2Ph A. (59) (0.02 eq.) Bu"Li (0.04 eq.) PhSiH3 (0.005 eq.),€12 (200Opsi) * / R-Ti-R or OK o^ B. (60)(5 eq.) MgBrz.OEt2 \i A. 93% 85%e.e. B. 70%,72% e.e. (59) R = (R,R)-1,l'-binaphth-2,2'-diolate H-B Scheme 26 The pyrrolidinoborohydride .(61) provides an air-stable reducing agent that can be used as a substitute for lithium aluminium hydride; it reduces most carbonyl groups except acids (Scheme 27). ' Triethoxysilane/titanium tetraisopropoxide also provides an air stable mixture for reducing esters to alcohols.' l1 Chiral binaphthalene112 and biaryl derivatives continue to see widespread use as catalysts.Meyers has used the biaryl(62) as a chiral modifier of lithium aluminium hydride to reduce acetophenone to the corresponding (S)-alcohol(97% e. e.).' l3 Chiral borohydride reagents from 9-BBN and sugar derivatives show selectivity in the reduction of ketones."4*"5 A new OMe 0 N H,B/-'H 'lo G. B. Fisher J. Harrison J. C. Fuller C. T. Goralski and B. Singaram Tetrahedron Lett. 1992,33,4533. ''I S.C. Berk and S. L. Buchwald J. Org. Chem. 1992 57 3751. ''' C. Rosini L. Franzini A. Raffaelli and P. Salvadori Synthesis 1992 503. D. Rawson and A.I. Meyers J. Chem. SOC.,Chem. Commun. 1992 494. '14 B.T. Cho and Y.S. Chun Tetrahedron Asymm. 1992 3 341. ''' B.T. Cho and Y. S. Chun Tetrahedron Asymm. 1992 3 73.268 N. Lawrence phosphine (63) has been designed for the intramolecular hydrosilylation of hydroxy ketones to give 1,2-diols (Scheme 28).' l6 0 OH > 15% 93% e.e. Scheme 28 Carboxylic acids are converted quantitatively to aldehydes by reduction of their thiophenyl esters with lithium metal.' '' Akibo has introduced a cheap and odour-free new variant of the borane reduction of a-amino acids to a-amino alcohols using sodium borohydride and sulfuric acid and observed little racemization.' l8 4 Oxidation Asymmetric dihydroxylation' l9 continues to be a fertile ground for the design of new chiral catalysts. The most impressive contribution to this area has been made by Sharpless and his group who have designed a system using the new phthalazine ligands dubbed (DHQD),-PHAL and (DHQ),-PHAL (Scheme 29).' 2o With these ligands the catalytic dihydroxylation of disubstituted and trisubstituted alkenes proceeds with exceptional enantioselectivity (e.e.> 97%); the selectivity with terminal alkenes is only slightly poorer (e.e. 77797%). Very low ratios of catalyst to substrate can be tolerated; the (alkene) (OsO,) :(ligand) ratio commonly used is 1 :0.002 :0.01. With even lower ratios 1 :0.002 :0.0001 the dihydroxylation of trans-stilbene is still highly selective (96% e. e.). Such low catalyst ratios can be used since it was observed that the addition of methylsulfonamide drastically improves the rate of osmate ester hydrolysis in the cases of di- and trisubstituted alkenes. Mixtures of K,OsO,(OH), K,Fe(CN), K,CO, and ligand are now commercially available as AD-mix a [containing (DHQ),-PHAL] and AD-mix [containing (DHQD),-PHAL].Although not enantiomeric catalytic systems AD-mix c1 and AD-mix p induce a near equal and opposite degree of stereoselection. The AD-mixtures have been used to dihydroxylate a wide variety of alkenes; (E)-eneynes (7347% e. e.) (2)-eneynes (29-62% e. e.) and terminal eneynes (38-79% e. e.);"' dimes selectively yielding enediols;'22 silyl enol ethers yielding a-hydroxy ketones.' 23 The reaction with sq~alene''~is mildly '" M. J. Burk and J. E. Feaster Tetrahedron Lett. 1992 33 2099. '" J. H. Penn and W. H. Owens Tetrahedron Lett.. 1992 33 3737. '18 A. Abiko and S. Masamune Tetrahedron Lett. 1992 33 5517. 'I9 B.B.Lohray Tetrahedron Asymm. 1992 3 1317. 12" K. B. Sharpless W. Amberg Y. L. Bennani G.A. Crispino J. Hartung K.4. Jeong H.-L. Kwong K. Morikawa 2.-M. Wang D. Xu and X.-L. Zhang J. Org. Chem. 1992,57,2768; For a review of this paper see C. H. Heathcock Cherntracts Org. Chem. 1992 5 70. K.4. Jeong P.J. Sjo and K. B. Sharpless Tetrahedron Lett. 1992 33 3833. 12* D. Xu G.A. Crispino and K. B. Sharpless J. Am. Chem. SOC. 1992 114 7570. 123 T. Hashiyama K. Morikawa and K. B. Sharpless J. Org. Chem. 1992 57 5067. lZ4 G. A. Crispino and K. B. Sharpless Tetrahedron Lett. 1992 33 4273. Synthetic Methods Me0 (DHQDh-PIIAL ligand for AD-mix p (DHQh-PHAL ligand for AD-mix a DHQD-IND AD-mix p attack HO OH AD-mix p AD-mix a Rs-.~HRM RL HO OH AD-mix a attack AD-mix p AD-mix a bis-Piperazine (68) Isoxazolidine (67) Trans-stilbene > 99.5 > 99.5 98 73 StyreneP-Methylstyrene 97 94 97 93 89 82 72 Rs = Small group RL = Large group RM= Medium group Scheme 29 regioselective but nevertheless very highly stereoselective (Scheme 30).The selectivity in the reaction between the AD-mixtures and (2)-alkenes is poorer; the indolinoyl dihydroquinidine derivative DHQD-IND is recommended for these cases.' 2s Sharp-less has used the system to synthesize 6-hydroxy-y-lactones from y,b-unsaturated esters b-hydroxy-y-lactones from P,y-unsaturated esters,' 26 and all the stereoisomers of di~paralure.'~' He has also used the AD-mix P to obtain a protected glyceraldehyde L. Wang and K. B. Sharpless.J. Am. Chem. Soc. 1992. 114 7568. lZ6 Z.-M. Wang X.-L. Zhang K. B. Sharpless. S. C. Sinha A. Sinha-Bagchi and E. Keinan. Tetrahedron Lett.. 1992 33 6407. E. Kienan S.C. Sinha A. Sinha-Bagchi Z.-M. Wang X.-L. Zhang and K. B. Sharpless Tetruhedron Lett.. 1992 33 641 1. 270 N. Lawrence equivalent from the alkene (64).128The method has been used by two groups in approaches to (-)-frontalin from alkenes (65)129and (66).I3O 84%.60-70% e.e.. a (65) 97%'e.e.,f3 (64) AD-mix p 90% 86% e.e. 79%.93% e.e. 73%e.e.,f3 (66) AD-mix a,72%,30-36%e.e. 46.2 34.6 19.2 35% total 96% e.e. Squalene Scheme 30 At much the same time Murahashi reported that moderately selective dihydroxyla- tion of alkenes can be obtained with the isoxazolidine ligand (67).'31 Similarly Fuji has used the bispiperazine ligand (68) stoichiometrically to give diols with high enan- tioselectivity.32 The chiral biphenylene diamine (69)catalyses the dihydroxylation of (E)-stilbene (94% 96% e. e.)133 Other catalytic oxidizing agents have seen attention. The use of chromium reagents for catalytic oxidation has been reviewed.' 34 Homochiral 1,2-amino alcohols and 1,2-benzyloxyalcohols can be oxidized with catalytic TEMPO/sodium hypochlorite in high yield with very little racemization.135 Primary alkyl iodides have been converted directly to the corresponding carboxylic acid by the action of catalytic ruthenium trichloride and periodic acid.' 36 Similarly alkyl bromides can be oxidized to aldehydes by the action of morpholine N-0~ide.l~~ a-Oxidation of chiral ketals by rhenium(vr1) oxide provides easy access to chiral cx-hydroxy ketones.13* The oxidation of terminal alkenes with the catalytic palladium complex [PdCl(NO,)(MeCN),] in the presence of bulky amides offers several advantages (faster reaction and no terminal alkene isomerization) over the standard conditions for the Wacker oxidation.39 Similarly R. Oi and K. B. Sharpless Tetrahedron Lett. 1992 33 2095. lZ9 J. A. Turpin and L. 0.Weigel Tetrahedron Lett. 1992 33 6563. 130 B. Santiago and J.A. Soderquist J. Ory.Chem. 1992 57 5844. 13' Y. Imada T. Saito T. Kawakami and %-I. Murahashi Tetrahedron Lett. 1992 33 5081. 13' K. Fuji K. Tanaka and H. Miyamoto Tetrahedron Lett. 1992 33 4021. 133 H. Haubenstock and K.Subasinghe Chirality 1992 4 300. 134 J. Muzart Chem. Rev. 1992 92 113. M. R. Leanna T. J. Sowin and H. E. Morton Tetrahedron Lptt. 1992 33 5029. 13' R. Hernandez D. Melian and E. Suarez Synthesis 1992 653. 13' W. P. Griffith J. M. Jolliffe S.V. Ley K. F. Springhorn and P. D. Tiffin,Synth. Commun. 1992,22 1967. 13' S. Tang and R. M. Kennedy Tetrahedron Lett. 1992 33 7823. 139 N. H. Kiers B. L. Feringa and P. W. N. M. van Leeuwen Tetrahedron Lett. 1992,33 2403. Synthetic Met hods 271 alkenes can be oxidized directly to carboxylic acids by hydroboration of alkenes with dibromoborane followed by oxidation of the alkylboronic acid with chromium trioxide/acetic acid.'40 Oxidations that can be carried out by oxygen in the absence of metal catalysts are increasingly receiving attention.Kaneda reports a potentially useful method for the epoxidation of alkenes using molecular oxygen and isobutyraldehyde; the reaction appears to proceed by autoxidation of the aldehyde to a pera~id,'~' and shows the same stereoselectivity and chemoselectivity as in peracid epoxidations. Tandem alcohol oxidation and Baeyer-Villiger oxidation can be performed in a one-pot procedure using mCPBA and Corey's chromate ester (70) (Scheme 31).'42 (70) 95% Scheme 31 A review of Davis's N-sulfonyl~xaziridine~~~ -which has seen an improved large-scale -has appeared. Another topical oxidizing agent dimethyl- dioxirane has been used by Adam to oxidize thioesters to the corresponding a-ketosulfones with no observed sulfoxide formation.'45 U.S. Racherla V. V. Khanna and H.C. Brown Tetrahedron Lett. 1992 33 1037. 14' K. Kaneda S. Haruna T. Irnanaka M. Hamarnoto Y. Nishiyarna and Y. Iishi Tetrahedron Lett. 1992 33 6827. 14' M. L. Morrin-Fox and M. A. Lipton Tetrahedron Lett. 1992 33 5699. 143 F.A. Davis and B.-C. Chen Chem. Reo. 1992,92 919. I. Mergelsberg D. Gala D. Scherer D. DiBenedetto and M. Tanner Tetrahedron Lett. 1992 33 161. W. Adam and L. Hadijiarapoglou Tetrahedron Lett. 1992 33 469. 14' 272 N. Lawrence Pseudornonas putida continues to provide access to cyclohexa-3,5-diene- 1,2-diols. 146 Some newly reported substrates for this microorganism include x-chl~rostyrene'~~ and benzofuran.' 48 Magnus has developed a host of methods based on the synthesis of azido triisopropylsilyl enols (Scheme 32)'49 which can be regarded as formal oxidations.In the first of his reactions the silyl enol ether (71) reacts with sodium azide and ceric ammonium nitrate to give an a-azido ketone (72).150 Secondly (71) reacts with iodosobenzene and trimethylsilyl azide to give the p-azido enol ether (73) the chemistry of which is currently being explored but is already proving to be rich and of great potential. Simple treatment of (73) with tetrabutylammonium fluoride results in elimination of the azide to give the corresponding enone.' 51 Alternatively the azide can be displaced by a variety of carbon nucleophiles to give products such as (74) that would be obtained from a Michael addition to the appropriate enone.152 Ph (72) 72% (73) 83% (74) 98% Scheme 32 5 Protection There are very few examples of multi-step syntheses that do not make use of protecting group chemistry.Indeed it is one area that unites synthetic chemists of differing specialities and although not often seen as very challenging is of great importance. Silyl ethers have proven as popular as ever with a large number of new or modified conditions for their deprotection; diisobutylaluminium hydride;' 53 ammonium fluor- ide in methanol (providing a cheap alternative to tetrabutylammonium fluoride);' 54 silicon tetrafluoride;' 55 tert-butyldimethylsilyl groups are selectively removed in the presence of a triisopropylsilyl group with hexafluorosilicic acid (H,SiF,);' 56 dich-lorodicyanoquinone provides an exceptionally mild neutral method for the cleavage of tert-butyldimethylsilyl groups.'57 Quayle has reported that silylmethyl groups are sometimes unexpectedly deprotonated by strong bases -a point worth bearing in mind when using silyl protecting groups.' 58 H. A. J. Carless Tetrahedron Assym. 1992 3 795. T. Hudlicky E.E. Boros and C. H. Boros SYNLETT. 1992 391. ''* D. R. Boyd N. D. Sharma R. Boyle R. A. S. McMordle J. Chima,and H. Dalton Tetrahedron Lett. 1992 33 1241. Id9 P. Magnus and J. Lacour J. Am. Chem. SOC. 1992 114 767. P. Magnus and L. Barth Tetrahedron Lett. 1992 33 2777. 15' P. Magnus A. Evans and J. Lacour Tetrahedron Lett. 1992 33 2933. 15' P. Magnus and J. Lacour J. Am. Chem. SOC. 1992 114 3993. 153 E. J. Corey and G.B.Jones J. Org. Chem. 1992 57 1028. 15' W. Zhang and M. J. Robins Tetrahedron Lett. 1992 33 1177. 155 E. J. Corey and K.Y. YI Tetrahedron Lett. 1992 33 2289. A. S. Pilcher D. K. Hill S. J. Shimshock R. E. Waltermire and P. DeShong J. Org. Chem. 1992,57,2492. 15' K. Tanemura T. Suzuki and T. Horaguchi J. Chem. Soc. Perkin Trans.1 1992 2997. 15' H. Imanieh P. Quayle M. Voaden J. Conway and S. D. A. Street Tetrahedron Lett. 1992 33 543. ''13 Synthetic Met hods Alcohols have also been protected as their (1R)-menthoxymethyl ethers providing an internal measure of asymmetric induction without the need for further derivatiz- ation.' 59 Takeuchi16* has used a more conventional approach for measuring the optical purity of alcohols and has developed an alternative to Mosher's ester.He has shown that the fluoroacylchloride (75) reacts rapidly with even hindered alcohols thus 0 reducing the complications of partial kinetic resolution which can give a false measurement of enantiomeric excess. The phenoxydimethylmethyl group has been used to protect homochiral cyanohydrins without racemization providing an ultra-violet active blocking group. 16' Benzyl ethers are resistant to the conditions (1,4-cyclohexadiene Pd/C EtOH)16' used to remove benzyl esters; the reverse selectivity can be obtained with dimethyldioxirane.163 Similarly p-methoxybenzyl ethers have been removed in the presence of benzyl ethers by the action of a mixture of stannous chloride trimethylsilyl chloride and anisole. 64 Trans-diequatorial alcohols can be protected as dispiroketals by treatment with the bis-enol ether (76) (Scheme 33).165 As well as being used to protect carbohydrates HrqQ-0(7s) c CSA.CIICI3. A HO $&$Me OH Ho OMe (77) (77) 76% (78) Scheme 33 159 D. Dawkins and P. R. Jenkins Tetrahedron Asymm. 1992 3 833. Y. Takeuchi N. Itoh and T. Koizumi J. Chem. Soc.. Chem. Commun.. 1992. 1514. 161 P. Zandbergen. H. M. G. Willems G. A. van der Marel J. Brussee and A. van der Gen Synth. Commun.. 1992 22 2781. J. S. Bajwa Tetrahedron Lett. 1992 33 2299. '63 B.A. Marples J.P. Muxworthy. and K. H. Baggaley SYNLETT. 1992. 646. 164 T. Akiyama H. Shima and S. Ozaki SYNLETT. 1992 415. 165 S. V. Ley R. Leslie P. D. Tiffin and M. Woods Tetrahedron Lett. 1992 33 4767.274 N. Lawrence [OMe galactopyranoside -,(77)] bis-enol ether (76) has been used to make a stable glyceraldehyde equivalent (78).'66 Curran has shown that free-radical chemistry can be used to create so called self-oxidizing protecting. groups which should prove very useful since deprotection followed by oxidation is an often encountered tandem operation (Scheme 34a). The primary alcohol of a diol is selectively protected as the bromotrityl ether (79). When treated with tributylstannane the radical thus generated undergoes 1,5-H abstraction of the carbinol hydrogen to give a new radical (80)which fragments to the aldehyde (81). The method is a rare example of an oxidation that is selective for primary alcohols.' 67 0 &A OH -o-BrPhCCPh2 AIBN BySnH 41% 58% OH &OH (79) Ph' Ph Scheme 34 Hoffmann has studied another branch of chemistry that has seen little use in protecting group methodology namely photochemistry.He has shown that quinaldine ethers (82) can be photochemically transformed to ketones (Scheme 34b) and can therefore be regarded as latent ketones.'68 The protection of carbonyl groups has also seen much activity; Parsons describes the S. V. Ley M. Woods and A. Zanotti-Gerosa Synthesis 1992 52. 16' D. P. Curran and H. Yu Synthesis 1992 123. "* V. Rukachaisirikul U. Koert and R. W. Hoffmann Tetrahedron 1992 48 4533. Synthetic Methods 275 formation of acetals from a$-unsaturated ketones and alcohols with concomitant reduction of the double bond under standard hydrogenation conditions (5% Pd/C THF alcohol).'69 Acetals have been cleaved by a variety of methods including stannous chloride; '70 catalytic dichlorodicyanoquinone; ' 'trichlorosilyl iodide (gen- erated in situ from tetrachlorosilane and sodium iodide).'72 Diethyl acetals can be deprotected with concomitant oxidation to afford ethyl esters by the action of pyridinium dichromate/tert-butyl hydroperoxide.'73 Thioacetals have been made by zeolite ~atalysis,'~~ and can be cleaved under neutral conditions by simply heating in dimethyl sulfoxide at 140 "C.'75 Hindered carboxylic acids can be protected as their cyanomethyl esters' 76 by reaction of their sodium salt with chloroacetonitrile avoiding activation of the acid.The ester is easily cleaved by using mildly basic sodium sulfide. Esters can be hydrolysed by treatment with boron triiodide.'77 Borane provides a rare protecting group for phosphines; the borane-phosphine is stable to o~idation.'~~ Masamune has used the bis(trimethylsilylethy1)phosphonate group as a protecting group of phosphate monoesters developed specifically for his calyculin synthesis.' 79 Davis' 8o reports the use of pyrrole -compatible with Grignard and cuprate reagents -as a latent primary amine in organometallic synthesis. The amine can be liberated by ozonolysis to give a formamide. 6 Miscellaneous Preparations Significant progress has been made in the study of amide bases. Wakefield has detailed a practical synthesis of sodium diisopropylamide (NDA) made from the amine and sodium by isoprene mediated electron transfer and shown it to possess higher reactivity than lithium diisopropylamide;' diphenylacetic acid is obtained in 80% yield from deprotonationxarboxylation of diphenylmethane with NDA and in only 15% with LDA.Ketones have been deprotonated with a variety of homochiral base^.'^^-'^^ In particular Kogalg5 has reported his X-ray 6Li and 5N NMR studies of (83) which is particularly selective for the synthesis of (84) (Scheme 35a). Simpkins reports the intriguing use of (85) to control both regio- and stereochemistry of deprotonation; racemic (86) gave after deprotonation and silylation the isomeric silyl enol ethers (87) and (88) (Scheme 35b).lg6 169 P. Hudson and P. J. Parsons SYNLETT 1992 867.170 K. L. Ford and E. J. Roskamp Tetrahedron Lett. 1992 33 1135. 17' K. Tanemura T. Suzuki and T. Horaguchi J. Chem. SOC.,Chem. Commun. 1992 979. S. S. Elmorsy M. V. Bhatt and A. Pelter Tetrahedron Lett. 1992 33 1657. 173 N. Chidambaram S. Bhat and S. Chandrasekaran J. Org. Chem. 1992 57 5013. 174 P. Kumar R.S. Reddy A. P. Singh and B. Pandey Tetrahedron Lett. 1992 33 825. C.S. Rao M. Chandrasekharam H. Ila and H. Junjappa Tetrahedron Lett. 1992 33 8163. 176 H. M. Hugel K.V. Bhaskar and R. W. Longmore Synth. Commun. 1992 22 693. 177 G. W. Kabalka C. Narayana and N. K. Reddy Synth. Commun. 1992 22 1793. P. Pellon Tetrahedron Lett. 1992 33 4451. A. Sawabe S. A. Filla and S. Masamune Tetrahedron Lett. 1992 33 7685. A. P. Davis and T.J.Egan Tetrahedron Lett. 1992 33 8125. In'D. Barr A.J. Dawson and B.J. Wakefield J. Chem. Soc. Chem. Commun. 1992 204. '" K. Koga K. Aoki and K. Tomioka Jpn. Kokai Tokkyo Koho JP 04 82865 [92 8286.51. lR3M. Majewski and D. M. Cleave J. Org. Chem. 1992 57 3599. P.J. Cox and N.S. Simpkins SYNLETT. 1992 194. D. Sato H. Kawasaki I. Shimada Y. Arata K. Okamura T. Date,and K. Koga J. Am. Chem. Soc. 1992 114 761. K. Bambridge N. S. Simpkins and B. P. Clark Tetrahedron Lett. 1992. 33 8141. 276 N. Lawrence r 1 ‘u’ u Me3SiC1 THF -78°C v 1 I But Bu‘ (84) 86%,84% e.e. (86) (87) 55%,60% e.e. OSiMe3 BocN H 63 (88) 45% 83% e.e. Scheme 35 a-Amino acids have been made by several new methods including one devised by Oppolzer who used the a-chloro-a-nitroso derivative (89) to form homochiral nitrones from zinc enolates.These were hydrolysed and reduced to give erythro amino alcohols (Scheme 36a).I8’ Evans reports of some observations in the use of triisopropylbenzenesulfonyl azide for the selective amination of chiral oxazolidinone derived enolates.’ In some cases the intermediate triazine is remarkably stable and does not decompose in situ. In these cases the isolated triazine (90)can be treated with sodium acetate and sodium iodide in acetone to effect the overall azide transfer (Scheme 36b). Trost has reported the interesting intramolecular allylic substitution of the meso diurethane derivative (91),by the action of palladium (0) and a variety of bidentate bis(2-diphenylphosphinobenzoyl)derivatives; the ligand (92) is the best (Scheme 37a).’89 Asymmetric halolactonization has been successfully employed in a number of cases;’90 Shibuya”’ has put the reaction to use in a synthesis of (+)-mesembrine.He la’ W. Oppolzer 0.Tamura G. Sundarababu and M. Signer J. Am. Chem. SOC. 1992 114 5900. D.A. Evans D.A. Evrard S.D. Rychnovsky T. Friih W.G. Whittingham and K.M. DeVries Tetrahedron Lett. 1992 33 1189. B. M. Trost and D. L. Van Vranken Anyew. Chem. Int. Ed. Engl. 1992 31 228. I9O Y. Ding J. Li and L. Wang Chin. J. Chem. 1991 9 543. 19’ T. Yokomatsu H. Iwasawa and S. Shibuya J. Chem. SOC..Chem. Commun. 1992,728; T. Yokomatsu H. Iwasawa and S. Shibuya Tetrahedron Lett. 1992 33 6999. Synthetic Methods uses Oppolzer's auxiliary to direct the iodination of the meso diallyl acid (93)with high enantioselectivity (Scheme 37b).R2N02i Nao SO2NR2 65%,90:10 anti:syn 90% e.e. 98.2%e.e. (90) Nal. NaOAc. MQCO 25°C. 5 h 1 Scheme 36 Hayashi has used asymmetric hydrosilylation to desymmetrize prochiral alkenes with a binaphthalene derivative (R)-MOP (Scheme 38). 192 A variety of halogenation methods have been reported including an interesting chemoselective bromination of alkenes that takes plack when the bromine has been absorbed into a zeolite; cyclohexene is brominated in preference to (E)-dec-5-ene ( >95%).193a,@-Unsaturated ketones can be converted into a-iodo-a,@-unsaturated ketones by the action of iodine and ~yridine.'~~ Among the variety of reagents that have been used to perform straightforward transformations that are worthy of mention are acetone cyanohydrin a readily available but rarely used cyanide source employed to open ep~xides;'~' cobalt(I1) chloride used to make mixed acid anhydrides by coupling of acids and acid chlorides;196 1,8-diazabicyclo[5.4.O]undec-7-ene 192 Y.Uozurni S.-Y. Lee and T. Hayashi Tetrahedron Lett. 1992 33 7185. 193 K. Smith and K.B. Fry J. Chem. SOC.,Chem. Commun. 1992 187. 194 C. R. Johnson J. P. Adams M. P. Braun C. B. W. Senanayake P. M. Wovkulich and M. R. Uskokovic Tetrahedron Lett. 1992 33 917. 19' D. Mitchell and T.M. Koenig Tetrahedron Lett. 1992 33 3281. 196 R. R. Srivastava and G.W. Kabalka Tetrahedron Lett. 1992 33 593. 278 N.Lawrence hydrobromide :bromine (DBU.HBr,) used to selectively brominate aromatic com- pounds. 97 \ Ts 94%,88% e.e. Ar= PPh2 I(collidine)$304 -50°C. 48 h (b) gso2 (93) 88% e.e. 83%,4.5:l Scheme 37 i HSiCl~.O.OOl%PdC(n-CjH5h 0.02% (R)-MOP ii. KF KHC4. H24 93% e.e. (R)-MOP Scheme 38 The introduction of fluorine into organic molecules is an important process and has been reviewed re~ently.”~ Banks has reported a new class of air-stable N-F fluorinating agents derived from triethylenediamine derivatives such as (94) provid-ing an excellent source of electrophilic fluorine (Scheme 39).19’ 19’ H. A. Muathen J. Org. Chem. 1992 57 2740. J. A. Wilkinson Chem. Rev. 1992 92 505. 19’ R. E. Banks S. N. Mohialdin-Khaffaf G.Sankar Lal I. Sharif and R. G. Syvret J. Chem. SOC.,Chem. Commun. 1992 595. Synthetic Met hods F 95%. 90% d.e. Scheme 39 7 Enzymes Biocatalysts see an ever increasing use as reagents for organic synthesis and have been impressively surveyed by Santaniello in a review containing 880 references.200 The most widely used method involves the hydrolysis of esters but there are nevertheless many reports of less popular biotransformations. Immobilized glucose isomerase an enzyme used industrially to make high fructose content syrup from glucose has been OH Immobilized Glucose Isomerase &H20H ~ (a) Bnob-OH OH BnA HoA 72% Chloroperoxidase L KBr. HzQ. 2 h. pH 3 HO OH Br 85% 0 Acinetobacter NCIB9871 c 37%.> 95% e.e. 43% > 95% e.e. Scheme 40 E. Santaniello P. Ferraboschi P. Grisenti and A. Manzocchi Chem. Rev. 1992 92 1071. 280 N. Lawrence used to make a range of pyran derivatives from glucofuranosides (Scheme 40a).201 Bromohydration of glycals is catalysed by chloroperoxidase (Scheme 40b).202 An enzymic Baeyer-Villiger reaction has been carried out on cyclobutanones; each enantiomer gives a regioisomeric lactone (Scheme 40c).203Flores has written an interesting account of ‘hairy root’ culture that may in future provide access to complex plant metabolites.204 A. Berger A. de Raadt,G. Gradnig M. Grasser,H. Low,and A. E. Stutz Tetrahedron Lett. 1992,33,7125. 202 K.K.-C. Liu and C.-H. Wong J. Ory. Chem. 1992 57 3748.203 V. Alphand and R. Furstoss J. Org. Chem. 1992 57 1306. 204 H.E. Flores Chem. Ind. (London) 1992 374.

ISSN:0069-3030    

DOI:10.1039/OC9928900249

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

10 Enzyme Chemistry By A. G. SUTHERLAND School of Applied Chemistry University of North London London N7 8DB 1 Introduction The use of isolated enzyme and whole cell catalysis in synthetic organic chemistry has become ever more widespread reflected by the advent of an ‘Organic Syntheses’ style publication on the subject.’ Perhaps unusually for a developing area impetus is provided as much by successful industrial application as by academic research.2 This area has been comprehensively reviewed in monograph form3 which given the current rate of publication in the primary literature is likely to be the last time this is possible. The application of biotransformations to the provision of chiral building blocks has also been ~overed.~ The use of lipases and esterases in the kinetic resolution of secondary alcohols through hydrolysis or formation of esters is crossing the threshold to become a routine technique that any chemist involved in asymmetric synthesis should be able to consider.Accordingly in contrast to previous year^,^.^ the present report will devote less attention to this topic in order to cover the many developments in other areas more deeply. 2 Hydrolysis and Condensation Reactions Complex Alcohols.-The kinetic resolution and desymmetrization of racemic and nteso (or prochiral) alcohols respectively by enzyme catalysed acylation has been re~iewed.~ The use of these techniques -and the corresponding hydrolytic procedures -to provide low molecular weight enantiomerically pure chiral synthons continues to be the main thrust of this area.8-’ Anecdotal evidence has suggested that few tertiary alcohol esters are subject to ’Preparative Biotransformations’ ed.S. M. Roberts K. Wiggins and G. Casy Wiley England. 1992. ‘Chirality in Industry’ ed. A. N. Collins G. N. Sheldrake and J. Crosby Wiley England 1992. K. Faber ‘Biotransformations in Organic Chemistry’ Springer-Verlag Berlin 1992. E. Santaniello P. Ferraboschi P. Grisenti and A. Manzocchi Chem. Rec.. 1992 92 1071. A.G. Sutherland Annu. Rep. Prog. Chem. Sect. B Org. Chem. 1991 88 263. N. J. Turner Annu. Rep. Prog. Chem. Sect. B Org. Chem. 1990. 87 333. ’ K. Faber and S. Riva Synthesis 1992 895. H.-J. Gais H. Henmerle and S. Kossek Synthesis 1992 169. B. Herradon Tetrahedron Asymmetry 1992 3 209.lo M. Mekrami and S. Sicsic Tetrahedron Asymmetry 1992 3 431. S. Takano T. Yamane M. Takahashi and K. Ogasawara SYNLETT 1992 410. C.R. Johnson A. Golebiowski and D.H. Steensma J. Am. Chem. Soc. 1992 114. 9414. 28 1 A. G. Sutherland enzymatic hydrolysis and that only low enantiomeric excesses are accessible.' However O'Hagan has reported a reasonable enantioselectivity in the hydrolysis of the trifluoromethyl substituted acetate (1) (Scheme l) which may stimulate new interest here. l4 87%e.e. 75%e.e. Reagents i Candida cylindracea lipase 40% conversion Scheme 1 The particular difficulties involved in resolving 1,2-diols have received attention but as yet no common solution has become apparent. Thus transesterification acylation and hydrolytic procedures have been m~oted.'~-'~ The last of these methods highlighted the hitherto unrecognized potential of enzymes to hydrolyse carbonates (Scheme 2),' which coincides with a report on the analogous use of vinyl carbonates as acylating agents.' 40% 78% e.e.Reagents i Pig liver esterase DMSO pH 7 buffer Scheme 2 The potential for the use of enzymes in the separation of diastereoisomers has been realized in the treatment of (2) with porcine pancreatic lipase when only the anti-acetate was hydroly~ed.'~ The elements of diastereoisomer separation kinetic resolution and desymmetrization have all been combined in the Pseudornonas sp. lipoprotein lipase catalysed acylation of the diol mixture (3). Thus the (R,R)diol was converted to the diacetate the (S,S) diol was recovered unreacted and the rneso-diastereoisomer was enantioselectively monoacetylated at the (R) alcohol centre.20 l3 I.C. Cotterill S. M. Roberts and A. G. Sutherland; K. Faber unpublished observations. l4 D. O'Hagan and N. A. Zaidi J. Chem. SOC.,Perkin Trans. 1 1992 947. D. Bianchi A. Bosetti P. Cesti and P. Golini Tetrahedron Lett. 1992 33 3231. l6 A. Bosetti D. Bianchi P. Cesti P. Golini and S. Spezia J. Chem. Soc. Perkin Trans. I 1992 2395. P. Barton and M.I. Page Tetrahedron 1992 48 7731. l8 M. Pozo R. Pulido and V. Gotor Tetrahedron 1992 48 6477. l9 J. Mulzer S. Greifenberg A. Beckstett and M. Gottwald Liebigs Ann. Chem. 1992 1131. '' S.J. Wallace B. W. Baldwin and C. J. Morrow J. Org.Chem. 1992 57 5231. Enzyme Chemistry A detailed attempt to understand the relationship between choice of organic solvent and enantioselectivity in lipase catalysed acylation reactions has failed to find any obvious correlation suggesting the possible significance of bound solvent molecules within the active site.21 It is likely that much more progress will have to be made in the understanding of the structure and function of active sites before further advances are made in this field.22-25 Complex Acids.-In marked contrast to the above work with lipases Klibanov has reported a marked correlation between solvent hydrophobicity and enantioselectivity in the transesterification of the phenylalanine ester (4)catalysed by Aspergillus oryzae protease.26 In polar solvents the L-enantiomer reacted selectively.This was rationaliz- ed in terms of the aromatic group being bound in a hydrophobic pocket in an orientation that favoured the selective transformation of that enantiomer. It was suggested that in hydrophobic solvents the molecule would show a greater tendency to bind with the side chain exposed to the solvent and that the orientation in the active site arising from this mode explained the consequent reversal to D-selectivity. The hydrolysis of neopentyl esters has been shown to provide good access to enantiomerically pure quaternary centres. Thus the regio- and enantioselective hydrolysis of dihydroisoxazole (5) at the more hindered ester moiety followed by chemical modification provided access to esters of the otherwise inaccessible (R)-citramalic acid (6).2’ Similarly an esterase obtained from a crude Candida lipolytica lipase preparation was used to resolve a range of apdialkyl amino acids (e.g.7) by ester hydrolysis.’* 0 AcNHfiOCH2CH2Cl EtO,C C02Et CH2Ph 0-N (4) 21 F. Secundo S. Riva and G. Carrea Tetrahedron Asymmetry 1992 3 267. 22 P.G. Hutlin and J.B. Jones Tetrahedron Lett. 1992 33 1399. 23 Z. Vimmer Tetrahedron 1992 48 8431. 24 C. Exl H. Honig G. Renner R. Rogi-Kohlenprath V. Seebauer and P. Seufer-Wasserthal,Tetruhedron Asymmetry 1992 3 1391. 25 M.-J. Kim and H. Cho J. Chem. SOC.,Chem. Commun. 1992 1411. 26 S. Tawaki and A.M. Klibanov J. Am. Chem. SOC. 1992 114 1882. 27 S. Yang W. Hayden K. Faber and H. Griengl Synthesis 1992 365.28 C. Yee T.A. Blythe T.J. McNabb and A.E. Watts J. Org. Chem. 1992 57 3525. A. G. Sutherland 0 Me*<C02Me Me02C OH H2N CH3 An unusual application of ester hydrolysis was demonstrated in the lipase mediated resolution of the isotopically labelled ester (8). Subsequent reduction of the recovered ester and introduction of a guanine residue led to the antiviral agent (9) in an isotopically chiral form that could be used to examine stereorecognition in the biosynthesis of the corresponding triph~sphate.~~ Sih has explored the effect of chemical modification of an enzyme on enantioselectiv- ity with some success. Thus nitration of the tyrosine residues of Candida cylindracea lipase with tetranitromethane resulted in a marked increase in efficiency in the resolution of a number of esters (e.g.0 Regioselective Ester Reactions.-There has been a marked increase in activity in the study of regioselective hydrolysis or formation of esters of homochiral polyols particularly in the carbohydrate field. Most instances of this procedure to date have involved selective reaction at a primary alcohol in the presence of one or more secondary groups and examples of this continue to appear.31 The scope of these reactions has been extended by the increased realization that subsequent induced acyl migration to the primary centre from a neighbouring secondary ester can be highly selective. This was elegantly exploited in the synthesis of the antifungal phospholipid lysofungin (1 1) from a readily available starting material (Scheme 3),32 and has also seen application in carbohydrate ~ynthesis.~ It has also been clearly demonstrated that it is feasible to discriminate between secondary alcohols in a variety of carbohydrate systems even in the context of vicinal diequatorial die~ters.~~-~’ Similarly the selective acylation of the secondary alcohol in 29 J.T.Sime R. D. Barnes S. W. Elson R. L. Jarvest and K. J. O’Toole J. Chem. SOC. Perkin Trans. I 1992 1653. 30 Q.-M. Gu and C. J. Sih Biocatalysis 1992 6 115. 31 0. Kirk F. Bjorkling S. E. Godtfredsen and T.0.Larsen Biocatalysis 1992 6 127. F. VanMiddlesworth M. Lopez M. Zweerink A. M. Edison and K. Wilson J. Org. Chem. 1992,57,4753. D. Chaplin D.H. G. Crout S. Bornemann D. W. Hutchinson,and R. Khan J.Chem.Soc.,Perkin Trans. I 32 33 1992 235. Enzyme Chemistry 0 ROA li roHO lii 0 ROYo* Reagents i Rhizopus arrhizus lipase pH 6.5; ii pH 8.5 buffer Scheme 3 deoxynucleosides has been shown to be a~hievable.~**~~ Selective enzymatic hydrolysis has also been successfully applied to the glycopeptide field. The alkaline protease from Thermoactinomyces vulgaris has been shown to cleave C-terminal t-butyl esters without competing chain hydr~lysis,~' while the near quantitative hydrolysis of the heptyl ester in (12) is a striking example of the degree of regio- and chemoselectivity available in these proce~ses.~~ Amide Hydrolyses and Condensations.-The kinetic resolution of amino acids via the hydrolysis of an N-acyl derivative of the L-enantiomer using aminoacylase from pig kidney or Aspergillus oryzae is well e~tablished.~' Wang and co-workers have 34 M.J. Chinn G. Iacazio D. G. Spackman N. J. Turner and S. M. Roberts J. Chem. Soc. Perkin Trans. I 1992 661. 35 C. Vogel B. Liebelt W. Steffan and H. Kristen J. Carbohydr. Chem. 1992 11 287. 36 F. Nicotra L. Panza G. Russo and L. Zucchelli J. Org. Chem. 1992 57 2154. 37 M. Marek I. Raich K. Kefurt J. Jary and I. M. Rouwenhart Biocatalysis 1992 6 135. 38 F. Moris and V. Gotor J. Org. Chem. 1992 57 2490. 39 V. Gotor and F. Moris Synthesis 1992 626. 40 P. Braun H. Waldemann and H. Kunz SYNLETT 1992 39. 41 M. Schultz P. Herman and H. Kunz SYNLETT 1992 37.42 H. K. Chenault J. Dahmer and G. M. Whitesides J. Am. Chem. Soc. 1989 111 6354. A. G. Sutherland however reported the use of an enantiocomplementary D-aminoacylase from Al-caligenesfaecalis which may have operational advantages in certain contexts but does not appear to hydrolyse as wide a range of substrates with so near complete enantio~electivity.~~ None of these enzymes have been found to hydrolyse N-alkyl-N-acyl amino acids so the discovery that the N-acyl-L-proline acylase from Cornarnonas testosteroni does accept these substrates (e.g. 13) highlights a useful entry to enantiometrically pure N-alkyl amino acids that should see wider appli~ation.~~ CH3 F3 CH3 Proline acylase -.NJ\C02H + H 0 The use of proteases in peptide synthesis continues to prove fruitful.Thus alcalase (a subtilisin preparation) has been shown to catalyse the formation of a wide range of dipeptide~.~’ The repeated application of this type of reaction was applied to a more ambitious synthesis of N-acyl enkephalin amides (Scheme 4).46 Cbz-Tyr-OEt + Gly-Gly-OEt Phe-OEt + Met-NH2 li li Cbz-Tyr-Gly-Gly-OEt Phe-Met-NH2 lii 89% 89% Cbz-Tyr-Gly-Gly-Phe-Met-NH2 60% Reagents i Chymotrypsin; ii Proteinase K Scheme 4 43 H.-P. Chen S.-H. Wu Y.-C. Tsai Y.-B. Yang and K.-T. Wang Bioorg. Med. Chem. Lett. 1992 2 697. 44 U. Groeger K. Drauz and H. Klenk Angew. Chem. Int. Ed. Engl. 1992 31 195. 45 S.-T. Chen S.-Y. Chen and K.-T. Wang J. Org. Chem. 1992 57 6960. 46 I. Gill and E.N. Vulfson J.Chem. Soc.. Perkin Trans. I 1992 667. Enzyme Chemistry 287 A novel approach to the synthesis of peptide C-terminal amides was reported by Green and Marg~lin.~~ The condensation of an alkyl ester of the appropriately protected peptide with the benzyl amine (14) was catalysed by papain. Subsequent acid-catalysed removal of the protecting groups resulted in N-benzyl cleavage and formation of the required primary amide linkage. OMe (14) Papain 1 OMe BocMet -Met-Leu-NH2 Me0 OMe 76% Nitrile Hydrolysis.-The chemoselectivity and enantioselectivity of isolated enzyme systems from Rhodococcus sp. which convert nitriles to the corresponding amide under nitrile hydratase catalysis and thence to the carboxylic acid utilizing an amidase have been critically examined.Griengl and co-workers have demonstrated that a wide range of aliphatic alicyclic and heterocyclic nitriles are accepted as substrates and that for the most part other functional groups present were not hydr~lysed.~~,~~ The enantioselectivity available from these processes has been largely5' attributed to the amidase and has been applied to the resolution or desymmetrization of both racemic and meso-substrates (Scheme 5).50*5 The use of a nitrilase which catalyses direct nitrile to acid conversion from Rhodococcus rhodochrous in the conversion of a-amino nitriles to the appropriate amino acids was reported. The enzyme showed high enantioselectivity producing L-leucine in ca. 97% e.e.52 G1ycosidations.-The syntheses of a wide range of disaccharides using a variety of commercially available glycosidases and transferases have been reported 3-5 while 41 J.Green and A. L. Margolin Tetrahedron Lett. 1992 33 7759. 48 A. de Raadt N. Klernpier K. Faber and H. Griengl J. Chem. Soc. Perkin Trans. I 1992 137. 49 N. Klempier A. de Raadt H. Griengl and G. Heinisch J. Heterocycl. Chem. 1992 29 93. 50 M. A. Cohen J. S. Parratt and N. J. Turner Tetrahedron Asymmetry 1992 3 1543. 51 J. A. Crosby J. S. Parratt and N.J. Turner Tetrahedron Asymmetry 1992 3 1547. 52 T.C. Bhalla A. Miura A. Wakamoto Y. Ohba and K. Furuhashi Appl. Microbiol. Biotechnol. 1992,37 184. 53 B. Sauerbrei and J. Theim Tetrahedron Lett. 1992 33 201. 54 Y. Nishida T. Wiemann and J. Theim Tetrahedron Lett.1992 33 8043. 55 D. H.G. Crout S. Singh B. E. P. Swoboda. P. Critchley and W.T. Gibson J. Chem. Soc. Chem. Comrnun. 1992 704. A. G. Sutherland 22%,> 98%e.e. 3 1% 90%e.e. OCH Ph OCH2Ph ~ NC&CN i NCAC02H 73% 83% e.e. Reagents i amidase and nitrile hydratase from Rhodococcus sp. pH 7 30 "C Scheme 5 the specificity of P-mannohydrolase in the synthesis of alkyl mannopyranosides has been explored in The synthesis of glycolipids presents an attractive target for this area of enzyme chemistry. The potential in this field has been realized by Flitsch in the synthesis of a glycosphingolipid (15) where a sequence of transferase catalysed reactions were utilized to construct the carbohydrate portion with the lipid moiety in place through the whole reaction sequence (Scheme 6)." Reagents i galactosyl transferase UDP-glucose UDP-glucose epimerase; ii sialyl transferase CMP- Neu-5-Ac Scheme 6 3 Reduction Reactions Whole Cell Ketone Reductions.-The enantioselective reduction of /3-keto esters to the corresponding P-hydroxy esters remains the most active field of whole cell reduction 56 N.Taubken and J. Theim Synthesis 1992 517. 57 B. Guilbert T. H. Khan and S.L. Flitsch J. Chem. Soc. Chem. Commun. 1992 1526. Enzyme Chemistry work. Although the majority of these reductions are still performed with bakers’ yeast (Saccharomyces cerevisiae) as a consequence of availability and ease of handling the advantages of using other microorganisms to transform these substrates are being emphasized.Thus while S. cerevisiae can be used to reduce ethyl 30-0x0-3-phenylpropanoate to the corresponding (S)-alcohol with reasonable efficiency higher yields and enantioselectivities are available through the use of other fungi (Scheme 7).58 Similarly the P-keto ester (16) is reduced by S. cerevisiae with moderate (R)-selectivity but higher optical purities of either enantiomer are available through the use of different species of the genus Clostridia.” uoEt Microorganism ph ~ Ph Microorganism Yield/% e.e./% Saccharomyces cerevisiae 63 93 Beauveria sulfurescens 72 96 Geotrichium candidum 64 298 Scheme 7 However bakers’ yeast was found to be the organism of choice in the reduction of a range of N-protected amino P-keto esters.The prochiral substrate (17) was reduced enantioselectively as part of a high yielding synthesis of the anticonvulsant (R)-GABOB (18).60 High diastereoselectivity was observed in the reduction of the enantiomers (19) and (20) of the y-methyl substituted analogue although surprisingly the erythro dias-tereoisomer was formed in both cases (Scheme 8).60 The reduction of the similar a-keto ester (21) was also successfully performed with Saccharomyces sp. again leading to a GABA inhibitor after deprotection (Scheme 9).61 Tremendous stereoselectivity was displayed in a rare example of a reduction of an enolizable /I-diketone bearing both endocyclic and exocyclic carbonyl groups (22). The rapid rate of epimerization of the substrate allowed formation of only one R.Chenevert G. Fortier and R. B. Rhlid Tetrahedron 1992 48 6769. 59 M. Christen D. H.G.Crout R. A. Holt J.G. Morris and H. Simon J. Chem. SOC.,Perkin Trans. 1 1992 491. 6o S. Hashiguchi A. Kawada and H. Natsugari Synthesis 1992 403. K. J. Harris and C. J. Sih Biocatalysis 1992 5 195. A. G. Sutherland BocN. P O M e Bo:..? OMe (19) 87% 94% d.e. 1 OMe -B o c g POMe (20) 86%,99% d.e. Reagents i S. cereuisiae sucrose EtOH H,O Scheme 8 (21) 54% 88% e.e. (22) 66%. 100%d.e.,97%e.e. (23) 51% Reagents i Saccharomyces sp. Edme glucose; ii S. cereuisiae sucrose; iii Ra-Ni MeOH Scheme 9 diastereoisomer with high enantioselectivity. Desulfurization of the resultant thianol gave ready access to the weevil pheromone sitophilure (23) Scheme 9.62 Isolated Enzyme Ketone Reductions.-In an upsurge of interest in the use of isolated enzymes for carbonyl reduction the use of alcohol dehydrogenases from Pseudomonas SP.,~~ and pig liver6’ has been described.All show considerable Lactobacillus I~ejir,~~ potential in asymmetric synthesis and representative reactions are depicted in Scheme 10. Although the use of D-and L-lactate dehydrogenases (from Staphylococcus epidermis and rabbit muscle respectively) has been shown to give high chemical and optical yields 62 T. Fujisawa B.I. Mobele and M. Shimizu Tetrahedron Lett. 1992 33 5567. 63 C. W. Bradshaw H. Fu G.4. Shen and C.-H. Wong J. Org. Chem. 1992 57 1526. 64 C. W. Bradshaw W. Hummel and C.-H.Wong J. Org. Chem. 1992 57 1532. 6s Y. Hirose M. Okutsu M. Anzai K. Naemura and H. Chikamatsu J. Chem. SOC.,Perkin Trans. 1 1992 317. Enzyme Chemistry 29 1 of a-hydroxy acids of predictable stereochemistry the narrow substrate specificity of these enzymes has rather limited their application.66 OH 0 “AOMe “aoMe 76%. 98% e.e. 46%. > 97% e.e. 0 H+ iii OCOBu‘ OCOBu‘ 86%.95% e.e. Reagents i Pseudomonas sp. dehydrogenase NADH; ii Lactobacillus kejr dehydrogenase NADPH; iii Pig liver dehydrogenase NADPH Scheme 10 The range of possible substrates has been extended by the use of the enzyme from Bacillus stearothermophilus which also accepts y-monoalkyl P,y-unsaturated a-keto acids.67 Even bulkier substrates (e.g.24) can be reduced after modification of the enzyme active site by site directed mutagenesis.68 The isolation of a new (R)-2-hydroxyisocaproate dehydrogenase (R-HicDH) from Lactobacillus casei with a wide substrate selectivity should provide enantiocomple- mentary activity.69 The synthetic applicability of this enzyme was illustrated in the high yielding enantioselective reduction of the ‘parent’ substrate (25). The bugbear of the use of isolated enzymes in reductions has tended to be the need to recycle the enzyme cofactor. No universally accepted method has yet been found for NADPH regeneration while formate dehydrogenase recycling of NADH is rather limited by expense. It has been reported that both problems may be surmounted by the 66 (a)M.-J.Kim and J.Y.Kim,J. Chem.Soc. Chem. Commun. 1991,326;(6)M.-J. Kim and G. M. Whitesides J. Am. Chem. SOC.,1988 110 2959. 67 G. Casy T.V. Lee and H. Lovell Tetrahedron Lett. 1992 33 817. G. Casy T.V. Lee H. Lovell B.J. Nichols R.B. Sessions and J.J. Holbrook J. Chem. Soc.. Chem. Commun. 1992,924. 69 H. K.W. Kallwas Enzyme Microb. Technol. 1992 14 28. A. G. Sutherland B. steurothermpWus D C02H lactate. dehydrogenase CO2H 91% 99% e.e. MCOIH Lactobacillus R-HicDHcasei flC02H 88%. > 99% e.e. common sdution of non-enzymic cofactor regeneration. Thus [(C,Me,)-Rh(bpy)(H,O)]Cl can be used to catalytically regenerate either cofactor by utilizing sodium formate as a source of hydride. The efficacy of the procedure was illustrated in the stereoselective reduction of 4-phenylbutan-2-one by a range of both NADH and NADPH utilizing enzymes.70 Other Reductions.-The bakers' yeast reduction of thiophenpropenal (26) provides a neat general entry to (S)-2-methylalkanols.Reduction of both alkene and aldehyde moieties gives the corresponding alcohol in high enantiomeric excess. Subsequent Friedel-Crafts acylation Huang-Minlon reduction and Raney Nickel desulfuriz- ation/hydrogenation then leads to the required products (Scheme 1 1).71 H -40% > 98% e.e. (26) Scheme 11 Asymmetry is also induced by reduction of the alkene moiety of butenolides (27) and (28) giving the corresponding (S)and (R)enantiomers respectively in moderate yield and high optical purity (Scheme 12).72,73 The most unusual reduction of the year is the conversion of the a-chloro keto ester (29)to the corresponding dechlorinated alcohol.The halogen reduction would appear to be an enzyme catalysed process as higher substrate concentrations than 1 gl-' inhibit the dechlorination reaction although the carbonyl reduction still occurs.74 70 D. Westerhausen S. Herrmann W. Hummel and E. Steckham,Angew. Chem..Int. Ed. Engl. 1992,31,1529. 71 H. E. Hagberg E. Hedenstrom J. Fagerhag and S. Servi J. Org. Chem. 1992 57 2052. 72 K. Takabe M. Tanaka M. Sugimoto T. Yameda and H. Yoda Tetrahedron Asymmetry 1992,3 1385. 73 K. Takabe H. Hiyashi H. Sawada M. Tanaka A. Miyazaki T. Yamada T. Katagiri and H. Yoda Tetrahedron Asymmetry 1992 3 1399. 74 0.Cabon M. Larcheveque D. Buisson and R. Azerade Tetrahedron Lett.1992 33 7337. Enzyme Chemistry 4 Oxidation Reactions Cyclohexadienedio1s.-The synthesis and chemistry of the cyclohexa-3,5-dien- 1,2-diols obtained through the oxidation of arenes by mutant strains of Pseudomonas putida has been reviewed in depth.75 Most of the work in this field to date has utilized mono- or unsubstituted substrates however Hudlicky and co-workers have demonstrated that more complex systems can be biotransformed. Thus o-chlorostyrene can be converted to the diol (30) in enantiomerically pure form.76 0 0 PhCHzO -PhCH2O ,, (27) 34% 95% ex. 0 0 (28) 4 1% 99% ex. Reagents i S. cerevisiae sucrose Scheme 12 S. caevisiac * Ph HOJ" Ps.putido * (ca.l:2) Recent efforts to provide ever more direct approaches to the conduritols from these starting materials would appear to have been topped by Carless who reported the conversion of the chlorobenzene derived diol (31) to (-)-conduritol C in three steps 75 H.A. J. Carless Tetrahedron Asymmetry 1992 3. 795. 76 T. Hudlicky E.E. Boros and C.H. Boros SYNLETT 1992 391. A. G. Sutherland (Scheme 13).77 Given that a two-pot modification of this procedure is possible a shorter route would seem to be hard to find! __c OH OH OH OH OH (31) 61% 90% 70% Reagents i MCPBA; ii H,O cat. CF,CO,H; iii Na NH Scheme 13 Researchers in this field now seem to be taking on more challenging targets. The alkaloid (+)-lycoricidine (32) has been prepared in a short synthesis from the bromobenzene diol via a Heck-type coupling proced~re,~ while model studies toward morphine incorporating all of the required chiral centres have been reported.” OH 0 Sulfoxidation Reactions.-The use of commercially available enzymes to catalyse the oxidation of sulfides by hydrogen peroxide has attracted some interest.Horse radish peroxidase was found to have only limited use in terms of asymmetric synthesis. An enantiomeric excess of 68% was reported for the oxidation of p-tolyl methyl sulfide but all the other substrates examined were transformed with lower or no enan tioselectivi ty . O However the chloroperoxidase from Caldariomyces fimago displays much greater potential. Colonna and co-workers reported the oxidation of a series of aryl alkyl sulfides to the (R)-sulfoxide.B1 The majority of methyl sulfides were converted with enantiomeric excesses greater than 85% although poorer optical purities were obtained with larger alkyl groups.The main problem with this chemistry appears to be in minimizing the background non-catalysed and therefore racemic oxidation. Colonna approached this by slow 77 H. A.J. Carless J. Chem. Soc.. Chem. Commun. 1992 234. 78 T. Hudlicky and H. Olivo J. Am. Chem. SOC.,1992 114,9694. 79 T. Hudlicky C. H. Boros and E. E. Boros Synthesis 1992 174. S. Colonna N. Gaggero G. Carrea and P. Pasta J. Chem. SOC. Chem. Commun. 1992 357. S. Colonna N. Gaggero L. Casella G. Carrea and P. Pasta Tetrahedron Asymmetry 1992 3 95. Enzyme Chemistry addition of hydrogen peroxide to the enzyme and substrate.Wong and colleagues found that by adding separately both substrate and oxidant the enantioselectivity could be markedly improved for many substrates (Scheme 14).82 Reagents i C. fumago chloroperoxidase addition of H,O to substrate and enzyme (98% 91 % e. e.); ii C. fumago chloroperoxidase addition of H,O and substrate to enzyme (92% 98% e.e.) Scheme 14 Catalytic Deracemization.-Two reports have emerged which couple an enzyme catalysed enantioselective oxidation with a chemical non-selective reduction. The net outcome of these processes is the accumulation of the enantiomer of starting material that is not a substrate for the enzyme i.e. a catalytic deracemization with a theoretical yield of 100% as opposed to a kinetic resolution (maximum yield of 50%).Moiroux and co-workers performed a deracemization of lactic acid by coupling the L-lactic acid dehydrogenase oxidation of the parent substrate to pyruvic acid with an electrochemical reduction. In this manner D-lactic acid was obtained in >97% yield (Scheme 15).83 aMde NAD+ -NADH Scheme 15 Similarly Huh et al. coupled the D-amino acid oxidase catalysed conversion of proline with the sodium borohydride reduction of the resultant A’-imine to give L-proline in near quantitative yield.84 Other Oxidations.-The enantioselective Baeyer-Villiger oxidation of a series of rneso-bicyclic ketones (e.g. 33) with the isolated monooxygenase from Acinetobacter calcoaceticus has been e~plored.~’ Furstoss has investigated the similar oxidation of H.Fu H. Kondo Y.Ichikawa G.C. Look and C.-H. Wong J. Org. Chem. 1992 57 7265. 83 A.-E. Biade C. Bourdillon J.-M. Laval G. Mairesse and J. Moiroux J. Am. Chem. Soc. 1992 114,893. 84 J.W. Huh K. Yokiogawa N. Esaki and K. Soda J. Ferment. Bioeng. 1992 74 189. 8s M. J. Taschner and L. Peddada J. Chem. Soc.. Chem. Comrnun. 1992 1384. A. G. Sutherland the enantiomers of a series of monoterpenes such as dihydrocarvone (34) using a whole cell preparation of Acinetobacter (Scheme 16).86 0 (33) 70%. > 98% e.e. 0 / 95% / 66% Reagents i Acinetobacter NC1B 987 1 monooxygenase; ii Acinetobacter TD63 Scheme 16 The oxidation of methyl groups on a range of aromatic heterocycles to the corresponding carboxylic acids using Pseudornonas putida has been investigated.The oxidations are generally high yielding and show good selectivity dimethylheteroaro- matics are converted to monocarboxylic acids with no dicarboxylic analogues being detected. The process was shown to be amenable to scale-up with 2,s-dimethyl- pyrazine being converted in excellent yield on a 25 kg scale (Scheme 17).87 Ps.purida ATCC 33015 pH7 xylene > 95% Scheme 17 86 V. Alphond and R. Furstoss Tetrahedron Asymmetry 1992. 3 379. '' A. Keiner Angew. Chem.. Int. Ed. Engl. 1992 31 114. Enzyme Chemistry 5 Carbon-Carbon Bond Forming and Cleaving Reactions The past year has seen considerable activity in the isolation and use of enzymes capable of catalysing carbon-carbon bond forming reactions which although characterized in biochemical terms have seen little application in synthetic chemistry.0 OH 0 8,+ HO,),,O@ Aldolase R OH Scheme 18 As last year’s report predicted the use of the fourth stereocomplementary dihydroxyacetone phosphate utilizing aldolase (Scheme 1S) namely tagatose 1’6-bisphosphate aldolase has been reported.88 While the enzyme was shown to be of use in preparing the otherwise inaccessible sugar that is the natural substrate (3S,4S stereochemistry) non-natural aldehydes reacted to give fructose (3S,4R)stereochemis-try with only moderate diastereoselectivity. The deoxyribose-5-phosphate aldolase from Escherichia coli was found to utilize ketones as well as aldehydes as nucleophilic (‘donor’) components of the reaction.The potential of the reaction in utilizing a range of azido aldehyde ‘acceptors’ as a route to new aza-sugars was explored (Scheme 19).89 66% OH 93% Reagents E. co[i deoxyribose-5-phosphate aldose; ii Pd/C H (50psi) MeOH Scheme 19 The utility of two pyruvate aldolases 2-keto-3-deoxy-6-phosphogluconate (KDPG) aldolasegO and 4-hydroxy-2-ketoglutarate (HKG) aldolase,’ has been examined. While both enzymes are useful preparative catalysts for the natural reactions (Scheme 88 W.-D. Fessner and 0.Eyrisch Angew. Chem.. lnt. Ed. Enyl. 1992 31 56. 89 L. Chen D. P. Dumas and C. H. Wong J. Am. Chem. SOC. 1992 114 741. 90 S.T. Allen G.R. Heintzelman and E.J. Toone J. Org. Chem. 1992 57 426. 91 N.C.Floyd M. H. Liebster and N. J. Turner J. Chem. Soc. Perkin Trans. I 1992 1085 A. G.Sutherland 20)’ only KDPG aldolase was found to accept a range of aldehyde donors -HKG aldolase being highly substrate specific. ii -0 OH 0 Reagents i KDPG aldose; ii HKG aldose Scheme 20 The use of transketolase has come under greater scrutiny. The enzymes from both bakers’ yeast and spinach were examined of which the former was found to have greater appli~ability.~~ This enzyme was shown to accept a wide range of 2-hydr~xyaldehydes~**~~ to give products not readily accessible by aldolase chemistry (Scheme 21).” OH 0 OH 0 +o + HoJ(coi i+OH OH OH 60% Reagents i S. cereuisiae transketolase Scheme 21 Enzymatic carbon-carbon bond cleavage procedures are a less than obvious approach to inducing chirality in a molecule.Nonetheless Ohta has demonstrated that incubation of a range of a-substituted-a-aryl malonic acids (35) with Alcaligenes bronchosepticus results in enantioselective decarboxylation (Scheme 22).94 The reaction was shown to proceed with inversion of stereochemi~try~~ and to be intolerant of ortho-substituted aryl groups. (35) 5699%. >95% e.e. R,X = CH3 H; CH3 m-F; CH3 p-CF3; F H Scheme 22 92 Y. Kobori D. C. Myles and G. M. Whitesides J. Org. Chem. 1992 57 5899. 93 F. Efknberger V. Null and T. Ziegler Tetrahedron Letr. 1992 33 51 57. 94 K. Miyamoto S.Tsuchiya and H. Ohta J. Fluorine Chem. 1992 59 225. 95 K. Miyamoto S. Tsuchiya and H. Ohta J. Am. Chem.SOC. 1992 114 6256.

ISSN:0069-3030    

DOI:10.1039/OC9928900281

出版商:RSC    

年代:1992

数据来源: RSC

摘要:

Author Index Abad J.-A. 228 Abdallah Y.M. 254 Abd-El Aziz AS. 155 224 Abd-El Ghani A.A. 148 Abe S. 236 Abe Y. 44 Abelman M.M. 239 Abiko A. 268 Abraham R.J. 26 30 Abramovitch R.A. 160 Abu-Shqara E. 161 Achiwa K. 108 241 Adachi T. 151 Adam D. 192 Adam M. 110 Adam R. 148 Adam W. 59 167 190 271 Adams J. 243. 277 Adams J.P. 236 Adlington R.M. 86 87 181 Afarinkia K. 143 173 Agbossou F. 21 1 Ager D.J. 108 Agnel G. 130 Ahmed H. 220 Aicher T.D. 249 Aihara J. 163 Akermark B. 214 Akita M. 21 1 Akiyama K. 235 Akiyama T. 273 Akritopolou I. 115 Akutagawa S. 242 Akutagawa T. 242 Alajarin M. 41 48 197 Alavosus T.J. 220 Alayrac C. 226 Albini A. 167 Albrecht K.162 Alcaide B. 133 173 Alcami M. 38 Alcudia F. 116 Aldridge T.E. 61 Aleman C. 28 Alex A, 41 Alexakis A, 223 Alexander J. 164 Alexanyan M.S. 129 228 Alexeev S. 197 Alfonso. C.A.M. 115 262 Ali N.M. 235 Allemand P.M. 56 Allen A.D. 63 Allen D.J. 157 Allen F.H. 33 Allen M.P. 26 Allen S.T. 297 Allinger N.L. 27 28 Almario A. 116 Alonso D.E. 49 Alonso P.J. 48 Alper H. 182 186 194 230 Alphand V. 280 296 Al-Qaradawi S.Y . 151 Alvarado J. 161 Alvarez C. 161 Alvarez R.M. 113 Alvarez-Larena A. 227 Amanokura N.,152 Amatore C. 159 Arnberg W. 268 Amos R.D. 39 44 Amouri H.E. 225 Amyes T.L. 56 68 An H. 205 An Z. 233 Andemichael Y.W. 105 Anders E.184 Andersen M.W. 51 Anderson K.W. 27 Anderson P.G. 185 210 Ando K.. 71 Andraos J. 63 Andres J.L. 42 Andrews J.S. 39 Andrievski A.A. 246 Andzelm J. 35 Angara G.J. 152 Angelici R.J. 221 Angel] R. 263 Angle S.R. 50 58 Aniss K. 150 221 Anjeh T.E.N. 133 Ankianiec B.C. 150 Ansink H.R.W. 153 Antoni G. 237 Anunziata J. 142 Anunziata R.,142 Anzai M. 290 Aoki K. 275 Aoki S. 210 245 Appelt K. 23 Arai K. 138 237 Araki M. 134 Arakyan V.G. 37 Arata Y. 275 Arcadi A. 237 239 Ariens E.J. 25 Arienti. A. 159 Arif A.M. 21 1 220 Arnaiz D.O. 50 Aroca P. 17 Artaud I. 149 Asao N. 119 Asaro M.F. 230 Asensio G. 152 Ashe A.J. 111 221 Ashimori A, 233 Ashton P.R.138 Ashworth P.A. 241 Assfeld X. 47 Astley M.P. 89 Astley S.T. 217 Astruc D. 55 225 Aten N.F. 161 Attwood J.L.. 223 Aube J. 223 Aubert T. 157 Auclair S.X. 210 Austin D.J. 125 Avendano C. 159 Ay M. 146 228 Azerade R. 292 Azimioara M.D. 46 119 134 265 Azzena U. 158 Baba A. 168 Babin P. 154 Bach R.D. 42 Bachrach S.M. 36 41 47 Baciocchi E. 161 Bacon EX. 235 Bacquet R.J. 23 Baeckstrom P. 239 Backvall J.-E. 46 116. 185 210 214 Baeg J.-O. 186 Bagatti M. 44 299 300 Baggaley K.H. 273 Baig T. 209 231 Baird M. 29 Bajwa J.S. 273 Baker G.R. 107 Bakhrnutov V.I. 246 Bakouetila M. 124 Bakshi R.K. 119 265 Baldoli C.221 Baldridge K.K. 141 Baldwin B.W. 282 Baldwin J.E. 86 87 182 204 Ballester P. 124 260 Ballestri M. 100 101 Balrne G. 239 Balssa F. 150 Baltisberger J.H. 15 Balzer B.L. 243 245 Barnbridge K. 275 Banait N.S. 56 Banasczyk M.G. 142 Bando T. 212 Bando Y. 145 Banerji A. 50 Banks B.J. 232 Banks R.E. 278 Barakat M.T. 25 Bardon I. 149 Barguenga J. 152 Barlow J.J. 72 Barnes R.D. 284 Barr D. 275 Barrett A.G.M. 249 262 Barrett D.G. 163 Barros D. 116 Barth L. 272 Bartlett C.A. 23 Bartlett P.A. 23 Bartlett R.J. 101 Barton A. 61 Barton D.H.R. 100 103 107 118 Barton J.C. 113 177 Barton P. 282 Bashkin J.K. 155 Basso N. 57 Basu S. 50 Batsanov A.S.199 Batta G. 8 Battaglia L.P. 233 Batty D. 87 136 Bauer W. 226 Bauerrneister M. 218 Bauld N.L. 40 48 78 Baurngartner M.T. 160 Baumstark A.L. 179 Bauschlicher C.W. Jr. 38 Bauta W.E. 145 Bax A, 5 6 7 11 Bayon J.C. 231 Bays J.P. 30 Beak P. 51 55 157 Beau J.-M. 236 Beaudet I. 237 Beaudoin S. 263 Beck A.K. 121 Beck J.P. 186 Beck M.T. 163 Beck W. 220 Becke A, 35 Becker D.P. 85 Beckhaus R. 233 Beckstett A. 282 Beddoes R.L. 112 Bedeschi A, 158 238 Beebe X. 175 Beer P.D. 246 Beeson C. 124 Behnen W. 266 Behrrnan E.J. 153 Beletskaya I.P. 238 Bell P.T. 218 Bell R.A. 151 Belsky K.A. 230 Ben-David Y. 237 Bender B.R. 216 Bennani Y.L.268 Bennet A.J. 55 Bennetau B. 154 Bennett A.E. 18 Bennett F. 145 Bennett S.C. 225 Benny J.C.N. 197 Benoit S. 213 Bentley T.W. 74 Berendsen H.J.C.,21 Bergens S.H.,242 Berger A, 280 Bergrnan J. 183 Bergrnan R.G. 145 260 Berk S.C. 267 Berlage U. 46 Bernardi F. 42 143 Bernardinelli G. 53 129 222 Bernasconi C. 55 Bernocchi E. 212 Berrisford D.J. 108 Berry A. 146 Berson J.A. 72 107 143 Bertran J. 41 44 Besayon J. 222 Besler B. 39 Bestrnann H.J. 226 Bethell D. 74 Betschart C. 245 Beusen D.D. 14 Beviere S.D. 100 Bhalla T.C. 287 Bharucha K.N. 260 Bharucha K.W. 145 Bhaskar K.V. 275 Bhat S. 275 Bhat S.V. 133 Bhatarah P. 146 228 Bhatt M.V. 275 Bhattacharjee A.K.40 Bhushan V. 265 Biade A.-E.,295 Author Index Bialas J. 167 Bialecki M. 155 Bianchi D. 282 Bianchi E. 22 Bickelhaupt F.. 177 213 240 Biehl E.R. 144 Bierer D.E. 188 Biggadike K. 108 Biggers C.K. 75 135 260 Biggers M.S. 75 135 260 Bigi F. 159 Billedeau. R.J. 157 Bingel C. 109 213 Bingharn R.C. 28 Bitterwolf T.E. 222 Biurru C. 133 Bjorkling F. 284 Bjorkroth J.-P. 36 44 Black K.A.,44 Blake C. 31 Blakernore D.C. 150 Blaney J.M. 22 31 Blart E. 158 238 Block M.H. 72 Blokzijl W. 48 74 Blornberg M.R.A.,37 38 Bloor D. 246 Blurne T. 113 Bly R.K. 207 Bly R.S. 207 Blythe T.A. 283 Bock C.W.,40 45 Bodenhausen G. 8 13 Boeckman R.K.Jr. 257 Bohmer V. 70 Bohmer W.-H. 233 Bokman F. 214 Boese R. 44 215 Boesten W.H.J. 86 Bohacek R.S. 23 Bohrn A, 163 Bohrn H.J. 24 Bohman O. 214 Bolger M.B. 24 Bolm C. 251 Bonnert R. 249 Boobbyer D.J. 23 Booth C.L.J.,23 Borden W.T. 40 Bordner J. 46 134 257 Bornemann S. 284 Boros C.H. 149 272 293 294 Boros E.E. 149 272 293 294 Borredon E. 133 Borrell J.I. 196 Borthwick A.D.,83 108 Bose D.S. 201 Bosetti A, 282 Bosnich B. 122 134 242 Bott S.G. 223 Bottomley F.. 220 Boucher W. 5 Bourdillon C. 295 Author Index Bourgeois P.. 154 Bouyssi. D. 239 Bovonsombat P. 152 Bowen J.P.. 29 Bowman W.R. 87. 92 Box V.G.S. 167 Boy P. 159 Boyd D.R.272 Boyd J.. 11 Boyle R. 272 Bradley D.H. 225 Bradshaw C.W.. 290 Bradshaw J.S. 205 Brady J.W.. 29 Brakta. M. 235 Branchadell V. 45 48 Brandenburg J.. 131 239 Brandsma. L. 156 162 Brandsteterova. E.. 149 Bratcher. M.S.. 162 Braun M.P. 143. 236 277 Braun P.. 285 Brausch J. 57 Breault G.A. 258 Brehm E.C..237 Breimair J.. 220 Breneman C.M. 35 Breslow R.. 67. 69 Breyer R.A. 124 Bridges. A.J. 157 180 Brikman H.R. 150 Bringmann G. 266 Brinker. U.H. 127 Brintzinger H.H.. 247 Brocard J. 221 Broka. C.A. 178 Bronnimann C.E.. 16 Brook D.J.R. 198 Brouard. C.. 175 Brouillard-Poichet A. I34 Brown A.G. 158 Brown 9.9.. 45 Brown. D.S. 92 Brown F.K..40 45 50. 132 Brown G.R. 138 Brown H.C. 266 271 Brown J.H. 220 Brown J.M. 11 1 Brown. M. 245 Brown. R.S. 55 Brown S.J.. 98 Brckner. R.. 237 Bruggmann K. 149 Bruhn P.R.. 224 Bruhnke J.D. 124 Brunel J.-M.. 120. 266 Brunet J.-J.. 241 Brunner. H. 108 Brussee J.. 273 Bryce M.R. 199 Buback. M. 45 Bucher G. 141 Buchert M. 245 Buchholz. H. 57 124 Buchwald S.L.. 119. 130 228 266. 267 Buck J. 194 Buckle D.R.. 198 Bucsi. I. 153 Buda A.. 53. 129 Budesinsky M. 142 Budzinski B. I16 Buisson. D.. 292 Bulman Page P.C. 212 Buncel E.. 65. 66 Bunnett. J.F.. 55 Bunting H.E. 246 Buono G.. 120 266 Burdisso M.. 44 Burger J. 97 Burgess K.. 126 242 Burini A..237 239 Burk M.J. 119 122. 242 268 Burke L.A. 50 Burns 9.. 131. 240 Burns C.A.. 92 Burns E.E.. 244 Burridge J. 31 Burton. D.J.,108 Burton N.A.. 37 Bushweller C.H. 220 Buszek. K.R. 249 Butler. A.R. 191 Butler J.R. 246 Butler R.N.. 50 Butlin R.J. 138 Buttke K.. 154 Button R.G.. 62 Bye M.R. 152 Byers. L.D. 69 Cabon 0..292 Cabri W.. 158. 238 Cacchi S. 212. 232. 237. 239 Cacciapaglia. R.. 70 Caddick. S. 83 Cadogan J.I.G. 160 173 Cai J. 190 Cailhot N. 241 Caldwell J.W. 29 Calkins T.L.. 105 145. 260 Callstrom. M.R.. 247 Cambie. R.C..224 240 Campbell M.G. 158 Campi. E.M.. 183 Campiani. G. 202 Campos P.J.. 152 Camps F.. 130 245 Candiani. I. 158. 238 Canela E.I.28 Cano A.C. 161 Caplan. F.R.. 205 Caple. R. 129. 228 Capon. 9.. 141 Capps N.K. 189 Carapetyan A.A.. 129. 228 Cardani. S.. 170 Cardi N.. 100 Carless. H.A.J. 108 149. 272. 293. 294 Carlson J.A.. 158 Carlton. L. 220 Carmen Carreno M. 116 Caro. 9..223 Carpenter. A, 122 Carpenter. K.A. 6 Carpenter. T.A. 11 Carpentier. J.F..221 Carpita A. 235 Carrasco-Flores 9.. 230 Carrea. G. 283 Carry. T.4. 133 Carta. A,. 202 Carter. J.D. 246 Carter P.. 145 Casado C.M. 223 Casas. R.. 45 Casebier. D.S. 147 Casella. L. 294 Casewit. C.J.. 27 Casey C.P.. 214 245 Casey. M. 116 Casnati G. 159 Caspar. M.L. 75 135 260 Casper D. 126 Cassels. B.K. 156 Cassidy F..217 Castanet Y.. 221 Castaiio. A.M.. 245 Castedo L.. 86 135. 238 Castillon. S.. 231 Caswell. L.R. 156 Casy G. 291 Catellani M.. 233 Cativiela. C. 47 48 Cattana R.. 142 Catteau. J.-P.. 180 Cazanoue M. 243 245 Ceccherelli. P.. 243 Celli A,. 47 Cerfontain. H.. 153 Cermola. F. 49 129 Cesti. P.. 282 Chalin. A.P.. 187 Chakraborty. R. 152 Chamberlain S. 244 Chan E.T.T. 178 Chan. T.H.. 253 Chan. T.Y.. 258 Chan W.H. 178 Chandrasekaran. S. 275 Chanet-Ray J.. 50 Chang. C.K.. 205 Chang C.-Y.. 132 Chang T.H.. 15 Chao. Y. 32 Chaplin D. 284 Charushin V. 197 Chatgilialoglu. C. 100. 101 Chatrousse. A.P. 67 Chau P.-L.. 24 Chaudret. B.. 224 225 Author Index Chavasiri W.100 Chelain E. 245 Chemin D. 236 Chen B.-C. 271 Chen C. 66 135 155 Chen C.-T. 263 Chen H. 122 Chen H.-P. 286 Chen J. 220 221 Chen J.H. 32 Chen J.J.. 94 Chen K. 27 Chen L. 297 Chen P. 141 Chen S.-T. 286 Chen S.-Y. 230 244 286 Chen X. 121 Chenault H.K. 285 Chenevert R. 289 Cheng C.-Y. 215 Cheng M.-H. 133 215 Cherepanov I.A. 222 Cherfils J. 32 Cherif M. 180 Chern S.S. 205 Chertkov V.S. 129 228 Chesney. A, 133 Chiang Y. 70 Chiba K. 161 Chidambaram N. 275 Chieffi A. 113 Chikamatsu H. 290 Childs R.F. 57 Chima J. 272 Chini M. 134 Chinn M.J. 285 Chiusoli G.P. 229 233 234 Cho B.T. 267 Cho C.S. 159 Cho H.283 Choi S. 122 253 Choi S.-C. 87 Choi S.S.-M. 203 Chou L. 231 241 Chou T.-S. 132 Choudary B.M. 159 Choul L. 242 Chounan Y. 124 Chow J.-F. 133 Christen M. 289 Christiaens L.E. 199 Christl M. 143 Christoffers J. 228 Chu K.-H. 211 Chu K.-P. 263 Chun Y.S. 267 Chung T.-M. 223 Chung Y.K. 223 Chupakhin O. 197 Ciattini P.G. 237 Cieplak P. 29 Cillissen P.J.M. 171 Cimminiello G. 49 129 Cimprich K.A. 119 266 Cinquini M. 142 Cintas P. 108 Clairborne C.F. 133 Claret F. 133 Clark B.P. 275 Clark K.B. 100 Clark K.J. 23 Clark T. 41 Claver C. 231 Clayden J. 117 212 Close D.M. 39 Clough J.M. 152 Clubb R.T. 6 Coburn C.A. 155 Coffman H. 97 Cohen M.A.287 Colberg J.C. 110 Cole K.A. 224 Colebrook L.D. 11 Coleman R.S. 122 Collington E.W. 117 Collington J. 212 Collins M.A. 229 Collum D.B. 109 Colombo M.I. 108 Colonna S. 222 294 Colson A.-O. 39 Colton I.J. 70 Colwell K.S. 27 Comar D. 231 Comasseto J.V. 113 Combellas C. 159 Comins D.L. 110 195 Comminos F.C.M. 149 Concepcion A.B. 258 Conley D.L. 146 Connor. S.C. 198 Conrad M. 11 3 Constable E. 107 Contelles J.M. 132 Conway J. 272 Coombs M.M. 161 Corcorran R.C. 122 Cordes M.H. 72 Cordier C. 246 Corey E.J. 46 119 122 134 253 256 257 263 265 266 272 Corley L.D. 156 Corma A. 241 Cornelisse J. 161 Cornell W.D. 29 Cosstick K.B. 151 Cossu S.161 Costa M. 229 233 Cotelle P. 180 Cottens S. 143 Cotterill I.C. 282 Coustard J. 154 Coville N.J. 220 Cox D.N. 219 Cox P.J. 275 Cox R.A. 66 Coxon J.M. 124 Cozens F. 64 Coui F. 142 Craig D. 46 133 Craig R. 217 Cram D.J. 31 32 Cramer C.J. 52 Crameri A, 22 Creary X.,61 169 Cremer D.. 141 Creuzet F.J. 16 Crich D. 87 124 135 136 Crimmin M.J. 158 Crimmins M.T. 127 Crippen G.M. 26 Crisp G.T. 233 236 237 Crispino G.A. 117 268 269 Crispino G.R. 67 Critchley P. 287 Croisat D. 67 Crosby J.A. 287 Cross K.J. 19 Crotti P. 134 Crouch R.C. 6 Crout D.H.G. 284 287 289 Crowther D.J. 246 Csuhai E. 100 Cuadrado I. 223 Cucciolito M.E. 214 Cueras G.108 Cullen W.R. 247 Cunningham A. Jr. 222 Curini M. 243 Curran D.P. 80 82 84 85 104 124 260 274 Curtiss L.A. 35 Cywin C.L. 122 253 Da Y.-Z. 25 Dabin G. 156 Dahmer J. 285 Dai L.-X. 209 Dai W.M. 145 Dai X. 222 Dailey W.P. 42 Dalcanale E. 233 Dalidowiez P. 148 Dalton D.M. 21 1 Dalton H. 272 Damhaut P. 231 Damm W. 124 260 Dang H.-S. 91 d’Angelo J. 108 Danheiser R.L. 147 Dannock M.C. 236 Danziger D.J. 23 Daran J.-C. 245 Daruwala K.P. 223 Datcheva V.K. 212 Date T. 275 Dauelsberg C. 266 Dau-Schmidt J.-P. 74 Daves G.D. Jr. 235 Davidson J. 266 Davies. A.G. 190 Author Index Davies G.M. 189 237 Davies H.M.L. 130 243 Davies I.W.239 Davies K. 29 Davies S.G. 222 Davis A.P. 115 122 275 Davis D.G. 135 260 Davis F.A. 42 271 Davison G.R. 199 Dawkins D. 273 Dawson A.J. 275 Dean P.M. 23 24 25 Dearing A. 31 Decian A, 222 de Denus C.R. 224 Deerburg J. 119 Defin A, 134 Dehghani A, 110 de Kanter F.J.J. 177 213 240 Deker P.B. 120 Deker P.D. 242 de la Hoz A. 151 del Buttero P. 221 Delgao F. 161 Dell C.P. 47 Della E.W. 93. 129 Dellerba C. 156 Delrnastro M. 237 239 del Pino C. 241 De Lucchi O. 161 de Meijere A. 57 124 131 146 162 212 239 De Menorval L.C. 48 De Mesmaker A, 82 Dernik N.N. 238 Denenrnark D. 82 Denmark S.E. 257 263 Depezay J.C. 136 Deprneier W. 15 de Raadt A, 280 287 de Renus C.R.155 Dereu N. 199 Desai S.R. 133 DeShong P. 272 de Silva S.O. 157 Desimoni G. 47 237 DesJarlais R.L. 24 Desrnaele D. 108 Destabel C. 94 De Torna C. 170 Devasagayaraj A. 231 DeVries K.M. 276 Dewar M.J.S. 28 DiBenedetto D. 118 271 Dickens M.J. 184 220 Diebold J. 247 Diederich F. 107 Dietze P.E. 59 Diez-Martin D. 232 Dillon M.P. 138 DiMagno S.G. 67 DiMeglio C.M. 220 Ding W. 146 Ding Y. 276 Dinur U. 28 Dinya Z. 163 Diorazio L.J. 152 Disbrow G.L. 146 Dix T.A. 124 Dixon J.S. 22 Dixon N.J. 241 Dixon R.P. 60 Djakovitch L. 225 Dobeli H.. 6 Dobler M. 107 Doepp D. 170 Dotz K.H. 147 228 244 245 Doi T. 46 Dolata D.P. 48 Dolbier W.R.Jr.. 142 Doller D. 100 107 Dombroski M.A. 75 Dorneier L.A. 32 Dorninguez D. 86 Dorninguez G. 173 Donaldson W.A. 215 217 218 Donovan R.J. 228 Dore A, 161 Doring D. 149 Dority J.A. 235 Doss G.A. 8 Doubleday C. Jr. 43 Dougherty D.A. 59 Dowd P. 40,87 93 96 136 Downton P.A. 223 Doyle M.P. 124 125 Dozono T. 156 Drago R.S. 74 Dragovich P.S. 145 146 Draowicz J. 116 Draths K.M. 146 Drauz K. 286 Drenth W. 56 Drurnright R.E. 94 Drysdale N.E. 144 D’Souza M.J. 55 Dubbert R.A. 228 Dubois E. 237 Duchamp J.C. 143 Duckett S.B. 242 Duclos O. 136 Duer M.J. 18 Dumas D.P. 297 Dumas F. 108 Dumas J. 135 239 Dunn S.F.C. 168 Dunogues J. 154 Duong T.T.122 Dupre C. 222 Duquerroy S. 32 Duran M. 41 44 Dureault A, 136 Durst F. 226 Durst T. 174 Dust J.M. 66 Duthbaler R.O. 121 Dutt M. 144 Dwyer T. 142 Dyker G. 158 190 236 238 Dzhemilev U.M. 242 East M.B. 108 Eaton P.E. 107 129 130 Eberhardt A. 110 Eberson L. 151 Echavarren A.M. 245 Eckert H. 14 56 Edelrnann F.T. 247 Edison A.M. 284 Edmunds J.J. 249 Edwards J.P. 257 Edwards P.D. 158 Effenberger F. 298 Egan T.J. 275 Eggenberger U. 9 Eggleston D.S. 198 Eguchi M.,252 Eichele K. 13 Ejiri S. 50 Elemes Y. 51 El-Fadl A.A. 70 Elgemrie G.E.H. 146 Elguero J. 41 151 Elia G.R. 57 Eliel E.E. 121 Eliel E.L. 199 Elliott J. 145 Elmorsy S.S.275 Elsley. D.A. 237 Elson S.W. 284 El’yanov B. 51 Elzanate A.M. 146 Ema T. 143 Emerson S.D. 9 Emmanuel A.L. 157 Emonds M.V.M. 112 254 Ernsley L. 13 Endo Y. 67 Ene D. 124 Enemoto M. 173 Engberts J.B.F.N. 48 74 Engelhardt G. 15 England W.P. 52 Enkelmann V. 110 Epa. W.R.. 110 Ephretikhine M.. 148 Eppers O. 7 Epstein L.M. 220 Er E. 172 Erabi T. 158 Erdik E. 108 Erdman P. 124 Ericsson A.M. 116 Erikson M.S. 246 Ermekov D.S. 246 Ernst R.D. 220 Ernst S.. 17 Esaki N. 295 Eschenrnoser A, 107 Esser F. 155 Estevez V.A. 145 Evans A, 272 Evans D.A. 242 249 257 266 Evans. H.J. 31 Evanseck J.D. 41 108 Evers M.J. 199 Evrard D.A. 276 Exl C.283 Exner O. 74 142 Eyrisch O. 297 Ezcurra J.E. 53 Faber K. 281 282 283 287 Faerber G. 50 Fagerhag J. 292 Fahrni C. 213 Faita G. 47 Faller A. 198 Fallon G.D. 183 Fan L. 35 Fan R. 124 Fan W.Q. 55 Fang D. 48,49 Fang F.G. 249 Fang Y. 190 Fannes C. 46 Farmer B.T. 5 Fateyev O.V. 37 Fatheree P. 113 Faure B. 120 266 Feaster J.E. 119. 122 242. 268 Feaux de Lacroix S. 19 Fedotova. O.A. 242 Feng AS. 67 Feng S.G. 229 Feng Y. 17 Feringa B.L. 270 Fernandez I. 116 Fernandez M. 197 Ferraboschi P. 279 281 Ferreira J.T.B. 112 254 Ferrin T.E. 24 Ferris K.F.. 101 Fesik S.W. 7. 23 Fessner W.-D. 297 Fetizon M. 137 Fevig L. 124 Field L.D.. 19 Fieser M.250 Figueras F. 48 Filla S.A. 275 Fillaut J.-L. 225 Finch H. 218 Finckh W. 247 Finn M.G. 243 245 Finney N.S. 105 Fiorini I. 202 Firouzabadi H. 161 Fischer B. 71 Fischer J. 222 Fischer M.A. 170 Fish P.V. 212 Fishbein J.C. 61 Fisher G.B. 267 Fitzgerald J.J.. 144 Fitzpatrick. N.J. 220 Flamant J.P. 47 Flanagan M.E.. 97 Flatau S. 233 Fleck A.E. 148 Fleming S.A. 127. 258 Flippin L.A. 134 Flitsch S.L. 288 Flores 280 Floyd N.C. 297 Flygare J.A. 113 Flynn D.L. 85 Fokas D. 104 Folkins P.L. 180 Foote C.S. 51 Forbes I.T. 194 Ford K.L. 275 Foresman J.B. 35 Forsyth C.J. 249 Fort R.C. Jr. 40 Fortier G. 289 Fortt S.. 145 Fossatelli M.162 Foubelo F.. 145 259 Fox D.J. 35 Fox M.E. 194 Fox P.C. 29 Fox T. 7 Fraile J.M. 48 Frampton C.S. 218 Francisco J.S.. 44 Franco R. 28 Franke D. 14 Frank-Neumann M. 231 Franz J. 101 Franzini L. 267 Fraser F.A. 201 Fravel B. 144 Freeman R. 9 12 Freer A.A. 192 Freer S.T.,23 French A.N. 133 Frey M. 214 Friedrichs M.S. 4 Frisch M.J. 35 Fronczek F.R. 246 Frost C.G. 108 Frost J.W. 146 Fruh T. 276 Fry. K.B. 277 Frye S.V.. 121 Fu G.C. 200. 242 266 Fu H. 290 295 Fu X. 48 50 Fu. X.Y. 49 Fuchigami T. 173 Fuchs P.L. 131 Fueno H. 44 Fugami K. 111 212 Fuhry M.A.M. 23 Fuji K. 117 270 Fujieda H. 51 Fujihara H. 180 Fujii T. 188 Author Index Fujimoto K.127 Fujimoto T. 79 Fujimura. T. 245 Fujio M. 74 Fujisawa T. 257 290 Fujita M. 93 Fujitsuka. H.. 49 Fujiwara H. 25 Fukawa 1.. 156 Fukumoto K. 133 Fukushima S. 159 Fukuyo E. 235 Fuller J.C. 267 Funatsu K. 74 Fung B.M. 13 Furaune M. 159 Furey W.S.. 223 Furstoss R. 280 296 Furuhashi K. 287 Furukawa N. 180 Furuune M. 233 Fyfe. C.A. 14 17 Gabbutt C.D. 192 Gabriele B. 233 Gabrielson K. 69 Gadamastii K.G. 124 Gadgil V.R. 132 Gadja C. 214 Gaeta F.C.A. 32 Gage J.R.. 249 Gaggero N. 294 Gais H.-J. 116 281 Gajewski J.J. 29 53 74 Gala D. 118 271 Galarini R. 237 Gallagher T. 239 Gallegos R. 97 Galtress C.L. 61 Candler J.R.66 155 Gandolfi R.. 44 Gandour R.D.. 69 Gann S.L.. 15 Gao G. 256 Garafolo A. 202 Garcia A.M. 135 238 Garcia J.I. 47 48 Garcia M.L. 197 Garcia 0..161 Garcia-Martin M.A. 152 Garcia-Raso A, 236 Garcia-Ruano J.L. 116 Garner C.D. 196 Garotta G. 6 Garratt P. 107 Garst M.E. 178 Gasparski C.M. 72 Gassman P.G. 50. 68 Gates B.D.. 148 Gaul M.D. 257 Gautam R.K. 124 Geake E. 22 Gehring M.R. 23 Geib S.V.. 124 260 Author Index Gelling A, 225 Gellman S.H. 163 Gelormini A.M. 217 Gemmecker G. 7 Genet J.P. 158 238 241 Genicot C. 127 Gennari C. 170 Gentric D. 223 Gentz R. 6 George C.F. 187 Gerber P.R. 27 129 Gerlt J.A. 68 Gerst M. 160 Getty S.J.40 Ghosez L. 127 Ghosh A.K. 122 Giannotti G. 247 Gibbs A. 7 Gibson W.T. 287 Giese B. 97 124 260 Gilardi R.D. 187 Gilbert A, 150 151 Gilbert A.M. 247 Gilbert K.E. 29 Giles M. 249 Giles P.R. 192 Gill I. 286 Gill P.M.W. 35 Gillespie R.J. 36 Gilloir F. 214 Gil-Rubio J. 228 Gilson M.K. 29 Ginzburg A.G. 220 Giolando D.M. 157 Giuffrida D. 138 Gladfelter W.L.,224 Gladiali S. 161 Gladysz J.A. 21 1 Glass W.K. 220 Cleave D.M. 275 Gleiter R. 107 143 Glinka T. 97 Gloaguen B. 225 Gneugnot S. 236 Coda K. 173 Goddard J.D.,44 Goddard W.A. 27 Godtfredsen S.E. 284 Gogoll A. 214 Gokel G.W. 205 Goldstein S.W. 186 Golebiowski A, 281 Golini P.282 Gonikberg E.M. 51 Gonser P. 216 Gonzalez J. 40 41 45 47 48 Gonzalez J.M. 152 Gonzalez S.M. 113 Good A.C. 25 Goodfellow C.L. 222 Goodford P.J. 23 Goodsell D.S.,21. 22 Goralski C.T. 267 Gore J. 239 Gore V.K. 133 Gornitzka H. 247 Gorshkova L.S. 242 Goto M. 74 Gotor V. 282 285 Gottlieb L. 150 Gottwald M.. 282 Could I.R. 29 37 Goumont R. 245 Goux c. 212 Gozin M. 237 Gozlan I. 156 Gracza T. 233 Gradnig G. 280 Graham B.F. 34 Granberg K.L. 214 Grant G.H. 30 Grasser M. 280 Gravel D. 213 Gray J.L. 127 Graziano M.L. 49. 129 Cree R. 116 216 Green D.V.S. 36 37 Green J. 287 Green J.R. 214 Green M.L.H.. 246 Greene A.E. 227 Greeves N. 252 Greifenberg S.282 Grein F. 48 Grennberg H. 149 Grese T.A. 213 Grev R.S. 41 Grieco P.A.,253 Griengl H. 283 287 Grierson D.S. 47 Griesinger C. 9 Griffin R.G. 15 16 18 Griffith W.P. 270 Griffiths. L. 30 Grigg R. 111 131 132 189 240 Grigsby W.J. 240 Griller D. 100 Grimmer S.S.,231 241 Grisenti P. 279 281 Grissom J.W. 105 145 260 Groeger U. 286 Grondey H. 14 17 Gronowitz S. 43 152 Grossi L. 154 Grossman R.B. 130 228 Grotjahn D.B. 245 Grubbs R.H. 200 Gruselle M. 223 225 246 Gryff-Keller. A, 223 Grzesiek S. 5 6 7 Gu Q.-M. 284 Guenther B. 46 Guerchais V. 246 Guerra M. 100 Guerrini A. 100 Guest M.F. 36 Gueugnot S. 113 Guevara M. 156 Guha S. 40 Guibe G.212 Gui Gu Y. 105 Guijarro D.,254 Guilbert B. 288 Guile S.D.,21 1 Guingant A, 45 Guingent A, 108 Guir F. 137 Gullion T. 14 Gunther H. 7 Guo Y. 137 Guo Z.R. 73 Gurjar M.K. 266 Gurski A, 147 Gussio R. 32 Gustafson S.M..44 Gutierrez. A.R.. 162 Guzman A, 197 Gybin A.S.. 129 228 Ha T.-K.,43 Habaue S. 263 Hachiya I. 134 Hacksell U. 222 Hadad. C.M. 35 Hadjiarapoglou L. 167 271 Hadjisoteriou M.. 132 189 Haffner C.D. 52 Hafner A.. 121 Hafner K. 164 Haga N. 67 Hagawara H. 135 Hagberg H.E. 292 Hagemeyer A, 19 Hagen. G. 57 Hagen W. 113 Hagler A.T. 28 Haight A.R. 111 Hajipour A.R. 170 Hajnal. M.R. 43 Hajouji H. 241 Halgas J.250 Halgren T.A.. 29 Hall L.D. 11 Hallberg A. 238 Halle J.-C.. 65 67 Hallows W.H. 220 Haltiwanger R.C. 198 Halton B. 44 Hamarnoto M. 271 Hambley. T.W. 149 Hamilton A.D. 60 Hamley P. 133 257 Hamon L. 245 Hamper B.C. 186 Hanafusa T. 71 Hanamoto T. 144 Hanamusa S. 150 Hanaoka M. 129. 222 225 228 Handy N.C. 39 44 Haneef I. 32 Hanessian S. 78 132 263 Haning H. 252 Hansson S. 214 Hanton L.R. 142 Hanzawa Y. 45 122 Hara T. 210 Harada N. 232 Harada T. 113 238 Harcourt D.A. 178 Harding C.E. 62 Harkema S. 70 Harling J. 145 Harman M.E. 246 Harman W.D. 65 Harmat N. 121 252 Harms K. 45 147 237 244 245 251 Harp J.J. 131 Harpp D.N. 180 Harring D.S.146 Harring L.S. 228 Harring S.R. 135 Harris J. 232 241 Harris K.D.M. 32 Harris K.J. 289 Harrison J. 267 Hart T.M. 32 Hartmann A, 215 Hartshorn M.P. 151 Hartung J. 124 164 266 268 Haruna S. 271 Harvey D.F. 147 245 Harvey G. 153 Harvey R.G. 161 Harvey S.C. 26 Harwood L.M. 48 56 Hasegawa E. 91 Hashemi M.M. 162 Hashiguchi S. 289 Hashimoto S. 98 127 243 Hashiyama T. 269 Hasskerl T. 124 Hassner A. 71 Hatakeyama S. 257 Hatanaka T. 251 Hatanaka Y. 159 Hatouaka T. 119 Hatoum H.N. 61 Hattori K. 256 Haubenstock H. 270 Havel T.F. 26 Hawkes G.E. 149 Hawkes J.E. 149 Haworth IS.. 26 30 Hawthorne M.F. 221 Hayashi M. 81 261 Hayashi T. 109 112 158 225 233 234 277 Hayashi Y.127 222 223 Hayden W. 283 He H.M. 173 He X.-D. 224 225 Head N.J. 93 129 Head-Gordon M. 35 Healy E.F. 28 Heathcock C.H. 157 268 Heaton S.B. 225 Heber J. 228 Hedenstrom E. 292 Hegarty S.C. 122 Hegedus L.S. 245 Heiber M. 52 Heibronner E. 141 Heidbreder A. 77 Heil M. 59 Heiliger L. 57 Heimgartner H. 169 202 Heinisch G. 196 287 Heintzelman G.R. 297 Heinze J. 163 Helgeson R.C. 32 Hellman G. 116 Helmchen G. 133 257 Hemken H.G. 29 Hendrix J.A. 249 Hengge A.C. 66 70 Henke S.L. 174 Henly. T.J. 221 Henmerle H. 281 Henniges H. 146 Henry K.J. Jr. 253 Heppert J.A. 223 Hepworth J.D. 192 Herman P. 285 Hermann R.B.25 Hernandez A.E. 252 Hernandez R. 270 Herndon J.W. 129 131 245 Heron B.M. 192 Herradon R. 281 Herrmann S. 292 Herrmann S.M. 23 Herron D.K.. 25 Herzfeld J. 15 Heumann A. 239 Hiberty P.C. 44 Hibino H. 263 Hiemstra H. 86 Higashiyama K. 119 193 Hileman F.D. 155 Hill D.K. 272 Hill J.M. 262 Hillier I.H. 36 37 Hing A.W. 14 Hino T. 266 Hinrichs H. 171 Hioki K. 116 Hioki T. 163 Hipskind P.A. 238 Hirai M. 210 Hiraiwa A. 158 Hirano T. 79 Hirao K. 38 Hiraoko R. 151 Hirayama N. 237 Hirose Y. 251 290 Hirsch A. 56 Hisada Y. 263 Author Index Hitchcock S.A. 89 260 Hiyama T. 159 Hiyashi H. 292 Ho K.-K. 126 Ho T.L. 250 Ho Y.-H. 215 Hobart J.A.148 Hodgkin E.E. 25 Hodgson D. 112 Hodgson J. 22 Hoerrner R.S. 243 Hoffman D.H. 32 Hoffmann H.M.R. 108 214 Hoffmann R.V. 72 Hoffmann R.W. 274 Hogan J.C. 69 Hojo M. 183 Holbrook J.J. 291 Holden M.S. 224 Holl S.M. 14 Holland H.H. 250 Hollis T.K. 134 156 Holmes A.B. 133 194 257 Holmes J.M. 178 Holmes R.J. 149 Holt R.A. 289 Holzapfel C.W. 220 Hon Y.-S. 263 Honda T. 234 253 Hong F.T.. 148 Hong P.-C. 263 Hong Y. 122 253 Hongwen H. 237 Honig B. 29 Honig H. 283 Hoogsteen K. 245 Hoops S.C. 27 Hoornaert G.J. 46 144 Hopf H. 107 Hoppe D. 119 Horaguchi T. 91 272 275 Hori K. 44 57 Horie Y. 180 Horii T. 44 Hornbuckle S.F. 125 Horne S. 133 157 Hornfeck A.246 Hornfeldt A. 152 Hornfeldt A.-B. 43 Hortelano E.R. 121 Horvinen J. 61 Hosmane R.S. 141 Hosokawa T. 167 210 Hossain M. 126 215 Houk K.N. 40 41 44 45 47 48 50 51 53 108 124 129 132 142 Hoveyda A.H. 242 266 Howard J.A.K. 199 Howarth J. 108 Howe W.J. 24 Howland E.F. 23 Hoye T.R. 245 Hoz S. 74 Author Index Hrovat D.A. 40 Hu B. 130 243 Huang Y.-H. 211 Huang Y.-S. 225 Hudalla C. 14 Hudlicky T. 124 149 272 293 Hudrlik A.M. 254 Hudrlik P.F. 254 Hudson J.A. 72 Hudson P. 275 Hudson S.E. 98 Huebsch T. 45 Hugel H.M. 275 Huh J.W. 295 Hull J.W. Jr. 196 224 Hulme C. 182 Hummel C.W. 249 Hummel W. 290 292 Hunag C. 24 Hung S.-H.132 Hunt S. 65 Hunter A.D. 223 Hunter C.A. 142 Hunziker D. 121 Hurd R. 11 Hursthouse M.B. 246 Huru J.R. 160 Hutchinson D.W. 284 Hutchinson H.S. 160 Hutler O. 124 Hutlin P.G. 283 Huttenloch M.E. 247 Hwang C.-K. 133 249 Iacazio G. 285 Ianelli S. 239 Ibata T. 51 243 Ibbotson A. 215 216 Ibragimov A.G. 241 Ibuka T. 124 Ichikawa H. 50 163 Ichikawa Y. 295 Ichimura T. 141 Iesce M.R. 49 129 Iglesias M. 241 Iguchi H. 93 Iino Y. 163 Iishi Y. 271 Iitaka Y. 45 Ikariya T. 241 Ikeda I. 214 Ikeda M. 153 183 Ikegami S. 127 243 Ikegami Y. 235 Ikemoto M. 241 Ikuta S. 44 Ila H. 146 llhama T. 157 Imada Y. 270 Imanaka S. 113 Imanaka T.271 Imanieh H. 272 Imming P. 107 Inagaki J.-i. 188 Inamoto N. 52 Inanaga J. 144 Inoguchi K. 108 Inoue A, 25 Inoue H. 44 112 119 151 Inoue S. 251 Invernizzi A.G. 237 loffe D. 156 Ipaktschi J. 215 Isaacs N.W. 192 Ischichi Y. 200 Ishibashi H. 153 183 Ishihara K. 134 256 Ishii N. 232 Ishii Y. 241 Ishikawa M. 131 262 Ishikawa S. 205. Ishitani H. 134 Ishiyama K. 91 Ishizuka T. 251 Isoe S. 200 Isogami Y. 51 Issacs N.S. 138 Itai A, 24 25 Itaya T. 188 Ito H. 122 Ito K. 25 189 251 Ito Y. 81 261 Itoh K. 232 238 Itoh. N. 159 273 Itoh O. 159 Itoh T. 204 Ivanov P.M. 27 Iwao M. 183 Iwaoka T. 50 Iwasa S. 132 Iwasaki F. 180 Iwasaki T. 158 Iwasawa H.276 Iwasawa N. 227 Iwata T. 201 Iyoda J. 154 Iyoda M. 235 Izatt R.M. 205 Jabconova A, 149 Jackson A, 184 Jackson D.E. 26 31 32 Jackson P.M. 144 Jackson R.F.W. 11 1 168 237 Jackson W.R. 183 231 Jacob K. 247 Jacob] P.A. 235 Jacobson R.A. 221 Jacquemin P.V. 199 Jacquesy J. 154 Jaeger D.A.,48 Jager V. 233 Jagoe C.T. 253 Jagtap P.G. 146 190 James D.M. 152 James K. 11 1 Janin J. 32 Janoschek R. 143 Janson C.A. 23 Janssen L.H.M. 32 Janssen S.J. 224 Jaouen G. 223 225 246 Jarman M. 217 Jarvest R.L. 284 Jary J. 285 Jaspars M. 115 Jastrzebski T.B.H. 111 Jasys V.J. 175 Jaszberenyi J.C. 103 118 Jayasuriya K. 36 Jeffery S.M.. 59 Jeffery T.113 238 Jefford C.W. 53 129 Jelinek R. 15 Jemsen M. 194 Jenck J. 209 Jenkins P.R. 273 Jennens D.C. 212 Jenner G. 51 Jensen F. 42 Jensen M.S.. 263 Jeong E. 224 Jeong K.-S. 117 268 Jiang B.. 110 237 Jimeno M.L. 132 151 Jiminez L. 59 Jin M.-J. 218 Jixiang C.. 235 John B. 11 Johnson B.G. 35 Johnson C.C. 94 Johnson C.R. 236 277 281 Johnson C.S. 8 Johnson W.S. 212 Jolliffe J.M. 270 Jones D. 156 Jones G.B. 201 225 272 Jones J. 63 Jones J.B. 283 Jones J.R. 65 Jones P.G. 44 149 Jones. R.J. 246 Jones R.O. 74 Jones S.W. 239 Jones T.R. 23 Jones W.M. 246 Jongsrna T. 231 Jordan J. 155 Jordan K.D. 38. 40 Jordi L. 228 245 Jorgensen E.31 Jorgensen W.L. 51. 52 Jose J.. 25 41 Jouczyk A, 66 Joule J.A. 184 196 Journet M. 83 Juarista E.. 108 Jubian V. 60 Juge S. 241 Jung D.K. 127 Jung M.E.. 93 Jung S.H. 249 Junjappa H. 146 Juntunen S.K.. 116 Jutand A, 159 Kabachnik M.M. 238 Kabalka G.W. 275 277 Kabuto C. 133 Kaduk J.A. 130 Kagan H.B. 255 Kagawa H. 143 Kaiser M. 46 Kaiwar V. 266 Kajimara H. 214 Kakehi T. 112 Kakikawa T. 266 Kakuta. S. 21 1 Kalck P. 209 231 Kalinin V.N. 222 Kallwas H.K.W. 291 Kallweit H. 262 Kamada H. 44 Kamae K. 163 Kambe N. 80 126 209 Kameyama Y. 174 Kamigata N.. 44 Kamiyama H. 171 Kamochi Y. 161 Kampf J.W. 221 Kamphuis J. 86 Kan C.-C.,23 Kanabus-Kaminska J.100 Kanagasabapathy V.M. 56 Kanai M. 252 Kandaanarachchi P. 70 Kandzia C. 161 Kaneda K. 271 Kaneko C. 50 Kaneko Y. 122 Kanematsu K. 180 Kang K.-T. 112 Kang S.-K. 213 Kang T.W. 97 Kanno Y. 144 Kanomata N. 163 Kaplan L.J. 32 Kappe C.O. 50 Kaptein B. 86 Karikomi M. 172 Kasai N. 214 Kashap R.P. 124 Kashimoto M. 194 Kasinos N. 32 Kassir J.M. 243 Katagiri T. 292 Kataoka. K. 67 Katayama T. 143 Kathardekar V. 23 Kato M. 243 Kato T. 91 Kato Y. 25 Katritzky A.R. 55 167 Katsuki T. 251 Katuoka Y..115 Katz T.J. 161 247 Kauffmann T. 155 262 Kaufmann F.-P. 57 Kaupp M.. 37 Kawada A, 289 Kawai T. 241 Kawakami T. 270 Kawakita S.24 Kawamura Y. 212 Kawano H. 241 Kawasaki H. 275 Kawashima T. 52 Kawate T. 266 Kay L.E. 4 Kayano A. 93 Kayser F. 45 Kayyar N.K. 72 Kazanis S. 63 Kazi A.B.. 243 Kazlauskas R.J. 70 Kazmaier U. 113 Kearney AS. 63 Kearney T. 184 Keegstra M.A. 156 Keese R. 129 Kefurt K. 285 Keil R. 113 Keinan E. 117 269 Keiner. A, 296 Keki S. 163 Kelbaugh P.R. 175 Kellogg G.W. 7 Kennard O. 33 Kennedy R.M. 270 Kennewell P. 111 132 189 Kephart S.E. 122 Kesselheim C. 97 Kessler R.J. 58 Kevill D.N. 55 Khac D.D. 137 Khan F.A. 124 Khan M.A. 225 Khan M.N. 159 Khan R. 284 Khan T.H. 288 Khanna V.V.. 271 Khemani K.C. 56 Khiar N. 116 Kice J.L.59 179 Kido F. 243 Kiehl A, 110 Kiers N.H. 270 Kihara M. 194 Kiji J. 232 Kikuchi I. 163 Kikugawa Y.,152 Kilburn J.D. 94 Kilway K.V.. 223 Kim C.K. 53 Kim C.S. 249 Kim J.-S. 62 Kim J.Y. 291 Kim M.-J. 283 291 Kim N.D.. 53 Author index Kim S. 91 Kim S.-G.,213 Kim T. 78 Kim Y.J. 225 Kimura K. 251 Kimura T. 180 Kimura Y. 251 Kindermann R. 46 King J.F. 61 73 King S.L. 62 Kini R.M. 31 Kinney D.R. 16 Kinoyama I. 180 Kirby A.J. 44 Kirby G.W. 192 203 Kirihara M. 153 Kirk O. 284 Kirmse W. 56 Kirschbaum K. 157 Kise N. 79 Kishi Y.,249 Kita Y. 173 Kitahara H. 124 Kitahara Y. 197 Kitamura T. 44 Kitamuri Y. 163 Kiyooka S.-i.122 Kizilian E. 65 Klabunde K.U. 164 Klabunovskii E.I. 242 Klarner F. 164 Klassen D.F.,73 Klein D.P. 21 1 Klempier N. 287 Klenk H. 286 Klibanov A.M. 283 Klinekole B.W. 72 Klinowski J. 17 Klumpp G.W. 177 213 240 Knobler C.B.. 32 221 Knochel P. 113 119 251 266 Knolker H.-J. 216 218 228 Knol A, 240 Kobayashi K. 144 Kobayashi O. 143 Kobayashi S. 44 125 134 257 Kobayashi Y. 194 Kobori Y. 298 Koch A, 56 Koch T.H. 198 Kocienski P.J. 110 241 Kociolek K. 14 KoEovsky P. 214 Kodomari M. 152 Koenig T.M. 277 Koepsel R.R. 98 Koert U. 274 Kover K.E. 8 Koga K. 32 252 275 Koh H.J. 59 Koh J.S. 91 Kohnke F.H. 138 Koizumi T. 273 Kokotailo G.T. 17 Author Index Kolb H.C..167 Kolbert. A.C. 16 Kolinsky P.V. 246 Kollenz. G. 50 Koller H. 15 Koller M. 216 Kollman. P.. 31 Kollman P.A.. 29. 40 45 Kolodziejski W.. 17 Kolshorn. H. 164 Kornatsu N. 115 Komen. C.M.D. 240 Kondo H. 295 Kondo. K. 158 Kondo T.. 241 Kondo Y. 109 231 234 236 Kong W.. 49 Konings M.S.. 67 Konno A, 173 Kon-No K. 135 Koomen G.-J. 184 Koontz. J.I.. 65 Kopola. N. 157 Kosir I.. 152 Kosnikov A.Y. 129 228 Kossek S. 281 Kostense A.S. 32 Kotani. T.. 238 Kotecha N.R. 232 Kozak J. 21 1 Kozhushkov S.I. 246 Krafft M.E. 129 227 Kraka E.. 35 141 Kraus G.A. 84 153 Krause H.. 241 Kreek. T. 29 Kresge A.J. 63 70 Kretzschmann H.164 Krishnarnurthy V. 91 Kristen H. 285 Krogh E. 68 Krohn. K. 149 Kroll F.. 147 244 Kroll F.E.K. 245 Kroto H.W. 107. 250 Krow G.R. 224 Kruft D. 70 Kruger. F.W.H.. 220 Krumpe K.E. 108 243 Krylov A.N. 220 Krylov. E.N. 65 Krysan D.J. 147 Kubo A, 109 158 197 233 Kubo T. 183 Kucera D.J. 239 Kuczowski. R.L. 42 55 Kudo T. 161 Kuma A. 120 Kumagai J.. 203 Kumanovic. S. 213 Kumar. K.T.K. 132 Kumar P.. 275 Kumar V. 235 Kumashiro. K.K.. 143 Kumboyashi. H. 242 Kume K.-i. 122 Kundig. E.P. 222 Kunieda T. 251 Kunishirna. M. I16 Kuniyasu H. 209 Kuntz. I.D.. 24 Kuntz J.S. 24 Kunz H. 285 Kuo. E.Y.. 146 Kupte E.. 9 Kuraishi. T.. 183 Kurasawa. K. 159 Kurella.M.G.. 129. 228 Kurita J.. 201 Kuroki R. 24 Kurosawa. H.. 214 Kurth M.J.. 175 Kurtzweil. M.L. 186 Kusabayashi. S. 199 Kutateladze. A.G. 59 Kutateladze. T.G.. 179 Kuwajima I.. 51 Kuwatani Y. 235 Kuzubski A, 266 Kwak C.G. 63 Kwang. I.. 63 Kwon D.S.. 74 Kwon T.. 76 Kwong H.-L.. 268 Labaudiniere L. 237 Labhardt. A.M. 6 LaBounty L.. 231. 241 Lacour J. 272 Laffitte J.A.. 241 Lagters J. 169 Lahti P.M. 40 Lai M.T. 96 Lai Y.S.. 219 Lajis N.H.J.. 159 Lallemand J.Y _,1 13 Lam. J.N. 167 Lam J.Y.L. 61. 73 Lamas C. 86 Larnaty. F.. 238 LaMunyon. D.H. 195 Landscheidt H.. 56 Langer V. 46 Langhoff S.R. 38 Langridge. R. 24 Langstrom B. 237 Lapinte.C.. 246 Larcheveque M. 292 Largess. K .. 156 Larsen T.O.,284 Laskshmi K.A. 124 Lathbury. D.. 239 Lattuada. L. 245 Laue. E.D. 5 Lauri. G.. 23 Laval J.-M.. 295 Leach. A. 72 Leanna M.R. 270 Le Bihan. J.-Y. 223 Lee A.W.M.. 178. 180 Lee. B.S.. 53 Lee. C.H. 212 Lee D.-H. 122. 253 Lee E.. 87 Lee G.C.M.. 178 Lee. G.-H. 133. 215 Lee. G.J.. 74 Lee I. 53 55. 59. 74 Lee. J.-S.. 213 Lee. J.C.. 112 Lee. K.C.. 63 Lee. K.S. 148 Lee S.-Y.. 112 277 Lee. S.A. 162 Lee S.W. 63 Lee. T.H.. 87 Lee. T.V.. 291 Lefour J.M. 47 Leger. R.. 78. 132 Legeune. J.. I13 Legters. J. 168 Lehmann P.A. 29 Lehn J.M. 31 le-Hocine. M.B.. 137 Leibfritz D.. 9 Leibovitch.M.. 63 Leighton. J.L. 249 Leiras H.O.. 36 Leite M. 158 Lemaire. C. 231 Lennhoff. N.S.. 220 LeNoble. W.J.. 55 124 Lensen N.. 93 Leonardo. C.L. 41 LePage T.J.. 35 Le Parco J.-M.. 9 Leplauy. M.T. 14 Lesher. G.Y. 235 Leslie R.. 118. 273 Lester W.S. 225 Leszczynski J.. 37 Leung. S.W. 46 Leutenegger. U. 109. 213 Leveque. S. 246 Lew. S.Q.. 141 Lewis K.K.. 23 Lewis. R. 24. 145 Ley. S.V..118. 232. 270. 273. 274 Lhoste P.. 212 Li. J.. 64. 123. 276 Li. L.. 21 1 Li. X.. 153 Li. Y.. 41. 108 Liang G.B. 163 Liang. G.Y. 29 Liao C.C.. 148 Licandro. E.. 245 Licklss. P.D.. 57 Liebelt. B. 285 Liebeskind. L.S.. 147 Liebman. J.F.. 141 Liebster M.H.297 Liedholrn B. 154 Lievense J.C. 146 Lii J.H. 27 28 Liljefors T. 27 Lilley G.A. 32 Lin S.-H . 2 15 Lindeman S.V. 129 228 Linden A. 202 216 Lindroos J. 44 Link J.O. 119 265 Linstrurnelle G. 113 236 Liotta F. 21 1 Lipshutz B.H. 109 113 177 Lipton M.A. 271 Liras S. 125 Littlejohn A, 192 Liu A. 145 259 Liu H. 104 260 Liu H.-M. 132 Liu H.-W. 96 Liu J. 78 Liu K.K.-C. 280 Liu M. 41 47 Liu Q.-Y. 122 Liu R.-S. 215 Liu S.Y. 29 Liu W.-G. 100 Livinghouse T. 135 194 Llebaria A, 130 245 Lledos A. 44 Llera J.M. 116 Llewellyn G. 74 Llorus M.E. 160 Lo D.H. 28 Loakes D. 189 Lochrnann L. 122 Loebach J.L. 147 Loefstroern C. 46 Low H. 280 Loewenthal E.107 Loewenthal H.J.E. 150 Loffet A, 212 Loft M.S. 221 Loftus P.J. 30 Loh T.-P. 46 134 Lohray B.B. 108 265 268 Loirn N.M. 220 Lornis T.J. 98 Loncharich R.J. 51 Londridge J.L. 72 Longrnore R.W. 275 Look G.C. 295 Loonat M.S. 220 Lopes C.C. 157 Lopes R.S.C. 157 Lopez L. 77 Lopez M. 284 Lopez-Alvarado P. 159 Lorente A, 197 Losada J. 223 Lottes A.C. 50 Lotz S. 223 Lough. A, 247 Loupy A. 55 Lovell H. 291 Lowe C. 171 Lu L. 263 Lucarini M. 100 101 Lucchini V. 72 Ludwig M. 74 Luelo C. 94 Lugtenburg J. 15 161 Lui L. 161 Lukin K.A. 246 Lurnini T. 219 Lund H. 164 Lund K.P. 147 245 Lund T. 164 Lupi A, 232 Luz Z. 18 Lyford L.252 Lyngdon R.H.D. 44 Lyons J.E. 44 101 Lysaght F.A. 50 Ma J. 122 Ma S. 50 Maas G.,107 McAllister M.A. 63 McCague R. 217 McCamrnon J.A. 26 Macchia F. 134 McClelland R.A. 56 63 64 McClinton D.A. 152 McClinton M.A. 152 McComb S. 145 259 McCoy M.A. 4 12 McCullough K.J. 199 McCurdy A. 59 McDermott A.E. 15 16 McDonald D.Q. 124 McDonald R. 223 McDouall J.J.W. 42 44 McElwee-White L. 246 McGaughey G.. 29 McGlinchey M.J. 218 223 McGrane P.L. 194 Maciel G.E. 16 Mclntyre L. 9 McKay R.A. 14 McKee M.L. 43 McKee S.P. 122 McKervey M.A. 243 McKie J.A. 80 McKillop A. 235 MacKinnon J.W.M. 133 257 McLaughlin M.L. 246 McLeod D. 112 237 McMartin C. 23 McMordie R.A.S.272 McMullen L.A. 129 245 McNab H. 160 McNabb T.J. 283 Mcheill A.H. 112 254 McNelis E. 152 McNichols A.T. 228 Macomber D.W. 245 Author Index McPhail A.T. 124 McQuire L. 249 McWhinnie P.M. 23 Madeley J.P. 194 Mader G. 153 Madhukar P. 245 Madkour A.E. 151 Maduakor E.C. 180 Maduakur C. 157 Maestro M.C. 116 Maffei M. 46 Magar S.S. 131 Maggi R. 159 Maggio E.T. 22 Magnus P. 145 249 272 Magnuson M.L. 13 Mahajan M.P. 203 Mahler C.H. 228 Mahon M.F. 239 Mahrwald R. 252 Main B.G. 72 Main L. 240 Maiorana S. 221 245 Mairesse G. 295 Majewski M. 275 Majurndar D. 40 Makosza M. 55 155 Mal D. 146 Malacria M. 83 124 214 Malecha J.W.249 Maleev A.V. 129 228 Malet R. 212 Mali R.S. 146 190 Mallart S. 241 Mallon P. 93 129 Malloni G. 158 Mamedyarova I.A. 247 Manaut F. 25 Mancheiio. B. 254 Mandal A.K. 266 Manderville R.A. 66 Mandolini L. 70 Manek M.B. 94 Manfredi A. 222 Mangeney P. 223 Manners I. 247 Mansour A.K. 146 Mansuy D. 149 Mantegani S. 232 Mantell S.J. 181 Manzocchi A, 279 281 Maple J.R. 28 Maquestiau A, 184 March J. 56 Marchwald R. 121 Marcinow Z. 124 Marcotullio M.C. 243 Marcuccio S.M. 236 Marcuzzi A, 2 16 Marder S.R.. 246 Marek I. 223 Marek M. 285 Margaretha P. 171 172 Margolin A.L.. 287 Author Index Marinelli F. 237 239 Mealli C. 231 Marinic Z. 124 Meegalla S.K.159 238 Marino J.P. 112 254 Meeholz K. 163 Marino M. 116 Meerpoel L. 46 Markandu J. 132 189 Meguri H. 160 Marko I.E. 133 Mehta G. 124 Markus T. 14 Meier A. 158 Marples B.A. 92 212 273 Meier H. 164 Marquet J. 160 Mejias. M. 228 Marsh R.M. 145 260 Mekrarni M. 281 Marshall D.R. 133 257 Melian D. 270 Marshall G.R. 14 Melikyan G.G. 226 Marshall J.A. 51 138 Mernarian H.R. 170 Marson C.M. 192 Mendez M.I. 43 Martens J. 108 265 266 Mentndez J.C. 159 232 Marti R. 121 Menger F.M. 69 142 Martin A.R. 235 Menichetti S. 68 Martin G.E. 6 Mergelsberg I. 118 271 Martin S.F. 125 Medic C.A. 244 Martin V.S. 116 Merritt A. 249 Martin Y.C. 22 23 Merwin L.H. 13 14 Martinez A.G. 113 Merz K.M. 27 29 Martinez A.V.156 Merzouk A. 212 Martinez J.P. 133 Messeri T. 235 Martinez M.C. 199 Metropolis N. 26 Martinho-Sirnoes J.A. 100 Metz P. 212 Martorell G. 236 Metzler M.R. 240 Maruoka K. 52 134 258 Meunier B. 205 Maruyarna K. 205 Meyer A, 163 Maruyarna T. 256 Meyer A.G. 233 Marzi M. 181 Meyer F.E. 131 146 239 Marzoni G.P. 23 Meyers A.G. 145 Masarnune S. 122 253 268 275 Meyers A.I. 120 158 237 267 Mascareiias J.L. 135 238 Miao G. 252 Mascharak P.K. 98 Michelotti E.L. 231 Mashima K. 242 Midland M.M. 266 Masi D. 231 Miginiac L. 175 Masuda R. 183 Mihira A, 222 Matelich M.C. 213 249 Mikarna K. 253 Mathias J.P. 107 138 Mikarni E. 108 Matsuba N. 183 Miki K. 214 Matsuda F. 237 Miki S. 143 Matsuda H. 168 Mikolajczyk M. 116 Matsuda I.112 Miles W.H. 150 224 Matsuda P.T. 119 Miller J.A. 237 Matsuda Y. 113 Miller M.J. 72 Matsurnoto J. 164 Milligan M.L. 223 Matsurnoto K. 152 Mills G. 124 Matsurnoto Y. 225 234 Milner D.J. 152 Matsuyama H. 44 Milstein D. 237 Matt C.F. 109 Minami T. 109 222 223 Mattay J. 77 186 Minetti P. 181 Matthews D.A. 23 Minto R.E. 145 260 Matthews I. 152 Mioskowski C. 226 Mattson-Arnaiz H.L. 58 Mirafzal G.A. 78 Maugein N. 116 Miravitlles C. 130 Maxwell R. 14 Misiti D. 181 Mayelvaganan T. 133 Mistryukov E.A. 242 Mayence A, 184 Mita N. 183 Mayer J.M. 32 Mital A, 120 Maynard G.D. 52 Mitchell D. 277 Mayoral J.A. 47 48 Mitchell M.B. 235 Mayr A.J. 230 Mitchell. T.J. 24 Mayr H. 57. 74 Mitchell T.N. 108 311 Mitsudo T.241 Mitsui K. 152 Miura A. 287 Miura K. 101 Miurd M. 159 232 233 Miyai J. 115 Miyakawa M. 222 Miyake R. 225 234 Miyake T. 170 Miyamoto H. 117 270 Miyarnoto K. 298 Miyaura N. 131 158 236 262 Miyazaki A, 292 Miyazawa T. 119 Mlinaric-Majerski K. 124 Mo O. 38 Mobele B.I. 290 Moberg C. 239 Modena G. 72 Moffat M.R. 231 Moharnad M.M. 146 228 Mohialdin-Khaffaf S.N. 278 Mohr C. 23 Mohr P. 117 Moise C. 222 Moiroux J. 295 Moiseev S.K. 222 Mokhallalati M.K. 150 Molander G.A. 80 261 Moldval I. 183 Molina P. 41 48 197 Molins E. 130 228 Molloy K.C. 239 Mornchilova T.G. 27 Montelione G.T. 9 Montgomery J.A. Jr. 42 Moody C.J. 144 Moomaw E.W. 23 Moon J.B.24 Moorcroft D. 112 Moore E.J. 231 241 Moore H.W. 53 147 186 Moore P.B. 7 Moore R.E. 205 Moorfield C.N. 107 Moran M. 223 Moreau P. 32 Moreno-Mafias M. 160 212 214. Morera E. 212 237 Moreto J.M. 130 228 245 Morgan M. 144 Mori A. 251 Mori M. 199 Moriarty R.M. 110 Morikawa K. 268 269 Moris F. 285 Morita H. 79 Moritani Y. 158 Moriwake T. 210 Morley J.O. 37 Morley S.D. 26 31 32 Moro-oka Y. 21 1 Morreno I.. 116 312 Morrin-Fox M.L. 271 Morris G.A. 7 Morris J. 190 Morris J.G.. 289 Morris K.F. 8 Morris. K.G.. 208 Morris M.. 210 Morrow C.J. 282 Morrow G.W. 148 Morrow P.R. 61 Morse. C.A.,23 Morton H.E. 270 Mortreux. A..221 Moss W.O. 111 Mosset P. 116 216 Motherwell. W.B. 101 115 124 125 262 Motoyoshiya J. 109 Moulines F. 225 Mouri M.. 256 Mouriiio A, 135. 238 Mowlern T.J.. 184 220 221 Moyano A, 227 Mozek I.. 152 Mozol. V. 223 Muathen H.A. 278 Mucciaro T.P. 137 Muchowski. J.M. 197 Muller F. 186 Mueller. K.T.. 14. 15 Mueller L. 4 12 Mues C. 212 Mukai C.. 129. 222. 225 228 Mukherjee A, 124 Mukhurgee I. 116 Mullay J. 30 Mullen K.. 110 163. 164 Muller G. 143 Muller P. 124 Mulzer J. 282 Murahashi S.-I. 167 194 210. 270 Murai. A,. 129 Murai. S. 214 Murakami M.. 78. 81. 261 Murata S. 52 Murray C.M. 39 Murty K.V.S.N. 146 Musco A, 237 Muxworthy. J.P. 273 Muzart J.270 Myers A.G. 105. 122 146 Myers W.H. 65 Myles. D.C. 298 Nacci. V.. 202 Nachtingall. P.. 40 Naemura K. 290 Nag S. 61 Nagarni K.. 225 Nagareda K. 71 Nagashirna H. 112 238 Nagashirna. M. 159 Nagata K.. 204 Nairn A, 124 Najirne R.. 168 Nakada M. 249 Nakadaira Y. 221 Nakagawa M. 266 Nakagiri. H.. 101 Nakahara. S.. 197 Nakahata K. 193 Nakai T. 108 253 Nakajirna N.. 241 Nakarnura E. 50 245 Nakarnura. T. 51. 122 Nakamura Y. 98 Nakanishi E. 174 Nakanishi M.. 183 Nakano. H. 243 Nakao R. 44 Nakatani K. 237 Nakatsuji H. 143 Nakawa H.. 51 Nakaya C. 161 Nakayarna J. 171 Nakayasu S. 238 Naota T. 194 Narasaka K. 78 127 133 Narayana C. 275 Nardelli M.239 Narisawa. S.. 108 253 Narizuka. S. 173 Naruta. Y. 205 Nash J.J. 40 Nasman J.H. 157 Nason. D.M. 175 Natatani. K. 138 Natchus. M.G. 149 Nation J.E. 246 Natsugari. H.. 289 Naylor A, 263 Ndjanga J.-C. 241 Nefedova M.N. 247 Negishi E. 130 146 228 238 Negron G. 50 Neibecker D. 241 Neidlein R. 163 Neil D.A.. 147. 245 Neis S. 216 Nelson S.F. 165 Nelson. S.G.,257 Neu T.. 145. 259 Neunhoeffer H. 197 Newcornb M.. 94 Newkorne. G.R. 107 Nguyen M.T. 43 150 Ni F. 6 Ni Z.. 116 208 Nicholas K.M. 225 Nichols B.J. 291 Nicholson B.K. 240 Nicholson S. 72 Niclas H.J.. 154 Nicolaou K.C.. 107. 133 145 200 249 259 Nicotra F. 285 Nidip. G.M.133 Author Index Niedoba S. 59 Nieger. M.. 165 Nielsen A.T. 187 Nihira T. 235 Niihata. S.. 127 Nilesi. M. 25 Nilsson K.. 238 Nilsson Y. 183 Nishi K. 74 Nishi M. 188 Nishi N. 141 Nishibata Y.. 24 Nishibayashi Y. 115 Nishida Y.. 287 Nishii. S. 124 Nishirnura H.. 225 234 Nishirnura M. 257 Nishino. H. 159 Nishiyarna Y. 271 Nissan R.A.. 187 Nitta M. 163 Niwa S. 250 Niwayarna S. 53 129 Noe M.C. 46 134 Nohara F. 188 Noheda P. 242 Nojirna M. 199 Nolke M. 160 Nornura M. 159 232 233 Nonoshita K. 52 Norin T. 21 1 Norrnant J.-F. 237 Norrby P.-0.. 214 Norris. D.J. 157 Nosal R. 85 Novak. M. 56 Novi M. 156 Novikova Z.S. 238 Nozoe T. 205 Nuber.R. 165 Nugent. T.C. 149 Nugent W.A. 108 Null V.. 298 Nunn K. 116 216 Oalmann C.J. 125 Oarnura H.. 251 Oatley S.J.. 23 31 O’Connell J.F. 188 O’Connell T.J. 231 241 Oda H. 222 Oda M. 235 O’Dell R. 89 Odenkirk W. 122 134 Odiaka T.I. 219 Oelze J. 45 O’Gara J.E. 42 Ogasawara K. 115 226 281 Ogasawara. M. 241 Ogawa A. 80 126 209 Ogawa K.. 188 Ogawa S. 180 Ogden R.C.. 23 Ogiku T.. 158 Author Index Ogoshi S. 214 Ogura K. 93 Oh H.K. 59 O’Hagan D.,282 Ohard T. 116 Ohashi. K.. 141 Ohashi M. 79 Ohba Y. 287 Ohe T. 159 Ohfume Y. 108 Ohlrneyer M.J. 242 Ohrnizu H. 158 Ohno M. 125. 257 Ohsawa A, 204 Ohshirna M. 172 Ohsumi T.197 Ohta H. 298 Ohta T. 170 Ohyarna Y. 113 Oi R. 270 Ojima I. 228 Ok J.H.. 18 Okada E. 183 Okada M. 204 Okada S. 44 Okada T. 45 Okamura K.. 212 275 Okano T. 232 Okauchi T. 78 Okazaki R. 52 O’Keefe D.F. 236 Oku A, 113 Okurnoto H. 238 239 Okuro K. 233 Okutsu M. 290 Olah G.A. 56 57 124 153 Olefirowicz E.M.. 199 Olejniczak E.T. 7 Oliva A. 41 45 48 Oliveira. A.R.M. 112 254 Olivo H. 294 Olivucci M.. 42 143 Ollivier J. 212 Olmstead M.M. 98 Olofson R.A. 144 Olson A.J. 21 22 Onyido I. 66 Oppolzer W. 119 121 122 251 276 Orahovats A.S. 202 Organ H.M. 232 Ori A, 44 Orozco M. 28 Ortar G. 212 237 Ortuno R.M. 45 48 Osakada K. 241 O’Shea D.M.115. 262 Oshima K. 101 Osterhout M.H. 119 O’Toole K.J. 284 Ott. c.,45 Otte A.R.. 214 Otterson K. 196 Out G.J.J. 177 Overman L.E. 109 186 231 233. 239 Owczarczyk Z. 130 146 228 238 Owen D.A.. 218 Owens. W.H.. 268 Owensby A.L.. 42 Ozaki H. 238 Ozaki. S. 273 Ozawa F. 109. 158 233 234 Ozin G.A. 15 Ozkar S. 15 Pace J.M. 221 Paddon-Row M.N.. 38 124 Paderes. G.D. 51 Padmakumar R. 133 Padwa. A, 108. 116 125 147 208 243 Page M. 43 Page M.I. 282 Pages L. 130 Paglietti G. 202 Pakkanen T.A. 36 44 Pal R. 146 Palenik G.J. 246 Palmer A.J. 231 Palmer I.J. 42 143 Palmer K.W. 142 Pandey B. 275 Pandiarajan K. 197 Pandit. U.K. 184 Pankas. S.M.223 Pankov A.A.. 67 Pannek. J.-B. 218 Pannell. K.H. 230 Panov. V.N. 129 228 Panza L. 285 Papadopoulos C. 25 Papagni A, 245 Paquette L.A. 52 124 Parchment. O.G.. 37 Pardigan O. 120 266 Pardini V.L. 149 Pardo C.. 151 Parella T. 45 Park D.J. 52 Park J.G. 224 Parkanyi C. 162 Parkanyi L. 230 Parker J.K. 44 Parker K.A. 104 155 Parker V.D. 74 Parkinson C.J. 149 249 Parlier A, 245 Parmee E.R. 122 253 Parquette J.R. 188 Parrain. J.-L. 236 Parratt J.S. 287 Parsons P.J.. 83 131. 239 263 275 Partridge H. 38 Pascal Y.L. 50 Pascual M.C. 223 Pasini D.. 47 Pasquato L. 72 Pasta P. 294 Pasto D.J.. 43. 49 Patani. M.A.. 136 Paterson. I.. 122 Pathiaseril.A,. 27 Pdtil S.R.. 190 Patonay. T. 167 Pattenden. G. 89 194 260 Patterson. G.M.L.,205 Patterson. I.. 108 Patterson. R.G. 252 Patzelt H.. 100 Paul. G.C. 53 Paulini K.. 243 Pavlenko. N.O.. 67 Pavlov V.A.. 242 Pawar P.N.. 190 Pazenok S.A. 67 Peacock S.C.,32 Pearlman. D.A. 29 Pearson A.J. 217 218 219 224. 228 Pearson. M. Ill Peddada L. 295 Pedregal. C. 113 185 Pedulli. G.F.. 101 246 Pei. D. 97 Pelern K. 116 Pellon P. 275 Pelter A.. 148 275 Penco. S. 158 Peng S.-M. 133 205 215 Peng. T.-S. 21 1 Penn J.H. 268 Pennell A.K.M. 101 Pepe G.. 30 Perakyla M.. 36. 44 Percy J.M. 44 Periasamy. M. 231 Pericas M.A. 227 Perichon J. 159 Perlmutter P. 231 250 Perrier H.157 Perrier. RE.,218 Person. M.. 222 Perutz R.N.. 242 Pessi A, 22 Petasis N.A.. 115. 123. 136 Peters E.-M. 190 Peters K. 190. 216 Peters P.M.. 94 Peters. T.H.A. 156 Petersson G.A. 42 Petit F.. 221 Petrillo. G. 156 Pettersson I.. 27 Pettersson L.G.M. 214 Petts. J.. 21 Pfaltz. A,. 109 213 Pfrengle W. 239 Pham C.. 53 Pharn. N. 124 314 Pienta N.J. 58 Pierens G.K. 11 19 Pierini A.B. 160 Pietroni B.R. 237 239 Pike R.D. 220 Pilard S. 168 Pilcher AS. 272 Pimm A, 110 Pines A. 15 Pineschi M. 134 Pinhey J.T. 149 Piniella J.F. 227 Pinkerton A, 217 Pino M.J. 217 Pinto I.L. 198 Piras P.P. 212 Piroddi A.M. 158 Pirrung F.O.H.86 Pitel C. 241 Pitsinos E.N. 249 Pitterna T. 145 Pkaro K. 159 Plant D. 11 Platonov D.N. 242 Platt K.L. 161 Plattner D.A. 121 Pleixats R. 212 Plenevaux A, 231 Plobeck N.A. 116 Plug J.M. 184 Plumet J. 133 173 Pochapsky S.S. 11 Pohjala E. 36 Polo A, 231 Pomplians P.L. 146 Ponec R. 45 Pontellini R. 237 Pook K. 155 Pople J.A. 35 Poppe L. 8 Pornet J. 175 Porter N.A. 124 Portnoy M. 237 Posner G.H. 133 143 Postena M.H.D. 108 Potter G.A. 217 Pou S. 32 Pouet M.J. 67 Poupko R. 18 Powell D.R. 165 Pozo M. 282 Prakash G.K.S. 124 Prakash Reddy V. 56 57 Prange T. 137 Prat M. 214 Pretzer W.R. 231 241 Prigden L.N. 150 Prinsep M.R. 205 Pritchard M.241 Proctor G.R. 201 Protopopova M.N. 124 125 Pruszynski P.. 70 Pu J. 146 211 Pu Y. 171 Pudelski J.K. 247 Pulido R. 282 Purvis D.H. 142 Purvis G.D. 29 Pyne S.G. 170 Qian Z. 156 Quadrelli P. 237 Quayle P. 107 112 237 272 Quazzotti S. 222 Quesnelle C. 157 158 Quintard J.-P. 236 Raap J. 15 Rabideau P.W. 124 Rabinowitz M.H. 186 Racherla US. 271 Radetski C. 156 Radinov R.N. 121 251 Radom L. 38 Rafel S. 48 Raffaelli A, 267 Raghavachari K. 35 Raghavan S. 52 Rahman M.S. 27 192 Raich I. 285 Raimondi L. 40 45 50 132 Raj N. 32 Raja M. 207 Rajagopal D. 251 Rajeswari S. 235 Rakeeb Deshmukh A. 144 Ramage R. 162 Rama Rao A.V. 266 Ramcharitar S.H..86 204 Ramirez M.A. 116 Ramsden J.A. 21 1 Ranu B.C. 152 Rao K.K. 159 Raphy R. 162 Rapoport H. 188 Rappe A.K. 27 Rappoport Z. 55 Raslan D.S. 158 Rastelli A. 44 Rasul G. 56 57 Rathore R. 73 Ratovelomanana V. 159 Rau A. 245 Rawal V.H. 91 132 Rawson D.J. 158 267 Rawson R. 120 Rayner C.M. 117 Razaname A. 133 Read R.J. 32 Reader J.C. 46 133 Readshaw S.A. 198 Real J. 231 Rebek J. Jr. 124 260 Rebelo R.A. 235 Reboul J.P. 30 Reddy K.R. 200 Reddy M.R. 23 Reddy N.K. 275 Author Index Reddy R.S. 275 Reddy S.P. 212 Reddy V.P. 124 153 Redlinski AS. 14 Redpath J. 201 Reduto dos Reis A.C. 216 Reed J.N. 157 Reed J.W. 124 Rees C.W. 173 Reetz M.T.45 121 252 Reich S.H. 23 Reiher T. 154 Reinhoudt D.N. 70 Reiser 0.. 162 Reissig H.-U. 108 243 245 Renner G. 283 Renson M.J. 199 Rentsch D. 216 Resek J.E. 51 Rettig S.J. 247 Reynolds J.H. 143 Rezende M.C. 156 Rheingold A.L. 134 Rhlid. R.B. 289 Riant O. 255 Ribas J. 214 Ricart S. 228 245 Ricca D.J. 239 Richard J.P. 56 68 Richards W.G. 25 25 Riche C. 47 Richer J.-C. 108 Rickard C.E.F. 240 Rico R.J. 43 Ridenour C.F. 16 Rief U. 247 Rieke R.D. 113 223 Riemer C. 145 Riera A. 227 Righetti P.P. 47 237 Rihs G. 121 Riiz P.R. 132 Ripka W.C. 22 Rischer M. 135 Riva S. 281 283 Rivera I. 110 Rizzo C.J. 48 Robb M.A. 42 143 Robert F.223 Roberts B.P. 91 Roberts L.R. 115 125 262 Roberts R.M.G. 224 Roberts S.M. 282 285 Robertson T.A. 236 Robins M.J. 272 Robinson N.P. 134 Rocha J. 18 Rodrigo R. 133 157 159 Rodriguez A, 116 Rodriguez C.M. 116 Rodriguez J.H. 199 Rodriguez M.S. 263 Rodriguo R. 238 Roe D.C. 24 Author Index Roesselet. K.J. 224 Roger C. 21 1 Rogi-Kohlenprath R. 283 Roi C. 161 Rollman B. 130 Romero M. 197 Romero R.H. 129 227 Roncali J. 179 Rondon D. 224 Roper T.D. 46 122 134 253 Ros J. 245 Rosati O. 243 Rosato. G.C. 161 Rose E. 221 223 Rose-Munch F. 150 221 223 Rosen M.K. 250 Rosenblum M. 21 1 Rosenbluth A.W. 26 Rosenbluth M.N. 26 Rosenstein I.J. 124 Rosini C.267 Roskamp E.J. 275 Ross R.A. 160 Rossi R. 235 Rossiter B.E. 252 Roth G.P. 232 Roth K.-D. 225 Roth M. 124 260 Roth W.R. 46 52 Rothe-Streit P. 121 Rothwell I.P. 150 Roulet R. 219 Roush W.R. 45 Roussi G. 50 Rouwenhart I.M. 285 Rowley E.G. 227 Royo A.J. 41 Rozema M.J. 251 Ruano J.L.G. 199 Rubello A, 143 Rubin Y. 107 Ruchardt C. 160 Rudakov B. 197 Ruder S.M. 261 Rudler H. 245 Rudler M. 245 Rudler R.H. 161 Ruhland B. 178 Ruiz A. 231 Ruiz-Cabello J. 11 Ruiz-Lopez M.F. 47 Rukachaisirikul V. 274 Russell J.R. 196 Russo G. 285 Rutledge P.S. 224 240 Ruveda E.A. 108 Ryan. W.J. 220 Rychnovsky S.D. 216 Ryu I. 80 126 209 Rzepa H.S.44 48 Saa C. 86 Saa. J.M. 236 Saalfranck R.W. 116 216 Sabat M. 247 Saberi. S.P. 208 216 Sabo-Etienne S. 225 Saburi M. 241 Sadakane M. 239 Saegusa T. 233 Saeki Y. 74 Saha A.K. 126 Sailer C. 241 Saimoto H. 249 Saitmacher K. 165 Saito E. 194 Saito K. 189 Saito S. 134 210 Saito T. 188 270 Sakai Y. 145 Sakakibara J. 112 Sakamoto M. 151 Sakamoto T. 109 152 231 234 236 Sakamoto Y. 46 Sakarabu S.. 108 Sakashita. H. 153 Sakata S. 251 Sakuraba S. 241 Sakuragi H. 74 Salaiin J.-P. 212 226 Salerno G. 233 Salvadori P. 267 Salvatella L. 47 Samoson A, 15 Sanchez B. 132 Sanchez F. 241 Sanchez J. 246 Sandball J.P.B. 65 Sander W. 141 Sanders J.155 Sankar Lal G. 278 Sanna P. 202 Santaniello E. 279 281 Santarsiero B.D. 223 Santhakumar V. 131 240 Santi R. 237 Santiago B. 270 Sanz F. 25 Sappok-Stang A. 162 Sarker D.C. 152 Sarma R.M. 159 Sarshar S. 46 119 134 257 265 Sartori. G. 159 Sasaki A. 173 Sasaki D.Y. 89 Sasao S. 194 Sato D. 275 Sato F. 200 Sato K.-I. 209 Sato N. 232 Sato R. 203 Sato. Y.. 234 235 245 253 Satoh S.-i. 203 Sauerbrei B. 287 Saunders M.R. 26 31 Saura-Llamas I. 21 1 Saveant J.M. 55 Savignac M. 158 238 Savina T.I. 67 Sawabe A. 275 Sawada H. 292 Sayer B.G. 223 Scarlato G.R. 249 Schaefer H.F. 111 37 38 41 44 141 Schaefer J. 14 Schafer T. 244 245 Schafer J.124 Schafer T. 147 Schaffers T. 52 Schaller T. 14 Scheffold R. 74 Scheiner A.C. 141 Scherer D. 118 271 Scheuplein S.W. 237 Schiesser C.H. 44 101 Schindehutte M. 223 Schink H.E. 214 Schlegel H.B. 42 55 Schleich A, 56 Schleyer P.von R. 37 Schlick S. 18 Schlingloff G. 251 Schlosser M. 143 Schmid G. 215 Schmidt T. 216 Schmidt-Radde R.H. 163 Schmitt M. 196 Schoch T.K. 246 Schoemaker H.E. 86 Schoettlin W.S. 23 Schofield C.J. 182 Schogl K. 163 Schoop A. 212 Schore N.E. 175 Schreiber S.L. 250 Schroder G. 163 Schiitz M. 215 Schulte D. 223 Schultz M. 285 Schulz J.E. 165 Schwartz A, 11 3 Schwartz C.E. 157 180 Schwarz H. 250 Schwarzenbach F. 121 Schwerdtfeger J.119 Scola P.M.. 249 Scolastico C. 170 Scott I.L. 129 227 Scott L.T. 162 Scott M.J. 257 Scotton M. 47 Sebald A, 13 14 Sebastiani G.V. 161 Seconi G. 100 Secundo F. 283 Seebach D. 121 250 Seebauer. V. 283 Seel C. 107 Sega A. 47 Seibel G.L. 24 Seidl E.T. 38 41 Seishi T. 133 Seitz W.J. 126 Seitze P. 107 Sekiguchi M. 80 126 Seko S. 144 Semmelhack M.F. 145 259 Semones M.A. 125 Semra A. 223 Senanayake C.B.W. 236 277 Senechal D. 223 Senechal-Tocquer M.-C. 223 Sengupta S. 109 158 Seong C.M. 84 85 Servi S. 292 Sessions R.B. 291 Setiabudi F. 161 Setiarahardjo I.U. 66 155 Seto H. 156 Severance D.L. 52 Sevilla M.D. 39 Seyfer-Wasserthal P.283 Shaik S. 44 55 141 Shakya S. 174 Shao L. 241 Shao Y. 265 Sharif I. 278 Sharifi A, 161 Sharma N.D. 272 Sharma V. 122 Sharp M.J. 231 Sharpe S.M. 129 228 Sharpless K.B. 117 167 268 269 270 Shashkov A.S. 129 228 Shaw G.S. 57 Shaw R.W. 239 Shay. W.R. 228 Shea G.T. 23 Shea K.J. 52 62 89 Sheih W.-C. 263 Sheldrick W.S. 46 Shelvin P.B. 124 Shen G.-J. 290 Shepherd R.E. 98 Sheridan R.P. 24 Sherman M.A. 24 Shi G. 143 Shi X. 51 Shi X.-X. 209 Shiao M. 160 Shiba S.A. 143 Shibasaki M. 234 235 253 Shibata I. 168 Shibata N. 173 Shibayama K. 249 Shibuya M. 145 Shibuya S. 276 Shieh W.C. 158 Shiga F. 236 Shigekui M. 164 Shiina S.79 Shilliday L. 223 Shim J.Y. 29 Shima H. 273 Shima K. 150 Shimada I. 275 Shimadzu H. 127 Shimizu M. 253 290 Shimizu R. 143 Shimizu T. 91 Shimizu Y. 74 Shimshock S.J. 272 Shin H. 224 Shindo K. 205 Shing T.K.M. 133 Shinohara H. 141 Shiomori K. 150 Shiro M. 212 222 223 Shishido K. 145 Shively R.J. Jr. 228 Shockcor J.P. 6 Shono T. 79 Shore N.E. 227 Shubina E.S. 220 Shudo K. 67 Shvedov V.I. 242 Sibille S. 159 Sicsic S. 281 Sidduri A.R. 113 251 Siegbahn H.O.G. 214 Siegbahn P.E.M. 37 38 Siegel J.S. 141 142 Siegel M.G. 32 Siegel S. 223 Sieger P. 15 Siehl H.-U. 57 Sierra M.A. 173 Signer M. 119 276 Sih C.J. 284 289 Sikorski J.A. 63 Silber J.J.142 Silverberg L.J. 120 242 Silverman R.B. 95 Simard M. 122 Sime J.T. 284 Simig G. 195 Simler R. 231 Simon H. 289 Simonelli F. 112 254 Simpkins N.S. 250 275 Sin M.S. 117 Sinbanhit S. 246 Singaram B. 267 Singh A.P. 275 Singh B. 235 Singh O.M. 146 Singh R. 87 Singh S. 287 Singh U.C. 40 45 Singh V.K. 108 Singleton D.A.,40 46 47 133 Sinha S.C. 117 269 Sinha-Bagchi A, 117 269 Sini G. 44 Sinnott M.L. 70 Sinou D. 212 Author Index Siri D. 30 Sitamze J.-M. 196 Sivaramakrishnan H. 213 Sjo P.J. 117 268 Sjogren M. 214 Sket B. 151 Skiff W.M. 27 Skokotas G. 200 Skonieczny S. 61 Slawin A.M.Z. 138 184 208 216 220 Slebocka-Tilk H. 55 Smadja W.124 Smalley T.L. 61 Smiley P.M. 224 Smit W.A. 129 228 Smith A.B. 127 136 Smith A.L. 107 249 Smith B.J. 38 Smith C.D. 205 Smith D.F. 133 257 Smith D.G. 198 Smith D.R. 138 Smith E.H. 146 228 Smith K. 152 156 277 Smith M.J. 223 Smith P.E. 30 Smith W.B. 127 Smith W.W. 23 Smith Vosejpka J. 245 Smythers G.W. 32 Snatzke G.,247 Snider B.B. 75 76 Snieckus V. 157 158 Snyder J.P. 22 SO,S.-S. 25 Soai K. 119 250 Soda K. 295 Soderquist J.A. 110 270 Soffe N. 11 Sogah G.D.Y.,32 Sokolov V.I. 246 247 Sola M. 44 Solladie G. 116 Solladie-Cavallo A. 222 Sollazzo M. 22 Somayajula K.V. 82 Sommazzi A. 100 Sonada N. 126 Song Z. 51 Sonoda N. 80 209 Sordo J.A.41 43 48 Sordo T.L. 41 43 48 Sorenson E.J. 133 Sossa C. 101 Soto J.L. 197 Souma Y. 154 Sowin T.J. 270 Spackman D.G. 285 Spanton S. 217 Speckamp W.N. 86 Spellmeyer D.C. 29 53 129 Spero D.M. 243 249 Spezia S. 282 Author Index Spiess H.W. 18 19 Spitzer. T.D. 6 Springer R. 124 Springhorn K.F. 270 Srdanov G. 56 Sridharan V. 131 240 Srinivasan K. 217 218 219 Srinivasa Rao C. 146 Srivastava R.R. 277 Srivatava N. 120 Stack D.E. 113 Stack J.G.. 124 260 Stammen B. 46 Stanchev S. 252 Stang P.J.. 109 113 228 Starkemann C. 122 Stary I. 214 Stauber S. 152 Stauffer D.A. 59 Staversky R.J. 146 Steckhan E. 48 161 292 Steeman W.J.M. 86 Steenken S.,56 64 Steensma D.H.281 Steffan W. 285 Stek. B. 152 Stella V.J. 63 Stengel. P.J. 112 254 Stenstrom Y. 258 Stephenson G.R. 217 218 Stern M.K. 155 Stevens K.L. 113 Stevenson P. 131 240 Stewart E.L. 29 Stewart J.J.P.,28 Stichter H.. 177 Stille J.K. 237 Stinson S.C. 250 Stirling C.J.M.,59 68 124 Stoddard G.J. 52 Stoddart J.F. 107 138 Stolle A, 212 Storer J.W. 142 Stork G. 258 Street S.D.A. 110 272 Streith J. 134 Streitweiser A. 67 Strnad M. 45 Struchkov Yu.T. 129 220 228 Stuart N.W. 111 Sturgess M.A. 210 Stussi D. 222 Stutz A.E. 280 Su (3.-M. 215 Su. J. 245 Su M.D. 44 su Y. 221 Suirez E. 270 Subasinghe K. 270 Subba Rao G.S.R.,52 Subbarao N.32 Subramanian L.R. 113 Suehiro K.. 164 Suffert. J. 237 Suga H. 51 Sugawara K. 257 Sugi K.D.,49 Sugihara T. 226 Sugihara Y . 115 Sugimoto A, 151 Sugimoto M. 292 Sugimoto S. 21 1 Sugimoto Y. 144 Suginome. H. 144 Sugita T. 115 Sugiura M. 232 Sugiyama E. 251 Sugiyama T. 199 Sulikowski. G.A. 127 Sulikowski M.M. 127 Sulzbach W. 215 Sumitani N. 93 Sunagawa M. 173 Sundarababu. G. 119 276 Suriano. J.A. 245 Surya Prakash G.K. 56 57 153 Sutej K. 101 Sutherland A.G. 281 282 Sutton K.H. 222 Suzuki A, 131 158 236 262 Suzuki H.. 161 Suzuki K.. 225 Suzuki. M. 45 Suzuki N. 245 Suzuki. T. 56 272. 275 Svensson M. 38 Swanson S. 218 Sweigart D.A.220 Swenton J.S.. 148 Swindell C.S.,249 Swingle N.M..252 Swoboda B.E.P.,287 Sykora J. 149 Syren C. 164 Syvret R.G. 278 Szabo K.J.. 43 152 Szantay C. 183 183 Szczecinski P. 223 Szewczak A.A. 7 Szewczyk J. 223 Szymoniak J. 222 Taber D.F. 120 242 243 Tada M. 101 161 Tada T.. 107 Tadokoro. O. 238 Taguchi T. 45 122 Takabe K. 292 Takagashi. H.. 119 Takagi M. 241 Takahashi H. 125. 193 257 Takahashi K. 189 235 Takahashi M. 158 281 Takahashi N. 210 Takahashi T. 46 212. 241 Takahori T.. 134 Takai K. 115 Takami N. 80. 126 Takanabe H. 111 Takano S. 115 226 257 281 Takase K. 163 Takaya H. 170 242 Taketomi T. 242 Takeuchi I. 241 Takeuchi K.. 152 241 Takeuchi R.232 Takeuchi S. 189 Takeuchi Y. 273 Talaba. A. 247 Talamas F.X.. 197 Tamaru Y. 212 Tamura H. 49 51 Tamura O. 119 276 Tamura Y. I1 1 Tan J.D.,98 Tanabe T. 156 Tanaka H. 174 Tanaka K. 78. 117 270 Tanaka M. 154 292 Tanaka S. 91 111. 212 Tanaka T. 197 Tanemura. K. 272 275 Tang B.-Z. 247 Tang S. 270 Tang Y.. 133 Tani F.. 205 Tani S. 116 Taniguchi H. 44 Taniguchi S.. 44 Tanino K.. 51 Tanko J.M.. 94 Tanner D.D.,94 173 Tanner M. 118. 271 Taschner M.J.. 295 Tashika H. 231 Tashiro M. 164 Ta-Shma R. 55 Tau S.-I. 214 Taubken N. 288 Tavani C. 156 Tawaki. S. 283 Taylor E.C.,40 48 Taylor N.J. 159 238 Taylor P.J., 62 Tazawa K..124 Tchoubar B.. 55 Teasdale A.J. 11 1 Tebben A,. 148 Teeter. M.M.,29 Teets K.A. 123 Tegenfeldt J. 239 Teixido J. 196 Telfer S.J.,23 Teller A.H. 26 Tempkin O. 122 253 Templeton. J.L. 229 Teng M. 72 Tenhaeff S.C.,220 Tensfeldt T.G. 42 Terada M. 21 I 253 Terashima. S. 138 237 Tereda. M. 108 Terrier F. 65 67 Terry M.L. 19 Tezuka M. 115 Thacher T.S. 28 Thanabal V. 5 Theim J. 287 288 Theodorakis E.A. 103 118 Theys R.D. 126 Thiebault A, 159 Thiel W. 28 Thijs L. 168 169 171 Thoma G. 124 Thomas B.E. IV 51 Thomas E.J. 112 254 Thomas J.A. 232 Thomas R.D. 217 Thomas S.E. 208 215 216 Thompson C.M. 188 Thompson D.K. 245 Thompson L.K.15 Thompson M. 194 246 Thornley D.L. 156 Thornton-Pett M. 132 Thurston D.E. 201 Tidwell T.T. 63 Tietze L.F. 45 135 Tiffin P.D. 270 273 Tildesley D.J. 26 Tillyer R.D. 122 Timofeeva T.V. 220 Titman J.J. 18 19 Toda T. 172 Todres Z.V. 246 Tohjo T. 173 Tokuhisa K. 164 Tokumaru K. 74 Tomaszewski M.J. 103 159 Tominaga N. 79 Tomioka K. 252 275 Tomioka N. 25 Toone E.J. 297 Toppet S. 46 Toppet S.M. 144 Torii S. 174 238 239 Tornero T. 149 Toru T. 124 Tost W. 45 Totleben M.J. 80 124 Tottie L. 239 Toyota M. 133 Trabsa H. 116 Trace R.L. 246 Trakarnpruk W. 220 Tramontano A. 22 Tran L. 144 Tran V.D. 239 Tran Huu Dau M.E. 47 Treptow B. 143 Triffin P.D.118 Trifunovich I.D. 93 Troisi L. 77 Troitskaya L.L. 246 Trost B.M. 109 113 135 185 21 1 213 238 239 263 276 Trucks G.W. 35 Truhlar D.G. 52 Tsai S.D. 223 Tsai Y.-C. 286 Tschantz M.F. 61 Tsuaka M. 124 Tsuchiya S. 298 Tsuchiya T. 201 Tsuda T. 233 Tsuji K. 164 Tsuji Y. 112 Tsukahara T. 241 Tsukazaki M. 157 Tsuno Y. 74 Tsushima K. 129 Tucci F.C. 113 Tucker C.E. 251 266 Tufon C. 66 155 Tumer S. 129 245 Turner N.J. 281 285 287 297 Turpin J.A. 117 270 Tustin G.J. 215 216 Tyler D.R. 220 Tyrell E. 263 Uchibori Y. 156 Uchida M. 231 Uchida Y. 241 Uchiyama D. 236 Uchiyama M. 129 227 Uda H. 135 Uemura M. 222 223 225 234 Uemura S. 159 Ueno N.235 Ueno Y. 124 Ugrak B.I. 246 Uhrin D. 8 Ujjainwalla F. 101 Ukaji Y. 257 Um I.H. 74 Umbricht G. 109 213 Umeno M. 156 Unelius C.R. 21 1 Unrau C.M. 158 Uozumi Y. 112 277 Urabe H. 239 Urmura S. 115 Uskokovic M.R. 277 Utimoto K. 101 115 Uyehara T. 119 Vaissermann J. 221 225 245 246 Van Brueck P.I. 144 Van den Eynde J.-J. 184 van der Baan J.L. 177 213 240 van der Gen A. 273 van der Louw J. 177 213 240 van der Marel G.A. 273 van der Wielen C.M. 15 van Duren P.E. 144 van Eck E.R.H. 15 van Eldik R. 219 Author Index van Fijk A.M.J. 170 van Gunsteren W.F. 21 van Haeringen C.J. 161 van Halbeek H. 8 van Helden S.P. 32 van Koten G. 108 111 van Leeuwen P.W.N.M.270 VanMiddlesworth F. 284 Vanquickenborne L.G. 43 van Rooyen P.H. 223 Van Vranken D.L. 109 213 276 van Zijl P.C.M. 11 Vargas R.M. 126 Varick T.R. 94 Varma C.A.G.O. 170 Varney M.D. 23 Varrea G. 294 Vasquez P.C. 179 Vasquez S.A. 39 Vaugh J.S. 61 Vaultier M. 168 Vawter E.J. 238 Vedejs E. 111 Vederas J.C. 171 Veeman W.S. 15 Vega S. 14 18 Velasco L. 161 Venemalm L. 183 Venkataraghavan R.,24 Venter E.M.M. 124 Ventura M. 48 Venturini S. 22 Verboom W. 70 Verdaguer X. 227 Veretenov A.L. 129 228 Vernier J.M. 231 Vernon P. 239 Vessiere R. 50 Vicente J. 228 Vichard D. 225 Vicker N. 249 Victory P.J. 196 Vidal A. 48 197 Viertler H.149 Villa M. 239 Villafranca J.E. 23 Villalgordo J.M. 169 Villiers C. 148 Vimmer Z. 283 Viiias J.M. 245 Viiias M. 228 Vincent M.A. 36 37 Vincent S.J.F. 8 Vinder V. 143 Vinkovic V. 124 Vinter J.G. 26 31 Violeau B. 154 Vitagliano A. 214 Voaden M. 272 Voerckel V. 190 Vogel C. 285 Vogel P. 133 143 Vogt W. 70 Author Index Vogtle F. 107 165 Wasylishen R.E. 13 18 Volkmann R.A. 175 Watanabe N. 127 243 Vollhardt K.P.C. 163 Watanabe S. 235 253 von Matt P. 213 Watanabe T. 158 von Philipsborn W. 216 Watanabe Y. 124 241 von Schnering H.G. 116 191 0 Waterman S. 23 Watson J. 133 Vontor T. 56 Watson W.A. 124 Vorontsova L.G. 129 228 Watts A.E. 283 Vostrowsky O. 226 Webb H.M.56 Vuister G.W. t 1 Webber S. 23 Vulfson E.N. 286 Webber S.E. 23 Weber B. 121 250 Waali E.E. 40 Weber J. 222 Waas J.R. 113 Weber M. 162 Wada M. 158 Weigel L.O.. 117 270 Wade R.C. 23 Weiner P. 31 Wadman S.N.,241 Weitkamp J. 17 Wagner G. 5 Welsh K.M. 23 Wagner P.J. 151 Welzel P. 46 Wakabayashi H. 205 Wen Y.-S. 215 Wakabayashi S. 241 Wender P.A. 137 Wakamoto A, 287 Weng X. 75 135 260 Wakamuri H. 158 Wengui D. 37 Wakefield B.J. 275 Went M.J. 225 Wakisaka A. 74 Wentrup C. 43 50 Walder L. 74 Wermuth C.G. 196 Walder P. 74 Westerhausen D. 292 Waldmann. H. 255 285 Westlake P.J. 87 Waldner A. 82 Westwell A.D. 117 Walker A.J. 108 Whelan J. 122 242 Wallace E.M. 262 Whitby R.J. 241 Wallace S.J. 282 White A.D.232 Wallbank P.J. 235 White D. 220 Wallbaum S. 108 265 266 White J. 23 Waltermire R.E. 272 White J.D. 138 263 Walton J.C. 93 129 White P.A. 229 Wan P. 68 Whitesides G.M. 285 291 Wang D. 253 298 Wang F. 161 Whitmire K.H. 242 Wang J. 48 265 Whittingham W.G. 276 Wang K.K. 105 Wiberg K.B. 35 38 Wang K.-T. 286 286 Wickens D.N. 61 Wang L. 117,269 276 Widdowson D.A. 152 184 Wang M.D. 194 220 221 Wang Q. 153 Wiemann T. 287 Wang S. 148 Wieser M. 220 Wang S.-L.,215 Wiest O. 48 Wang S.L.B. 245 Wikjord B. 69 Wang S.-Z. 212 Wilbrandt D. 233 Wang T.-F. 215 Wilde A. 214 Wang X. 116 157 Wilk B. 96 Wang X.-J. 138 Wilk B.K. 96 Wang Y. 53 129 Wilkin J.A. 161 Wang Y.M. 121 Wilkinson J.A. 278 Wang Z.-M.117 268 269 Willard P.G. 122 Warakua T. 131 Willems H.M.G. 273 Ward R.S. 148 Williams A, 55 Ward R.W. 23 Williams D.J. 138 184 208 Ward S.C. 127 258 216 220 Warkentin J. 103 159 Williams D.R. 119 Warren S. 117 212 Williams G.M. 217 Wasada H. 38 Williams J.M.J. 108 Wasserman H.H. 174 Williams P.M. 32 Williams R.M. 97 108 Willker W. 9 Willmore N.D. 161 Willoughby C.A. 119 266 Wilson K. 284 Wilson L.Y. 25 Wimmer E. 35 Winkler T. 82 Wipf P. 80 Wipff G. 31 Wishart N. 237 Wishka D.G. 190 Wiiniewski K. 223 Withers M. 33 Wittekind M. 4 Wittmer T. 97 Woerner G. 45 Woerpel K.A. 257 Woggon W.-D. 100 Wojciechowski K. 155 Wold S. 74 Wolfe S. 55 Wolff J.J. 165 Wolff M.E.22 Wollborn U. 9 Wong C.-H. 280 290 295 297 Wong F.F. 160 Wong H.N.C. 177 Wong M.W. 38 Wong-Moon K.C. 14 Wood A, 111 Wood J.L. 136 Wood W.W. 161 Woodcock S. 36 Woodgate P.D. 224 240 Woods M. 118 273 274 Woodward R.B. 108 Wooten E.W. 15 Worakun T. 240 Wovkulich P.M. 236 277 Wrackmeyer B. 9 Wu G. I8 WU,M.-C. 132 Wu M.J. 150 WU S.-H. 286 Wu W. 205 WU W.-X. 124 wu x.-L. 12 Wu Y. 84 WU Y.-D.,50 124 Wu Y.-L. 191 Wudl F. 56 Wuest J.D. 122 Wulff W.D. 244. 245 246 Wythes M.J. 11I 237 Xiao X.-Y. 200 Xu D. 117 244 268 Xu L. 127 Xu L.H. 239 xu P. 12 Xu S.L. 147 147 Xu Y. 110 237 320 Author Index Yadav J.S. 132 Yee C. 283 Zefirov N.S.179 246 Yagupol’skii Y.L. 67 Yeh M.C.P. 214 Zehnder M. 124 260 Yamabe S. 38 44 49 Yeh W.-Y. 132 Zeitz H.-G. 124 Yamada H. 212 Yerxa B.R. 186 Zelechonok Y. 95 Yamada M. 25 Yamada T. 292 Yi C.S. 214 Yi K.Y. 119 272 Zeng Z. 145 259 Zenk P. 223 Yamago S. 50 Yamaguchi K. 67 204 Yi P. 238 Yin J. 246 Zepik H.H. 161 Zeroual A, 50 Yamaguchi Y. 44 Yamaji K. 243 Yamamoto H. 52 134 256 Yamamoto I. 133 Yamamoto K. 212 Yamamoto T. 233 241 258 263 Yoda H. 292 Yokiogawa K. 295 Yokomatsu T. 276 Yokoyama M. 133 Yoneda H. 214 Yoneda T. 124 Yonesaka K.,203 Zhang B. 69 Zhang C. 146 Zhang H. 144 Zhang J. 50 Zhang Q. 75 Zhang S.-W. 241 Zhang W. 87,93 136 272 Yamamoto Y. 119 124 Yoo B. 124 260 Zhang X. 141 242 Yamanaka H. 109 231 234 Yoon C.H. 87 Zhang X.-L. 117 268 269 236 Yoon H.W.74 Zhang Y. 17 Yamane T. 281 Yoon S.K. 249 Zhang Y.-Z. 209 Yamasaki H. 168 Yamashita M. 231 Yoshida J.-i. 200 Yoshida M. 172 Zhang Z. 246 Zhao Y. 112 Yamashita R. 98 Yoshida N. 173 Zhdankin V.V. 113 Yamashita T. 150 251 Yoshida R. 183 Zhen W. 211 Yamashita Y. 91 Yoshida Z. 143 212 Zhorov E.Yu. 242 Yamataka H. 71 Yoshikoshi A. 243 Zhou D.L. 74 Yamato T. 164 Yoshino T. 74 Zhou J.-Q. 182 230 Yamauchi T. 174 Yoshioka H. 156 Zhou J.P. 129 Yamazaki S. 49 Yoshioka M. 125 257 Zhou X. 265 Yanada K. 160 Yoshitomi S. 152 Zhou Z. 229 Yanada R. 160 Young D.W. 189 Zhu P.Y. 224 Yanagisawa A. 263 Young P. 37 Zhu X.-Y. 211 Yanez M. 38 Younger G.G. 151 Zhuangyu Z. 237 Yaiiez R. 245 Yu D. 251 Ziegler T. 35 298 Yang C. 161 Yu H. 82 274 Ziglar S.K.61 Yang D.T.C. 161 Yu J.S. 150 Zilberman J. 156 Yang G.-M. 133 215 Yuan H.L. 162 Ziller J.W. 133 Yang J. 246 Yuh Y.H. 28 Ziller W. 257 Yang S. 283 Yulin J. 156 Zilm K.W. 143 Yang Y. 171 235 Yuncheng Y. 156 Zimmermann H. 18 Yang Y.-B. 286 Yus M. 254 Zimmermann K. 31 Yang Z.-Y. 108 Zinczuk J. 108 Yao T. 24 Zabrowski D.L. 85 Zipse H. 124 Yasuda M. 150 Zahouily M. 124 Zoebisch E.G. 28 Yasuhara A, 231 236 Zaidi N.A. 92 282 Zolotarev A.P. 241 Yasui K. 11 1 ZajiEek J. 214 Zoretic P.A. 75 135 260 Yasuike S. 201 Zakrzewski J. 247 Zuccarello G. 145 Yasunami M. 163 Zandbergen P. 273 Zucchelli L. 285 Yatsugi K. 74 Zanotti-Gerosa A. 245 274 Zupan M. 152 Ye T. 243 Yeates C.I.,241 Zaworotko M.J. 223 Zeerink M. 284 Zupancic N. 151 Zwahlen C. 8

ISSN:0069-3030    

DOI:10.1039/OC9928900299

出版商:RSC    

年代:1992

数据来源: RSC