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8 Organometallic Chemistry Part (i) The Transition Elements By G. R. STEPHENSON School of Chemical Sciences University of East Anglia Norwich NR4 7TJ 1 Introduction Within a single reaction sequence transition metals can be made to form a series of new bonds providing exceptionally rapid routes for use in organic synthesis. Over the last year there has been an increasing variety of methods that make successful multiple use of the transition metal. Although these reactions are not new in type so much progress has been made in this area that this topic has become the most striking feature of 1991 and so will be discussed at the start of this report. Advances have been made in both catalytic and stoichiometric methods. The former typically employ insertion reactions involving carbonyl groups alkenes and alkynes while the latter most normally use transition metal wcomplexes as electrophiles.2 Multiple Coupling Processes The most common substrates for insertions reaction are transition-metal complexes that contain both u-and .rr-bound ligands. The insertion process requires that the u-bound unit migrates to become attached to the .rr-bound unit (Scheme 1). In the 0 LnM-C=O 5Lnh4-f Id I R L’ R Scheme 1 case of carbonyl and alkene ligands this process changes the nature of the bonding between the metal and the receiving ligand. The effect is to produce a free coordina- tion site on the metal so that ligand migration is frequently accompanied by the availability of an additional ligand to drive the reaction forward by taking up the emerging coordination site.It can be seen that in both these processes bonding between the transition metal and the original r-bound ligand becomes altered to form a new u-bond. It follows that this bond can be used in a further insertion step (Scheme 2). Double Carbonyl Insertion.-An example from Tamaru’s group illustrates both of the common mechanisms for carbonyl insertion (Scheme 3). 185 G. R. Stephenson Scheme 2 OMe The initial coordination of the alkene as a palladium .rr-complex is followed by addition of the alcohol group to a carbonyl ligand. An acyl intermediate inserts into the palladium alkene .rr-bond. In this case the incoming ligand is carbon monoxide presenting the opportunity for a second carbonyl insertion step.Finally addition of methanol and reductive elimination liberates (l).' The construction of compound (2) can also be approached by a sequence of two carbonyl insertion reactions although the mechanism is probably different from the first case. Oxidative addition of palladium into the carbon-chlorine bond has been suggested as the first step in this process (Scheme 4).*Related reactions make use of the palladium ene reaction followed by ~arbonylation.~ Scheme 4 (2) 78% Carbonyl Insertions Combined with Leaving Group Displacements.-Attachment of transition metals to organic ligands through the displacement of a leaving group can provide an important initiation process in a reaction sequence. Opening of vinyl epoxides by ironcarbonyl reagents extensively developed by Ley provides a good example.Approach of the metal to the alkene linkage of vinyl epoxides is combined with oxidative addition into the carbon-oxygen bond of the adjacent epoxide unit. A recent example can be found in the synthesis of valilactone. The required relative stereochemistry was ensured by employing an alcohol to direct vanadium-catalysed epoxidation. This also permitted regioselective oxidation of the diene starting material.4 A related approach to the alkaloid isoretronecanol (3) (Scheme 5) has also been recently reported.' ' Y. Tamaru M. Hojo,and Z.4. Yoshida J. Org. Chem. 1991 56 1099. * G. Wu I. Shimoyama and E.-i. Negishi J. Org. Chem. 1991 56 6506. W. Oppolzer J.-Z. Xu,and C.Stone Helv. Chim. Acta 1991 14 465. R. W. Bates R. Fernandez-Moro and S. V. Ley Tetrahedron 1991 41 9929. J. G. Knight and S. V. Ley Tetrahedron Lett. 1991 32 7119. Organometallic Chemistry -Part (i) The Transition Elements co -(305atm) i BH 100" ii NaOH H20, 0v iii HCI 0 80% (3) Scheme 5 In a route to a-vinylidene-P-lactams Tsuji and Mandai's groups have selected the carbonate derivative of a propargyl alcohol to provide the leaving group. Initial rearrangement to an allenyl metal complex is followed by carbonyl insertion. Again an intramolecular incoming ligand (in this case the adjacent nitrogen substituent) is employed leading to the formation of the p-lactam ring in (4)by reductive elimination (Scheme 6).6 \ C6H13y* NHTs F OKoMe Ts 0 K,CO, CO(1 atm.) 71% (4) Scheme 6 C02Me C02Me HH (5) OC02Me 94% 1 o*p Pd,(dba) Ph P b PPh 2 C,H, MeOH 50-60°C Scheme 7 Vinyl substituted allenes can be used in cycloaddition reactions (Scheme 7).1,3-Dienes such as (5) result from this annulation step.' Alkyne substituted dienes can also be formed by multi-step coupling processes. An example that is targeted towards the synthesis of the A ring of neocarzinostatin begins by insertion into the vinyl halide to form an intermediate that is picked up by the alkyne to produce a new vinyl complex for reaction with a tin-substituted T. Mandai K. Ryoden M. Kawada and J. Tsuji Tetrahedron Lett. 1991 32 7683. ' T. Mandai S. Suzuki A. Ikawa T.Murakami M.Kawada and J. Tsuji Tetrahedron Lett. 1991,32,7687. G. R. Stephenson alkyne. A single alkene stereoisomer is formed in this way.8 Cyclization following addition of an allyl alcohol to ethylvinylether completes a five-membered ring. The u-bound intermediate is intercepted in a Heck-coupling reaction. This proceeds in the normal fashion with p-elimination to form an en~ne.~ This same strategy has also been employed in carbacyclin synthesis (Scheme 8). In this case an enolether intermediate is produced using palladium catalysed vinylepoxide opening but cyclization combined with the Heck-coupling step pro- duces the bicyclic compound (6)." Pd(OAc) NaI K,CO b 0.. .-TBDMSO TBDMSO 0 Scheme 8 Oppolzer has employed tandem palladium ene/ Heck insertions to form polycyclic systems." Again an allylic leaving group initiates the reaction sequence but in this case the allyl species itself is intercepted by an adjacent alkene.Three new rings are formed (Scheme 9) to create the tetracyclic product (7). Pd(dha)> b trifurylphosphine HOAc " 50% OAc Scheme 9 (7) An allylic leaving group also figures in Trost's route towards (-)-dendrobine.'* A similar cyclization has been described by Lu.13 Variants on this approach can make use of nucleophile addition to the allyl unit before coupling between alkyne and alkene group^.'^ A more unusual process effects the insertion of an alkyne between the two ends of an alkene. Cyclization to form a cyclobutene followed by ring-opening to produce a diene has been proposed to account for the course of this reaction.A relatively specialized form of catalyst has been employed. It is notable that the allylic oxygen ' J. M. Nuss B. H. Levine R. A. Rennels and M. M. Heravi Tetrahedron Lett. 1991 32 5243. R. C. Larock and N. H. Lee J. Am. Chem. Soc. 1991 113 7815. 10 R. C. Larock and N. H. Lee Tetrahedron Lett. 1991 32 5911. I' W. Oppolzer and R. J. DeVita J. Org. Chem. 1991 56 6256. I' B. M. Trost A. S. Tasker G. Ruther and A. Brandes J. Am. Chem. SOC.,1991 113 670. l3 S. Ma and X. Lu J. Org. Chem. 1991 56 5120. 14 B. M. Trost M. Lautens C. Chan C. J. Jebaratnam and T. Mueller J. Am. Chem. SOC.,1991 113 636. Organometallic Chemistry -Part (i) The Transition Elements 189 substituent is protected as a silyl derivative and so is much less able to serve as a leaving group.15 Progress in the fine details of control of palladium catalysed reactions often rely on the precise control of catalyst structure and conditions.A nice example16 is the reversal of diastereoface selectivity in the cyclization of 2-alkene ligands. Palladium catalysed electrocyclic reactions also continue to be developed. Scott’s group at Iowa have described oxyhexatriene cyclizations to produce bicyclic enones.” Much mechanistic work is necessary to unravel the control features in reactions of this type. Examples from France18 probe the rates and mechanism of reversible oxidative addition steps. A detailed exploration of the carbon-carbon bond forming step in catalytic cross-coupling involves a collaboration between Portuguese and U.K.groups.” Studies such as these are gradually mapping the precise routes of multi-step catalytic cycles of the types employed in this complex field of chemistry.20 3 Versatility of Palladium Coupling While the multiple use of coupling reactions can lead to spectacularly short routes the approach is also specialized in its application to particular classes of target molecules. The more versatile use of single-step palladium coupling is still a valuable approach. This is because of the great variety of groups that can be coupled and the impressive tolerance of this type of bond-forming reaction to the presence of other functionality within the reactants.Originally aryl halides were one of the most popular starting materials and development of these Heck-type couplings still continues. Control of reaction conditions has been employed by Jeffrey” to form either substituted allyl alcohols or ketones and aldehydes as products from the combination of aryl iodides with allyl alcohols. Selectivity is affected at the p-elimination step. A detailed examination of the control of intramolecular couplings has been made by Grigg’s group.22 In intramolecular Heck reactions addition of Tl“’ salts suppress alkene isomeri~ation.~~ Selectivity between halogen substituents provides another dimension of control. The reaction sequence leading to (8) (Scheme 10) illustrates the step-wise replace- ment first of the aryl iodide and then of the aryl bromide.24 In another case tin is distinguished from silicon by transmetallation steps prior to the palladium catalysed coup~ing.~~ Is B.M. Trost and M. K. Trost J. Am. Chem. Soc. 1991 113 1850. 16 A. Heumann L. Tottie and C. Moberg J. Chem. SOC. Chem. Commwn. 1991 218. ” C. M. Hettrick and W. J. Scott J. Am. Chem. Soc. 1991 113 4903. In C. Amatore M. Azzabi and A. Jutand J. Am. Chem. Soc. 1991 113 1670. M. J. Calhorda J. M. Brown and N. A. Cooley Organometallics 1991 10 1431. 20 A. Arcadi S. Cacchi M. Delmastro and F. Marinella SYNLETT. 1991 409; J. K. Stille H. Su D. H. Hill P. Schneider M. Tanaka D. L. Morrison and L. S. Hegedus Organometallics 1991 10 1993; T. Mandai M. Ogawa H. Yamaoki T. Nakata H. Murayama M. Kawada and J.Tsuji Tetrahedron Lett. 1991 32 3397; R. C. Larock N. G. Berrios-Pefia and C. A. Fried J. Org. Chem. 1991,56,2615; J.-M. Gaudin Tetrahedron Lett. 1991 32 6113. 21 T. Jeffrey Tetrahedron Lett. 1991 32 2121. 22 R. Grigg V. Santhakumar V. Sridharan P. Stevenson A. Teasdale M. Thornton-Pett and T. Worakun Tetrahedron 1991 47 9703. 23 R. Grigg V. Loganathan V. Santhakumar V. Sridharan and A. Teasdale Tetrahedron Lett. 1991 32 687. 24 A.-S. Carlstrom and T. Frejd J. Org. Chem. 1991 56 1289. 25 R. Rossi A. Carpita F. Bellina and M. De Santis Gazz. Chim. Ital. 1991 121 261. G. R. Stephenson C02Me i.c NHC02(CH2)2SiMe3 Br Br I =(co=Bu NH Boc ___3 Pd(OAc)> Pd(OAc), \ Bu,NCI Bu,NCI I NaHCO c NaHCO \ NHBoc DMF HBoc hydroquinone I DMF I C02Bn C02Bn Scheme 10 Cross-couplings of heteroaryl halides with arylboronic acids,26 and between iodouracil and vinyltin reagents27 have attracted the attention of industrial laboratories.A further development of this last reaction again employing an organotin co-reactant involves the use of nucleoside halides as the starting material.28 These cases illustrate the ccmpatibility of the coupling reaction with the presence of unprotected ketone and alcohol substituents in the starting materials. Highly reactive carbonyl compounds can be used. An example is the coupling of tin derivatives of quinones to form symmetrical bis-q~inones,~~ or the cross-coupling between bromonaphthoquinones and organ~stannanes.~' Both ketone and alcohol groups can be present in couplings involving halotrop~lones.~' Vinyl halides have been popular substrates.A typical example is the reaction of (9) with vinylzinc chloride (Scheme 11). Coupling in the presence of an unprotected alcohol gives a direct route to ipsenol ( Tin hydrides can be used to reduce a vinyl halide.33 Another unusual co-reactant can be seen in Scheme 12 in the formation of (1l).34 Coupling between vinyl halides and alkynes in the presence of copper iodide and the palladium catalyst is now a classic process. Enyne products are formed in this way in a reaction that is versatile in its application as seen for example in the 26 M. B. Mitchell and P. J. Wallbank Tetrahedron Lett. 1991 32 2273. 27 V.Farina and S. I. Hauck SYNLETT 1991 157. 28 M. E. Hassan Collect. Czech. Chem. Commun. 1991 56 1944. 29 L. S. Liebeskind and S. W. Riesinger Tetrahedron Lett. 1991 32 5681. 30 N. Tamayo A. M. Eschavarren and M.C. Paredes J. Org. Chem. 1991 56 6488. 31 H. Horino T. Asao and N. Inoue Bull. Chem. SOC.Jpn. 1991,64 183; M. G. Banwell J. M. Cameron M. P. Collis G. T. Crisp R. W. Gable E. Hamel J. N. Lambert M. F. Mackay M. E. Reum and J. A. Scoble Aust. J. Chem. 1991 44 705. 32 S. Hara and A. Suzuki Tetrahedron Lett. 1991 32 6749. 33 M.Taniguchi Y.Tdkeyama K. Fugami K. Oshima,and K. Utirnoto Bull. Chem. SOC. Jpn. 1991,64,2593. 34 K. Hartke H.-D. Gerber and U. Roesrath Liehigs Ann. Chem. 1991 903. 191 Organometallic Chemistry -Part (i) The Transition Elements (11) 60-90% Scheme 12 work of Alami and Lin~trumelle.~~ A similar example shows the use of an unprotected carboxylic acid deri~ative.~~ The reaction is popular in the formation of enediynes as seen in routes to dynemicin.Two examples of this have recently been rep~rted.~’ Selectivity between halogens can be seen in vinyl examples. Formation of fluorine-substituted enynes occurs in the reaction between difluorovinyliodides and alkyne~.~~ Fluorine sub- stituents on arenes can also easily be retained.39 In a further example directed towards enediynes a vinyltin co-reactant was used with the alk~ne.~’ Again selec- tivity of reaction can be seen as in the replacement of tin in the presence of enolethers:’ and organosulfur derivative^.^^ In this latter example a vinyl triflate reagent has been employed as the co-reactant.Organotriflate reagents have been receiving particular attention over the year. A typical application is again targeted at nucleoside synthesis. In this case the vinyl group is introduced by Heck-type coupling to the heterocyclic ring. There is no need for a halogen in the heter~cycle.~~ Coupling with enol acetates also proceeds in a Heck fashion to produce an acetoxydiene.a Coupling between enol triflates and alkyne derivatives is another effective process. Alkynyltin reagents can be similarly used as the co-rea~tant.~~ Scheme 13 In a further case (Scheme 13) the normal copper mediated process is employed to replace two triflate groups in the same structure to form the bis alkyne (12).46 Another example (Scheme 14) employs triethylamine again a typical reaction condition.In this case laY25-dihydroxyvitamin D3 precursor ( 13) is produ~ed.~’ 35 M. Alami and G. Linstrumelle Tetrahedron Lett. 1991 32 6109. 36 A. Arcadi S. Cacchi M. Delmastro and F. Marinella SYNLEn 1991 409. 37 T. Nishikawa A. Ino M. Isobe and T. Goto Chem. Lett. 1991 1271; T. Nishikawa M. Isobe and T. Goto SYNLETT. 1991 393. 38 Z.-Y. Yang and D. J. Burton J. Fluorine Chem. 1991 53 307. 39 C. Pugh and V. Percec Chem. Mater. 1991 3 107. 40 P. A. Magriotis M. E. Scott and K. D. Kim Tetrahedron Lett. 1991 32 6085. 41 J.-B. Verlhac M. Pereyre and H. A. Shin Organometallics 1991 10 3007. 42 V. Farina and S. I.Hauck J. Org. Chem. 1991 56 4317. 43 M. E. Hassan Can. J. Chem. 1991 692 198. 44 P. G. Ciattini E. Morera and G. Ortar Tetrahedron Lett. 1991 32 1579. 45 1. N. Houpis Tetrahedron Lett. 1991 32 6675. 46 J. Suffert and R. Briickner Tetrahedron Lett. 1991 32 1453. 47 J. L. Mascareiias L. A. Sarandeses L. Castedo and A. Mouriiio Tetrahedron 1991 47 3485. G. R. Stephenson 91% TBSO‘ (13) Scheme 14 Coupling between vinyl triflates and alkynes under these conditions can be combined with carbonyl in~ertion.~’ The combination of triflate and tin methods has been receiving attention from Farina and Roth at Bristol-Myers Sq~ibb.~~ Aryl triflates have been popular in the Heck-coupling process. In Cabri’s group in Milan the reaction has been applied to anthraquinone derivatives.” Similar couplings have employed trimethylsilylketene acetals51 and furan derivative^^^ as the co-reactants.A less common reaction has been described by Aoki and Nakarn~ra.~~ Here an aryl triflate is used to effect opening of a disubstituted cyclopropane with concomitant carbonyl insertion. There are alternatives to the use of triflates. Roth and Fuller have used aryl fluor~sulfonates,~~ while mesolates have been employed in Scott’s group,55 and by Suz~ki.~~ In the examples encountered so far two main strategies have been employed for regiocontrol. The simplest is the direct replacement of a substituent in the coupling step by insertion at the point of attachment to the substrate. The second case occurs in the Heck reaction where a u-bound organometallic intermediate is intercepted by an alkene in a step that is followed by p-elimination.A third approach for regiocontrol employs adjacent groups in ortho-metallation. Direct ortho-metallation can occur in some palladium catalysed couplings as seen in the combination of 48 P. G. Ciattini E. Morera and G. Ortar Tetrahedron Lett. 1991 32 6449. 49 V. Farina and G. P. Roth Tetrahedron Letr. 1991 32 4243. 50 W. Cabri 1. Candiani S. DeBernardinis F. Francalanci S. Penco and R. Santi J. Org. Chem. 1991 56 5796. 51 C. Carfagna A. Musco G. Sallese R. Santi and T. Fiorani J. Org. Chem. 1991 56 261. 52 W. A. Christofoli and B. A. Keay Tetrahedron Letr. 1991 32 5881. 53 S. Aoki and E. Nakamura Tetrahedron 1991 47 3935.54 G. P. Roth and C. E. Fuller J. Org. Chem. 1991 56 3493. 55 C. M. Hettrick J. K. Kling and W. J. Scott J. Org. Chem. 1991 56 1489. 56 T. Matsumoto T. Hosoya M. Katsuki and K. Suzuki Tetrahedron Letr. 1991 32 6735. Organometallic Chemistry -Part (i) The Transition Elements 193 2-aryloxazoline derivatives with alkyl and vinyl halides.57 In similar reactions aldehydes can be protected as imines. In an example described by Jendralla,58 coupling with Grignard reagents is followed by hydrolysis to reveal the substituted arylaldehyde. 4 Alternatives to Palladium in Coupling Reactions The coupling between Grignard reagents and vinyl bromides can be affected using nickel catalysts. In an example from the work of Hosomi’s group dienes for use in Diels- Alder cycloadditions are obtained.59 Another nickel catalysed process effects the symmetrical coupling of halopyrimidines.60 Rhodium complexes are best known as hydrogenation and rearrangement catalysts (as described in the next section) but they are also capable of catalysing head-to-head dimerizations of enones,61 and the photolytic combination of alkynes with unacti- vated arenes.62 Ruthenium has also received attention in coupling reactions.Alkynes and alkenes can be combined to form trisubstituted dienes provided the alkene carries an electron withdrawing An alternative route to dienes is found in the dimerization of phenylethyne also a ruthenium catalysed 5 Hydrogenation Hydrosilation Hydroformylation Hydroboration and Hydrocyanat ion Work on homogeneous hydrogenation catalysts now focuses on selectivity.Arene tricarbonylchromium complexes are attractive when 1,4-hydrogenation of dienes is required. This process has been applied to control the exocyclic alkene stereochemistry in (14) in a route to carbocyclin and its analogues (Scheme 15).65 Selective hydrogenation of alkenes in the presence of aldehyde and ketone groups still receives attention.66 In another case selective reduction of the alkene in an C02Me (Co2Me THPO’dT.... Scheme 15 57 J. C. Clinet and G. Balavoine J. Organomet. Chem. 1991 405 C29. sn H.Jendralla Liebigs Ann. Chem. 1991 295. 59 A. Hosomi T. Musunari Y. Torninaga and M. Hojo Bull. Chem. SOC.Jpn. 1991 64 1051. 60 J.Nasielski A. Standaert and R. Nasielski-Hinkens Synth. Comm. 1991 27 901. I. P. Kovalev Y. N. Kolrnogorov Y. A. Strelenko A. V. Ignatenko M. G. Vinogradov and G. I. Nikishin J. Organomet. Chem. 1991 420 125. 62 W. T. Boese and A. S. Goldrnan Organometallics 1991 10 782. 63 T. Mitsudo S.-W. Zhang M. Nagao and Y. Watanabe J. Chem. Soc. Chem. Commun. 1991 598. 64 A. M. Echavarren J. Lbpez A. Santos and J. Montoya J. Organomet. Chem. 1991 414 393. 65 M. Sodeoka Y. Ogawa Y. Kirio M. Shibasaki and T. Iirnori Chem. Pharm. Bull. 1991,39,309 and 332. 66 V. V. Grushin and H. Alper Organometallics 1991 10 831. 194 G. R. Stephenson a,a-unsaturated aldehyde is performed in the presence of another alkene unit within the Polyenes too can survive.This is illustrated in the ruthenium catalysed reduction of retinal to retino1.68 Alper has employed homogeneous rhodium catalysts for the reduction of acid chloride^.^^ Examples of hydrosilation of alkenes have used cobalt ruthenium and rhodium catalyst^.^' Hydrosilation of an alkyne using a more unusual platinum catalyst has also been )reported. 71 Hydroformylation has been applied by a number of groups in amino acid synthesis. In an example that uses cobalt catalysis either aldehyde or alkene starting materials can be employed.72 Another cobalt catalysed case produces a proline derivative by isomerization of the alkene prior to insertion of the carbonyl In a further example carbonylation and amidocarbonylations are performed in the presence of a cyclopropane ring.74 Stereoselective rhodium catalysed hydroformylation has been described by Jack- son et a175An unusual cyclization has been described in a reaction sequence that commenced with rhodium catalysed hydrof~rmylation.~~ simple examples In regiocontrol is the issue.Neibecker and Reau have described examples of selective rhodium catalysed hydroformylation of ethyl a~rylate.~~ Binap remains popular for asymmetric reduction. A recent example comes from the work of Taber and Sil~erberg.~' New chiral auxiliaries are being developed for asymmetric hydrosilation. Brunner has employed chelating oxazolidinopyridine derivative^.^^ In Helmchen's laboratory similar systems with C2 symmetry have been explored." Another approach would be to employ a chiral metal atom.Brunner has reported the synthesis of a catalytically active intermediate in the hydrosilation of acetophenone.81 In studies on asymmetric hydroboration of 1,3-dienes Matsumoto and Hayashi have achieved good results again using the Binap catalyst.82 Oxidative work-up afforded 1,3-diols from the diene starting materials. In an extension of the Binap concept Baker and Pringle have produced diphosphites containing three chiral binaphthyl units.83 Chelating diphosphine complexes are effective for hydro- ~yanation.'~ 67 S.-Y. Zhang L.-F. Wang M.-M. Gu and X. Gao Youji Huaxue 1991 11 306. 68 G. Allmang F. Grass J. M. Grosselin and C. Mercier J. Mol. Catal. 1991 66 L27. 69 V. V. Grushin and H. Alper J. Org. Chem. 1991 56 5159.70 Y. Seki K. Kawamoto N. Chatani A. Hidaka N. Sonoda K. Ohe Y. Kawasaki and S. Murai J. Organomet. Chem. 1991 403 73. 71 A. Herunsalee M. Isobe and T. Goto Tetrahedron 1991 47 3727. 72 Y. Amino and K. Izawa Bull. Chem. SOC.Jpn. 1991 64 613. 73 Y. Amino S. Nishi and K. Izawa Bull. Chem. SOC.Jpn. 1991 64 620. 74 Y. Amino and K. Izawa Bull. Chem. SOC.Jpn. 1991 64 1040. 7s W. R. Jackson P. Perimutter G.-H. Suh and E. E. Tasdeler Aust. J. Chem. 1991 44 951. 76 I. Ojima A. Korda and W. R. Shay J. Org. Chem. 1991 56 2024. 77 D. Neibecker and R. Rkau New J. Chern. 1991 15 279. 78 D. F. Taber and L. J. Silverberg Tetrahedron Lett. 1991 32 4227. 79 H. Brunner and P. Brandl Tetrahedron Asymmetry 1991 2 919. 80 G. Helmchen A.Krotz K.-T. Ganz and D. Hansen SYNLETT. 1991 257. 81 H. Brunner and K. Fisch J. Organomet. Chem. 1991,412 C11. 82 Y. Matsumoto and T. Hayashi Tetrahedron Lett. 1991 32 3387. 83 M. J. Baker and P. G. Pringle J. Chem. SOC.,Chem. Commun. 1991 1292. 84 M. J. Baker K. N. Harrison A. G. Orpen P. G. Pringle and G. Shaw J. Chem. SOC.,Chem. Commun. 1991 803. Organometallic Chemistry -Part (i) The Transition Elements 6 Alkyne Cyclotrimerization and Related Processes Over the last year there has been a renaissance of interest in alkyne cyclotrimerization reactions. A detailed investigation of indium phosphine complexes by variable temperature NMR spectroscopy has identified an q4 arene complex as an intermedi- ate in the cyclotrimerization reaction.85 Ruthenium carbonyl catalysts can also affect cyclotrimerization.86 Nickel catalysts have been used in a co-cyclization (Scheme 16) that forms the tricyclic product (15).87 0 GO -=-CO,Me +G -=-C02Me CO,Me (15) 78% Scheme 16 An alternative route has been explored by Huffman and Liebeskind who combined cyclobutenones with alkynes under nickel catalysis to produce substituted phenols.88 A nickel catalyst has also been used to combine three molecules of malononitrile to form a pentasubstituted ~yridine.~~ Palladium catalysts can perform a different type of cyclization (Scheme 17).This reaction is related to the multi-step processes discussed in Section 2. A vinyl halide and two alkynes can be cyclized to produce tricyclic arenes such as (16)90 and (17).9' COzEt (16) 61% Et OH PPh Cul Et,N OH (17) 81% Scheme 17 85 C.Bianchini K. G. Caulton C. Chardon 0.Eisenstein K. Folting T.J.Johnson A. Meli M. Peruzzini D. J. Rauscher W. E. Streib and F. Vizza J. Am. Chem. Soc. 1991 113 5127. 86 E. Lindner and H. Kiihbauch J. Organomel. Chem. 1991,403 C9. 87 P. Bhatarah and E. H. Smith J. Chem. Soc. Chem. Comrnun. 1991 277. 88 M. A. Huffman and L. S. Liebeskind J. Am. Chem. Soc. 1991 113 2771. 89 G. Lbpez G. Sanchez G. Garcia J. Ruiz J. Garcia M. Martinez-Ripoll A. Vegas and J. A. Hermoso Angew. Chem. Int. Ed. Engl. 1991 30 716. 90 F. E. Meyer and A. de Meijere SYNLETT. 1991 777. 91 S. Torii H. Okumoto and A. Nishimura Tetrahedron Lett.1991 32 4167. 196 G. R. Stephenson Cobalt catalysts provided the original conditions for cyclotrimerization. Newer versions of the cobalt catalysed reaction now combine two alkynes and an alkene to form cyclohexadienes. This has been used in a synthesis of illudol (Scheme 18) using the intermediate (18).92 The CuC12 serves to remove the cobalt from the ~~-diene complex produced by the cyclotrimerization. OTBDMS v OTBDMS I Cpco(co)2 b ii CuCI (18) 92% Scheme 18 The same approach has been used in the construction of the stemodane framew~rk,~~ and in cyclizations elaborating uracyl derivative^.^^ These cyclizations employ C~CO(CO)~ as catalyst though in the last case the use of CpCo(C2HJ2 was also examined. 7 Cyclization of Carbene Complexes with Alkynes An alternative route to aromatics combines an alkyne carbon monoxide and vinyl or aryl carbenes.The original version of this process was the Dotz cyclization reactions leading to the formation of hydroquinones. (See a recent review by Grotjahn and Dotz.’’) Opportunities to employ the process are revealed by the 1,4-dioxygenation pattern on the aromatic ring. In particular one phenolic group in the product must be present in the free form while the other is formed as an ether derivative. Recent examples using chromium tungsten and molybdenum carbenes have been described. Selectivity between routes to quinones [e.g. ( 19)],96 and indanones [e.g. (20) which lack the carbonyl insertion step] have been examined (Scheme 19).97A similar theme appears in recent work by Wulff9* in his attempts to gain access to daunomycinone derivatives.Q~ayle~~ has examined this type of cyclization reaction as a route to oxasteroids. In a modification of this procedure (Scheme 20) Merlic and Xu”’ have replaced the alkyne component by a two atom extension of the .rr-system of the carbene. The result is the formation of ortho-dioxygenated aromatic products such as (21). 92 E. P. Johnson and K. P. C. Vollhardt J. Am. Chem. Soc. 1991 113 381. 93 J. Germanas C. Aubert and K. P. C. Vollhardt J. Am. Chem. SOC.,1991 113 4006. 94 R. Boese J. Rodriguez and K. P. C. Vollhardt Angew. Chem. Int. Ed. EngL 1991 30,993. 95 D. B. Grotjahn and K. H. Dotz SYNLEn. 1991 381. 96 K.H. Dotz and V. Leue J. Organorner. Chem. 1991 407 337. 97 K. H. Dotz and H. Larbig J. Organomet. Chem. 1991 405 C38. 98 M. E. Bos W. D. Wulff R. A. Miller S. Chamberlin and T. A. Brandvold J. Am. Chern. SOC.,1991 113 9293. 99 J. D. King and P. Quayle Tetrahedron Lett. 1991 32 7759. 100 C. A. Merlic and D. Xu J. Am. Chem. SOC.,1991 113 7418. Organometallic Chemistry -Part (i) The Transition Elements 0 i -SiMe ,MewsiMe3 ii Ce'" ij (19) 69% OMe 0 (20) 53% Scheme 19 87% 42% (21) Scheme 20 Other Products from Carbene Insertions.-By omitting the vinyl substituent on the carbene other reaction pathways become available such as those described by Rudler which lead ultimately to the formation of a furan (22) (Scheme 21)."' Ph NMePh (22) Scheme 2 1 This reaction appears to proceed initially uia a nitrogen heterocycle and leaves the tricarbonylchromium group attached in an q6 fashion to the N-methylaniline substituent.These reaction pathways have been explored in detail."* Wulff's research group has examined methods to divert the normal course of the vinyl carbene cycli~ations.'~~ Depending on the nature of the substituent stabilizing the Fischer carbene either bicyclic aromatic products (23) or tricyclic heterocycles (24) can be obtained (Scheme 22). I01 H. Rudler A. Parlier R. Gournont J. C. Duran and J. Vaissermann J. Chem. SOC.,Chem. Commun. 1991 1075. B. Denise P. Dubost A. Parlier M. Rudler H. Rudler J. C. Daran J. Vaissermann F. Delgado A.R. Arevalo R. A. Toscano and C. Alvarez J. Organomet. Chem. 1991,418 377. '03 T. A. Brandvold and W. D. Wulff J. Am. Chem. SOC.,1991 113 5459. G. R. Stephenson XR = 0Me:l 1 65% XR = N-morpholino 1 :3 81% Scheme 22 In routes to naphthoquinones and indanones Dotz and Larbig have studied the control of reactions of molybdenum carbene cornplexe~.'~~ There has been much attention given to aminocarbenes. Both dot^'^' and Hegeduslo6 have been exploring new routes to aminocarbenes and new methods to employ them in synthesis. The groups of Harvey'" and Katz108 have examined the addition of Fischer carbene complexes to a,w-enynes. Bicyclic cyclopropanes can be obtained in this way. An intermolecular version of the reaction has also been exp10red.l~' With a carbocyclic system further rearrangements have been induced using Lewis acids."' A more unusual route to extended polyenic carbenes has been described by Le Bozec Coset and Dixneuf who effects the direct combination of an alkyne with a metal hexacarbonyl."' Direct cyclopropanation of one alkene linkage within a diene has also been described.lI2 Closure of amino carbenes to alkenes produces heterocyc- lic ~ysterns."~ When a cyclopropane ring is included within the carbene portion cyclization with alkynes produces enones.Both 5-114 and 7-"' membered-ring products have been obtained. 8 Cyclization of Alkyne Complexes with Alkeoes Carbonyl insertion offers interesting possibilities for an unusual cyclopentenone synthesis in which carbon monoxide an alkene and an alkyne are coupled together.This can be achieved using the now well known Pauson-Khand reaction in which a dicobalt alkyne complex is heated with the alkene and carbon monoxide. An important recent development of this reaction combines the Pauson-Khand pro-cedure with the use of cobalt-stabilized propargyl cations in the preparation of the substrate for the cyclization step. 104 K. H. Dotz and H. Larbig J. Organomet. Chem. 1991 405 C38. K. H. Dotz and A. Rau J. Organomet. Chem. 1991 418 219. 106 M. A. Schwindt J. R. Miller and L. S. Hegedus J. Organomet. Chem. 1991 413 143. 107 D. F. Harvey K. P. Lund and D. A. Neil Tetrahedron Lett. 1991 32 6311. 1ox T. J. Katz and G. X.-Q.Yang Tetrahedron Lett. 1991 32 5895.109 D. F. Harvey and M. F. Brown Tetrahedron Left. 1991 32 5223. 110 D. F. Harvey and M. F. Brown Tetrahedron Len. 1991 32 2871. 111 H. Le Bozec C. Cosset and P. H. Dixneuf J. Chem. Soc. Chem. Commun. 1991 881. 112 D. F. Harvey and K. P. Lund J. Am. Chem. Soc. 1991 113 8916. 113 E. Chelain A. Parlier H. Rudler J. C. Daran and J. Vaissermann J. Organomet. Chem. 1991,419 C5. I I4 J. W. Herndon and S. U. Turner J. Org. Chem. 1991 56 286. I15 J. W. Herndon G. Chatterjee P. P. Patel J. J. Matasi S. U. Turner J. J. Harp and M. D. Reid J. Am. Chem. SOC.,1991 113 7808. Organometallic Chemistry -Part (i) The Transition Elements A typical example (Scheme 23) of a Pauson-Khand reaction is provided by the intramolecular carbonyl insertion leading to bicyclic products [ e.g.(23)].lt6 Good nucleophilic centres next to the site where the alkyne complex will be required provide the clue for the use of the double cobalt-mediated process. (co),co-co(co), '-' Scheme 23 The analogous process employing zirconium has been used by Negishi in a route to pentalenic acid (24).' l7 Stereoselectivity in the cyclization step sets up stereocon- trol throughout the reaction sequence (Scheme 24). Another alternative can be seen in Pearson's use of organoiron complexes to effect cyclopentenone synthesis; v4-cyclopentadienone complexes can be formed when bis-alkynes are used as sub- strates."' SiMe3 qz-SiMe3 ii,c0-200 i BnLi/Cp,ZrCI (1.1 am.) wo 68% BnO BnO I steps COZH (24) Scheme 24 Control of intermolecular Pauson-Khand reactions has always been a more difficult problem.Kram has examined the directing effect of heteroatom substituents on the alkene c~mponent."~ A successful case is illustrated by the formation of (25) (Scheme 25). A modification of the normal reaction sequence involving attachment of the heteroatom to a cobalt centre has been proposed. Schore has been examining applications of intermolecular Pauson-Khand processes in particular the cycload- duct obtained from norbornadiene and a propyne.'*' I16 N. Jeong S.-e. Yoo S. J. Lee S. H. Lee and Y. K. Chung Tetrahedron Lett. 1991 32 2137. I17 G. Agnel and E.-i. Negishi J. Am. Chem. Soc. 1991 113 7427. I I8 A. J. Pearson and R. A. Dubbert J.Chem. Soc. Chem. Commun. 1991 202. 1 I9 M. E. Krafft C. A. Juliano 1. L. Scott C. Wright and M. D. McEachin J. Am. Chem. SOC.,1991 113 1693. I 20 S. E. MacWhorter and N. E. Schore J. Org. Chem. 1991 56 338. 200 G. R. Stephenson SiMe 0 I + OSiMe2Bu' (25)79% L Scheme 25 The rate of the Pauson-Khand reaction has been much improved by use of N-oxides to detach a carbonyl ligand to make room for the incoming alkene.12' In principle the Pauson-Khand reaction should be catalytic in the metals. In practice however stoichiometric amounts of the dicobalt unit are normally employed. A catalytic version of the reaction has at last been described by Rauten- strauch though this is not a general procedure since it relies on the use of particularly reactive substrates.'22 In cases where stoichiometric organometallic units are employed the most advan- tageous procedures make multiple use of the transition metal centre.Routes to fenestrane intermediates provide a good example in which the synthetic plan employs a Pauson-Khand cyclization to produce an enone substrate- for a photochemical [2 + 21 ring closure to complete the tetracyclic unit. Thus the precursor for the Pauson-Khand step contains a metal-bound alkyne and two potential alkene partners in the reaction. Regioselectivity of the Pauson-Khand step depends on the ring sizes and substitution patterns of the starting materials. Propargyl cation chemistry has been put to good use in this reaction sequence providing a convenient method to introduce the second alkene chain by a carbon-oxygen bond formation so making multiple use of the metals.'23 Four fused carbocyclic five-membered rings have been completed using an amine-oxide promoted Pauson-Khand reaction to close the final ring.'24 The tetracyclic diketone (26) provides an illustration of the benefits in synthesis design that can arise from the multiple use of the transition metal unit.The Pauson-Khand process shown in Scheme 26 is an obvious disconnection for the tetrasubstituted cyclopentenone ring. This approach would place the alkyne com- ponent in the starting material at the position of the alkene linkage in (26). The alkoxy substituent at the adjacent ring junction could be introduced as a nucleophile to a cobalt stabilized propargyl cation.This suggested a strategy for the introduction of the second carbonyl group by acylation of an electrophilic enyne complex.'25 121 N. Jeong Y. K. Chung B. Y. Lee S. H. Lee and S.-E. Yoo SYNLEn. 1991 204. 122 V. Rautenstrauch P. Megard J. Conesa and W. Kiister Angew. Chem. Int. Ed. Engl. 1991 29 1413. 123 W. A. Smit S. M. Buhanjuk S. 0. Simonyan A. S. Shashkov Y. T. Struchkov A. I. Yanovsky R. Caple A. S. Gybin L. G. Anderson and J. A. Whiteford Tetrahedron Lett. 1991 32 2105. 124 M. Thommen P. Gerber and R. Keese Chimia 1991 45 21. 125 A. L. Veretenov W. A. Smit L. G. Vorontsova M. G. Kurella R.Caple and A. S. Gybin Tetrahedron Lett. 1991 32 2109. Organometallic Chemistry -Part (i) The Transition Elements 201 0 TA ii MeOH iii 60 "C (oc)~co-co(co)3 Scheme 26 Stereoselectivity is one of the advantages of the Pauson-Khand reaction.In a route to pentalenic acid stereocontrol in the cyclization to form three fused five- membered rings has been examined in Three of the four possible stereoisomeric products are obtained but the two major products possess the necessary exo-methyl substituent for elaboration into pentalenic acid. Enantioselec- tive routes to starting materials for the cyclization step are of particular value because of the stereoselectivity of the subsequent reaction. In an examination by Roush and Park,'27 asymmetric allylboration of aldehyde substituents in dicobalt alkyne com- plexes prepares for a highly diastereoselective intramolecular Pauson-Khand reaction.Two variants on the Pauson-Khand reaction are also of note. Takahashi's group'28 has examined a carbonylation of diphenylethyne under the water gas shift conditions to effect carbonylation to form an indanone. It is interesting to compare these processes with the cobalt mediated reactions developed by which combine acid chlorides and alkynes under the action of the tetracarbonylcobalt anion (Scheme 27). Substituted butadienolides for .example (27) are obtained in this way. (27) 84% Scheme 27 There is now a simple synthesis of both dicobaltoctacarbonyl and sodium tetra- carbonylcobalt by reduction of cobalt chloride under carbon monoxide at atmos- pheric pressure.'30 I26 E. G. Rowley and N. E. Schore J.Organomet. Chem. 1991 413 C5. 127 W. R. Roush and J. C. Park Tetrahedron Lett. 1991 32 6285. I28 T. Joh K. Doyama K. Fujiwara K. Maeshima and S. Takahashi Organometallics 1991 10 508. 129 M. E. Krafit and J. Pankowski SYNLEm.. 1991 865. 130 A. Devasagayaraj S. A. Rao and M. Periasamy J. Organomet. Chem. 1991 403 387. 202 G. R. Stephenson 9 Rhodium Carbene Complexes Much progress has been made with multiple reaction sequences employing rhodium carbene complexes. Padwa has examined reactions that combine a diazoketone with an alkyne (Scheme 28). Relatively complicated structures such as (28) and (29) can be formed by a series of metal catalysed processes initiating from carbene addition to the a1k~ne.l~~ 0 Me0 0 Scheme 28 Simple adducts from rhodium carbene addition to alkynes have also been obser- ved.A nitro-substituted cyclopropene has been obtained by the addition of a nitro-substituted carbene complex to an alkyne.l3* Padwa's group has examined the rearrangements of intermediate acyl-substituted cyclopropenes as a route to fur an^.'^^ In another example a bridged dihydrofuran is formed.134 Vinyl-substituted carbene complexes cyclize with dienes to form a variety of seven-membered ring systems.'35 The reaction has been applied to provide a versatile synthesis of tr~pones.'~~ A related cyclization is used in a route to pyrr~les.'~~ A detailed examination of the mechanisms of rhodium catalysed additions to alkynes has been performed. 13* These reactions commence by cyclopropanation.A highly enantioselective cyclopropanation reaction has been performed using a novel chiral dirhodium catalyst.139 A more conventional example cyclopropanation has been performed using transition metal salts of soluble polyethylene carbo~ylates.'~~ 13' A. Padwa K. E. Krumpe Y. Gareau and U. Chiacchio J. Org. Chem. 1991 56 2523. 132 P. E. O'Bannon and W. P. Dailey J. Org. Chem. 1991 56 2258. 133 A. Padwa J. M. Kassir and S. L. Xu J. Org. Chem. 1991 56 6971. I34 A. Padwa R. L. Chinn S. F. Hornbuckle and Z. J. Zhang J. Org. Chem. 1991 56 3271. 135 H. M. L. Davies T. J. Clark and H. D. Smith J. Org. Chem. 1991 56 3817. I36 H. M. L. Davies T. J. Clark and G. F. Kimmer J. Org. Chem. 1991 56 6440. 137 H. M. L.Davies E. Saikali and W. B. Young J. Org. Chem. 1991 56 5696. 138 T. R. Hoye and C. J. Dinsmore J. Am. Chem. Soc. 1991 113 4343. I39 M. P. Doyle R. J. Pieters S. F. Martin R. E. Austin C. J. Oalmann and P. Miiller J. Am. Chem. Soc. 1991 113 1423. 140 D. E. Bergbreiter M. Morvant and B. Chen Tefruhedron Lett. 1991 32 2731. Organometallic Chemistry -Part (i) The Transition Elements 203 Rhodium carbene complexes offer considerable versatility. Beside additions to alkenes and alkynes insertion into other bonds can be achieved. Examples include insertion into OH bonds,14' a reaction that has been employed to construct the skeleton of is~laurepinnacin.'~~ Further examples of cyclizations form bicyclic P-lactone~.'~~ Cases involving ally1 thioethers leave exocyclic alkenes in the prod- ucts.'44 The scope of this reaction in a variety of ring sizes has been examined.*45 10 Other Applications of Carbene Complexes Cationic carbene complexes have also been studied extensively in cyclopropanation reactions.Considerable effort has been expended on enantioselective versions of these reactions. A detailed mechanistic analysis has identified key features of the rea~ti0n.I~~ In a separate study the stereochemistry of the iron-carbon bond cleavage step has been ~r0bed.l~' Much of the motivation in this work is the synthesis of chiral complexes for application as new reagents. Routes using hydride and alkoxide abstraction have been reported.'48 Iron acyl complexes can be made to form metallocyclic carbene derivatives by photolysis.These neutral species can undergo further rearrangements to form cationic produ~ts.'~~ Cationic vinylidine complexes have been converted into metal- substituted cycl~butenes.'~~ In the case of ruthenium analogues the intermediates have been examined as electrophiles in reactions with n~cleophiles.'~' Analogous osmium-substituted compounds react with alcohols in a similar way.'52 An unusual reaction that forms q4-dihydropyridine complexes commences with a tricarbonyliron complex with q2-alkene and carbene moieties bound to the iron atom.'53 11 Electrophilic .rr-Complexes q2-Complexes.-A palladium catalysed cyclization provides an example of an q2 alkene complex as an electrophile. The overall process forms two carbon-carbon bonds combining an alkyl halide an alkene and a nucleophilic centre.Oxidative addition of the alkyl halide to the palladium complex is followed by coordination of the alkene. The resulting electrophilic .rr-complex undergoes reaction with the nucleophilic centre producing a a-bound metal complex which affords the organic product (30) by reductive elimination (Scheme 29).ls4Alkyne complexes of rhenium have also been examined.'55 Iron q2complexes have been most extensively studied. 141 M. J. Davies C. J. Moody and R. J. Taylor J. Chem. SOC.,Perkin Trans. 1 1991 1. 142 M. J. Davies and C. J. Moody J. Chem. SOC.,Perkin Trans. 1 1991 9. 143 M. A. Williams C.-N. Hsiao and M. J. Miller J. Org. Chem. 1991 56 2688. 144 F.Kido T. Abiko A. B. Kazi M. Kato and A. Yoshikoshi Heterocycles 1991 32 1487. 145 F. Kido Y. Kawada M. Kato and A. Yoshikoshi Tetrahedron Lett. 1991 32 6159. 146 M. Brookhart Y. Liu E. W. Goldman D. A. Timmers and G. D. Williams J. Am. Chern. SOC. 1991 113 927. 147 M. Brookhart and Y. Liu J. Am. Chem. SOC. 1991 113 939. 148 M.-J. Tudoret V. Guerchais and C. Lapinte J. Organomet. Chem. 1991 414 373. I49 S. Tivakornpannarai and W. M. Jones Organometallics 1991 10 1827. 1 50 D. Bauer P. Harter and E. Herdtweck J. Chem. SOC. Chern. Commun. 1991 829. 151 S. G. Davies and A. J. Smallbridge J. Organornet. Chem. 1991 413 313. 152 W. Knaup and H. Werner J. Organomet. Chem. 1991,411 471. 153 R. Aumann B. Trentmann C. Kruger and F. Lutz Chem. Ber.1991 124 2595. 154 G. Fournet G. Balme and J. Gore Tetrahedron 1991 47 6293. 15' J. J. Kowalczyk A. M. Arif and J. A. Gladysz OrganometaNics 1991 10 1079. G. R. Stephenson Me Ph i Bu'O-ii Ph-I C02Me C02Me Pd(dba) 71% -&:.;.. (30) Scheme 29 A new method for the preparation of cationic Fe(CO)*Cp complexes that involves a carbon-carbon bond formation has been explored. Lewis acid catalysed addition of ketones to T~ allyl complexes hold the key to this rea~ti0n.l~~ A more unusual cobalt alkene complex has been reported. A tetradentate phosphine ligand occupies four of the five possible sites around the metal system; the alkene takes up the fifth (axial) coordination ~ite.'~' In cases where the metal atom bound to the alkene is chiral detailed studies of conformational effects have been underway.Examples involving organomolyb- denum complexe~,'~~ and a continuation of Gladysz's studies on rhenium nitrosyl complexes'59 provide typical examples. Gladysz16* has also continued the investiga- tions of T~ ketone complexes while SuttonI6l has explored C-H activation in alkene complexes to give allyl hydrido derivatives. Electrophilic properties at positions adjacent to dicobalt alkyne complexes still attract attention. Nicholas has shown'62 that substituted furans are useful nucleophiles with propargyl cation complexes to afford products that can be conver- ted into lactone derivatives. Lewis acid catalysed aldol chemistry has also been examined as a key step in a synthesis of the chromophore A core of neocarzino- tati in.'^^ Alcohol leaving groups have been employed in enediyne synthesis.In this way Tf20 has been used to catalyse a cyclization in an entry to the dynemicin core.'64 A similar route has been used in a partially saturated series which is oxidized to the enediyne after removal of the Further work towards neocarzinostatin has demonstrated that the cobalt mediated aldol reaction can be performed in the presence of the 4,5-epo~ide.'~~ When different ligands are placed on the dicobalt unit chiral complexes are f~rrned.'~' In related systems the cations derived by acid treatment of propargyl alcohol complexes show complex NMR properties which arise from the 156 G. E. Agoston M. P. Cabal and E. Turos Tetrahedron Lett.1991 32 3001; S. Jiang and E. Turos Tetrahedron Lett. 1991 32 4639. L 57 C. Bianchini M. Peruzzini and F. Zanobini Organornetallics 1991 10 3415. 158 S. E. Kegley D. T. Bergstrom L. S. Crocker E. P. Weiss W. G. Berndt and A. L. Rheingold Organometallics 1991 10 567. 159 C. Roger G. S. Bodner W. G. Hatton and J. A. Gladysz Organometallics 1991 10 3266. 160 D. P. Klein D. M. Dalton N. Q. Mhdez A. M. Arif and J. A. Gladysz J. Organomet. Chem. 1991 412 C7. 161 J.-M. Zhuang and D. Sutton Organometallics 1991 10 1516. I62 J. G. Stuart and K. M. Nicholas Heterocycles 1991 32 949. 163 P. Magnus and T. Pitterna J. Chem. SOC. Chem. Commun. 1991 541. I64 P. Magnus and S. M. Fortt J. Chem. SOC.,Chem. Commun. 1991 544. M. E. Maier and T.Brandstetter Tetrahedron Lett. 1991 32 3679. 166 P. Magnus and M. Davies J. Chem. SOC.,Chem. Commun. 1991 1522. 167 J. A. Dunn and P. L. Pauson J. Organomet. Chem. 1991 419 383. Organometallic Chemistry -Part (i) The Transition Elements stereochemical and functional behaviour of the metal bound complexes. Detailed NMR studies on an organomolybdenum system have been described.'68 q3-Complexes.-By far the most extensively developed 73system for use in synthetic chemistry employs palladium catalysis to form .rr-bound intermediates in the stereocontrolled displacement of allylic acetates or carbonates. An intramolecular addition to an q3 complex formed from (31) provides an example (Scheme 30).'69 Related tandem processes such as that shown in Scheme 31 are of note.In the case of substrate (32) an organometallic ylide is trapped by the activated alkene to produce an intermediate carbanion that is intercepted by the 773 complex. Two carbon-carbon bonds are formed in this process which leaves an alkene linkage exocyclic to the new ring.'70 62% (32) Pd(0Ac) Scheme 31 A methylene cyclopropane opening has been used to form a related ylide complex that was employed in an intramolecular addition to an a$-unsaturated e~ter.'~' Epoxide openings have also been much employed in palladium catalysed reac- tions. A convenient route to the carbocyclic nucleoside carbovir can be planned on this basis. A sequence of two palladium catalysed nucleophilic displacements is required.'72 The combination of palladium ally1 chemistry with other palladium-mediated bond forming processes can provide powerful methods for synthetic chemistry.A strategy for the introduction of the five-membered ring in (33) is suggested by the 168 C. Cordier M. Gruselle G. Jaouen V. I. Bakhmutov M. V. Galakhov L. L. Troitskaya and V. I. Sokolov Organometallics 1991 10 2303 169 B. M. Trost and P. H. Lee J. Am. Chem. SOC.,1991 113 5076. 170 9. M. Trost and T. A. Grese J. Am. Chem. SOC.,1991 113 7363. 171 W. B. Motherwell and M. Shipman Tetrahedron Lett. 1991 32 1103. 172 M. R. Peel D. D. Sternbach and M. R. Johnson J. Org. Chem. 1991 56 4990. 206 G. R. Stephenson presence of the gem diester unit and the alcohol group. Palladium catalysed opening of a vinyl epoxide could employ a stabilized enolate to introduce the right hand portion of the molecule (Scheme 32).Ring closure and vinyl ligand migration completed the five-membered ring; while /3-elimination removed the palladium to introduce the alkene linkage.'73 C02Me 0 / HO 60% Pd(OAc) PPh NaH Scheme 32 Stoichiometric 773 allyl complexes can employ the tetracarbonyliron group. A recent example of this type of electrophile is seen in Nicholas and Li's use of substituted allyl complexes in isoprenylation ~eacti0ns.l~~ A detailed discussion of the use of palladium catalysis in intramolecular cycloaddi- tions of trimethylenemethane has now appeared.'75 Reduction of palladium allyl complexes by formate has also been explored f~rther."~ Electrochemical reduction can be ernpl~yed.'~' Use of palladium catalysis to effect elimination to form dienes is well established.An asymmetric modification of this reaction has been de~cribed.'~~ A further variant is the use of palladium catalysis to effect direct ether synthesis by decarboxylation of allylic aryl ~arb0nates.l~~ Another possibility employs vinyl-extended allyls.'80 Improvements in reaction conditions have been reported. Procedures requiring sulfonated arylphosphine ligands can be performed in biphasic aqueous organic media and under phase transfer conditions. ''' Palladium catalysed amination of allylic carbonates can be performed under neutral conditions.'82 Internal attack on allyl units forms metallocyclobutanes a reaction that can be performed using either iridiumlg3 or platinum'84 complexes.A more surprising report describes this pathway in palladium catalysed reactions employing silyl ketene acetaIs and chelating phosphines. In this case cyclopropana- 173 J.-M. Gaudin Tetrahedron Lett. 1991 32 6113. I74 Z. Li and K. M. Nicholas J. Organomet. Chem. 1991 402 105. 175 B. M. Trost T. A. Grese and D. M. T. Chan J. Am. Chem. SOC. 1991 113 7350. 176 M. Oshima I. Shimizu A. Yamamoto and F. Ozawa Organometallics 1991 10 1221. 177 P. Zhang W. Zhang T. Zhang Z. Wang and W. Zhou J. Chem. Soc. Chem. Commun. 1991 491. I78 T. Hayashi K. Kishi and Y. Uozumi Tetrahedron Asymmetry 1991 2 195. 179 R. C. Larock and N. H. Lee Tetrahedron Lett.1991 32 6315. 180 P. G. Andersson and J.-E. Backvall J. Org. Chem. 1991 56 5349. 181 M. Safi and D. Sinou Tetrahedron Lett. 1991,32,2025; G.-Y. Wu and X. Huang Youji Huaxue 1991 11 431. 182 A. Arcadi E. Bernocchi S. Cacchi L. Caglioti and F. Marinelli Gazz. Chim. Ztal. 1991 121 369. 183 J. B. Wakefield and J. M. Stryker J. Am. Chem. SOC. 1991 113 7057. 184 C. Carfagna R. Galarini A. Musco and R. Santi Organometallics 1991 10 3956. Organometallic Chemistry -Part (i) The Transition Elements tion occurs.185 Cyclopropanes equipped with leaving groups can be carried through palladium catalysed allylic disp1acement.lg6 An unusual reduction process has been reported with molybdenum hexacarbonyl. In this reaction an allylic acetate is converted into an alkene with migration of the position of the double bond.18’ A molybdenum cyclopentadienyldicarbonylcomplex has been formed during a cyclization reaction which proceeds with carbonyl insertion.’” q4-Complexes.-As the size of the .rr-ligand becomes greater the potential for use of stoichiometric intermediates grows.In the case of q4 complexes cationic cyclo- pentadienyldicarbonylmolybdenum complexes have received much attention. Recent examples can be found in work from the Liebeskind group which has examined nucleophile additions to the cyclopentadienone complex (34) (Scheme 33).lg9 + Mo(CO)2Cp I MeMgCl o a - 0 0 92% (34) Me Scheme 33 Dienes bound to metal centres normally adopt a cisoid conformation. Transoid structures [e.g.(35)] are also possible however and when these are involved in alkylation reactions syn v3 complexes are formed. Low temperature conditions were used to access (Scheme 34) a transoid q4 cyclopentadienyldicarbonylmolyb-denum cation complex which if alkylated at a temperature below -40 “C could be trapped in the transoid form. At higher temperatures equilibrium to the more normal cisoid form resulted in a different stereoisomer of the neutral q3 prod~ct.”~ Me Me OMe + Mo( CO)2Cp MO(CO)~C~73% +Mo(CO)zCp Scheme 34 185 C. Carfagna L. Mariani A. Musco G. Sallese and R.Santi J. Org. Chem. 1991 56 3924. 186 A. Stolle J. Salaun and A. de Meijere SYNLEm. 1991 327. 187 Y.Masuyama K. Maekawa T. Kurihara and Y. Kurusu Bull. Chem.SOC.Jpn. 1991 64 2311. 188 G.-M. Yang G.-H. Lee S.-M. Peng and R.-S. Liu J. Chem. SOC.,Chem. Commun. 1991 478. lS9 L. S. Liebeskind and A. Bombrun J. Am. Chem. Soc. 1991 113 8736. 190 W.-J. Vong S.-M. Peng S.-H. Lin W.-J. Lin and R.3. Liu J. Am. Chem. Soc. 1991 113 573. 208 G. R. Stephenson In cases where unsymmetrical substituents are present on the coordinated ligand regioselectivity is of importance. The Liu group has examined the effect of an ester substituent at C-2 of an acyclic alkene (Scheme 35).I9l In the case of many nucleophiles preferential addition at the substituted terminus of structure (36) has been observed though the product ratio depends on the type of nucleophile. PhCH,NH Me 7 rrni vle027 / Scheme 35 The combination of nucleophile addition to an electrophilic .rr-complex with subsequent carbonyl insertion makes good use of stoichiometric metal complexes since the metal promotes a sequence of two reactions (Scheme 36).New examples of this type of reaction have been described by Yeh.'92 Nucleophile addition to (37) occurs trans to the metal but the carbonyl insertion step adds the acyl group to the face of the ligand bound to the metal. Examples employing substituted diene complexes have now been described. A\ Me0 Ph 2) MeI/CO 40% Scheme 36 q4-Complexes have been the subject of detailed physical study. Investigations of their dynamic NMR properties have revealed evidence for diastereoisomer discrimi- nation.193 The influence of ligands on the conformer populations of cyclic acyclic diene complexes has been examined.'94 Assignments of circular dichroism bands for neutral tricarbonyliron complexes have been extended to included cyclic corn pound^.'^^ I91 M.-H.Cheng Y.-H. Ho G.-H. Lee S.-M. Peng,and R.3. Liu J. Chem. SOC.,Chem. Commun. 1991,697. 192 M.-C. P. Yeh and C.-C. Hwu J. Organomet. Chem. 1991,419 341. 193 J. A. S. Howell M. G. Palin M.-C. Tirvengadum D..Cunningham P. McArdle Z. Goldschmidt and H. E. Gottlieb J. Organomet. Chem. 1991 413 269. 194 .I.A. S. Howell G. Walton M.-C. Tirvengadum A. D. Squibb M. G. Palin P. McArdle D. Cunningham Z. Goldschmidt H. Gottlieb and G. Strul J. Organomet. Chem. 1991 401 91. L95 G. R. Stephenson P. W. Howard and S. C. Taylor J. Chem.SOC.,Chem. Commun. 1991 127. Organometallic Chemistry -Part (i) The Transition Elements 209 Reactions adjacent to the tricarbonyliron unit are important in stereoselective synthesis. Attention has focussed on acyclic complexes where intramolecular reac- tions have been exploited in search of stereocontrol. Both D~naldson'~~ and GrCe'97 have used oxygen nucleophiles in the ring-closure step. Analogous reactions with a nitrogen substituent at the end of the chain afford piperidines with good stereocon- tr01.l~~ These reactions have been applied to HETE synthesis. Friedel-Craft acylation of acyclic complexes is particularly effective. The method provides a first step which gives access to the elusive mono-oxides of 774-1,3,5-triene complexe~.'~~ Osmylation adjacent to the metal complex was used in a total synthesis of (1 1R,12S)-diHETE.200 The process has been applied in an elegant synthesis of the natural leukotriene (5S,6S)-LTA4.201In this synthesis acylation of the iron complex is followed by chlorination next to the acyl group.Protection of the alcohol functional group manipulation at the ester followed by a Wittig reaction establishes the cis-alkene linkage. q4-Complexes of enones have a specialized chemistry of their own; their reactions with nucleophiles are particularly valuable. Stereoselective access to oxadiene com- plexes has now been achieved using a sulfoxide chiral auxiliary as a substituent on the enone.202 Azadienes can also be obtained stereoselectively using the nitrogen to attach the chiral auxiliary.203 Unusual vinylketene complexes have been prepared.*04 A still more unusual route to vinylketene complexes uses carbene precursors in a cycloaddition reaction.205 a,p-Unsaturated thioamide and thioester complexes participate in novel cyclo- addition reactions with alkynes.206 Just as with diene complexes oxadiene complexes can also be used to impart stereocontrol at unbound positions.This can be seen in the functionalization of fumaraldehyde 714 complexes by nucleophile addition to the aldehyde Unusual bis-enone complexes of molybdenum and tungsten have been prepared.208 q5-Complexes.-Tricarbonyliron complexes have been extensively used in combina- tion with 775 ligands to provide powerfully electrophilic cationic complexes.A recent example of the use of these compounds in natural product synthesis can be found in the work of Knolker.209 Both the electrophilic n-complex and a conventional leaving group in (38) are employed to create two sites for reaction with an incoming 196 W. A. Donaldson and C. Tao SYNLETT. 1991 895. 197 A. Teniou L. Toupet and R. Grie SYNLETT. 1991 195. 198 A. Hachem A. Teniou and R. Grie Bull. SOC.Chim. Belg. 1991 100 625. 199 M. Franck-Neumann A. Abdali P.-J. Colson and M. Sedrati SYNLETT. 1991 331. 200 A. Gigou J.-P. Beaucourt J.-P. Lellouche and R. GrCe Tetrahedron Lett. 1991 32 635. 20 I M. Franck-Neumann and P.-J. Colson SYNLETT. 1991 891. 202 A. Ibbotson A. M. Z. Slawin S. E. Thomas G. J. Tustin and D. J. Williams J.Chem. Soc. Chem. Commun. 1991 1534. 203 K. G. Morris and S. E. Thomas J. Chem. SOC.,Perkin Trans. 1 1991 97. 204 L. Hill S. P. Saberi A. M. Z. Slawin S. E. Thomas and D. J. Williams J. Chem. Soc. Chem. Cornmun. 1991 1290. 205 J. Park S. Kang D. Whang and K. Kim Organometallics 1991 10 3413. 206 H. Alper and D. A. Brandes Organometallics 1991 10 2457. 207 H. Cherkaoui J. Martelli and R. GrCe Tetrahedron Lett. 1991 32 7259. 208 T. Schmidt C. Kriiger and P. Betz J. Organomet. Chem. 1991 402 97. 209 H.-J. Knolker R. Boese and K. Hartmann Tetrahedron Lett. 1991 32 1953. G. R. Stephenson nucleophilic reagent (Scheme 37). An approach2" towards intermediates for the synthesis of the alkaloids discorhabdin and prianosin has been based on this method.Me b Me 0 I OMe (38) Scheme 37 Tricarbonyliron complexes can provide an excellent approach to enantioselective organic synthesis. In these circumstances an unsymmetrical substitution pattern is essential on the ligand to be incorporated into the target molecule. Recent work in Norwich has been examining the effect of new directing groups on the control of regioselectivity of nucleophile addition. Trifluoromethyl groups at either C-1 (39) or C-2 (40) of the dienyl system have both been found to direct nucleophiles predominantly to the far terminus.211 Optically active starting materials (Scheme 38) have been readily available for this work through the complexation of micro- bially-derived cyclohexadienediol ligands.+Fe(CO) PF; A (40) Me02C COiMe Scheme 38 H.-J. Knolker and K. Hartmann SYNLEn. 1991 428. 21 1 G. R. Stephenson P. W. Howard and S. C. Taylor J. Organomer. Chem. 1991 419 C14. Organometallic Chemistry -Part (i) The Transition Elements 21 1 Comparable directing groups with opposite directing effects are important to introduce flexibility in synthetic planning. Recently acetoxy substituents have been shown to have the opposite directing influence to alkoxy Cross-conjugated qs complexes can be formed and alkylated in situ by the displacement of leaving groups. This allows a comparison to be made between the reactivity of transoid and cross-conjugated q5 Akyclic 77' trienyl com- plexes have also been in~estigated.~'~ As with other stoichiometric systems multiple use of the transition metal centre is important in efficient synthetic applications.Examples from Pearson's group combine stereoselective nucleophile addition with the use of reduction and enolate methodologies to position endo-sub~tituents.~'~~~~~ In the six-membered ring series it is usually impossible to perform hydride abstraction following a nucleophile addition step. The use of leaving group chemistry to overcome this limitation is illustrated by an organoiron route (Scheme 39) to 0-methyljoubertiamine (41).217 NMe2 +Fe(CO)3 PF; (41) Scheme39 The Knolker cyclization method has been used with 4-hydroxyanilines to afford products which upon oxidation cyclize to form dihydrocarbazol-3-ones.These can be stereoselectively functionalized by conjugate addition to the enone sub-unit.218 Dienyl complexes have been used as precursors to i~oquinuclidines,~~~ and in arylations in which functionalized nucleophiles are introduced as the first step of a synthetic route to lycorine.220 Organozinc and copper nucleophiles were compared in this investigation. Zinc/copper bimetallic reagents can also be successfully employed with tricarbonyliron v5dienyl cations.221 Even metal anions can be used as nucleophiles. Examples include NaRe(CO)5-,222 and C~MO(CO)~-.~~~ Open sandwich complexes provide a rich and far less fully explored field of chemistry. The extent of bonding of pentadienyl ligands can be adjusted by the 212 G. R. Stephenson P. W. Howard D.A. Owen and A. J. Whitehead J. Chem. Soc. Chem. Commun. 1991 641. 213 M. Frank-Neumann A. Kastler and P.-J. Colson Tetrahedron Lett. 1991 32 7051; W. A. Donaldson and M. A. Hossain Tetrahedron Lett. 1991 32 7047. 214 G. R. Stephenson M. Voyle and S. Williams Tetrahedron Lett. 1991 32 5265. 215 A. J. Pearson and K. Srinivasan J. Chem. SOC.,Chem. Commun. 1991 392. 216 A. J. Pearson and K. Chang J. Chem. SOC.,Chem. Commun. 1991 394. 217 G. R. Stephenson D. A. Owen H. Finch and S. Swanson Tetrahedron Lett. 1991 32 1291. 218 H.-J. Knolker P. G. Jones J.-B. Pannek and A. Weinkauf SYNLETT. 1991 147. 219 G. R. Stephenson R. D. Thomas and F. Cassidy J. Organomer. Chem. 1991 402 C59. 220 G. R. Stephenson I. M. Palotai W. J. Ross and D. E.Tupper SYNLEn. 1991 586. 221 M.-C. P. Yeh M.-L. Sun,and S.-K. Lin Tetrahedron Lett. 1991 32 113. 222 B. Niemer J. Breimair B. Wagner K. Polborn and W. Beck Chem. Ber. 1991 124 2227. 223 R.E. Lehmann and J. K. Kochi Organometallics 1991 10 190. G. R. Stephenson number of phosphine ligand~.~~~ Similar methods have been employed with tricar- bonylmanganese complexes. Complexes of manganese containing pentadienyl and pentadiene ligands have been and cis to trans isomerizations have been explored.226 q6-Complexes.-Neutral tricarbonylchromium complexes of arenes have been by far the most widely studied q6system. Recently emphasis has been on nucleophile addition/leaving group displacement reactions with leaving groups positioned on the aromatic ring.Fluoride displacement from the tricarbonylchromium complex of fluorobenzene has been effected in an enantioselective fashion using an enolate nucleophile carrying a chiral auxiliary. The method provides convenient access to a-aryl carboxylic When an excess of a nucleophile is employed a second addition can follow halogen displacement. Lithiated nitrile reagents have been used in this way to convert fluoroarene complexes into difunctionalized cyclohexadienes.228 Cationic complexes such as (42) (Scheme 40) are more powerful electrophiles than a comparable neutral species. In the case of arene complexes Mn(CO), FeCp and RuCp complexes are commonly employed.229 Fe(C 69% Scheme 40 While nucleophile addition to a cationic arene complex affords a neutral q5 intermediate additions to neutral electrophiles lead to anionic intermediates that can be employed in subsequent reactions as powerful nucleophiles in their own right.Trapping the anion with an alkylhalide can promote initial reaction at a carbonyl group to form an any1 ligand that is transferred from the metal to the q5 complex. Recently improved procedures (Scheme 41) of this type have been demon- strated with heteroatom substituents in side-chain to the aromatic ring in (43).230 Similar nucleophile addition/ arene trapping reactions have been performed on methoxynaphthalene complexes in routes towards the AB ring system of akl avi n one. 23 224 J. R. Blecke and R. J. Wittenbrink J. Organomet. Chem. 1991 405 121. 22s N.Z. Villarreal M. A. Paz-Sandoval P. Joseph-Nathan and R. 0.Esquivel Organometallics 1991 10 2616. 226 J. W. Freeman N. C. Hallinan A. M. Arif R. W. Gedridge R. D. Ernst and F. Basolo J. Am. Chem. Soc. 1991 113 6509. 227 M. Chaari A. Jenhi J.-P. Lavergne and P. Viallefont J. Organornet. Chem. 1991 401 C10. 228 F. Rose-Munch L. Mignon and J. P. Souchez Tetrahedron Lett. 1991 32 6323. 229 D. A. Brown W. K. Glass and K. M. Kreddan J. Organomet. Chem. 1991,413,233; R. G. Sutherland C. Zhang and A. Pibrko J. Organornet. Chern. 1991 413 357; R. C. Cambie S. A. Coulson L. G. Mackay S. J. Janssen P. S. Rutledge and P. D. Woodgate J. Organornet. Chem. 1991 409 385. 230 E. P. Kiindig G. Bernardinelli R. Liu and A. Ripa J.Am Chem. SOC. 1991 113 9676.23 1 E. P. Kundig M. Inage and G. Bernardinelli Organometallics 1991 10 2921. 213 Organometallic Chemistry -Part (i) The Transition Elements Q I i MeLi ii Me1 Tricarbonylchromium complexes of phenoxyoxazoline and imine complexes both undergo highly regioselective reactions with carbon nucleophiles. Complete ortho- selectivity is possible in many case^.'^' Nucleophilic substitution reactions are complicated by the variety of available pathways. Tele-meta substitution pathways have been observed with ortho-chloro and ortho-fluoro trialkylsilylarene complexes.233 With methylamino complexes both cine and tele-meta substitution can occur.234 Carbanions derived from a-iminoesters or nitriles have also been combined with haloarene tricarbonylchromium c~rnplexes.’~~ Palladium coupling provides an alternative to nucleophilic displacement of halogens.The reaction has been explored further in Widdowson’s group. Benzofuran derivatives have been connected to the aromatic ring by means of this rea~tion.’~~ Similar coupling but employing a chlorobenzene complex has been used to promote ~arbonylation.~~~ Sulfur sub- stituents can also be intr~duced.’~~ Full details of the microbial resolution of ortho and meta substituted tricar- bonylchromium complexes have appeared.239 Extensive work has been done to improve the complexation of arene~.’~’ Catalysts for the complexation of toluene have been examined in Acid catalysis has proved particularly effective with a number of arene~.’~’The synthesis of T~ pyridine complexes243 and their use in reactions with organolithium reagent? has been reported in full.When a chromium complex has been used in organic synthesis the removal of the chromium is an important step. A new method employs dimethyldi~xirane.’~~ 232 E. P. Kundig D. Amumo R. Liu and A. Ripa SYNLEm. 1991 657. 233 J.-P. Djukic P. Geysermans F. Rose-Munch and E. Rose Tetrahedron Lett. 1991 32 6703. 234 J.-P. Djukic F. Rose-Munch and E. Rose J. Chem. SOC. Chem. Commun. 1991 1634. 235 F. Rose-Munch K. hiss E. Rose and J. Vaisserman J. Organomet. Chem. 1991 415 223. 236 I. S. Mann D. A. Widdowson and J. M. Clough Tetrahedron 1991 47 7981. 237 J.-F. Carpentier Y. Castanet J. Brocard A. Mortreux and F. Petit Tetrahedron Lett.1991 32 4705. 238 M. J. Dickens J. P. Gilday T. J. Mowlem and D. A. Widdowson Tetrahedron 1991 47 8621. 239 S. Top G. Jaouen C. Baldoli P. Del Buttero and S. Maiorana J. Organomet. Chem. 1991 413 125. 240 P. HmEiar M. HudeEek G. K. I. Magomedov and 9. Toma Collect. Czech. Chem. Commun. 1991,56 1477. 241 M. HudeEek and 9. Toma J. Organomet. Chem. 1991 406,147. 242 P. HrnEiar and S. Toma J. Organomel. Chem. 1991 413 161. 243 S. G. Davies and M. R. Shipton J. Chem. SOC.,Perkin Trans. I 1991 501. 244 S. G. Davies and M. R. Shipton J. Chem. SOC. Perkin Trans. I 1991 757. 245 A.-M. Lluch F. SBnchez-Baeza F. Camps and A. Messeguer Tetrahedron Lett. 1991 32 5629. 214 G. R. Stephenson Unusual reactions can be effected when bischromium complexes of biaryls are reduced electrochemically.The dianions formed in this way can be reacted with electrophiles. The reaction has been extended to include a number of substrates where alkene and diene functionality separates the two chromium complexes.246 Carbanion addition to dichromium diphenyl complexes has also been followed by electrophile attack. Disubstituted compounds are formed.247 In another version of this reaction a monomeric tungsten arene complex has been reacted first with methyl-lithium and then with methyl iodide to form a methylalkylpentadienyl complex.248 Complexes can be obtained diastereoselectively by the use of lithiated monosubstituted compounds.249 The products are useful as chiral auxiliaries in enantioselective reactions between diethylzinc and ben~aldehyde.~~' Cationic v6complexes have also received sustained attention.Ruthenium cyclo- pentadienyl complexes of terpene~~~l and steroids,252 have been obtained. In this last case unusual dienonyl complexes have been formed and reversibly protonated with HPF,. Ring A complexes of steroids can be prepared by a remarkable aromatiz- ation of alkyl substituted steroids.253 The ruthenium complex used to achieve this is one of the most powerful dehydrogenation reagents known; C-H and C-C bond cleavage takes place so strong is the driving force to q6complex formation. Cyclopentadienyliron complexes of chloroarenes have been converted into optically active amine derivatives.254 As with all chiral ncomplexes reactions adjacent to the portion of the ligand bearing the metal are important in tricarbonylchromium chemistry.Stereoselective reactions are often possible in side-chain positions particularly when buttressed by an adjacent group. Even fluorine substituents adjacent to an aldehyde can promote considerable stereosele~tivity.~~~ An illustration of the stereocontrol influence of the chromium n-complex at some distance from the metal-bearing portion of the molecule is seen in conjugate addition reactions to 2-ar~lidine-l-tetralones.~~~ Of all the metal r-complexes the organochromium system has become the most fully developed. A great variety of reactions have now been explored at side-chain positions. Examples include titanium catalysed cy~lizations~~~>~~* Wittig rearrange- ment~~~~ and cyclization reactions employing the opening of the 4-membered ring of benzocyclobutene complexes.260 This last example has also been developed with intramolecular reactions,261 and can afford enantiomerically pure products.262 246 R.D. Rieke K. P. Daruwala and M. W. Forkner Organornetallics 1991 10 2946. 247 S. S. Yang B. T. Dawson and R. D. Rieke Tetrahedron Lett. 1991 32 3341. 248 C. G. Kreiter and T. Hellrnann J. Organomet. Chem. 1991 405 C6. 249 M. Uemura R. Miyake M. Shiro and Y. Hayashi Tetrahedron Lett. 1991 32 4569. 250 M. Uemura R. Miyake and Y. Hayashi J. Chem. SOC.,Chem. Commun. 1991 1696. 251 R. C. Carnbie L. G. Mackay P. S. Rutledge M. Tercel and P. D. Woodgate J. Organomet. Chem. 1991,409 263.252 D. Vichard M. Gruselle H. El Arnouri and G. Jaouen J. Chem. SOC.,Chem. Commun. 1991 46. 253 F. Urbanos J. Fernandez-Baiza and B. Chaudret J. Chem. SOC.,Chem. Commun. 1991 1739. 254 K. Bambridge and R. M. G. Roberts J. Organomet. Chem. 1991 401 125. 255 A. SolladiC-Cavallo and M. Bencheqroun J. Organomet. Chem. 1991 403 159. 256 S. Ganesh and A. Sarkar Tetrahedron Lett. 1991 32 1085. 257 S. G. Davies T. J. Donohoe and M. A. Lister Tetrahedron Asymmetry 1991 2 1085. 258 S. G. Davies T. J. Donohoe and M. A. Lister Tetrahedron Asymmetry 1991 2 1089. 259 M. Mahrnoudi L. Pelinski L. Maciejewski and J. Brocard J. Organornet. Chem. 1991 405 93. 260 H. G. Wey and H. Butenschon Angew. Chem. Int. Ed. Engl. 1991 30 880. 26 1 M. Brands H.G. Wey and H. Butenschon J. Chem. SOC.,Chem. Commun. 1991 1541. 262 E. P. Kundig G. Bernardinelli and J. Leresche 1. Chem. SOC.,Chem. Commun. 1991 1713. Organometallic Chemistry -Part (i) The Transition Elements 215 The ability of the tricarbonylchromium group to stabilize anions as well as cations is well known. Work in this area now focuses on issues of stereoselectivity. Again the effects of adjacent substituents is marked.263 Extended anions have been examined and found to exhibit regioselective Anions adjacent to q6 complexes of pyridine derivatives have also been explored.265 By the combination of direct addition and reactivity at side chain positions chromium arene complexes can be employed to direct the formation of a series of carbon-carbon bonds.In terms of versatility in multiple use the tricar-bonylchromium group is the most developed of the transition metal control centres currently available. A recent example of the multiple use of the chromium centre appears in Uemura’s route to dihydroxyserrulatic acid.266 Three important problems were addressed in this synthesis the trans relative stereochemistry across the satur- ated portion of the tetrahydronaphthalene unit the regiochemistry of functionaliz- ation of the aromatic ring and the side-chain stereochemistry at C-11. A sequence of three nucleophile addition reactions was employed in the partially saturated ring. 12 Organometallic Enolates Organoiron enolate chemistry is still dominated by work from the Davies group. An asymmetric synthesis of optically pure P-lactone~~~~ has been developed to provide access to tetrahydrolipstatin268 in a synthesis that provides an interesting parallel to the Imperial College approach described earlier in this report.Aldol reactions with 2,3-O-isopropylidine-~-glyceraldehyde have been studied using diethylaluminium enolate~.~~~ Double alkylations of chiral acetate equivalents give access to ethyl 2-methylhept-4-yne0ate.~~’ Pentamethylcyclopentadienylrheniumcomplexes with triphenylphosphine and nitrosyl ligands contain a chiral rhenium atom as an alternative to the iron system of Davies. Rearrangement of the organorhenium complexes can provide an q3 rhenium enolate complex.271 An unusual system is obtained by the addition of potassium enolates to hexacarbonylchromium.The intermediate adduct can be further deprotonated to produce an organometallic dianion. The use of potassium 18-crown-6 adducts is important in this 13 Organotitanium and Zirconium Complexes Insertion reactions are important in organotitanium and zirconium chemistry. Dox- see has shown that metallocyclobutenes can be combined with aldehydes to give titanocyclic intermediates that eliminate Cp2Ti=0 to produce 1,3-diene~.~~~ 263 A. Jenhi J.-P. Lavergne and P. Viallefont J. Organornet. Chem. 1991 401 C14. 264 M.-C. SCnCchal-Tocquer D. SCntchal J.-Y. Le Bihan D. Centric and B. Caro J. Organomet. Chem. 1991,420 185. 265 S. C. Davies A. J. Edwards and M. R. Shipton J. Chem. Soc. Perkin Trans. 1 1991 1009.266 M. Uemura H. Nishimura T. Minami and Y.Hayashi J. Am. Chem. Soc. 1991 113 5402. 267 S. C. Case-Green S. G. Davies and C. J. R. Hedgecock SYNLETT. 1991 779. 268 S. C. Case-Green S. G. Davies and C. J. R. Hedgecock SYNLEm. 1991 781. 269 G. J. Bodwell S. G. Davies and A. A. Mortlock Tetrahedron 1991 47 10077. 270 G. J. Bodwell and S. G. Davies Tetrahedron Asymmetry 1991 2 1075. 271 G. L. Edwards W. B. Motherwell D. M. Powell and D. A. Sandham J. Chem. SOC.,Chem. Commun. 1991 1399. 272 P. Veya C. Floriani A. Chiesi-Villa and C. Guastini Orgunornetullics 1991 10 1652. 273 K. M.Doxsee and J. K. M. Mouser Tetrahedron Lett. 1991 32 1687. 216 G. R. Stephenson Organometallic carbonyl groups can be combined with organozirconium reagents.Elaboration of a bis-cyclopentadienylzirconium complex of butadiene first with hexacarbonyltungsten and then by reaction with ketones provided an example of a lY5-asymmetric induction.274 v-Bound ligands at zirconium can also insert into the carbon-oxygen double bonds of ketones.275 Insertion reactions with alkynes can afford vinylzirconium species.276 Pyridine complexes of zirconium also have a rich preparative chemistry. Insertion into a variety of alkenes has been examined. These reactions can be extended to include vinylpyridine substrates forming more elaborate bis-pyridine-containing 14 Organometallic Oxidation Reactions This year the survey of organometallic reactions ends with a discussion of the oxidation chemistry of alkenes. In particular in the field of epoxidation there have been a variety of significant developments.Two papers have appeared from the Sharpless group which begin the process of the full description of the mechanism of the remarkable organotitanium/tartrate-based asymmetric epoxidation reaction that has had such a profound influence on organic synthesis. The kinetics of the reaction278 and details of the catalyst structure279 have been examined. Work on modification of the Sharpless catalyst continues. Takano has described an inversion of enantioselectivity in kinetic resolution based on epoxidation reactions.280 The current focus in organometallic epoxidation reactions however concerns the problem of epoxidation of unfunctionalized alkenes. A number of epoxidation catalysts have been examined in detail.Examples include organonickel catalysts,281 organoiron catalysts,282 including iron porphyrin catalyst systems and cytochrome P450 itself. These have been the subject of a theoretical and experimental analysis of absolute stereochemistry of oxidation products from 1-phenylpr~pene.~'~ Manganese porphyrin systems have also been described.284 A series of papers have appeared in which salen complexes have been used as the basis for asymmetric epoxidation. Enantiomeric excess in the range 20-80% has been achieved with a selection of styrene derivative^.^'^ In this case C2 symmetry in the epoxidation catalyst was achieved by the lY2-placement of phenylsubstituents at the centre of the ligand. The alternative (1,l-substitution) has also been examined.286 274 G.Erker F. Sosna P. Betz S. Werner and C. Kriiger 1. Am. Chem. Soc. 1991 113 564. 27s G. Erker and R. Zwettler J. Organomet. Chem. 1991 409 179. 276 D. R. Swanson T. Nguyen Y. Noda and E.-i. Negishi J. Org. Chem. 1991 56 2590. 277 A. S. Guram and R. F. Jordan Organomefallics 1991 10 3470. 278 S. S. Woodard M. G. Finn and K. B. Sharpless J. Am. Chem. SOC.,1991 113 106. 279 M. G. Finn and K. B. Sharpless J. Am. Chem. Soc. 1991 113 113. 280 S. Takano Y. Iwabuchi and K. Ogasawara J. Am. Chem. Soc. 1991 113 2786. 281 T. Yamada T. Takai 0.Rhode and T. Mukaiyama Bull. Chem. SOC.Jpn. 1991 64 2109. 282 H. Ogoshi Y. Suzuki and Y. Kuroda Chem. Leu. 1991 1547. 283 P. R. Ortiz de Montellano J.A. Fruetel J. R. Collins D. L. Camper and G. H. Loew J. Am. Chem. Soc. 1991 113 3195. 284 A. M. d'A. Rocha Gonsalves R. A. W. Johnstone M. M. Pereira and J. Shaw J. Chem. SOC.,Perkin Trans. I 1991 645. 285 R. Irie Y. Ito and T. Katsuki SYNLETT 1991 265. 286 N. Hosoya R. Irie Y. Ito and T. Katsuki SYNLEn. 1991 691. Organometallic Chemistry -Part (i) The Transition Elements 217 The alternative oxidation of alkenes to aldehydes or ketones is of considerable synthetic utility. A nice example gives selective terminal (to aldehydes) or internal (to methyl ketones) oxidation depending on the catalyst and the conditions.287 Stereoselectivity is an issue in the oxidation of dienes to effect 1,4-difunctionaliz- ation. In an example of ligand accelerated catalysts Backvall has described the use of sulfoxides as co-catalysts in the reaction.The sulfoxide carried a quinone ring which participates in the redox chemistry.288 Intramolecular 1,4-difunctionalization has been used in this way to form a series of oxaspirocyclic alkene~.~~~ 15 Unusual Structures Reactions and Processes There have been many new types of reactions and types of complexes appearing over the year. These illustrate the fact that organometallic chemistry retains its capacity to surprise and excite with new reactions and new structures as for example in the interconversion reactions of bimetallic complexes,290 and the rearrangement processes of hydrazone ligand~.~~~ The insertion of a disilane across an alkene,292 rearrangements of dienes via organochromium chemistry,293 and a novel metal mediated cyclization reaction,294 indicate the diversity of new reaction types.The catalytic reduction of simple enols using rhodium homogeneous catalysis has been explored by means of deuterium labelling.295 An unusual review article by Ryabov coins the term ‘organometallic biochemistry’ to describe investigations that combine organometallic chemistry with biological Examples of this type of work continue to appear as shown by the new use of lipases for the kinetic resolution of ferrocene derivatives,297 the organo- chromium example discussed earlier and the development of an organometallic substitute for the radioactive Boulton- Hunter reagent.298 This latter case illustrates the growing interest in the use of organometallic complexes as tools for biological investigations.Detection of organometallic species at exceptionally low concentrations in biological systems is possible by Fourier transform IR (FTIR) spectroscopy. Jaouen’s development299 of the CMIA (carbonyl- metallo-immunoassay) method illustrates the potential of this area. There has now been a detailed investigation of solvent shifts of organometallic species which will be important in the interpretation of biologically bound organometallic deriva- 2B7 T. Hosokawa S. Aoki M. Takano T. Nakahira Y. Yoshida and S.-I. Murahashi J. Chem. SOC.,Chem. Commun. 1991 1559. 288 H. Greenberg A. Gogoll and J.-E. Backvall J. Org. Chem. 1991 56 5808. 289 J.-E. Backvall and P.G. Anderson J. Org. Chem. 1991 56 2274. 290 C. A. Mirkin K.-L. Lu T. E. Snead B. A. Young G. L. Geoffroy A. L. Rheingold and B. S. Haggerty J. Am. Chem. SOC.,1991 113 3800. 29 I G.-M. Yang G.-H. Lee S.-M. Peng and R.3. Liu Organometallics 1991 10 1305. 292 M. Murakami P. G. Anderson M. Suginome and Y. Ito J. Am. Chem. Soc. 1991 113 3987. 293 H. Yamada M. Sodeoka and M. Shibasaki J. Org. Chem. 1991 56 4569. 2v4 G.-M. Yang G.-H. Lee S.-M. Peng and R.-S. Liu Organometallics 1991,10 2531. 295 S. H. Bergens and B. Bosnich J. Am. Chem. SOC.,1991 113 958. 296 A. D. Ryabov Angew. Chem. Znt. Ed. Engl. 1991 30,931. 291 M.-J. Kim H. Cho and Y. K. Choi J. Chem. SOC.,Perkin Trans. I 1991 2270. 298 M. Savignac A. Sasaki P. Potier and G. Jaouen J.Chem. SOC.,Chem. Commun. 1991 615. 299 M. Salmain A. Vessikres G. Jaouen and I. S. Butler Anal. Chem. 1991 63 2323. G. R. Stephenson ti~es.~" Electrochemistry has been examined as an alternative to the use of FTIR for the detection of organometallfc estradiol derivative^.^'^ Organometallic biochemistry (1991) may join organometallic new materials ( 1990) (discussed in the annual report last year) as rapidly developing fields that offer new opportunities for scientists working with organometallic complexes. 300 C. S. Creaser and G. R. Stephenson U.K. Patent Application 9110017.2 May 1991. 301 D. Osella E. Stein G. Jaouen and P. Zanello J. Organomet. Chem. 1991 401 37.

ISSN:0069-3030    

DOI:10.1039/OC9918800185

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

9 Synthetic Methods By D. R. KELLY School of Chemistry and Applied Chemistry University of Wales College of Cardiff PO Box 912 Cardiff CF13TB 1 Introduction ‘The problem with organic synthesis is that it is literally creative and that its practitioners range from the master builder who uses only the best materials (in extreme cases only materials and methods he has invented) to the scrap merchant who is prepared to knock you up a molecule out of any old synthons.” The award of the Nobel prize to E. J. Corey2 in 1991 possibly marks the maturation of organic synthesis3 from a pure science with internal goals to an applied science which can tackle significant problems in biology and make new materials with predictable proper tie^.^ There is certainly a wealth of techniques available particularly for asymmetric transformations.Artificial (abiotic) catalysts are now competitive with yeast5 and enzymes6 in terms of selectivity and yield. But the ability to change the reactivity of enzymes using protein enginee~ing,~ substrate imprinting’ and non-aqueous solvents’ means they are currently more versatile and this position will be augmented when catalytic antibodies (abzymes)” are available ‘off the shelf ’. ‘Biotransforma-tions’” have a further advantage that (with some exceptions) they all act under more or less the same conditions and so it is possible to perform multiple reactions S. Warren Chem. Ind. 1991 796. ’ E. J. Corey Angew. Chem. Znt. Ed. Engl. 1991 30,455. J. Mulzer H.J. Altenbach M. Braun K.Krohn and H. U. Reissig Organic Synthesis Highlights VCH Weinheim 1991. G. W. Gokel J. C. Medina and C. Li SYNLEZT. 1991,677. R. Cszuk and B. I. Glanzer Chem. Rev. 1991 91 49. Biocatalysis in Organic Chemistry ‘a symposium in print’ Red. Trau. Chim. Pays-Bas. 1991 110 (5) 151-263 63; Biotransformations of organometallics A. D. Ryabov Angew. Chem. Znt. Ed. Engl. 1991 30,931. ’ Z. Zhong J. L-C. Liu L. M. Dinterman M. A. J. Finkelman W. T. Mueller M.L. Rollence M. Whitlow and C.-H. Wong J. Am. Chem. SOC,1991,113,683; Z. Zhong J. A. Bibbs W. Yuan and C.-H. Wong 1.Am. Chem SOC.,1991 113 2259. M. Stahl U. Jeppsson-Wistrand M.-0. Mansson and K. Mosbach J. Am. Chem. Soc. 1991,113,9366. E. Rubio A. Fernandez-Moyorales and A. M. Klibanov J. Am. Chem. SOC.,1991 113 695; A.L. Gutman and M. Shapka J. Chem. SOC.,Chem. Commun. 1991 1467; P. Z. Fitzpatrick and A. M. Klibanov J. Am. Chem. SOC.,1991 113 3166; S. Panda and J. S. Dordick J. Am. Chem. SOC.,1991 113 2253. ‘Catalytic Antibodies’ Ciba Foundation Symposium 159 Chairman W. P. Jencks Wiley Chichester 1991; R. A. Lerner S. J. Benkovic and P. G. Schultz Science 1991 252 (5006),659. The activity in this area can be judged by the launch of the new journal Preparative Biotransformations. 219 220 D. R. Kelly in one pot e.g. ester hydrolysis,12 oxidation of the alcohol to an aldehyde cis-trans is~merization,'~ and carbon-carbon bond formation with an aldolase could all be achieved concurrently. There are intriguing possibilities offered by molecular recognition using or self assembling struct~res'~ supramolecular ~ystems'~ such as micelles or monolayers which can be visualized and modelled using computer graphics.16 However although there are a plethora of supramolecular abiotic systems capable of selective binding precious few are capable of effecting a chemical change." One system with enormous potential is the carcerands which are large hollow spherical molecules constructed by dimerization of two hemispherical units (cavitands18).At least one molecule of solvent is always impri~oned'~ during closure and if a solvent mixture is used the most polar solvent (assuming it is small enough) is preferentially incorporated. The linkages between the cavitands are typically acetals2' or thioethers21 which are formed by nucleophilic substitution on alkyl chlorides.The imprisoned solvent molecule( s) stabilize the polar SN2transition state which other- wise would have to take place in a vacuum. Cram has revolutionized isolation technology by infiltrating a-pyrone (2) into a hemicarcerand (1)22at high tem- perature and then photolysing it to give a trapped molecule of cyclobutadiene (3) and carbon dioxide which escaped. Prolonged photolysis effected retro [2 + 21 cycloaddition to give acetylene which also escaped the confines of the hemicarcerend (1).23 The hemicarcerends have much larger portals than the carcerands and guests as large as ferrocene can be in~orporated,~~ with discrimination between enan-ti0me1-s.~~ 12 I. Weinhouse R. A.Lerner R. A. Gibbs P. A. Benkovic R. Hilhorst and S. J. Benkovic J. Am. Chem. SOC.,1991 113 291; K. D. Janda M. I. Weinhouse T. Danon K. A. Pacelli and D. M. Schloeder J. Am. Chem. Soc. 1991 113 5427; S. Ikeda M. I. Weinhouse K. D. Janda R. A. Lerner and S. J. Danishefsky J. Am. Chem. SOC.,1991,113,7763; T. Kitazume J. T. Lin M. Takeda and T. Yamazaki J. Am. Chem. Soc. 1991 113 2123. l3 D. Y. Jackson and P. G. Schultz J Am. Chem. Soc. 1991 113 2319. 14 F. Vogtle 'Supramolecular Chemistry an Introduction' Wiley Chichester 1991; ed. H.-J. Schneider and H. Durr 'Frontiers of Supramolecular Organic Chemistry and Photochemistry' VCH Weinheim 1991. Is F. M. Menger Angew. Chem. Znf. Ed. Engl. 1991 30 1086. 16 Interactions computation W. L. Jorgensen Chemtracts Organic Chemistry 1991 4 91; W.C. Ripka and J. M. Blaney Top. Stereochem. 1991 20 1. l7 Ten news items and articles describing prospects for nanotechnology Science 1991 254(5036) 1300- '* These are essentially calixarenes with functional groups on one face see J. Vicens and V. Bothmer 1342. 'Calixarenes a Versatile Class of Macrocyclic Compounds' (Topics in Inclusion Science 3) Kluwer Dordrecht 1991. 19 'Host-Guest molecular Interactions From Chemistry to Biology' Ciba foundation Symposium 158 Chairman I. 0. Sutherland Wiley Chichester 1991. 20 J. C. Sherman C. B. Knobler and D. J. Cram J. Am. Chem. SOC.,1991 113 2194. 21 J. A. Bryant M. T. Blanda M. Vincenti and D. J. Cram J. Am. Chem. SOC.,1991 113 2167. 22 Hemicarcerands differ from carcerands in having portals through which guests can enter and leave.23 D. J. Cram M. E. Tanner and R. Thomas Angew. Chem. Inf. Ed. Engl 1991 30 1024; H. Hopf Angew. Chem. Int. Ed. Engl. 1991 30 1117. 24 M. L. C. Quan and D. J. Cram J. Am. Chem. SOC.,1991 113 2754; D. J. Cram M. E. Tanner and C. B. Knobler J. Am. Chem. SOC.,1991 113 7717. 25 J. K. Judice and D. J. Cram J. Am. Chem. Soc. 1991 113 2790. Synthetic Methods 22 1 Buckminsterfullerene.-The most vigorous area of research (as judged by citation analysis of papers published in 1991) continues to be the chemistry of buckminster- fullerene.26 The simple construction of the carbon spark generator27 enables even a novice to make practical amounts of fullerite (the raw mixture of c60 C70 and higher homologues) which can be separated crudely by soxhlet extraction28 and purified by HPLC.29 The spark generator appears to operate by formation of individual carbon atoms because mixtures of 12C and 13Cgraphite give C60in which the 13C atoms are randomly in~orporated.~' 26 Reviews H.W. Kroto A. W. Allaf and S. P. Balm Chem. Rev. 1991 91 1213; J. F. Stoddart Angew. Chem. Znt. Ed. Engf. 1991 30 70; A. Moody Chem. Ind. 1991 (lo) 346; R. Lee ibid. 349; J. S. Miller Adu. Mater. 1991 3 262; F. Diederich and R.L. Whetten Angew. Chem. Znt. Ed. Engl. 1991 30 678. 27 A. S. Koch K. C. Khemani and F. Wudl J. Org. Chem. 1991 56 4543. 28 D. H. Parker P. Wurz K. Chatterjee K. R. Lykke J. E. Hunt M. J. Pellin J. C. Hemminger D. M. Gruen and L.M. Stock J. Am. Chem. SOC.,1991 113 7499. 29 W. Pirkle and C. J. Welch J. Org. Chem. 1991 56 6973. 30 J. M. Hawkins A. Meyer S. Loren and R. Nunlist J. Am. Chem. SOC.,1991 113 9394; C. S. Yannoni P. P. Bernier D. S. Bethune G. Meijer and J. R. Salem J. Am. Chem. SOC.,1991,113,3190; for complete 2D NMR studies see J. M. Hawkins S. Loren A. Meyer and R. Nunlist J. Am. Chem. SOC.,1991 113 7770; R. D. Johnson G. Meijer J. R. Salem and D. S. Bethune J. Am. Chem. SOC.,1991 113 3619. 222 D. R. Kelly c60 and CT0 have eluded structyral characterization by X-ray crystallography because these nearly spherical molecules spin too quickly in the crystal lattice,31 however the cyclohexanone solvates reduce this rotation sufficiently to define the positions and general shape32 and the osmium tetraoxide dipyridine adduct was sufficiently ordered that the ‘football’ structure could finally be proven.33 A hexa(diethy1phosphino platinium) adduct of C60 is formed with octahedral symmetry and n2-bonding at the electron rich 6:6 fusions;34 similarly C70 reacts with Ir(CO)Cl(Ph3P)2 to give a mono n2-adduct at the most non-planar 6:6 fusion.35 In both cases the adducts were characterized by X-ray crystallography.The situation for p-block derivatives is much less satisfactory. The C600 and C700,36 the monoepoxides have been characterized well but other derivatives such as c~~(cH~)~-~~ c~~F~~, ,37 c~~F~() ~70~40, ,38 amongst other fluoro derivative^,^^ C6Oc112 ?o c60c12 C60Br~ C60(OCH3)1-26 C60Ph>22 C60HPh12 ,42 C60(morpho-line)643 are only characterized as amorphous mixtures.c60 readily forms stable radical anion saltsu which are semiconductors. It is reduced to a trianion4’ with alkali metals46 to produce materials that are supercon- ducting at 18 K which is unprecedentedly high for an ‘organic supercond~ctor’,4~ 31 J. M. Hawkins T. A. Lewis S. D. Loren A. Meyer J. R. Heath R. J. Saykally and F. J. Hollander J. Chem. Soc. Chem. Commun. 1991,775; W. I. F. David R. M. Ibberson J. C. Matthewman K. Prassides T. J. S. Dennis J. P. Hare H. W. Kroto R. Taylor and D. R. M. Walton Nature 1991 353 147 32 S. M. Gorun K. M. Creegan R. D. Sherwood D. M. Cox V. W. Day C. S. Day R. M. Upton and C. E. Briant J. Chem. Soc. Chem. Comrnun. 1991 1556. 33 J. M. Hawkins A.Meyer T. A. Lewis S. Loren and F. J. Hollander Science 1991 252(5003) 312. 34 P. J. Fagan J. C. Calabrese and B. Malone J. Am. Chem. Soc. 1991 113 9408; J. M. Hawkins A. Meyer T. A. Lewis S. Loren F. J. Hollander Science 1991 252 312; P. J. Fagan J. C. Calabrese and B. Malone Science 1991 252 1160. 35 A. L. Balch V. J. Catalano J. W. Lee M. M. Olmstead and S. R. Parkin J. Am. Chem. Soc. 1991 113 8953. 36 F. Diederich R. Ettl Y. Rubin R. L. Whetten R. Beck M. Alvarez A. Anz D. Sensharma F. Wudl K. C. Khemani and A. Koch Science 1991 252 548. 37 J. W. Bausch G. K. S. Prakash G. Olah D. S. Tse D. C. Lorents Y. K. Bae and R. Malhotra J. Am. Chem. Soc. 1991 113 3205. 38 J. H. Holloway E. G. Hope R. Taylor J. Langley A. G. Avent T.J. Dennis J. P. Hare H.W. Kroto and D. R. M. Walton J. Chem. Soc. Chem. Comrnun. 1991,966. 39 H. Selig C. Lifshitz T. Peres J. E. Fischer A. R. McGhie W. J. Romanow J. P. Cauley Jr. and A. B. Smith 111 J. Am. Chem. Soc. 1991 113 5475. 40 F. N. Tebbe J. Y. Becker D. B. Chase L. E. Firment E. R. Holler B. S. Malone P. J. Krusic and E. Wasserman J. Am. Chem. SOC. 1991 113,9900. 41 G. A. Olah I. Bucsi C. Lambert R. Aniszfeld N. J. Trivedi D. K. Sensharma and G. K. S. Prakash J. Am. Chem. Soc. 1991 113 9385. 42 G. A. Olah I. Bucsi C. Lambert R. Aniszfeld N. J. Trivedi D. K. Sensharma and G. K. S. Prakash J. Am. Chem. SOC.,1991 113,9387. 43 A. Hirsch Q. Li and F. Wudl Angew. Chem. Znt. Ed. Engl. 1991 30,1309. 44 P.-M. Allemand G. Srdanov A. Koch K. Khemani F. Wudl Y.Rubin F. Diedrich M. M. Alvarez S. J. Anz and R. L. Whetton J. Am. Chem. Soc. 1991 113 2780. 45 D. M. Cox S. Behal M. Disko S. M. Gorun M. Greaney C. S. Hsu K. B. Kollin J. Millar J. Robbins W. Robbins R. D. Sherwood and P. Tindall J. Am. Chem. Soc. 1991 113 2940; P.-M. Allemand A. Kochi F. Wudl Y. Rubin F. Diederich M. M. Alvarez S. J. Anz and R. L. Whetten J. Am. Chem. SOC.,1991 113 1050. 46 J. P. McCauley Jnr. Q.Zhou N. Coustel 0. Zhu G. Vaughan S. H. J. Idziak J. E. Fischer S. W. Tozer D. M. Groski N. Bykovetz C. R. Lin A. R. McGhie B. H. Allen W. J. Romanow A. M. Denenstein and A. B. Smith 111 J. Am. Gem. Soc. 1991 113 8537; R. M. Fleming A. P. Ramirez M. J. Rosseinsky D. W. Murphy R.C. Haddon S.M. Zahurak and A. V. Makhija Nature 1991,352 787.47 A. F. Hedard et al. Nature 1991 350(6319) 600; This was the most highly cited paper published in 1991 with 89 citations; see also R. C. Haddon et al. Nature 1991 350(6318) 920; J. H. Weaver et al. Chem. Phys. Lett. 1991 66 1741. Synthetic Methods whereas the tetra-anions are not superconductors.48 c60+and c6()-can be generated reversibly but only in ben~onitrile.~~ c60 and C70 are stable to light and readily yield the triplet states” which are good sensitizers for singlet oxygen formation.” Species such as AgC60 ,52 FeC60+,53and the ‘dumbbell’ Ni( C60)2+ 54 have the metal bound on the outer surface of the fullerene however C6,He’+ 55 and C60Ne-+ produced by collision in ion beamss6 may be the long sought after endohedral complexes.57 In another surprise in this area c76 (4)” and Cgqs9 both appear to have D2 symmetry and exist as pairs of enantiomers.By analogy with the helicenes they are expected to have extremely high optical rotations. The carbon oxides (5) are precursors of ‘cyclic carbon’ (6) (7).60 Ab initio calculations suggest that the most stable valence isomer of C18 is the cummulene (7) rather than the polyacetylene (6).61 Intriguingly the C30 (6c) (7c) homologue gives an extremely intense peak at 720amu in the positive ion laser desorption Fourier transform mass spectrum implying dimerization to c60. A new synthesis of corannulene (13) ([5]circulene) has two particularly striking steps (Scheme 1) Double Knoevenagel condensation yields a cyclopentadienone 48 R.M. Fleming M. J. Rosseinsky A. P.Ramirez D. W. Murphy J. C. Tully R. C. Haddon T. Siegrist R. Tycko S. H. Zahurak A. V. Makhija and C. Hampton Nature 1991 352 701. 49 D. Dubois K. M. Kardish S. Flanagan and L. J. Wilson J. Am. Chem. SOC.,1991 113 7773. M. R. Wasielewski M. P. O’Neil K. R. Lykke M. J. Pelin and D. M. Gruen J. Am. Chem. SOC.,1991 113 2774. 51 J. W. Arbogast and C. S. Foote J. Am. Chem. SOC.,,1991 113 8886. 52 J. A. Howard M. Tomietto and D. A. Wilkinson J. Am. Chem. SOC.,1991 113 7870. 53 L. M. Roth Y. Huang J. T. Schwedler C. J. Cassady D. Ben-Amotz B. Kahr and B. S. Freiser J. Am. Chem. SOC.,1991 113 6298. 54 Y. Huang and B. S. Freiser J. Am. Chem. SOC.,1991 113 8186. 55 T. Weiske D. K. Bohme J. Hrusak W. Kratschmer and H.Schwarz Angew. Chem. Znr. Ed. Engl. 1991,30 884. 56 K. A. Caldwell D. E. Giblin C. S. Hsu D. Cox and M. L. Gross J. Am. Chem. SOC.,1991 113 8519. 57 J. Cioslowski and E. D. Fleischmann J. Chem. Phys. 1991,94 3730; J. Cioslowski J. Am. Chem. SOC. 1991 113 4139; J. Cioslowski and S. T. Mixon J. Am. Chem. SOC.,1991 113 4142. 58 R. Etti I. Chao F. Diederich and R. L. Whetten Nature 1991 353 149. 59 P. W. Fowler J. Chem. SOC.Faraday Trans. 1991 87 1945. 60 Y. Rubin M. Kahr C. B. Knobler F. Diederich and C. L. Wilkins J. Am. Chem. SOC.,1991 113 495. 6’ V. Parasuk J. Almlof and M. W. Feyereisen J. Am. Chem. SOC.,1991 113 1049. 224 D. R. Kelly a n=l b n=2 c n=3 0 & \/ \/ (9) I @R&Eg c-\/ iv \/ \/ a R=E -'Jii b R=CH=CBr c R=C==CHd iii Reagents i Glycine norbornadiene; ii (a) LiAIH4 (b) PCC (c) Ph,P,Zn,CBr,; iii LDA; iv Flash vacuum pyrolysis Scheme 1 Synthetic Methods 225 (9) which undergoes a Diels-Alder reaction in situ with nonbornadiene.The adduct (10) eliminates cyclopentadiene by a retro Diels-Alder reaction and extrudes carbon monoxide to give diester (12a). This was converted to the tetrabromide (12b) or the diacetylene (12c) both of which gave corannulene (13) in about 10% yield upon flash vacuum pyrolysis.62 Low temperature NMR studies show that corannulene has a bowl like structure which inverts rapidly through the planar form at room temperat~re.~~ Thiophenes-There has been a renaissance in the chemistry of olig~thiophenes~~ due to their potential as electrical conductor^^^ and occurrence in plants of the Compositae family66 where they act as photo to xi^^^ nematocides (e.g.a-terthiophene (14a) and a-quinquethiophene (14b)68).Typically these systems are prepared by acylation of thiophenes with succinyl chloride to give 1,4 diketones which are converted to a thiophene ring with Lawesson's reagent. The longest characterized oligothiophene is the undecithiophene (19 which was substituted with aliphatic r 1 (14) a n=l b n=3 R' RZ R' (15) a R' = R2= C,,H2 b R' = n-C12H25,R2= "-C,H sidechains to enhance solubility69 and has comparable conductivity to polythiophene or poly(benzo[ ~]thiophene).~' The bis(terthi0phene) (16) in which the two .rr-systems are orthogonal has been proposed as a molecular switch7' and an extraordinary 'insulated wire' consisting of a fully conjugated porphyrin core almost 65 A long with an insulating sheath of t-butyl groups has been prepared.72 62 L.T. Scott M. M. Hasemi D. T. Meyer and H. P. Warren J. Am. Chem. SOC.,1991,113,7082. Although corannulene ws first made in 1966 the synthesis has apparently never been repeated and so for example the 13C NMR spectrum had never been recorded prior to the current work. 63 For a comparable study of [7]circulene and [7.7]circulene see K. Yamamoto Y. Saitho D. Iwaki and T. Ooka Angew. Chem. Znt. Ed. Engl. 1991 30 1173. 64 S.Gronowitz 'Thiophene and its Derivatives Pt 4' (Chemistry of Heterocyclic Compounds 44),Wiley New York 1991.65 Review of organic conductors K. Davidson Educ. Chem. 1991 28 155. 66 J. Kagan Prog. Chem. Org. Naf. Prod. 1991 56 88. 67 D. M. Perrine D. M. Bush E. P. Komak M. Zhang Y. H. Cho and J. Kagan J. Org. Chem. 1991 56 5095. A. Men and F. Ellinger Synthesis 1991 462. 69 W. ten Hoeve H. Wynberg E. E. Havinger and E. W. Meijer J. Am. Chem. Soc. 1991 113 5887. 70 T. Iyoda M. Kitano and T. Shimidzu J. Chem. SOC.,Chem. Commun. 1991 1618. 71 J. Nakayama and T. Fujimori J. Chem. SOC.,Chem. Commun. 1991 1614; For the benzanoid analogue see N. Harada H. Ono Y. Nishiwaki and H. Uda J. Chem. SOC.,Chem. Commun. 1991 1753. 72 M. J. Crossley P. L. Bum S. S. Chew F. B. Cuttance and I. A. Newsom J. Chem. SOC., Chem. Commun. 1991 1564; M.J. Crossley P. L. Bum S. J. Langford S. M. Pyke and A. G. Stark J. Chem. SOC.,Chem. Commun. 1991 1567; M. J. Crossley and P. L. Burn J. Chem. SOC.,Chem. Commun. 1991 1569. 226 D. R. Kelly Natural Products Synthesis.-Evans has achieved the synthesis of Ferensimycin B which bears a total of 16 chiral centres on a 24 carbon backbone. In the last step aldol reaction of the zinc enolate (17) and aldehyde (18) gave a mixture of adducts (65% yield) in which Ferensimycin (19) (the threo-Cram adduct) was the largest r 1 ClZn ~t $e OM OM component (41Y0).~~ Nicolaou has completed the synthesis of the FGHIJ rings of brevetoxin A74in about 100 steps starting from common sugars.75 The ABCD and E ring fragments were finished last year. Assembly and a one carbon homologation at the aldehyde terminus should complete this monumental task.A nine year study has culminated in the syntheses of all members of the phyllanthostatin family (23). A key bond construction was addition of the vinyl lithium (21) to the aldehyde (20) to give the pivitol intermediate (22).76 73 D. A. Evans R. P. Polniaszek K. M. DeVries D. E. Guinn and D. J. Mathre J. Am. Chem SOC,1991 113 7613. 74 For a review of polyether antibiotics see J. A. Robinson Bog. Chem. Org. Not. Prod. 1991 58 1. ’’ K. C. Nicolaou A. C. Veale C.-K. Hwang J. Hutchinson C. V. C. Prasad and W. W. Ogilvie Angew. Chem Int. Ed. EngL 1991 30,299. 76 A. B. Smith 111 M. Fukui H. Vaccaro and J. R. Empfield J. Am. Chem SOC,1991 113 2071; A. B. Smith 111 R.A. Rivero K. J. Hale and H. Vacarro ibid. 2092; A. B. Smith K. J. Hale H. Vaccaro and R.A. Rivero ibid 21 12. Synthetic Methods I R4 I Me 0 AcO OH (23) Phyllanthoside R’ = RZ= H R3= Ac R4,R5= 0 (epoxide) Phyllanthostatin 1 1 Rz= Ac R3= H Phyllanthostatin 2 1 R’ = OH Phyllanthostatin 3 1 R4= R5= OH Chiral Analysis.-The developments in ~hiral~~ synthesis78 have severely tested the techniques for the determination of enantiomeric excess. HPLC,79,80SFC,81GLC,82 and capillary zone electrophoresis (CZE)83give the most accurate results but NMR spectro~copy~~ is usually quicker. Circular dichroism is restricted to compounds with good chromosphores but enables the absolute configuration to be determined.85 2,2,2-Trifluoro-1-(9-anthryl)ethanol(24) (which is widely used as a chiral solvating agent and as the stationary phase in chiral HPLC) adopts a conformation in solution which places the trifluoro group orthogonal to the anthracene ring and locks the 77 ‘New Developments in Molecular Chirality’ ed.P. C. Mezey Kluwer Academic Publishers Dordrecht 1991. 78 For industrial chiral synthesis see J. Crosby Tetrahedron 1991 47 4789. 79 ‘Chiral Separations by Liquid Chromatography’ ed. S. Ahuja ACS Symposium series 471 ACS Washington 1991; N. Krause and G. Handke Tetrahedron Lett. 1991 32 7225; W. H. Porter Pure Appl. Chem. 1992 63 1119; J. N. Kinkel U. Gysel D. Blase and D. Seebach Helu. Chim. Acta 1991 74 1622. 80 For the determination of absolute configuration by HPLC see K.S. Rein and R. E. Gawley J. Org. Chem. 1991,56 839; K. Nilsson A. Hallberg R. Isaksson and J. Sandstrom Acta Chem. Scand. 1991 45 716. 81 V. Schurig D. Schmalzing and M. Schleimer Angew. Chem Znt. Ed. EngL 1991 30,987. 82 Y. Dobashi K. Nakamura T. Saeki M. Matsuo S. Hara and A. Dobashi J. Org.Chem. 1991,56,3299. 83 P. Camilleri and G. N. Okafo J. Chem. Soc. Chem. Commun. 1991 196. 84 D. Parker Chem Rev. 1991,91 1441; for a new techniques using 77Se NMR see L. A. Silks 111 J. Peng J. D. Odom and R. B.Dunlap J. Chem Soc. Perk Trans. I 1991 2495. 85 H. E. Smith and L. P. Fontana J. Org. Chem. 1991 56 432; T. Hargitai P. Rheinholdsson and J. Sandstrom Acta Chem Scand. 1991,45 1076; D. F. Colon and S.T. Pickard J. Org. Chem.1991,56 2322. 228 D. R. Kelly A HN NH HOOCd kCOOH // HOOC COOH (25) hydroxyl group in a highly asymmetric environment.86 In the solid state homochiral material forms face to face dimers with the hydroxyl groups facing inwards and the hydroxyl proton engaged in an unusual .rr-facial hydrogen bond.87 Chiral lanthanide shift reagents are convenient to use but are highly unpredictable cause line broadening and can only be used in very dry organic solvents. However the Europium( 111) complex of (S S)-ethylenediamine-N,N'-disuccinicacid (25) discriminates the 'H NMR signals of enantiomeric amino acids in aqueous solution.88 It is remarkable that after 22 years Mosher's acid chloride (26)89 is still the paramount derivatizing reagentg0 for assessing enantiomeric purity and for determin- ing absolute stereo~hemistry.~' The cyano fluoro analogue (27) has been suggested CF F I I Ph-C-COOH Ph-C-COOH I I OMe CN (26) (27) as a substitute because it gives larger A6 values in the 19F NMR spectrum.92 Chiral derivatives are not necessarily required.Achiral diphenyldichlorosilane forms diastereomeric silyl acetals with chiral alcohols. If the dl and meso compounds can be distinguished the enantiomeric ratio can be ~alculated.~~ Similarly if the enan- tiomers associate in solution (e.g.by hydrogen bonding) the enantiomeric ratio can be determined in the same way!94 Cholesteric liquid crystals attached to steroidal crown ethers change colour when they bind enantiomeric ammonium salts.In the best case the difference in (A)(A)max was only 81 nm but it is not difficult to imagine that this could be developed into the chiral equivalent of pH paper!95 86 C. Jaime A. Virgili R. M. Claramunt C. Lopez and J. Elguero J. Org. Chem. 1991 56 6521. 87 H. S. Rzepa M. L. Webb A. M. Z. Slawin and D. J. Williams J. Chem. Soc. Chem. Cornmun. 1991 765. 88 J. Kido Y. Okamoto and H. G. Brittain J. Org. Chem. 1991 56 1412. 89 J. A. Dale D. L. Dull and H. S. Mosher J. Org. Chem. 1969 34 2543. 90 D. E. Ward and C. K. Rhee Tetrahedron Lett. 1991 32 7165. 91 I. Ohtani T. Kusumi Y. Kashman and H. Kakisawa J. Am. Chem. Soc. 1991 113 4092; T. Kusumi Y. Fujita I. Ohtani and H. Kakisawa Tetrahedron Lett. 1991 32 2923; I. Ohtani T.Kusumi Y. Kashman and H. Kakisawa J. Org. Chem. 1991 56 1296; T. Kusumi T. Fukushima I. Ohtani and H. Kakisawa Tetrahedron Lett. 1991 32 2939. 92 Y. Takeuchi N. Itoh H. Note T. Koizumi and K. Yamaguchi J. Am. Chem. Soc. 1991 113 6318. 93 X. Wang Tetrahedron Lett. 1991 32 3651. 94 C. Giordano A. Restelli M. Villa and R. Annunziata J. Org. Chem. 1991 56 2270. 95 T. Nishi A. Ikeda T. Matsuda and S. Shinkai J. Chern. Soc. Chem. Cornmun. 1991 339; F. Vogtle and P. Knops Angew. Chem. Znt. Ed. EngZ. 1991 30,958. Synthetic Methods New Publications.-The Organic Syntheses Reaction Guide96 has been brought up to date and collectives will occur at five yearly intervals in future rather than ten yearly as at present. Wilen’s excellent review of reviews is also appearing more freq~ently.~’ A reasonably priced 4 volume compilation of drug syntheses98 has been published as well as second editions of Greene’s ‘Protective Groups in Organic Synthesis’99 and Lowenthal’s ‘Guide for the Perplexed Experimentalist’.’00 2 CC Connection and Disconnection Ketones.-A careful study has for the first time given convincing proof that chelation increases the rate of nucleophilic addition to ketones.”’ Thus the chelating benzyl ether (28a) reacts 140 times faster with dimethyl magnesiumlo2 at -78 “C than the non-chelating silyl ether (28b).In fact the latter is about as reactive as methyl butyl ketone (28c). A similar study with the chiral ethers (29a-c) showed a direct correla- tion between diastereoselectivity and reaction rate.’03 LRa R=OBn b R=Pr c R=OSi(Pri) OR 0rganolithiums.-When the 0-deutero quinoline (30) was treated with butyl lithium and then quenched with H20 the C-deutero quinoline (31) (66% incorporation of deuterium) was f~rmed,”~ repetition of this work under slightly different conditions gave a 27-32% incorp~ration.’~~ This result was attributed to initial halogen-lithium exchange followed by intramolecular transfer of deuterium however it is also possible that individual molecules undergo alkoxide formation followed by halogen-lithium exchange and the aryl lithium is quenched by unreacted 0-deuteroquinoline (30).These two possibilities can only be resolved by a double labelling experiment which shows the extent of intermolecular transfer of deuterium.96 D. C. Liotta and M. Volmer ‘Organic Syntheses. Reaction Guide’ Incorporating Collective Volumes 1-7 and Annual Volumes 65-68 John Wiley and Sons Inc. New York 1991. 97 S. H. Wilen J. Org. Chem. 1991 56 477 2597 4580 5966; 1992 57 412 2203. 98 D. Lednicer and L. A. Mitscher ‘Organic Chemistry of Drug Synthesis’ Wiley New York 1991. 99 T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ Wiley New York 1991. 100 H. J. E. Loewenthal ‘Guide for the Perplexed Experimentalist’ J. Wiley and Sons Chichester 2nd edition 1990. 101 For acyl silanes see S. Bienz and A. Chapeaurouge Helv. Chim. Acta 1991,74 1477; aldol condensation R. Carlson A. Nordahl and W. Kraus Acta Chem Scand. 1991 45 46. 102 For boron enolates as nucleophiles see A.Bernardi A. M. Capelli A. Comotti G. Gennari M.Gardner J. M. Goodman and I. Paterson Tetrahedron 1991 47 3471. 103 E. L. Eliel S. V. Frye E. R.Hortelano X. Chen and X. Bai Atre Appl. Chem. 1992 63 1591. 104 N. S. Narasimhan N. M. Sunder R. Ammanamanchi and B. D. Bonde J. Am. Chem. SOC.,1990 112 4431. 105 D. J. Gallagher and P.Beak J. Am. Chem. Soc. 1991 113 7984. 230 D. R. Kelly OH Ph Ph Bun Bun An intriguing similar result has been obtained during the addition of butyl lithium to benzoic acid (32) which yields roughly equal amounts of the ketone (33) and the alcohol (34). The conventional wisdom is that deprotonation is followed by nucleophilic attack to give the stable dialkoxide (35).It has been suggested in this case that nucleophilic attack occurs prior to deprotonation (36) and that loss of lithium hydroxide gives the ketone (33) which then undergoes a second addition but it is also possible that lithium oxide is eliminated from the dialkoxide (35).'06 Dihalo-organ~lithiurns~~~ (37) add to diesters (38) without elimination of the ,alkoxy group (39) (40),'08 as do acyl anions.'09 C02Me x)--Li+ ( - X C02Me C02Me C02Me (37) X = C1 Br Lithium naphthalenide and lithium p,p'-di-tert-butylbiphenyl(LiDBB)"' are nor- mally used stoichiometrically for the preparation of organolithium'll reagents from alkyl halides but a new catalytic procedure is claimed to be equally efficient."* para-Dilithium hexakis(trimethylsily1)benzenide has been isolated as a bis-THF adduct113 with both lithium atoms located on the concave side of the boat shaped aromatic ring."4 Addition of D,O gives the expected 'Birch' 1,6dihydrobenzene.Association between cation and carbanion,' l5 and the degree of aggregation116 106 C. Einhom J. Einhom and J.-L. Luche Tetrahedron Lezt. 1991 32 2771. 107 a,a-halolithiums are configurationally stable at -120 "C R. W. Hoffmann T. Ruhland and M. Bewersdorf J. Chem. SOC.,Chem. Commun. 1991 195. 108 J. Barluenga L. Llavona M. Yus and J. M. Concellon Tetrahedron 1991 47 7875; J. Barluenga L. Llavona J. Concellon and M. Yus J. Chem. SOC.,Perk Trans. I 1991 297. 109 D. Seyferth R. M. Weinstein R.C. Hui W.-L. Wang and C. M. Archer J. Org. Chem. 1991,!% 5768.110 D. J. Rawson and A. I. Meyers Tetrahedron Lett. 1991 32 2095; N. J. R. van Eikern Hornmes F. Bickelhaupt and G. W. Klumpp J. Chem. SOC.,Chem. Commun. 1991,438. For a new analytical method see H. Kiljunen and T. A. Hase J. Org. Chem 1991 56 6950. 112 M. Yus and D. J. Ramon J. Chem. Soc. Chem. Commun. 1991 398. 113 A. Sekiguchi K. Ebata C. Kabuto and H.Sakurai J. Am. Chem. SOC.,1991 113 1464. 114 A. Sygula and P. W. Rabideau J. Am. Chem. SOC.,1991 113 7797. 115 H. J. Reich and J. P. Borst J. Am. Chem. Soc, 1991 113 1835. 116 M. Buhl N. J. R. van Eikema Hornmes P. von R. Schleyer U. Fleischer and W. Kutzelnigg J. Am. Chem. SOC.,1991 113 2459; L. M. Jackrnan E. F. Rakiewicz and A. J. Benesi J. Am. Chem. SOC.,1991 113 4101; H.-J. Gais J.Muller J. Volhardt and H. J. Lindner J. Am. Chem. SOC.,1991 113 4002. Synthetic Methods 23 1 profoundly affect the reactivity of organometallics but these factors are not readily predictable. The enthalpies of deprotonation of isopropanol by alkyl lithiums and lithium amides in the presence and absence of lithium t-butoxide are the same indicating that the alkoxide does not associate with the base.'17 But the rates of deprotonation of toluene and ethyl benzene increase when more sterically hindered potassium alkoxides are used with alkyl lithiums."' Dithioacetals derived from aromatic ketones (41) undergo reductive cleavage by alkyl lithiums to give a benzylic anion (42);l19similarly the allyl thioether (44)is cleaved by lithium 1-(dimethy1amino)naphthalenideto give the allyl methyl anion (45) which is a useful reagent for terpene synthesis.'** In a more complex example -RsxLi RsxsR E+_ RsxE Ph Me Ph Me Ph Me (41) (42) (43) R= Me Ph or R-R= -(CH2)2 -(CH2)3- addition to the aldehyde (46) gives an alkoxide (47) which undergoes deprotonation adjacent to one thioether and intramolecular nucleophilic displacement of the other thioether group.A second deprotonation directed by the alkoxide gives the cis-dilithiocyclopropane (48) which can be trapped with dimethylformamide to give the lactol (49).12'Reductive cleavage of BF,-THF complex (50) with LDBB at room temperature yields a versatile 8-alkoxy organolithium (51) used in a synthesis of PhS&H 2BuLi I phs>CHO ___* \ Li ?Me PhS PhS (46) / Lid Li (47) 117 E.M. Arnett and K. D. Moe J. Am. Chem SOC,1991 113 7068. 118 L. Lochmann and J. Petranek Tetrahedron Lett. 1991 32 1483. 119 A. Kreif B. Kenda and P. Barbeaux Tetrahedron Lett. 1991 32 2509. 120 D. W. McCullough M. Bhupathy E. Piccolino and T. Cohen Tetrahedron 1991 47 9727. 12' K. Tanaka H. Matsuura I. Funaki and H. Suzuki J. Chem SOC.,Chem. Commun. 1991 1145. 232 D. R. Kelly the olive fly sex pheromone (52).122 N-methyl tetrahydroisoquinoline (53) is deprot- onated by butyl lithium at C-4 (54) but the BF3 complex (55) is deprotonated adjacent to the amino group by lithium tetramethyl ~iperidide.'~~ -BF3 (55) -The diene (57) undergoes initial deprotonation to give an ally1 lithium (58) which eliminates lithium h~dride'~~ to give the triene (59).Double deprotonation then gives a product best formulated as the p-xylene dianion (60).'25 Bu"Li 4 _7 2BuLi 0-QLi 0 ,$ TMEDA TMEDA \ Intermolecular addition of organolithiums to unactivated alkenes is generally very but the kinetically controlled 5-exo-trig cyclization of 5-hexen-1 -yl lit hi urn^'^^ is much faster and has been used in a novel synthesis of racemic 122 B. Mudryk and T. Cohen J. Am. Chem SOC.,1991 113 1866; for a related cleavage of oxetane with K+(18-Crown-6)K-see Z. Jedlinski A. Misiolek A. Jankowski and H. Janeczek J. Chem. SOC.,Chem. Commun. 1991 1513. 123 S. V. Kessar P. Singh R. Vohra N. P. Kaur and K. N. Singh J. Chem. SOC.,Chem. Commun. 1991 568;S.V.=Kessar P.Singh K. N. Singh and M. Dutt J. Chem. SOC.,Chem Commun. 1991 570. 124 J. J. Novoa M.-H. Whangbo and G. D. Stucky J. Org. Chem. 1991,56 3181. 125 S. D.Meyer N. S. Nills J. B. Runnels B. de la Torre C. C. Ruud and D. K. Johnson J. Org.Chem. 1991,56 947. 126 B. 0.T. Kammermeier G. W. Klumpp K. Kolthof and M.Vos Tetrahedron Lett. 1991 32 3111; T.Hattori T.Suzuki and S. Miyano J. Chem. SOC.,Chem. Commun. 1991 1375. 127 W.F. Bailey A. D. Khanolkar K. Gavaskar T. V. Ovaska K. Rossi Y. Thiel and K. Wiberg J. Am. Chem SOC.,1991,113 5720; for a comparable epoxide cyclization see V. Cere C. Paolucci P. Pollicino E. Sandri and A. Fava J. Org. Chem. 1991 56,4513. Synthetic Methods I' -OMLi cuparene.I2' Cyclization of the vinyl ether (61) effected p-elimination of the alkoxide (62) to give a novel [1,4]-Wittig reat~angement'~~ to (63).Similarly dihydropyran (64) can be deprotonated to give the a-lithiated vinyl ether (65),l3' which undergoes nucleophilic addition of alkyl lithiums to the carbanionic centre (!) and alkoxide elimination to give the ring opened vinyl lithium (66).131 Polylithio aromatics have been sought by several groups but at present dilithio derivatives132 seem to be the practical limit. Treatment of 1,3,5-trimethoxybenzene (68) with 6 equivalents of BuLi/TMEDA complex and trapping with propyl disulfide gave only the bis adduct (69) but in situ repetition of the reaction allowed a third group to be introduced (70).'33 Direct lithiation of the diphenol (71a) gave insoluble MeovoMe SPr - SPr i 6 BuLi/TMEDA Meo@oMe BuLi ii (RS) PrS (W PrS SPr OMe OMe OMe (68) (69) (70) TMEDA = N,N,Nt,Nt-tetramethyl-l,2-ethane diamine precipitates but halogen-lithium exchange'34 gave the sulfide (73) via (72) plus reduced starting material (71a).135 Attempted halogen-lithium exchange with the sterically congested bromide (74) gave the unexpected plumbane (75) a diplum- bane and the alcohol (76) presumably via single electron transfer and hydrogen 128 W.F. Bailey and A. D. Khanolkar Tetrahedron 1991 47 7727. 129 W. F. Bailey and L. M. J. Zarcone Tetrahedron Lett. 1991 32 4425. 130 N. J. Harris and J. F. Sebastian Tetrahedron Lett. 1991 32 6069. 131 T. Nguyen and E.Negishi Tetrahedron Lett. 1991 32 5903. 132 L. Lochmann M. Fossatelli and L. Brandsma Red. Trav. Chim. Pays-Bas. 1990 109 529; T. Lund and H. Lund Acta Chem. Scand. 1991,45 655. 133 S. Cabiddu L. Contini C. Fattuoni C. Floris and G. Gelli Tetrahedron 1991 47 9279. 134 H. J. Reich D. P. Green and N. H. Phillips J. Am. Chem. SOC.,1991 113 1414. 135 J. M. Saa J. Motey G. Suner A. Frontera and A. Costa Tetrahedron Lett. 1991 32 7313. D. R. Kelly OH OH OLi Li OH OH (71) a X=H (72) (73) b X=Br c X=I (74) (75) radical migrati~n.'~~ n-Deficient aromatics normally undergo nucleophilic addition of organolithi~ms,'~~ but if a directing group is present ortho metallation occurs.138 Grignard Reagents.-Butyl magnesium bromide and butyl lithium react in surpris- ingly different ways with para-substituted benzophenones.BuMgBr produces increasing amounts of 1 -phenyl ethanols as the electronegativity of the substituents increases and the rate increases (p = 1.45) whereas the late of reaction of BuLi is virtually independent of the substituents and the ratio of addition to reduction is more or less constant (70 30).'39 Dry magnetic stirring of magnesium powder under an inert atmosphere causes fragmentation to give a micro-crystalline powder which is much more reactive than conventional 'turnings'. This enables 0.4M solutions of Grignard reagents to be produced free from coupling products." Cyclopropyl magnesium bromide is notorious difficult to prepare because the intermediate cyclopropyl radical^'^' attack the solvent to give cyclopropane but if it is prepared in the presence of hexyl bromide or hexyl magnesium bromide (entrainment) the yield is greatly enhanced.14* Reduction of magnesium chloride with lithium naphthalenide gives extremely fine magnesium powder which undergoes cycloaddition to 1,4 dienes to give a magnesium rnetall~cycle,'~~ which in turn reacts with dihalides to give fused'44 or 136 R.Okazaki K. Shibata and N. Tokitoh Tetrahedron Lett. 1991,32,6601; cf. B. Dhawan and D. Redmore J. Org. Chem. 1991 56 833. 137 For addition reactions of Grignard reagents see T. Holm Acta Chem. Scand. 1991 45 276 or thiols see S. Prachayasittikul G. Doss and L. Bauer J. Her. Chem. 1991 28 1051. 138 G. Queguiner F.Marsais V. Snieckus and J. Epsztajn Ada Het. Chern 1991 52 189; J. A. Lepoivre Janssen Chernica Acta 1991 9(1) 20. 139 H. Yamataka N. Miyano and T. Hanafusa J. Org. Chem. 1991 56 2573. 140 K. V. Baker J. M. Brown N. Hughes A. J. Skamulis and A. Sexton J. Org. Chern 1991 56,698. 141 J. F. Garst Acc. Chem. Rex 1991 24 95. 142 J. F. Garst F. Ungvary R. Batlaw and K. E. Lawrence J. Am. Chem. Soc. 1991 113 5392 6697. 143 o-Phenylenemagnesium tetramer M. A. G. M. Tinga 0. S. Akkerman F. Bickelhaupt E. Horn and A. L. Spek J. Am. Chem. SOC.,1991 113 3604. 1J4 R. D. Rieke and H. Xiong J. Org. Chem. 1991,56 3109. Synthetic Methods 235 (77) ~piro'~~ carbocycles. A curious double metallation was observed during zirconocene dichloride catalysed addition of ethyl magnesium halides to the ally1 pyrrolidine (77).'46 Amide Bases.-Crystalline LDA exists as a helical polymer'47 in which the 'backbone' consists of unprecedented near linear N-C-N bonds.'48 In hexane it exists as a mixture of at least five different types of aggregate however in THF solution it is present exclusively as the cyclic dimer (80a).'49 Addition of lithium chloride gives the dimer adduct (81) at low concentrations and the monomer adduct (82) at high concentrations whereas addition of an enolate gives the 1:1 dimer (83).'" HMPA is purported to enhance reactivity by acting as a disaggregating agent; however X I I Y (80) a X=THF Y=THF b X =THF Y = HMPA c X = HMPA Y = HMPA 14' 145 H.Xiong and R.D. Rieke Tetrahedron Lett. 1991 32 5269. 146 D. P. Lewis P. M. Muller R. J. Whitby and R. V. H.Jones Tetrahedron Lett. 1991 32 6797; CJ P. Canonne R. Boulanger and P. Angers Tetrahedron Lett. 1991 32 5861. R. E. Mulvey Chem. SOC.Rev. 1991,20 167; U. Olsher R. M. Izatt J. S. Bradshaw and N. K. Dalley Chem. Rev. 1991,91 137; cf:organomagnesium compounds P. R.Markies 0.S. Akkerman F. Bickel-haupt W. J. J. Smeets and A. L. Spek Adv. Organometallic Chem. 1991 32 147. 148 N. D. R. Barnett R. E. Mulvey W. Clegg and P. A. O'Neil J. Am. Chem. SOC.,1991 113 8187. 149 The crystal structure of this dimer has been reported but the details were not published however comparable structures have been reported for bis(trimethylsily1) amide bases P. G. Williard and M.A. Nichols J. Am. Chem. SOC.,1991 113; 9671; and a sodium amide P. C. Andrews D. R. Armstrong W. Clegg M. MacGregor and R. E. Mulvey J. Chem. SOC,Chem. Commun. 1991,497. For a comparable study of silaamidide salts see G. E. Underiner R P. Tan D. R. Powell and R. West J. Am. Chern. SOC.,1991 113 8437. A. S. Galiano-Roth Y.-J. Kim J. H. Gilchrist A. T. Harrison D. J. Fuller and D. B. Collum J. Am. Chem. Soc 1991 113 5053. 236 D. R. Kelly spectroscopic studies demonstrate that it sequentially (80b) (80c) replaces the THF ligands in the dimer (80a) without changing the state of aggregati~n.'~' In fact even an amide base incorporating a crown ether group exists as the dimer in the solid state.'52 Crystalline unsolvated enolates can be isolated from hexane solutions of LDA'53 (up to 0.1 M at -78 "C) and ketones esters or carbo~amides.'~~ The elusive isoprene'55 anion'56 has now been prepared using LDA and potassium t-butoxide.Cuprates.-Organocoppers can be prepared directly by the reaction of alkyl halides and dispersed Cu(o). In a new procedure lithium napthalenide reduction of CuCNe2LiBr rather than copper iodide phosphine complexe~,'~~ enables the prepar- ation of organocopper reagents free from phosphine ligands which are appreciably more reactive particularly in conjugate additi011s.l~~ The cuprate reagent prepared from 13Clabelled ethyl lithium and 13C labelled copper cyanide has a 13C-13C two bond NMR coupling. This indicates that both moieties are attached to the copper atom (Et(CN)CuLi) however addition of further ethyl lithium abolishes the coup- ling to the cyanide carbon and so this reagent must be formulated as a dialkyl cuprate lithium cyanide complex (Et,CuLi.LiCN) rather than a higher order cuprate; R2(CN)CuLi2 .159 Curiously when lithio silanes are added to these com- plexes an alkyl lithium is displaced and can be detected uncomplexed in solution.16' Considerable effort has been expended in the design of chiral amino16' and phosphine'62 ligands for asymmetric conjugate addition.One extremely successful example is the synthesis of the highly prized fragrance muscone. Conjugate addition of dimeric chiral complex formed from the ligand (84) and dimethyl cuprate to the enone (85) gives (R)-( -)-muscone (86) enantiomerically pure with non-0 0 Me (84) 151 F.E. Romberg J. H. Gilchrist A. T. Harrison D. J. Fuller and D. B. Collum J. Am. Chem. SOC,1991 113 5751. 152 D. Barr D. J. Bemsforb L. Mendez A. M. Z. Slawin R. Snaith J. F. Stoddart D. J. Williams and D. S. Wright Angew. Chem. Int. lid. Engl. 1991 30 82. 153 For a new analytical method see R.$. Ireland and R. S. Meissner J. Org. Chem. 1991 56 4566. 154 Y.-J. Kim M. P. Bernstein A. S. Galiano-Roth F. E. Romesberg P. G. Williard D. J. Fuller A. T. Harrison and D. B. Collum J. Org. Chem. 1991 56 4435. 155 M. Bertrand B. Waegell and J. P. Zahra Bull. SOC.Chim. Fr. 1991 128 904. 156 P. A. A. Klusener L. Tip and L. Brandsma Tetrahedron 1991 47 2041. 157 G. W. Ebert and W. R. Klein J.Org. Chem. 1991 56 4744. 158 D. E. Stack B. T. Dawson and R. D. Rieke J. Am. Chem. SOC.,1991 113 4672. 159 S. H. Bertz J. Am. Chem. SOC.,1991 113 5470; S. H. Bertz G. Dabbagh and A. M. Mujsce J. Am. Chem. SOC.,1991 113 631. 160 R. D. Singer and A. C. Oehlschlager J. Org. Chem. 1991,56,3510; S. Sharma and A. C. Oehlschlager J. Org. Chem. 1991 56 770; S. Sharma and A. C. Oehlschlager Tetrahedron 1991 47 1177; R. D. Singer M. W. Hutzinger and A. C. Oehlschager J. Org. Chem. 1991 56 4933. 161 B. E. Rossiter M. Eguchi A. E. Hernandez D. Vickers J. Medich J. Marr and D. Heinis Tetrahedron Lett. 1991 32 3973. 162 A. Alexakis S. Mutti and J. F. Normant J. Am. Chem. SOC.,1991 113 6332. Synthetic Methods 237 enantiomerically pure ~ata1yst.l~~ This phenomenon known as chiral amplification comes about when the heterodimeric catalytic complex is more stable and the homodimeric complex is more reactive and enantioselective.In essence all of the less abundant enantiomer is trapped in the heterodimeric complex and hence the reactive homodimer is enantiomerically pure. Zinc.-The formation of organozincs by reaction of an organohalide and zinc metal is normally very slow however the reaction with alkyl iodides is accelerated by primary amine~'~~ and using precipitated zinc'65 even alkyl chlorides can be conver- ted quantitatively. Diorganozincs are unreactive with aldehydes however the complexes'66 formed with catalytic amounts of amine ligands (e.g. (87),'67 (88),16* (89),'69 (9O)l7O) or the titanium complex (91)171 promote highly enantioselective addition.&/ OH OH 3.' CH (87)=( -)-DAIB ( -)-3-exo-(dimethylamino)isoborneol Li (89) " xu (1R,2S)-(+)-dibutyl Li Ph Ph norephedrine (90) The reactivity of organozinc halides can be modified by transmetallation with a mixture of lithium chloride and copper cyanide to give reagents'72 with a similar but attenuated reactivity reminiscent of organocoppers or cuprates such as syn 163 K. Tanaka and H. Suzuki J. Chem. SOC.,Chem. Commun. 1991,101; K. Tanaka H. Ushio Y.Kawabata and H. Suzuki J. Chem. SOC.,Perk. Trans. I 1991 1445; K. Tanaka J. Matsui Y. Kawabata H. Suzuki and A. Watanabe J. Chem. SOC.,Chem. Commun. 1991,1632; for an alternative approach see T. Ogawa C.-L.Fang H. Seumune and K. Sakai J. Chem. SOC.,Chem. Commun. 1991 1438. 164 H. P. Knoess M. T. Furlong M. J. Rozeman and P. Knochel J. Org. Chem. 1991 56 5974. 165 L. Zhu R. M. Wehmeyer and R. D. Rieke J. Org. Chem. 1991 56 1445. 166 For an X-ray crystal structure of a zinc aldehyde complex see M. Bochmann K. J. Webb M. B. Hursthouse and M. Mazid J. Chem. SOC.,Chem. Commun. 1991 1735. R. Noyori and M. Kitamura Angew. Chem. Int. Ed. Engl. 1991 30 49. 168 M. Hayashi T. Kanekp and N. Oguni J. Chem. SOC.,Perk. Trans. I 1991 25. 169 K. Soai Y. Kawase and A. Oshio J. Chem. SOC.,Perk. Trans. I 1991 1613; S. Niwa T. Hatanaka and K. Soai J. Chem. SOC.,Perk. Trans. I 1991 2025; P. Chaloner E. Langadianou and S. A. R. Perera J. Chem. SOC.,Perk.Trans. I 1991,2731; for conjugate additions to enones see K. Soai M. Okudo and M. Okamoto Tetrahedron Lett. 1991 32 95. 170 S. Niwa and K. Soai J. Chem. SOC.,Perk. Trans. I 1991 2717; T. Shono N. Kise E. Shirakawa H. Matsumoyo and E. Okazaki J. Org. Chem. 1991 56 3063. 171 B. Schmidt and D. Seebach Angew. Chem. Int. Ed. Engl. 1991,30 99 1321; D. Seebach L. Behrendt and D. Felix Angew. Chem. Int. Ed. Engl. 1991 30 1008. 172 S. A. Rao and P. Knochel J. Org. Chem. 1991 56 4591. 238 D. R. Kelly addition to acetylene^,'^^ addition-elimination with nitroalkene~'~~ and coupling with vinyl halides.'75 Ally1 Silanes and Stannane~."~-An ultrasonicated mixture of allyl bromide and tin powder in ethanol-water effects diastereoselective addition (threo :erythro approx 5 1) of an allyl group to aldoses with good to excellent yields.'77 Similar results can be obtained with aldehydes and ketones by blending them with allyl br~mide"~ or propargyl bromide,'79 zinc and ammonium chloride in a mortar and pestle.The triene disilane (92) was acylated twice in one pot to give a diketotrienes (93)lg0and the distannane (94) reacted with oxalyl chloride in refluxing THF to give the useful cyclopentanone (95).18' 0 Me3Sn SnMe reflux (94) (95) The addition of alkoxy substituted allyl species18* to aldehydes'83 and a$ un-saturated ketones'84 has been a major theme this year and some perplexing results have been obtained. Addition of a-alkoxyallyl silanes and stannanes (96) to aliphatic aldehydes (97a) gives predominantly the syn E-isomer (98a) whereas aromatic aldehydes (97b) give the syn 2-isomer (99b) with the opposite facial sele~tivity,'~~ which was attributed to diastereomeric boron trifluoride complexes (102) (101).'86 But in general bidentate Lewis acids (e.g.TiC14'") give much better stereoselectivity 173 S. A. Rao and P. Knochel J. Am. Chem. SOC.,1991,113,5735; cf G. Courtemanche and J.-F. Normant Tetrahedron Lett. 1991 32 5317. 174 C. Retherford and P. Knochel Tetrahedron Lett. 1991 32 441. 175 S. A. Rao and P. Knochel J. Org. Chem. 1991 56,4593. 176 V. J. Jephcote and E. J. Thomas J. Chem. SOC.,Perk Trans. I 1991,429; see also allyl indiums S. Araki T. Shimizu P. S. Johar S.-J. Jin and Y. Butsugan J. Org. Chem. 1991 56 2538; allyl bariums A.Yanagisawa S. Habaue and H. Yamamoto J. Am. Chem. SOC.,1991 113 8955; and allyl tri- fluorosilanes Y.Hatanaka Y.Ebina and T. Hiyama J. Am. Chem. SOL 1991 113,7075. I77 W. Schmid and G. M. Whitesides J. Am. Chem. SOC.,1991 113 6674. 178 K. Tanaka S. Kishigama and F. Toda J. Org. Chem. 1991 56 4333. I79 J. J. DeVozz J. F. Jamie J. T. Blanchfield M. T. Fletcher M. G. O'Shea and W. Kitching Tetrahedron 1991,47 1985; C. Chen and D. Crich J. Chem. SOC.,Chem. Commun. 1991 1289. 180 F. Babudri V. Fiandanese and F. Naso J. Org. Chem. 1991 56 6245. 181 A. Degl'Innocenti P. Dembach A. Mordini A. Ricci and G. Seconi Synthesis 1991 267. lS2 J. A. Marshall and G. S. Welmaker Tetrahedron Lett. 1991 32 2101; J. A. Marshall G.S. Welmaker and B. Gung J. Am. Chem. SOC.,1991 113,647. 183 J. A. Marshall and D. V. Yashunsky J. Org. Chem 1991 56 5493; J. A. Marshall and G. P. Luke J. Org. Chem. 1991 56 483. 184 L. 0.Jeroncic M.-P. Cabal S. J. Danishefsky and G. M. Schulte J. Org. Chem. 1991 56 387. 185 B. W. Gung D. T. Smith and M. A. Wolf Tetrahedron Lett. 1991 32 13; B. W. Gung A. J. Peat B. M. Snook and D. T. Smith Tetrahedron Lett. 1991 32 453. 186 B. W. Gung Tetrahedron Lett. 1991 32 2867. 187 C. Nativi G. Palio and M. Taddei Tetrahedron Lett. 1991 32 1583. Synthetic Methods Ye Me OR‘ (97)RCHO R +OR’ + R+ BF,.Et,O IOH OH R’= (8-phenylmethy1)oxymethyl a = cyclohexyl SY n-(E 1 82 sYn-(Z) 18 b = C6HS <1 95 antiperiplanar ‘outside alkoxy’ than modentate Lewis acids (e.g.BF3),in which the stereocontrol results solely from steric interactions.’88 The stereoselectivity of ring opening of acetals (104) to (106) and (107) is lower with allyl silanes than allyl stannes (105p9 because the acetals undergo reversible ring ~pening’’~ prior to attack of the less reactive allyl silanes.”l Similar oxonium ion intermediates can be generated in situ from aldehydes and trimethylsilyl ethers’” and the intramolecular reaction has been used for a synthesis of medium ring ethers.193 188 Y. Nishigaichi A. Takuwa and A. Jodai Tetrahedron Lett. 1991,32,2383; J. A. Marshall and X.Wang J. Org. Chem. 1991 56 3211; 6264. 189 G. Hagen and H. Mayr J. Am. Chem. Soc. 1991 113 4954. 190 S.E. Denmark and N. G. Almstead J. Am. Chem. SOC.,1991 113 8089. 191 S. E. Denmark and N. G. Almstead J. Org. Chem. 1991 56 6458 6485. 192 A. Mekhalfia and I. E. Marko Tetrahedron Lett. 1991 32 4779. 193 R. Chakraborty and N. S. Simpkins Tetrahedron 1991 47 7689; for other cyclizations involving imminium ions H. H. Mooiweer H. Hiemstra and W. N. Spekamp Tetrahedron 1991,47,3451; epoxides M.Yoshitake M. Yamamoto S. Kohmoto and K. Yamada J. Chem. Soc. Perkin Trans. I 1991 2157 2161; enones G. Majetich J.-S. Song C. Ringold G. A. Nemeth and M. G. Newton J. Org. Chem. 1991 56 3973. 240 D. R. Kelly Cy~loadditions.'~~-[2+ I]. A stable crystalline carbene has been prepared it melts at 240-241 "C without decompo~ition'~~ and gives a 'reverse' ylide with iodopenta- flu~robenzene'~~ but no reactions with alkenes have been reported thus far.It was anticipated that methoxytrifluoromethylcarbene would be stabilized by a push-pull effect(cf:captodative radicals) but in fact it is much more reactive than most other carbenes and fails to discriminate between electron deficient and electron rich alkene~.'~' Highly reactive Simmons-Smith reagents'98 can be prepared from chloroiodomethane and diethylzinc in 1,2 di~hloroethane,'~~ but the reagents are less stable than in ethereal solvents2" and less regioselective.201 This method can also be applied to iodoform for the generation of iodocarbene.202 The metal complex catalysed203 asymmetric cyclopropanation of alkenes with diazoalkenes is a notoriously difficult reaction.The enantioselectivity is usually poor and cis/trans mixtures are produced. Accordingly most workers have effected double differentiation by using both a chiral catalyst and a chiral diazoester. However the technology has now progressed sufficiently far that the chirality in the diazoester can be dispensed with204 although a sterically hindered ester (108) is still required for trans/& selectivity. In the best case styrene (109) gave 95% of the trans cyclopropane (11 1) (97% ee).205 Intramolecular cyclopropanation206 with rhodium catalysts does not seem to suffer from the formation of &/trans mixtures and the enantioselectivities are excel~ent.~" 194 Enantiocontrolled Cycloadditions ed. L. M. Harwood a 'symposium in print' Tetrahedron Asymmetry 1991,2 1173-1444.195 A. J. Arduengo 111 R. L. Harlow and M. Kline J. Am. Chem. Soc. 1991 113 361 2801; M. Regitz Angew. Chem. Znt. Ed. Engl. 1991 30 674. 196 A. J. Arduengo 111 M. Kline J. C. Calabrese and F. Davidson J. Am. Chem. SOC.,1991 113 9704. 197 R. A. Moss T. Zdrojewski and G.-J. Ho J. Chem. SOC.,Chem. Commun. 1991 946. S. Durandetti S. Sibille and J. Perichon J. Org. Chem. 1991 56 3255. 198 199 S. E. Denmark and J. P. Edwards J. Org. Chem. 1991 56 6974. 200 The crystal structure of bis(iodomethy1) zinc coordinated to a bornane ether has been determined. S. E. Denmark J. P. Edwards and S. R. Wilson J. Am. Chem. Soc. 1991 113 723. 201 E. C. Freidrich and F. Niyati-Shirkhodaee J. Org.Chem. 1991 56 2202. 202 E. V. Dehmlow and J. Sutten Tetrahedron Lett. 1991 32 6105. 203 Review M. P. Doyle Red. Trav. Chim. Pays-Bas. 1991 110 305; for reusable polymer bound rhodium carboxylates see D. E. Bergbreiter M. Morvant and B. Chen Tetrahedron Lett. 1991 32 2731. 204 R. E. Lowenthal and S. Masamune Tetrahedron Lett. 1991,32,7373; some ofthe structural assignments in this paper have been criticised see D. A. Evans et al. next citation. 205 D. A. Evans K. A. Woerpel M. M. Hinman and M. M. Fad J. Am. Chem. SOC.,1991 113 726. 206 For racemic and achiral examples see 3. Adams C. Lepine-Frenette and D. M.Spero J. Org. Chm. 1991,56 4494; W. Kirmse and G. Homberger J. Am. Chem. Soc. 1991 113 3925. 207 M. P. Doyle R.J. Peiters S. F. Martin R.E. Austin C.J. Oalmann and P. Muller J. Am. Chem SOC. 1991 113 1423. Synthetic Methods 241 Dichlorocarbene is easily generated under phase transfer conditions by the deprotonation of chloroform with aqueous sodium hydroxide and subsequent elimi- nation of chloride;208 however difluorocarbene generated under the same conditions reacts with water before it can be intercepted by an alkene. Consequently in an attempt to generate it in the organic bulk phase dibromomethane anion (1 12) was used as a halogenophile to generate the difluorobromo anion (113) elimination of bromide gave difluorocarbene (1 14) which was efficiently trapped by alkene~.~'~ Alternatively treatment of the phosphonium salt (1 15) with potassium fluoride gives difluorocarbene which was trapped with alkynes to give difluorocyclopropenes (116).210 TBAH =tetrabutyl ammonium hydrogen sulfate -CHBr + -CHBr3+CBrF +:CF,+ Br- Br' 'F (113) (114) (112) [Ph3h-CF,Br] Br- -(115) FF [2 +21 Thermal.Cycloaddition of the cyanoketene (117) to the alkene (118) gave the expected cyclobutanones (1 19) plus the regioisomeric ene reaction products (120).211These were attributed to the anion stabilizing ability of the cyano group212 which enables a stepwise zwitterionic mechanism to operate.213 Ab initio calculations now favour a [~2s+ (1~2s+572s)] description over the Woodward-Hofmann [7r2s + v2a] mechanism for ketene-alkene cyl~additions.~~~ Whatever the precise 0 0 NC& + + Los(+ 208 J. D. Winkler and E. A. Gretler Tetrahedron Lett.1991 32 5733. 209 P. Balcerzak M. Fedorynski and A. Jonczyk =I. Chem. SOC.,Chem. Commun. 1991 826. 210 Y. Bessard and M. Schlosser Tetrahedron 1991 47 7323; H. Burger and S. Sommer J. Chem. SOC. Chem. Commun. 1991 456. 211 A H. Al-Husaini M. Muqtar and Sk. A. Ali Tetrahedron 1991 47 3845 7719. 212 For a general discussion of the effect of substituents on ketene structure see L. Gong M. A. McAllister and T. T. Tidwell J. Am. Chem. SOC 1991 113,6021. 213 W. T. Brady and M. M. Dad J. Org. Chem. 1991 56 6118; T. Gotoh A. B. Padias and H. K. Hall Jr. 1. Am. Chem. SOC.,1991 113 1308. 214 E. T. Seidl and H. F. Schaefer 111 J. Am. Chem. SOC.,1991 113 5195. 242 D. R. Kelly nature of the transition state it is clearly highly ordered.The addition of oxazolidine substituted ketenes to imines is essentially stereo~pecific~~~ (>97% absolute stereochemistry unknown) and similarly the cycloaddition of the keteniminium salt gives a single stereoisomer at the bridgehead positions completely overwhelming the stereorandom elements present.216 Electrocyclic ring opening of cyclobutenes has been used in two novel ring transformation reactions.217 Thermolysis of the cyclobutenone (121) gives the vinyl ketene (122) which undergoes cycloaddition to the distal alkene to give (123) a bicyc10[3.2.0]heptanone.~~~ Similarly Trost used palladium catalysed olefin meta- thesis219 to give the tricyclic complex (125) which underwent ring opening to give the bicyclo[6.2. llundecane (126) .220 + Me0a h Me0*-OMe Me3Si0 + Me3si0Q =-C02Me (124) i Me0,C-N=N-C0,Me The sulfonyl allene framework (127) demonstrates the subtle balance between the [2 + 21 and [4 + 2) cycloaddition pathways.221 When there is no substituent at C-2 (127a) fast (2 + 2) cycloaddition gives the cyclobutene (128a) whereas with a methyl substituent (127b) slow [4 + 21 cycloaddition gives the decalin (129b).222 215 L.S. Hegedus J. Montgomery Y. Narukawa and D. C. Snustard J. Am. Chem. SOC.,1991 113 5784; cf B. C. Borer and D. W. Balogh Tetrahedron Lett. 1991 32 1039. 216 L. Chen and L. Ghosez Tetrahedron Asymmetry 1991 2 1181. 217 H. Hesse Ring Enlargements in Organic Chemistry VCH Weinheim 1991. 218 S. L. Xu H. Xia and H. W.Moore J. Org. Chem. 1991 56 6094. 219 R. Hertel J. Mattay and J. Runsink J. Am. Chem. SOC.,1991 113 657. 220 B. M. Trost and M. K. Trost J. Am. Chem. SOC. 1991 113 1850; for the metal mediated [2 + 21 dimerization of benzene see R. L. Thompson S. J. Geib and N. J. Cooper J. Am. Chem. Soc. 1991 113 8961. 221 S. J. Getty and W. T. Borden J. Am. Chern. SOC.,1991 113 4334. 222 K. Kanematsu N. Sugimoto M. Kawaoka S. Teo and M. Shiro Tetrahedron Lett. 1991 32 1351 for intermolecular [2 + 21 cycloadditions to allenes see D. J. Pasto K. D. Sugi and J. L. Malandra J. Org. Chem. 1991 56 3781 3795; 6216. Synthetic Methods 0 0 0 II II (127) (128) (129) a R=H (l10°C,5hrs) b R=Me (160 "C,48 hrs) [2 + 21 Photochemical. Photolysis of the bis-styrene (130) gave a mixture of all the possible cis cyclobutane stereoisomers (131) in low yield however the mixture was quantitatively converted to [4.4] metacyclophane (132) by Birch reduction.223 Photoenolization of the ketone (133) and thermal ring closure gives the cyclo- butenols ( 135) as single diastereoi~omers;~~~ in contrast photochemical ring disrota- tory opening of cyclobutenes is only partially stereo~elective.~~~ (133) The photoaddition226 of alkenes to enones is particularly useful because it can give the highly prized trans adducts but the reaction is frequently complicated by isomerization of the alkene.In an attempt to overcome this intramolecular photo- addition of the 2-alkene (136) (or the E-isomer) was attempted but an equal amount of diastereomeric products ( 137) were obtained due to non-stereospecific ring closure of the 1,4 diradical intermediate.227 The photoaddition of cyclopentene to cyclohexenone gives four adducts (138)-( 141) (68 :41 :7 :25) which were isomer- 223 J.Nishimura Y. Horikoshi Y. Wada H. Takahashi and M. Sato J. Am. Chem. SOC. 1991 113 3485 see also K. Nakanishi K. Mizuno and Y. Otsuji J. Chem. Soc. Chem. Commun. 1991 90. 224 P. J. Wagner D. Subrahmanyam and B.-S. Park J. Am. Chem. Soc. 1991 113 709. 22s W. J. Leigh and K. Zheng J. Am. Chern. Soc. 1991 113 4019. 226 D. I. Schuster G. E. Heibel and J. Woning Angew. Chern. Znt. Ed. EngZ. 1991 30 1345. 227 D. Becker M. Nagler Y. Sahali and N. Haddad J. Org. Chem. 1991 56,4537. 244 D.R. Kelly 0 hv ___+ HH HH b b HH HH ized by base to the cis-isomers (138) (139) (75:25) in contradiction to an earlier report.228 [3 + 2). The [2 + 21 cycloaddition of a$-unsaturated ketones and alkenes has been extended in a novel way by placing an alkyne group at the p-position of the enone. 1,5 closure gives the carbene (146) which abstracts hydrogen to give a mixture of dienes or reacts with excess alkene to give a cy~lopropane.~~~ Reviews have appeared of the addition of diazomethane to nitrogen heterocycle^^^' and the Weiss reaction.231 [4 + 2). There have been two major issues in Diels-Alder chemistry this year the use of novel solvents232 and enantioselective catalysis.233 Several reactions including the Diels-Alder reaction are accelerated if run in ~ate8’~ or laterly lithium perchlor- 228 D.I. Schuster N. Kaprinidis D. J. Wink and J. C. Dewan J. Org. Chem. 1991 56 561. 229 H.-J. Rathjen P. Margaretha S. Wolff and W. C. Agosta J. Am Chem. SOC.,1991 113 3904. 230 B. Stanovnik Tetrahedron 1991 47 2925; for other heterocyclic [3 + 21 cycloadditions see A. Ando M. Kato and T. Akasaka J. Am. Chem. SOC.,1991 113 6286; T. Hudlicky and G. Barbieri J. Org. Chem. 1991 56 4598; H. H. Karsch K. Zellner and G. Muller J. Chem. SOC.,Chem. Commun. 1991 466; P. J. Smith D. J. Soose and C. S. Wilcox J. Am. Chem. SOC.,1991 113 7412; P. A. Wender and J. L. Mascarenas J. Org. Chem. 1991 56 6267. 231 A. K. Gupta X. Fu J. P. Synder and J. M. Cook Tetrahedron 1991 47 3665; for other carbocyclic [3 + 21 annulations see F.Fellga P. Nitti G. Pitacco and E. Valentin J. Chem. SOC.,Perk. Trans. I 1991 1645; J. Boivin C. Tailhan and S. Z. Zard J. Am. Chem. SOC.,1991 113 5874; D. A. Singleton C. C. Huval K. M. Church and E. S. Priestly Tetrahedron Lett. 1991,32 5765; M. P. Collins J. Mann N. Capps and H. Finch J. Chem. Soc. Perk. Trans. I 1991 239. 232 C. Reichardt ‘Solvents and Solvent Effects in Organic Synthesis’ VCH Weinheim 1988. 233 K. Naraska Synthesis 1991 1. 234 R. Breslow Acc. Chem. Res. 1991 24 159; W. Blokzijl M. J. Blandamer and J. B. F. N. Engberts J. Am. Chem. SOC.,1991 113 4241; A. Lubineau J. Auge and N. Lubin Tetrahedron Lett. 1991 32 7529; I. Hunt and C. D. Johnson J. Chem. SOC.,Perk Trans. 11 1991 1051. Synthetic Methods I I-60'C 40°C ate-diethyl ether.235 This has been attributed to solvoconstriction (hydrophobic effect); the forcing together of the reactants by the cohesive forces between the water molecules,236 hydrogen bonding,237 and catalysis by lithium ions.238 Similar effects are claimed for the surface of clay239 (in non-aqueous solvents).The current strength of chiral Diels-Alder technology can be demonstrated by three syntheses of the prostaglandin intermediate (149). C~rey~~' used the achiral amide (148a) and either of two chiral catalysts (150)241 (151)242 and in both cases obtained the endo adduct (149) (>95% endo >95% ee). Whereas Arai used the chiral ester (148b) and titanium tetrachloride243 as catalyst and obtained essentially identical results (endo adduct only de 9%0).~~ a-Methylene p-lactones (152)245 are versatile substitutes246 for allene~.*~~ They 235 P.A. Greico Aldrichimica Acta 1991 24 59; H. Waldmann Angew. Chem. Znt. Ed. Engl. 1991 30 1306; P. A. Greico R. J. Cooke K. J. Henry and J. M. VanderRoest Tetrahedron Lett. 1991,32 4665; P. A. Greico J. D. Clark and C. T. Jagoe J. Am. Chem. Soc. 1991; 113 5488; A. Thaler D. Seebach and F. Cardinsux Helu. Chim. Acta 1991 74 617 628. 236 R. Brewlow and C. J. Rizzo J. Am. Chem. Soc. 1991 113 4340. 237 J. F. Blake and W. L. Jorgensen J. Am. Chem. Soc. 1991 113 7430. 238 M. A. Forrnan and W. P. Dailey J. Am. Chem. SOC. 1991 113 2761; G. Desimoni G. Faiti and P. P. Righetti Tetrahedron 1991,47,5857; G. Desimoni G.Faita P. P. Righetti and G. Tacconi Tetrahedron 1991 '47 8399; D. A. Smith and K. N. Houk Tetrahedron Lett. 1991 32 1549. 239 C. Collet and P.Laszlo Tetrahedron Lett. 1991 32 2905. 240 For closely related studies using other catalysts see E. J. Corey N. Imai and H.-Y. Zhang J. Am. Chem. .Soc. 1991 113 728; E. J. Corey and T.-P. Loh J. Am. Chem. Soc. 1991 113 8966. 24 1 E. J. Corey N. Imai and S. Pikul Tetrahedron Lett. 1991 32 7517; for borane based catalysts and auxilaries see J. M. Hawkins and S. Loren J. Am. Chem. Soc. 1991 113,7794; X. Wang J. Chem. Soc. Chem. Commun.,1991 1515. 242 E. J. Corey and Y. Matsumura Tetrahedron Lett. 1991 32 6289; for the use of this catalyst with 1,4 benzoquinones see T. A. Enger M. A. Letavic and J. P.Reddy J. Am. Chem. Soc. 1991 113 5068; and BINOL titanium dichloride M. Terada K. Mikami and T. Nakai Tetrahedron Lett. 1991,32,935. 243 R. C. Corcoran and J. Ma J. Am. Chem. Soc. 1991 113 8973. 244 K. Miyaji Y. Ohara T. Tabahashi T. Tsuruda and K. Arai Tetrahedron Lett. 1991 32 4557. 245 W. Adams R. Albert N. D. Grau L. Hasemann B. Nestler E.-M. Peters K. Peters F. Prechtl and H. G. von Schnering J. Org. Chem. 1991,56 5778. 246 For the use of vinyl sulfoxides as allene equivalents see R. V. Williams and K. Chauhan J. Chem. Soc. Chem. Commun. 1991,1672or as acetylene equivalents see A. Sekiguchi I. Maruki E. Ebata C. Kabuto and H. Sakurai J. Chem Soc. Chem. Commun. 1991 341. 246 D. R. Kelly 0 (149) b R= do 6 Mexoco; Ar Ar CF,SOz-N N-SOzCFS TiClz Ar = A< Ph 0 0 Me ' I H Me Me Ar Ar (150) (151) readily undergo cycloaddition and cleanly generate either allenes (155) or alkenes (154) albeit at high temperature^.^^' The furan (156) undergoes cycloaddition with ethyl a~rylate~~~ at room tem- perature to yield (157) whereas the phorbol precursor (158) required 19 kbar pres- sure25o to produce (159) but with a shorter tether cyclization occurred so readily that the open chain compound (160) could not be isolated.251 247 D.L. Boger and M. Zhang J. Am. Chem. SOC., 1991 113 4230. 248 W. Adam R. Albert L. Hasemann V. 0. N. Salgado B. Nestler E.-M. Peters K. Peters F. Prechtl and H. G. von Schnering J. Org. Chem. 1991 56 5782. 249 J. J. McNally and J. B. Press J.Org. Chem. 1991,56,245; K. Ando N. Akadegawa and H. Takayama J. Chem. SOC.,Chem. Commun. 1991 1765. L. M. Harwood T. Ishikawa H. Phillips and D. Watkin J. Chem. SOC.,Chem. Commun. 1991 527 for other examples of high pressure Diels-Alder reactions see R. W. M. Aben L. Minuti H. W. Scheeren and A. Taticchi Tetrahedron Lett. 1991 32 6445; V. Branchadell M. Sodupe R. M. Ortuno A. Oliva D. Gomez-Pardo A. Guingant and J. d'Angelo J. Org. Chem. 1991 56 4135. 2s1 M. E. Jung and J. Gervay J. Am. Chem. SOC. 1991 113 224; see also A. P. Kozikowski and W. Tuckmantel J. Org. Chem. 1991 56 2826. Synthetic Methods SCHzPh CH,CI - 13h 68% R= Me R,R=(CH,), R= Et COOMe (160) (161) Other Cyc1oadditions.-The nature of the current frontier in organic synthesis is well illustrated by Taxol (162).’” It is obtained in very small quantities from yew bark and has exciting anti-tumour and anti-leukaemic activity.There are no par- ticularly bizarre functional groups present; it is the number of groups and their cocatenation that poses the problem. Moreover synthesis of a few milligrams has no practical value. Kilograms are required for clinical studies. An interesting approach to the fused central bicycle uses the [4 + 41 photodimerization of bis- pyridones (163) to give (164) which instals four new chiral centre^."^ There have 252 S. Blechert and A. Kleine-Klausing Angew. Chem. Int. Ed. Engl. 1991,30,412; J.-N. Denis A. Correa and A. E. Greene J. Org. Chem. 1991 56 6939. 253 S. McN. Sieburth and J.Chen J. Am. Chern. Soc. 1991 113 8163. 248 D. R Kelly hu __+ 63% f OH only been sporadic reports of [6 + 21 cycloadditions but by photolysing a chromium(0) tricarbonyl triene complex (165) in the presence of an electron deficient diene (166) good yields of the deligated adduct (167) can be obtained (36-93%) and prolonged photolysis gives the cyclobutene (168).254The two previous examples 0 I u I’ 58% CdCOL 2.5 mol% (dba),Pd,CHCl, 10 mol% Ph,Sb 10 mol% AcOH 86% yield demonstrate the rapid elaboration of complexity that can be achieved by cycloaddi- tion. Other vivid examples are provided by Trost’s synthesis of five rings (170) in a single step from (169) by what he terms ‘polyolefin polycycloisomerization’ using palladium and the construction of the entire steroid ring system (173) by Diels-Alder reaction (171) (172) (ring A) carbonylation and electrocyclic ring closure (ring c) (Scheme 2).256 254 J.H. Rigby and J. A. Henshilwood J. Am. Chem. SOC.,1991,113 5122. 255 B. M.Trost Janssen Chimica Acta 1991,9(1),3; B. M.Trost and Y. Shi J. Am. Chem. SOC.,1991,113 701. 256 J. Bao V. Dragisich S. Wenglowsky and W. D. Wulff J. Am. Chem. SOC 1991,113 9873. Synthetic Methods Me Reagents i CH3CN CO 25 "C 16 h; ii 110 "C 23 h Scheme 2 3 Functional Group Manipulation Oxidation.-Hydroxylution. It would be highly desirable to be able to emulate the ability of micro-organisms to introduce a iunctional group at a remote unfunctional- ized carbon centre.Progress in this area has been slow but practically useful methodology has been achieved. Ruthenium tetraoxide selectively oxidizes2" adamantane to 1-adamantanol in 62% yield with no isomeric contaminants.2s8 Metal insertion into unactivated C-H occurs via a concerted C-H oxidative addition pathway2s9 which may be followed by oxygen insertion,260 C-C bond cleavage,261 or by hydrogen elimination. The power of this technology is demonstrated by the elimination of 3 moles of molecular hydrogen from methylcyclohexane by the ruthenium complex (174) to give (175).262 I -H2,-3H Ru P/\ P W (175) 257 For general reviews of methane and hydrocarbon oxidation H. Schwarz Angew. Chem. Int. Ed. Engl. 1991 820; K. Eller and H. Schwarz Chem. Rev.1991 91 1121; D. H. R. Barton and D. Doller Coll. Czech. Chem. Commun. 1991 45 984; idem. fire Appl. Chem. 1992 63 1567. A comprehensive description of Barton's work in this area was given in last years Annual Report. 258 J. M. Bakke and J. E. Braenden Actu Chem. Scund. 1991 45 418; for a similar iodosyl benzene oxidation catalysed by a manganese complex C.-M. Che W.-T. Tang K.-Y. Wong W.-T. Wong and T.-F. Lai J. Chem. Rex 1991 (S) 30 (M)401; osmium trichloride S.-I. Murahashi T. Sato T. Naota H. Kumobayashi and S. Akutagawa Tetrahedron Lett. 1991 32 2145; a binuclear iron complex N. Kitajima M. Ito H. Fukui and Y. Moro-oka J. Chem. SOC.,Chem. Commun. 1991 102. 259 M. R. A. Blomberg P. E. M. Siegbahn U. Nagashima and J. Wennerberg J. Am. Chem. Soc. 1991 113 424.260 L.-C. Kao A. C. Hutsoj and A. Sen J. Am Chem SOC,1991 113 700. 261 P. A. M. van Koppen J. Brodbelt M. T. Bowsers D. V. Dearden J. L. Beauchamp E. R. Fischer and P. B. Armentrout J. Am. Chem. Soc. 1991 113 2359. 262 J. D. Koola and D. M. Roddick J. Am. Chem. Soc. 1991 113 1450. 250 D. R. Kelly The efficient conversion of benzene derivatives263 to enantiomerically pure264 cis-benzene glycols (177b-d) by Pseudomonus putidu is still unmatched by abiotic chemical synthesis. Most functional groups are tolerated at C-1 but those that are not (177d) can be introduced by substitution of the bromo (176b) or iodo compounds (176c) using the requisite stannane under palladium catalysis.265 The plane of symmetry in the meso-diol (176a) is removed by enantioselective galactosyl transfer using E.coli P-galactosidase266 or by P. cepuciu lipase catalysed hydrolysis of a tetrol derivative.267 R R (176) (177) a R=H d R=vinyl allyl alkyne b R=Br nitrile thiomethoxide c R=I Dihydroxylution. The cinchona alkaloid catalysed osmium tetraoxide dihydroxyla- tion of alkenes can now be applied to terminal alkenes268 by using a new rate enhancing ligands (e.g. 178),269 which seem to be evolving towards a BINAP type structure. The increased reactivity allows as little as 0.5 mol% of osmium tetraoxide (or the safer potassium osmate(v1) dihydrate) to be used with potassium ferricyanide as re~xidant.~~' The diene (179) undergoes diastereoselective hydroxylation to give the syn anti tetrol (180) (94%) and the syn syn stereoisomer YO).^" 263 For applications of this micro-organism to other aromatics see D.R. Boyd D. R. Bushman R. J. H. Davis M. R. J. Dorrity L. Hamilton D. M. Jerrina W. Levin J. J. McCullough R. A. S. McMordie J. F. Malone and H. P. Porter Tetrahedron Lett. 1991 32 2963; D. R. Boyd N. D. Sharma P. J. Stevenson J. Chima D. J. Gray and H. Dalton Tetrahedron Lett. 1991 32 3887. 264 D. R. Boyd M. R. J. Dorrity M. V. Hand J. F. Malone N. D. Sharma H. Dalton D. J. Gray and G. N. Sheldrake J. Am. Chem. SOC.,1991 113 666. 265 D. R. Boyd M. V. Hand N. D. Sharma J. Chimica H. Dalton and G. N. Sheldrake J. Chem. Soc. Chem. Commun. 1991 1630. 266 D. H. G. Crout D. A. MacManus and P. Critchley J. Chem. SOC.,Chem. Comun. 1991 376.267 C. R. Johnson P. A. Ple and J. P. Adams J. Chem. SOC.,Chem Commun. 1991 1006; cj H. A. J. Carless and 0.Z. Oak J. Chem. Soc. Chem. Commun.,1991 61. 268 K. B. Sharpless W. Amberg M. Beller H. Chen J. Hartung Y. Kawanami D. Lubben E. Manoury Y. Ogino T. Shibata and T. Ukita J. Org. Chem. 1991 56 4585. 269 Y. Ogino H. Chen E. Manoury T. Shibata M. Beller D. Lubben and K. B. Sharpless Tetrahedron Lett. 1991 32 5761. 270 Y. Ogino H. Chen J.-L. Kwong and K. B. Sharpless Tetrahedron Lett. 1991 32 3965. 271 C. Y. Park B. M. Kim and K. B. Sharpless Tetrahedron Lett. 1991,32,1003; cf M. Burdisso R. Gandolfi and A. Rastelli Tetrahedron Lett. 1991 32 2659. Synthetic Methods 251 OH OH Ph '''4,ph)-,+Ph Ph-NMO (179) OH OH NMO = N-methylmorpholine N-oxide (180) The dihydroxylation (and cleavage) of alkenes by permanganate is entirely sup- pressed by the addition of oxalyl chloride and trans vicinal dichlorides are formed instead.272 Stereospecific trans addition of dinitrogen tetraoxide to dimethyl cyclo- hexene (181) gives the dinitro adduct (182a) which is readily reduced to the diamine (182b Scheme 3).273 X (181) (182) a R=N02 b R=NH Reagents i N204 Et20; ii H2 RhCI(PPh,) Scheme 3 Epoxidation.A general method for the enantioselective epoxidation of unfunctional-ized alkene~~~~ continues to be elusive. The observation that cytochrome P450,, (which has an iron porphyrin prosthetic group) and related systems are capable of epoxidation of alkenes prompted the synthesis of model systems based on manganese275 and iron porphyrin~.~~~ But unfortunately most of the abiotic systems require aggressive regenerating reagents such as sodium hypochlorite (bleach) and peroxides or ozones which damage the p~rphyrin~~~ frequently the stereochemistry of the alkene is scrambled during epoxidation.The 'natural' substrate for Cytochrome P450,, is camphor but other substrates are accepted. For example cis-P-styrene is epoxidized with retention of alkene stereochemistry in 78% enan- tiomeric excess278 and an essentially identical result has been obtained using an abiotic tetraphenyl porphyrin with D4 symmetry.279 The most generally useful catalysts at present are those based on manganese(I1I) di-imine complexes280 (183). P-Methyl styrene is epoxidized with good stereoselectivity (92% ee 81% yield) and uniquely for these systems the electron deficient alkene cis-methyl cinnamate also gives good results (89% ee 65% yield).281 Non-metallic reagents in this area are 272 I.E. Marko and P. F. Richardson Tetrahedron Lett. 1991 32 1831. 273 W. Zhang and E. N. Jacobsen Tetrahedron Lett. 1991 32 1711; for the synthesis of vicinal diamines from diols see R. Oi and K. B. Sharpless Tetrahedron Lett. 1991 32 999. 274 Review; C. Born Angew. Chem. Int. Ed. Engl. 1991 30 403. 275 S. Campestrini A. Robert and B. Meunier J. Org. Chem. 1991 56 3725. 276 G.-X. He and T. C. Bruice J. Am. Chem. SOC.,1991 113 2747. 277 For the use of t-amine N-oxides in place of hydrogen peroxide see A.M. d'A. R. Gonsalves R. A. W. Johnstone M. M. Pereira and J. Shaw J. Chem. SOC.. Perkin Trans. I 1991 645; R. Ire Y. Ito and T. Katsuki SYNLEn 1991 266. 278 P. R. Ortiz de Montellano J. A. Fruetel J. R. Collins D. L. Camper and G. H. Loew J. Am. Chem. SOC.,1991 113 3195. 279 R. L. Halterman and S.-T. Jan J. Org. Chem. 1991 56 5253. 280 Review of C2 diamines as chiral catalysts C. Bolm Angew. Chem. Int. Ed. Engl. 1991 30 542. 281 E. N. Jacobsen W. Zhang A. R. Muci J. R. Ecker and L. Deng J. Am. Chem. SOC. 1991 113 7063; W. Zhang and E. N. Jacobsen J. Org. Chem. 1991 56 2296. 252 D. R. Kelly rare but useful enantiomeric excesses have been achieved with N-sulfonyl oxaziridines.282 The Katsuki-Sharpless rules for enantioselective epoxidation (Figure 1)283have remained essentially unbreached for the past 11 years but an exception has now been found.The combination of allylic and homoallylic hydroxyl groups in the D-( -)-DET L-( + )-DET 'f 'f 'E 11 I1 I1 /I I1 II L-( + )-DET D-( -)-DET L-(+)-DET Figure 1 (184) a R=H b R=Bn diene (184a) gives the unexpected (S)-epoxide (185) with D-( -)-diisopropyl tartrate (DIE) and no reaction with L-(+)-DIPT.Participation of the homoallylic hydroxyl group in the coordination sphere of the titanium complex284 is clearly demonstrated by the normal behavior of the monobenzyl derivative (184b) which gives the (R)-epoxide (186).285The success of the Katsuki-Sharpless methodology has 282 F. A. Davis R. ThimmaReddy J. P. McCauley Jr.R. M. beslawski M. E. Harakaland and P. J. Carroll J. Org. Chem. 1991 56 809; F. A. Davis A. Kumar and B.-C. Chen J. Org. Chem. 1991 56 1143. 283 Review of asymmetric epoxidation Y. E. Raifel'd and A. M. Vaisman Russ. Chem. Rev. 1991,6Q 123; for an alternative approach to the large scale synthesis of chiral epoxides see J. Dunigan and L. 0. Weigel J. Org. Chem. 1991 56 6225. 284 Mechanistic studies B. H. McKee T. H. Kalantar and K. B. Sharpless J. Org. Chem. 1991 56 6966; S. S. Woodward M. G. Finn and K. B. Sharpless J. Am. Chem. SOC.,1991 113 106; M. G. Finn and K. B. Sharpless J. Am. Chem. SOC.,1991 113 113. 285 S. Takano Y. Iwabuchi and K. Ogasawara J. Chem. SOC. Chem. Comrnun. 1991 820; S. Takano Y. Iwabuchi and K. Ogasawara J. Am. Chem.SOC.,1991 113 2786. Synthetic Methods 253 spawned a wealth of new methodology for the functionalization of epoxy alcohols286 and in particular the 'parent epoxy alcohol' glycid01.~~~ For those rare cases where it is simply not possible to make the epoxide enan- tiomerically pure Julia has developed a resolution technique in which the epoxide undergoes ring opening with dimethyl sulfide to give sulfonium salts which are resolved as dibenzoyl tartrate sulfonium salts. Base treatment regenerates the original epoxides.288 The dioxiranes (187a-~)~~~ are the most mild efficient reagents available for the epoxidation of alkene~~~' and this has enabled the synthesis of epoxides of unpre- cedented reactivity. Electron donating groups and ring strain both greatly increase the reactivity of epoxides but using DMD even two oxygen substituents (188) are 0-0 OSiMe3 OSiMe3 1 R' R2 -30°C.3 hrs OSiMe, (187) a R' = R2 = Me GosiMe3 b R'=Me,R2=CF3 (188) (189) c R'=R2=CF3 tolerated291 and the previously unknown flavonoid ep~xides,~~~ benzofuran ep~xides,~~~ have been isolated. Similarly lithio and fulvene endocyclic ep~xides~~~ enolates are converted to a-hydroxy ketones295 and phenols to orthoq~inones.~~~ Perhaps the most stunning application has been the steroselective conversion of allenes (190) to crystalline spiro-epoxides (191) which undergo regioselective SN2 substitution (192).297 Treatment of the cyclopropene (193a) with pera~id~~~ gives the fused epoxycyclopropane (194) which rapidly rearranges to an alkene which in turn undergoes a further epoxidation (195) in contrast dimethyl dioxirane has 286 Conversion of epoxy alcohols to aldols K.Maruoka J. Sato and H. Yamamoto J. Am. Chem. Soc. 1991,113 5449;2,3-epoxy-1,4-butanediols, Y. Aoyama H. Urabe and F. Sato Tetrahedron Lett. 1991 32; 6731;triols by kinetic resolution A. Ishikawa and T. Katsuki Tetrahedron Lett. 1991,32 3547; enantiomeric epoxy alcohols V.Jager D. Schroter and B. Koppenhoefer Tetrahedron 1991,47 2195. 287 Review of applications of glycidol R. M. Hanson Chem. Rev. 1991,91 437. 288 B. Cimetiere L. Jacob and M. Julia Bull. SOC.Chim. Fr. 1991 128 926. 289 W. Adam S. E. Bottle and R. Melo J. Chem. SOC.,Chem. Commun. 1991 770; W. Adam R. Curci M.E. G. Nunez and R. Mello J. Am. Chem. Soc. 1991,113 7654. 290 Mechanism; R. W. Murray D. L. Shiang and M. Singh J. Org. Chem. 1991,56 3677; A. Messeguer F.Sanchez-Baeza J. Casas and B. D. Hammock Tetrahedron 1991 47 1291. 291 W. Adam L. Hadjiarapoglou and X. Wang Tetrahedron Lett. 1991,32 1295. 292 W. Adam D. Golsch L. Hadjiarapoglou and T. Patonay Tetrahedron Lett. 1991,32 1041. 293 W. Adam L. P. Hadjiarapoglou T. Mosandl C. R. Saha-Moller and D. Wild J. Am. Chem. SOC.,1991 113,8005; furan epoxides rearrange to 1,4enediones before isolation B. M. Adger C. Barrett J. Brennan M. A. McKervery and R. W. Murray J. Chem. SOC.,Chem. Commun. 1991 1553. 294 W.Adam L. P. Hadjiarapoglou and A. Meffert Tetrahedron Lett. 1991,32 6697. 295 K. R. Guertin and T.-H.Chan Tetrahedron Lett. 1991,32 715. 296 J. K. Crandall M. Zucco R. S. Kirsch and D. M. Coppert Tetrahedron Lett. 1991,32 5441. 297 J. K.Crandall D. J. Batal D. P. Sebestra and F. Lin J. Org. Chem. 1991,56 1153. 298 K. W.Wood and P.Beak J. Am. Chem. SOC.,1991,113,6281;R.D. Bach A. L. Owensby C. Gonzalez H. B. Schlegel and J. J. W. McDouall J. Am. Chem. SOC.,1991,113 2338 254 D. R. Kelly (193) a R=CH b R=COOH (194) no effect on the alkene bond and instead oxidizes a methyl group to a carboxylic acid (193b).299 The oxidation of alcohols to ketones and carboxylic acids implicit in this reaction has been developed into a synthetically useful procedure using trifluoromethylmethyl di~xirane[b]~~' and goes by a mechanism in which oxygen is inserted directly into the a C-H bond.301 Dioxiranes also oxidize other heteroatom bonds.Diazoketones are converted to a-ket~aldehydes,~'~ hindered oxazolidines to hydro~yamines,3~~ and arenes can be released from chromium tricarbonyl arene complexes.304 Reduction.-Heterogeneous Hydrogenation.305 It is common knowledge that the reduction of alkenes on noble metal catalysts results from the cis addition of surface bound hydrogen to the less hindered side of the alke~~e,~'~ but beyond this almost nothing else is known. Whitesides has shown that soluble platinium alkene complexes are reduced on platinium black with incorporation of deuterium with retention of configuration of the platinium alkene bonds. If metathesis of the alkene between the 'soluble' platinium and the platinium surface also proceeds with retention of configuration then the reduction must also occur with overall retention of stere~chemistry.~'~ The incorporation of excess deuterium or tritium in saturated groups during reduction of alkenes is a common problem and a new system using platinium black in deuterium oxide and THF reduces cycloalkenes to predominantly the perdeuteroalkanes e.g.cyclodecene was converted to Cl0DZ0 in 60% yield.308 The mechanism for this process probably involves a r-ally1 or alkyl platinium complex similar to that implicated in the montmorillonite-diphenylphosphinepal-ladium(11)~'~ reduction of l,4-butyne-diol to cis-butene-l,4-diol and isomerization to 2-hydro~ytetrahydrofuran.~~~ Rieke zinc prepared from zinc bromide and potassium reduces alkynes to cis alkene~,~~' without using hydrogen!312 299 G.D. Maynard and L. A. Paquette J. Org. Chem. 1991 56 5480. 300 R. Mello L. Cassidei M. Fiorentiono C. Fusco W. Hummer V. Jager and R. Curci J. Am. Chem. SOC.,1991 113 2205. 30 1 B. A. Marples J. P. Muxworthy and K. H. Baggaley Tetrahedron Lett. 1991 32 533. 302 H. Ihmels M. Maggini M. Prato and G. Scorrano Tetrahedron Lett. 1991 32 6215. 303 C. Bonvalet F. Bourelle D. Scholler and A. Feigenbaum J. Chem. Rex 1991 (S) 348. 304 A.-M. Lluch F. Sanchez-Baeza F. Camps and A. Messeguer Tetrahedron Lett. 1991 32 5629. 305 For a review of chiral heterogenous catalysis H.-U. Blaser Tetrahedron Asymmetry 1991 2 843. 306 N.Ravasio and M. Rossi J. Org. Chem. 1991 56 4329. 307 T. R. Lee and G. M. Whitesides J. Am. Chem. SOC.,1991 113 368; T. R. Lee P. E. Laibinis J. P. Folkers and G. M. Whitesides Pure Appl. Chem. 1992 63 821. 308 T. R. Lee and G. M. Whitesides J. Am. Chem. SOC.,1991 113 369. 309 For other chiral phosphine ligands see H.-J. Zeiss J. Org. Chem. 1991 56 1783; M. J. Burk J. Am. Chem. SOC.,1991 113 8518. 310 J. S. Chickos J. Y.-J. Uang and T. A. Keiderling J. Org. Chem. 1991 56 2594. 311 W. N. Chou D. L. Clark and J. B. White Tetrahedron Lett. 1991 32 299. 312 For transfer hydrogenolysis in which no hydrogen gas is released see H. Weiner J. Blum and Y. Sasson J. Org. Chem. 1991 56 4481; 6145. Synthetic Methods Carbonyl The oxazaborolidine (~6)~~~ is emerging as a general catalyst for the enantioselective reduction of ketones315 and particularly aryl alkyl ketones.316 The lithium borohydride reagent derived from the 9BBN hydroboration of nopol reduces dialkyl ketones with good to excellent enantioselectivities but the stereoselectivity and reactivity drop if a potassium counter-ion is used.This presum- ably reflects the role of the lithium ion in coordination to the carbonyl Regioselectivity in the reduction of the diester (197) to the aldehyde (198) is achieved by selective formation of a five rather than a six membered chelate with magnesium bromide etherate and then reduction with di-isobutyl aluminium hydride (DIBALH),318similarly zinc bromide was used to organize the y-ketoacid (199) for reduction to (200).319 OMe H MeO#o MgBr2.0Et2DIBALH ~ 78% iOBn OBn 0 Protecti~n.~~-The migration of acyl groups from secondary or tertiary alcohols to primary alcohols or amines is commonly observed in partially protected aminols.The reverse migration can be induced by treatment with triphenyl phosphine-carbon 313 J. Seyden-Penne ‘Reductions by the Alumino- and Borohydrides in Organic Synthesis’ VCH New York 1991; G. D. Paderes P. Metiver and W. L. Jorgensen J. Org. Chem. 1991 56 4718. 314 Preparation D. J. Mathre T. K. Jones L. C. Xavier T. J. Blacklock R. A. Reamer J. J. Mohan E. T. T. Jones K. Hoogsteen M. W. Baum and E. J. J. Grabowski J. Org. Chem. 1991 56 751. 315 T. K. Jones J. J. Mohan L. C. Xavier T. J. Blacklock D.J. Mathre P. Sohar E. T. T. Jones R. A. Reamer F. E. Roberts and E. J. J. Grabowski J. Org. Chem. 1991 56 763. 316 E. J. Corey X.-M. Cheng K. A. Cimpich and S. Sarshar Tetrahedron Lett. 1991 32 6835; E. J. Corey and J. 0. Link J. Org. Chem. 1991 56 442. 317 M. M. Midland A. Kazubski and R.,E. Woodling J. Org. Chem. 1991 56 1068; for borane reagent based on aminohydroxyboranes see K. Tanaka J. Matsui and H. Suzuki J. Chem. Soc. Chem. Commun. 1991 1311; K. Soai S. Yokoyama and T. Hayasaki J. Org. Chem. 1991 56 4264. 318 G. E. Keck M. B. Andrus and D. R. Romer J. Org. Chem. 1991,56,417; for the use of DIBALH-BuLi”ate complexes see A. Anantanarayan and H. Hart J. Org. Chem. 1991 56 991. 319 R. Frenette M. Monette R. N. Young and T. R. Verhoeven J.Org. Chem. 1991 56 3083. 256 D. R. Kelly tetrabromide and indeed this is a convenient procedure for 0-acylation in the presence of primary amine~.~~' Ethers. It is a textbook paradigm that tertiary carbonium ions are more stable than primary or secondary carbonium ions.321 However the diol (201) (and its epimer at C-1) cyclizes with retention of configuration at the tertiary centre (202). Presumably a carbonium ion at C-1 is disfavoured by the adjacent electron withdrawing methoxyl and retention of the "0 label rules out direct neighbouring group parti~ipation.~~~ PH n 18 I I p-TsOH uivie PhCH,,A '\/) .'Me The Williamson synthesis of oxetanes (205) from 4-halo alcohols gives poor yields because the intermediate alkoxide fragments; however 3-chloropropyl acetate (203) cyclizes much more readily by rearrangement of the ortho-ester (204).324 n cola -&-H Homoallyl alcohols (206) and aldehydes undergo an intramolecular Prins reaction to give dihydropyrans (209);325however if a hydroxyl group is vicinal to the carbonium ion centre pinacol ring contraction gives an acyl tetrahydrofuran (210).326 The cleavage of ethers by acyl halides is greatly improved by catalysis with cobalt(11) chloride consequently even diethyl ether is cleaved in fair yield (49%).327 320 P.K. Dutta C. Chaudhuri S. B. Mandal A. K. Banerjee S. C. Pakrashi and B. Achari J. Chem. Res. 1991 (S) 201 (M) 2180. 321 For a related cyclisation with a secondary to tertiary carbonium ion rearrangement see A.F. Mateos C. M. Almena J. de P. Teresa and R.R.Gonzalez Bull. Soc. Chim. Fr. 1991 128 898. 322 Review of electronegatively substituted carbocations X. Creary Chem. Rev. 1991,91,1627; M. Saunders and H. A. Jimenez-Vazquez Chem. Rev. 1991 91 375. 323 L. A. Paquette and J. T. Negri J. Am. Chem. Soc. 1991 113 5072; J. T. Negri R. D. Rogers and L. A. Paquette J. Am. Chem. Soc. 1991 113 5073. 324 J. Dale and S. B. Fredricksen Acta Chem. Scund. 1991 45 82. 325 A. C. Razus M. D. Gheorgiu and E. Bartha Rev. Roumaine. Chem 1991 36 215; F. Perron-Sierra M. A. Promo V. A. Martin and K. F. Albizati J. Org. Chem. 1991 56 6188. 326 M. H. Hopkins L. E. Overman and G. M. Rishton J. Am. Chem. SOC.,1991 113 5354; M. J. Brown T. Hamson P. M. Hemngton H.H. Hopkins K. D. Hutchinson P. Mistra and L. E. Overman J. Am. Chem. Soc. 1991 113 5365; M. J. Brown T. Hamson and L. E. Overman J. Am. Chem. Soc. 1991 113 5378. 327 J. Iqbal and R. R. Srivastava Tetrahedron 1991 47 3155. Synthetic Methods (206) (207) (a) R'=R2=R3=H (b) R' =OH RZ= R3 = alkyl (211) a R'=R2=Me b R' = R2 = CHMe c R'=H,R2=Me d R'=H R2=CHMez (21 la) and isopropyl (21 lb) pyridine diethers are cleaved selectively at the 4-position by sodium thiomethoxide and aluminium chloride respectively.329 Terminal acetonides (212) are cleaved regioselectively to vinyl ethers (2 13) which are readily cyclopropanated. The 1-methyl cyclopropyl ethers (214) so formed are stable to strong base moderate acid and reduction but are cleaved by NBS or DDQ (Scheme 4).330 Silyl Ethers and Fluoride Reagents.It is a general perception that fluoride based reagents are the best choice for cleaving silyl ethers but all the various methods have disadvantages. Tetrabutylammonium fluoride is difficult to dry KF and CsF are not sufficiently reactive HF is difficult to handle and BF3-OEt2 is too acidic. Consequently several new reagents and old reagents in new guises have been 328 For the suppression of radical hydrogen abstraction by the use of trideutereromethyl ethers see D. L. J. Clive A. Khodabocus M. Cantin and Y. Tao J. Chem. Soc. Chem. Commun. 1991 1755; D.L.J. Clive A. Khodabocus P. G. Vernon A. G. Angoh L. Bordeleau D. S. Middleton C. Lowe and D. Kellner J. Chem. SOC.Perkin Trans.I 1991 1757. 329 S. G.Hedge J. Org. Chem. 1991,56 5726. 330 S. D. Rychnovsky and J. Kim Tetrahedron Lett. 1991,32 7219 7223. 258 D. R Kelly proposed. Tetrabutylammonium difluorotriphenylstannate is non-hydroscopic and is 18 times more reactive as a nucleophile to benzyl bromide than CSF.~~~ Another 'naked' fluoride reagent phosphazenium fluoride (216) shows unique E2 activity and readily gives 1-alkenes from 1-halides however it is sufficiently nucleophilic to effect coupling of ally1 silanes and l-i~doalkanes.~~~ Catalytic transfer hydrogena- tion is selective for the cleavage of primary t-butyl dimethylsilyl (TBDMS) ethers333 NMe NMe, I+l Me2N-P=N=P-NMe F-I I NMe NMe (216) and the acidity of BF3-OEt2 has been used to advantage334 in the elimination of tertiary silyl ethers and alcohols to alkene~,~~~ one pot cleavage and oxidation to a ketone has been achieved by photolysis w~~~DDQ.~~~ Phenols and alcohols and primary alcohols are converted to TBDMS ethers upon treatment with t-butyl- dimethylsilanol under Mitsunobo conditions337 and phenolic silyl ethers are selec- tively cleaved by potassium fluoride supported on alumina and irradiated with ultrasound.338 Despite the disadvantages mentioned above a column packed with glass helices covered in tetrabutyl ammonium fluoride sufficed to effect elimination from the silyl chloride (217) to give spiropentadiene (218) which was trapped in a Diels-Alder reaction to give (219).339 25 "C x-Q Bu,NF -78 "C 4 New Reaction Conditions If synthesis of a single natural product is a challenge then consider the possibilities of making hundreds at a time! Parallel synthesis is currently used by immunologists to prepare polypeptides as candidate antigens.The chemistry is similar to conven- 331 M. Gringas Tetrahedron Lett. 1991 32 7381. 332 R. Schwesinger R. Link G. Thiele H. Rotter D. Honert H.-H. Limbach and F. Mannle Angew. Chem. Znt. Ed. Engl. 1991 30 1372; for a study of fluoride solvation see G. T. Hefter fire Appl. Chem. 1992,63 1749. 333 J. F.Cornier Tetrahedron Letf. 1991 32 187. 334 Siloxanes and silyl ethers are appreciably less basic than dialkyl ethers J. F. Blake and W. L. Jorgensen J. Org. Chem. 1991 56 6052. 335 G.H. Posner E.M. Shulman-Roskes C. H. Oh J.-C. Carry J. V. Green A. B. Clark H. Dai and T. E. N. Anjeh Tetrahedron Lett 1991 32 6489. 336 0.Piva A. Amougay and J.-P. Pete Tetrahedron Left. 1991 32 3993. 337 D. L. J. Clive and D. Kellner Tetrahedron Left. 1991 32 7159. 338 E.A. Schmittling and J. S. Sawyer Tetrahedron Lett. 1991 32 7207. 339 W.E. Billups and M. M. Haley J. Am. Chem. SOC.,1991,113,5084;'for other triangulanes see K. A. Lukin S. I. Kozhushkov A. A. Andrievsky B. I. Ugrak and N. S. Zefirov J. Org. Chem. 1991,56,6176. Synthetic Methods 259 tional solid phase peptide synthe~is~~ except that the growing chains are attached to plastic pins (typically 96) on a backboard. Each synthetic step is conducted in a new plate with an individual well for each pin containing the requisite reagent.A new variant of this technique uses light cleavable protecting groups and an optical mask to differentiate the individual areas of a glass plate. The preparation of 1024 peptides on a single slide has been demonstrated and 250 000 syntheses per square centimetre are possible in principle using currently available masking technology.341 Techniques such as photocherni~try~~~ have been universally adopted but there are wealth of opportunities waiting to be discovered with other forms of energy such as ultrasound microwaves radioly~is,~~~ and electrochemistry. Ultrasound promoted reaction^'^ can be divided into two types heterogenous systems in which the effect of the ultrasound is to increase surface area by dispersion or ‘cleaning’.These typically involve metals such as lithium,345 Li/TiC13 ,346 potassium,347 magnesium zinc,349 or zinc-copper couple.350 This cleaning effect was used to destroy disordered domains on the surface of Raney Nickel in preference to the more robust crygalline domains prior to modification with tartaric acid.351 ‘True’ sonochemical reactions proceed exclusively via radicals or radical ions.352 But it is frequently difficult to distinguish the latter possibility because ultrasound also causes localized (and unquantifiable) heating which may promote ionic reactions.353 The dilemmas that this area presents are illustrated by the free radical polymerization of vinyl carbazole. The rate was studied as a function of ultrasound intensity.At the highest settings (100 Wcm-2) polymerization stopped but recommenced when the ultrasound was turned off .354 Equally what conclusions can be drawn from the observation that the 5’ acylation of adenosine by subtilisin is accelerated by ultrasound?355 340 T. Weiland and M. Bodansky ‘The World of Peptides A Brief History of Peptide Chemistry’ Springer- Verlag Heidelberg 1991. 341 S. P. A. Fodor J. L. Read M. C. Pirrung L. Stryer A. T. Lu and D. Solas Science 1991 251 767; G. von Kiederowski Angew. Chem. Int. Ed. Engl. 1991,30 822. 342 N. Turro ‘Modem Molecular Photochemistry’ University Science Books Mill Valley 1991. 343 For homolytic aromatic hydroxylation using radiolysis see M. K. Eberhardt in Reviews on Heteroatom Chemistry 4 ed.S. Oae MYU K. K. Tokyo 1991 and high pressure radiolysis for Co-C bond formation see R.van Eldik H. Cohen and D. Meyerstein Angew. Chem. Int. Ed. Engl. 1991 30 1158. 344 K. S. Stslick Science 1991 253 1397; K. S. Suslick Roc. Natl. Acad. Sci. USA 1991 88 7708; W. Worthy Chem. Eng. News 1991 Oct. Sth 18. 345 G. J. Price and A. A. Clifton Tetrahedron Lett. 1991 32 7133. 346 S. N. Nayak and A. Banerji J. Org. Chem. 1991 56 1940. 347 T. Chou S.-H. Hung M.-L. Peng and S.-J. Lee Tetrahedron Lett. 1991 32 3551. 348 K. S. Suslick S.-B. Choe A. A. Cichowlas and M. W. Grinstaff Nature 1991 353 414. 349 G. Etemand M. Rifqui P. Layrolle J. Berlan and M. Koenig Tetrahedron Lett. 1991 32 5965; A. P. Marchand and G. M. Reddy Synthesis 1991 198. 350 L.A. Sarandeses A. Mourino and J.-L. Luche J. Chem. Soc. Chem. Commun. 1991 818. 351 A. Tai T. Kikukawa T. Sugimura Y. Inoue T. Osawa and S. Fujii J. Chem. SOC. Chem. Commun. 1991 795; 1324. 352 M. J. Dickens and J.-L. Luche Tetrahedron Lett. 1991 32 4709. 353 T. Ando P. Bauchat F. Foucaud M. Fujita T. Kimura and H. Sohmiya Tetrahedron Lett. 1991 32 6379. 354 J. P. Lorimer T. J. Mason and D. Kershaw J. Chem. SOC.,Chem. Commun. 1991 1217; cf M. J. S. M. Moreno M. L. Sa e Malo and A. S. Campos Neves Tetrahedron Lett. 1991 32 3201 (perruthenate oxidations); B. C. Ranu and M. K. Basu Tetrahedron Lett. 1991,32,3243 (zinc borohydride reductions). 355 M. Criton GJ Dewynther and J.-L. Montero Recl. Trav. Chim. Pays-Bas. 1991 110 443. 260 D.R. Kelly The cycloaddition of aryl sulfonyl azides (220) to enol ethers (221) is promoted both by ultrasound356 and high pressure.357 It was assumed that the high pressures that result from the collapse of cavitation bubbles mimic the conditions of bulk high pressure reactions. A wide range of esters were cleaved by almost stoichiometric amounts of water and di-isopropyl ethylamine (Hunig's base) in acetonitrile at 8 Kba~-.~" N3 Br (221) (220) 46 hrs neat 35 "C ))) 78% 24 hrs CH,CN 80 "C <lo% 18 hrs CH,CN 25 "C 10kbar 85% The use of microwave ovens359 continues to attract controversy. The esterification of propan-1-01 with ethanoic acid proceeds at the same rate in a microwave oven as when heated con~entionally.~~~ In other cases the even heating that can be achieved with microwaves gives better and fasterS6' results than can be obtained conventionally particularly if the substrate rather than the solvent preferencially absorbs the microwaves.362 For example the p-lactam (223) undergoes hydrogena- tion and hydrogenolysis in 45 secs at 110 "C (Scheme 5).363 OMe Reagents i HC02NH4 Pd/C 10% (224) Scheme 5 356 D.Goldsmith and J. J. Soria Tetrahedron Lett. 1991 32 2457. 357 For general reviews of high pressure reactions see N. S. Isaacs Tetrahedron 1991,47,8463; K. Matsumoto and K. M. Acheson 'Organic Synthesis at High Pressure' Wiley New York 1991; M. Buback Angew. Chem. Int. Ed. Engl. 1991 30 641. 358 Y. Yamamoto T. Furata J. Matsuo and T. Kurata J. Org. Chem. 1991 56 5737; for the use of LiBr/DBU see D.Seebach A. Thaler D. Blaser and S. Y. Koo Helu. Chim. Acta 1991 74 1102. 359 General reviews D. M. P. Mingos and D. R. Baghurst Chem. SOC. Reu. 1991,20 1; R. A. Abramovitch Org. Preps. Proc. Int. 1991 23 683. 360 S. D. Pollington G. Bond R.B. Moyes D. A. Man J. P. Candlin and J. R. Jennings J. Org. Chem. 1991 56 1313. 361 A. K. Bose M. S. Manhas M. Ghosh V. S. Raju K. Tabei and Z. Urbanczyk-Lipowska Heterocycles 1990 30 741. 362 R. A. Abramovitch D. A. Abramovitch K. Iyanar and K. Tamareselvy Tetrahedron Lett. 1991,32,5251. 363 A. K. Bose M. S. Manhas M. Ghosh M. Shah V. S. Raju S. S. Bari S. N. Newaz B. K. Banik A. G. Chaudhary and K. J. Barakat J. Org. Chem. 1991 56 6968. Synthetic Methods 261 Electro~hemical~~~ of the diyne (225) to (226) in a single compart- carb~xylation~~~ ment cell is regio- and steroselective (Scheme 6).366 R Reagents i Ni” (lo%) Ligand Mg anode DMF Bu:N+BF4-; ii H20 Scheme 6 Many racemic compounds resolved spontaneously367 by chance cry~tallization~~~ of a single enantiomer and a recent report suggests that the enantiomeric excess may be improved by magnetically stirring the solution!369 This apparently implaus- ible observation has been attributed to fragmentation of the first seed crystal by the stirrer bar resulting in a much faster crystallization than normal.370 Solid state reactions in crystals frequently have different selectivities to the corres- ponding reactions in solution.Crystals of the alcohols (227a) (227b) were crushed with a mortar and pestle to give a c~crystal~~~ which was then mixed with p-toluenesulfonic acid to give exclusively the ‘mixed’ ether (228) whereas in refluxing toluene a statistical mixture of the possible products was formed.372 CI pTsOH Ph+ H OH (227) a R=H b R=C1 364 T.Shono Electroorganic Synthesis Best Synthetic Methods series Academic London 1991 ; J. S. Swenton and G. W. Morrow ‘Synthetic Applications of Anodic Oxidations Tetrahedron Symposia-In- Print’ 42 Tetrahedron 1991 47 531. 365 Review G. Silvestri S. Gambino and G. Filardo Acta Chem. Scand. 1991 45 987. 366 S. Derien J.-C. Clinet E. Dunach and J. Perichon J. Chem. Soc. Chem. Commun. 1991 549. 367 For rationale crystal engineering of diastereoisomers see F.J. J. Leusen H. J. B. Slot J. H. Noordik A D. van der Haest H. Wynberg and A. Bruggink Red. Trav. Chim. Pays-Ras. 1991 110 13; G. Coquerel N. Mofaddel M. N. Petit and R. Bouaziz Bull. SOG Chim. Fr. 1991 128 419 773. 368 For automated crystallization see M. Caron C. M.Moren J. C. Bondiou J. P. Bourgogne C. Porte and A. Delacroix Bull. SOC.Chim. Fr. 1991 128 684. 369 This should not be confused with the now discredited observation of chiral induction by spinning a reaction vertically relative to the earths gravitational field D. Edwards K. Cooper and R. C. Dougherty J. Am. Chem. Soc. 1980 102 381. 370 J. M. McBride and R.L. Crandall Angew. Chem. Int. Ed. EngL 1991 30,293. 371 For the use of triphenyl phosphine oxide as a crystallization aid see A.L. Llamas-Saiz C. Foces-Foces J. Elguero P. Molina M. Alajarin and A. Vidal J. Chem. SOC.,Chem. Commun. 1991 1694; for cholic acid inclusion complexes see K. Miki N. Kasai M. Shibakami K. Takemoto and M. Miyata J. Chem. Soc. Chem. Commun. 1991 1757 and tartaric acid inclusion complexes F. Toda A. Sato L. R. Nassimbeni and M. L. Niven J. Chem. Soc. Perk. Trans. ZZ 1991 1971. 372 F. Toda and K. Okuda J. Chem. Soc. Chem. Commun. 1991 1212. 262 D. R. Kelly 5 Epilogue This is my last year on the synthetic methods review and I think my attitude to the difficulties in compiling it can be encapsulated in another quote from Warren '. . .you have a nagging worry in the back of your mind that everything in the literature is interesting'.'

ISSN:0069-3030    

DOI:10.1039/OC9918800219

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

10 Enzyme Chemistry By A. G. SLITHERLAND Department of Chemistry University of Exeter Exeter EX4 400 1 Introduction Interest continues to increase in the use of isolated enzymes and whole cell systems in organic synthesis.' This has been reflected in an increasing specialization in the subject area of review articles that have appeared in the last year. Thus reviews on the biotransformation reactions of organometallic' and carbohydrate3 systems; ester condensation and hydrolysis reaction^;^ enzyme catalyzed peptide synthesis;' and reactions mediated by bakers yeast6 and -even more specifically -Pseudomonas fluorescens lipase7 have tended to replace the more general review of the recent past.* In this account we shall consider in turn the use of hydrolytic enzymes followed by reduction oxidation then carbon-carbon bond forming reactions which broadly represents a decreasing order of current interest in each area -to some extent reflecting the availability cost and ease of use of the corresponding enzyme systems.2 Hydrolysis and Condensation Reactions Complex Alcohols.-The kinetic resolution of secondary alcohols (and the desym- metrization of meso or prochiral diols) by lipase and esterase catalyzed acylation or hydrolysis of the corresponding esters remains the most heavily studied area in the field of biotransformations. Despite the ease of execution resolutions in the hydrolytic sense are becoming relatively uncommon. However illustrations of the power of this approach still appear for a wide range of substrates ranging in complexity from the carbacyclin precursor (1)9 through the carbocyclic nucleoside intermediate (2)'' to simple 'synthons' such as (3)" -all of which were successfully resolved by Pseudomonas fluorescens lipase (Scheme 1).' N. J. Turner Annu. Rep. Prog. Chem. Sect. B Org. Chem. 1990 333. 'A. D. Ryabov Angew. Chem. Int. Ed. Engl. 1991 30 931. D. G. Drueckhammer W. J. Hennen R. L. Pederson C. F. Barbas 111 C. M. Gautheron T. Krach and C.-H. Wong Synthesis 1991 499. W. Boland C. Frossl and M. Lorenz Synthesis 1991 1049. V. Schellenberger and H. D. Jakubke Angew. Chem. Znt. Ed. EngL 1991 30 1437. R. Csuk and B. I. Glanzer Chem. Rev. 1991 91 49. '2. F. Xie Tetrahedron Asymmetry 1991 2 733. For example J. B. Jones Tetrahedron 1986 42 3351.Z. F. Xie H. Suemune K. Funakoshi T. Oishi H. Akita and K. Sakai J. Chem. SOC. Perkin Trans. 1 1991 3087. S. M. Roberts and K. A. Shoberu J. Chem. Soc. Perkin Trans. 1 1991 2605. 'I U. Goergens and M. P. Schneider J. Chem. SOC. Chem. Commun. 1991 1066. 263 264 A. G. Sutherland G:OzMeOAcI MeOz:B?H 8t,02MeOAc (+)H 4 H+H - - - (1) (51% 96% e.e.) (47%,87% e.e.) (3) R = SiMe,'Bu (-50% >95% ex.) (-5o% >95% e.e.) Reagents i Pseudomonas fluorescens lipase pH 7 buffer Scheme 1 An original application of the lipase mediated desymmetrization of prochiral esters was demonstrated in a synthesis of chiral 5,Sdisubstituted barbiturates.12 Hydrolysis of a bis-N-(acyloxymethyl) substrate (e.g. 4),with subsequent loss of formaldehyde from the N-hydroxymethyl intermediate (Scheme 2) induced chirality at the 5-position allowing conversion to a chiral biologically active N-methyl derivative.A feature of this work was that enantiocomplementary lipases were discovered -a rare occurrence. Thus Candida rugosa lipase hydrolysed (4)with (S)-selectivity (92% e.e.) while Humanicola lanuginosa lipase showed increased selectivity for the (R)-enantiomer (990/ e.e.). This finding proved particularly impor- tant in this instance as the enantiomers of the active derivatives both have significant but different biological profiles. Attempts to predict the enantioselectivity of esterases and lipases have met with some success re~ently.'?'~ Kazlauskas has proposed a rule to predict which enan- tiomer of a secondary alcohol ester will react faster in hydrolysis reactions catalyzed 12 M.Murata and K. Achiwa Tetrahedron Lett. 1991 32 6763. 13 E. J. Toone M. J. Werih and J. B. Jones J. Am. Chem. SOC.,1990 112 4946. Enzyme Chemistry by cholesterol esterase and the lipases from Pseudomonas cepucia and Candidu rug~sa.'~ The study of the outcome of hydrolysis of a wide range of substrates has led to the prediction that all three enzymes will react more quickly with the enantiomer represented in Figure 1 where greater selectivity is observed as the difference in relative size of the groups increases. The utility of this rule was demonstrated by increasing the selectivity of some resolutions through rational substrate modifications prompted by the model.M = mediumsizegroup L = large size group Figure 1 An alternative approach to improving the enantioselectivity of a hydrolysis that has met with some success is the use of additives. In the study of a Pseudomonas species lipase mediated hydrolysis of a secondary acetate (5),15 it was found that while some additives had insignificant or even deleterious effects on the reaction the addition of L-methioninol (6) markedly improved the selectivity. Studies on the 0 A jc, individual enantiomers of (5) suggested that the observed enhancement was pre- dominantly a result of a reduction in the rate of hydrolysis of the less favoured (S)-enantiomer. The results were interpreted as a consequence of a remote binding of (6) to the enzyme causing a conformational change at the active site which promoted the selectivity.A similar effect was observed in the diastereoselectivity of the cholesterol esterase hydrolysis of 24 RS)-a-tocopheryl acetate (7),16 where a dramatic increase in selec- tivity was observed in the presence of taurocholate relative to other bile salts. The authors suggested that this result -all the more striking when the remoteness of the position of hydrolysis to the centre being discriminated is considered -might also 14 R. J. Kazlauskas A. N. E. Weissfloch A. T. Rappaport and L. A. Cuccia J. Org. Chem. 1991,56 2656. T. Itoh E. Ohira Y. Takagi S. Nishiyama and K. Nakamura Bull. Chem. SOC.Jpn. 1991 64 624. 16 H. A. Zahalka P. J. Dutton B. O'Doherty T.A. M. Smart J. Phipps D. 0. Foster G. W. Burton and K. U. Ingold J. Am. Chem. Soc. 1991 113 2797. A. G. Sutherlund arise from an interaction between the additive and enzyme but did not discount diastereomeric influences upon the epimeric acetates within the mixed micelles formed by the bile salt. A new protocol that is likely to have wide applicability for improving the selectivity of resolution of a C,-symmetrical diol has been rep~rted.'~ The pig liver esterase (ple) catalyzed hydrolysis of ( f)-trans-1,2-diacetoxycyclohexane(Scheme 3) proceeded with only moderate selectivity. It was observed that the first hydrolysis (*)-rrans Scheme 3 proceeded far more quickly than the second which contrasted with the accepted notion that such sequential resolution processes would give optimum selectivity when the two rates were equal." It was discovered that a marked increase in selectivity could be achieved by the simple expedient of adding a hexane phase to the reaction.This had the effect of reducing the relative concentration of diester to monoester available to the enzyme in the aqueous phase with the consequence that the rates of hydrolysis became similar. The enantiomeric excess of the product diol increased from 58% to 94% at similar conversions as a result of this simple modification. As indicated above there is an increasing trend to approach the kinetic resolution of secondary alcohols in the acylation rather than hydrolysis direction. The com- plexity of structure capable of resolution by this means again appears diverse -from simple structures to the highly complex.For example the calicheamicinone (analogue) precursors (8) and (9) were resolved by acylation at the secondary and primary hydroxyl positions respectively with vinyl acetate catalyzed by Pseudomunus cepuciu lipase." \\\ Ill \\\ IIl The popularity of this approach undoubtedly stems from the observation that changes in solvents in these reactions are often rewarded with improvements in the l7 G. Caron and R. J. Kazlauskas J. Org. Chem. 1991 56 7251. 18 E. L. A. Macfarlane S. M. Roberts and N. J. Turner J. Chem. SOC.,Chem. Commun. 1990 569. 19 (a) D. S. Yamashita V. P. Rocco and S. J. Danishefsky Tetrahedron Lett. 1991 32 6667; (6) V. P. Rocco S. J.Danishefsky and G. K. Schulte Tetrahedron Lett. 1991 32 6671. Enzyme Chemistry 267 observed enantioselectivity. A recent illustration is in the resolution of the mucolytic drug trans-sobrerol (10)” using vinyl acetate and a Pseudomonas species lipase. The selectivity towards acylation of the (IS 5R)-enantiomer was demonstrated to increase from moderate to essentially total through the series tetrahydrofuran acetone dioxane 3-pentanone to t-amyl alcohol. AcO’ OH That the solvent of choice can vary according to substrate and lipase was illustrated in the complete resolutions of ferrocene (11) in toluene;” glycal (12) in dimethoxyethane;22 halohydrin (13) in neat vinyl acetate;23 alkyne (14) in he~ane;’~ and sulfide (15) in t-b~tylrnethylether.’~ It was also demonstrated that selectivity in these processes can also be improved by immobilizing the enzyme on an epoxy resin.26 The range of alternative acylating agents to vinyl acetate continues to grow.Thus while isopropenyl acetatez7 and both trifl~oroethyl~~~~~ esters and trichl~roethyl~~ continue to prove useful other reagents such as methyl pr~pionate,~~ vinyl aler rate,'^ vinyl la~reate,~’ and even diethyl carbonate33 have been advocated. Scheme 4 20 R. Bovara G. Carrea L. Ferrara and S. Riva Tetrahedron Asymmetry 1991 2 931. 21 M.-J. Kim H. Cho and Y. K. Choi J. Chem. Soc. Perkin Trans. 1 1991 2270. 22 D. R. Berkowitz and S. J. Danishefsky Tetrahedron Lett. 1991 32 5497. 23 J. Sakai H. Sakoda Y. Sugita M. Sato and C.Kaneko Tetrahedron Asymmetry 1991 2 343. 24 K. Burgess and L. D. Jennings J. Am. Chem. Soc, 1991 113 6129. 25 U. Georgens and M. P. Schneider J. Chem. Soc. Chem. Commun.,1991 1064. 26 B. Berger and K. Faber J. Chem. SOC.,Chem. Commun. 1991 1198. 27 C. R. Johnson P. A. PIC and J. P. Adams J. Chem. SOC.,Chem. Commun. 1991 1006. 28 (a) S. Ramaswamy and A. C. Oehlschlager Tetrahedron 1991 47 1157; (b) B. Morgan A. C. Oehlschlager and T. M. Stokes Tetrahedron 1991 47 1611. 29 J. M. Chong and E. K. Mar Tetrahedron Lett. 1991 32 5683. 30 H. J. Bestmann and U. C. Philipp Angew. Chem. Int. Ed. Engl. 1991 30 86. 31 A. J. M. Janssen A. J. H. Klunder and B. Zwanenberg Tetrahedron 1991 47 7409. 32 G. E. Jeromin and A. Scheidt Tetrahedron Lett. 1991 32 7021.33 D. Pioch P. Lozana and J. Graille Biotechnol. Lett. 1991 13 633. A. G. Sutherlund The maximum yield of enantiometrically pure material from a resolution pro- cedure is of course 50%. Oda and co-workers have however developed a procedure for the resolution of aromatic cyanohydrins where theoretical yields of 100% are possible.34 This was achieved by developing conditions which were compatible with both a lipase catalyzed enantioselective acylation and a chemical equilibration between the corresponding aldehyde and cyanohydrin (Scheme 4). Hence unreacted (R)-cyanohydrin was continually racemized and yields of up to 96% of moderately optically pure (S)-cyanohydrin acetates could be obtained in practice -directly from aldehyde starting materials.Complex Acids.-The use of esterases lipases and proteases in the resolution of racemic complex acids has received very little attention in comparison with secondary alcohols. This may well be a reflection of the thinking processes of chemists rather than a reflection of the potential of the technique. The power of this approach was ably illustrated in a Streptornyces griseus protease catalyzed resolution of the threo-serine derivative (16).35Both the product acid and the enantiomeric recoversd ester (each obtained in >45% yield and >%YO enan-tiomeric excess) could be converted in an enantioconvergent fashion to the broad spectrum antibiotic (-)-florfenicol (17). 0 Jones has studied the pig liver esterase catalyzed resolution of a range of monocyc-lic esters (Scheme 5).36 It was found that otherwise similar cyclobutane and cyclo- hexane derivatives were hydrolyzed with essentially total but opposite enantioselec- tivity whilst a corresponding cyclopentyl analogue was hydrolyzed with poor selec- tivity.These results were found to fit well with Jones’ proposed active site m0de1.l~ (18) n = 4,5,8 Intriguing results were observed in a study of the Cundidu cylindrucea lipase catalyzed hydrolysis of the esters (18).37Hydrolysis was found to occur at the methyl ester rather than acetoxy moiety and enantioselectivity was found to increase as the length of the alkyl chain separating the ester from the point of discrimination increased. This apparently anomalous result was rationalized in terms of two hydro-34 M.Inagaki J. Hirate T. Nishioka and J. Oda J. Am. Chem. SOC.,1991 113 9360. 35 J. E. Clark P. A. Fisher and D. P. Schumacher Synthesis 1991 891. 36 E. J. Toone and J. B. Jones Tetrahedron Asymmetry 1991 2 207. 37 U. T. Bhalerao L. Dasaradhi P. Neelakatan and N. W. Fadnavis J. Chem. Soc. Chem Commun. 1991 1197. Enzyme Chemistry C02Me ,C02H <-El,. Me + Me (45% 297% e.e.) (32% 297% e.e.) (*)a12Me -@02H + (y02M' Me Me (28% 22% e.e.) (21% 17% e.e.) phobic binding sites near the active site of the enzyme which might induce folding in the longer chain substrate causing the chiral centre to be close in space to the reactive centre in the active site. This proposal is akin to the Jones' pig liver esterase model which also suggests two hydrophobic binding sites unlike proposed models for other lipases (only one).Resolutions of complex alcohols by condensation have also been shown to be potentially solvent dependant.38 Thus the lipase catalysed condensation of ary- loxypropionic acid (19) with n-butanol was shown to be (R)-selective in cyclohexane n-hexane and toluene but (S)-selective in dichloromethane ethyl acetate and tetrahydro furan. Regioselective Reactions.-The use of hydrolytic enzymes to catalyse regioselective reactions of chiral substrates continues to meet with success. The protease subtilisin has been shown to catalyse the selective acetylation of N-acetylglucosamine (20) at the primary hydroxyl position39 while porcine pancreatic lipase has been shown to selectively butyrylate one (C2) of the three secondary alcohols of the galac- topyranoside (21).40 38 S.H. Wu F. Y. Chu and K. T. Wang Bioorg. Med. Chem. Lett. 1991 1 339. 39 C.-H. Wong Y. Ichikawa T. Krach C. Gautheron-Le Narvor D. P. Dumas and G. C. Look J. Am. Chern. Soc. 1991 113 8137. D. Colombo F. Ronchetti and L. Toma Tetrahedron 1991 47 103. A. G. Sutherland Ho& H O h CH2C0,EtI HO OH NHAc Ho OMeHO CHC0,EtI CH2CO2Et (20) (21) (22) Regioselective acylation of peptides has also been shown to be possible.41 Both L-Phe-a-L-Lys-0-tBu and L-Ala-a-L-Lys-0-tBu were selectively acetylated at the &-position of the lysine residue in preference to the free a-amino group by trifluoroethyl acetate in Pseudornonas species lipoprotein lipase catalysed reactions.The regioselective hydrolysis of achiral substrates has also met with some study. The ‘retro-fat’ (22) is hydrolyzed non-selectively with pig liver esterase but subtilisin catalyzes only hydrolysis of the 2-e~ter.~* Glycosidation Reactions.-Biotransformations are being employed with increasing frequency in the synthesis of complex carbohydrates. The utility of this approach lies in the inherent selectivity of the enzymes -negating the need for protecting groups. HO OUDP OUDP jOH& OH HOk0& HO HO OH (20-40%) Reagents i UDP-glucose epimerase; ii P-1,CgalactosyI transferase Scheme 6 Uridine disphosphate galactose (UDP-galactose) generated in situ by the action of UDP-glucose epimerase on the less expensive UPD-glucose has been shown to react with a variety of sugar ‘acceptors’ such as 1-deoxynojirimycin (Scheme 6),39,43 under galactosyl transferase catalysis to give the corresponding disaccharide.The modest yields obtained are quite acceptable given the directness of the approach. The discovery that the UPD-glucose required can also be generated in situ from catalytic amount of uridine diphosphate and stoichiometric quantities of glucose-6- 41 L. Gardossi D. Bianchi and A. M. Klibanov J. Am. Chem. Soc. 1991 113 6328. 42 L. Kvittingen V. Partali J. U. Braenden and T. Anthonsen Biotechnol. Lett. 1991 13 13. 43 C. Gautheron-Le Narvor and C.-H. Wong J. Chem. Soc. Chem. Commun. 1991 1130. Enzyme Chemistry 27 1 phosphate by an enzyme catalysed sequence,& should only increase the attractiveness of this procedure.Even more complex targets would seem approachable by this route -for example the tetrasaccharide sialyl Le" (23) has been readily synthesized by a similar fucosyl transferase catalyzed pr0cedu1-e.~~ HO HO OH (23) Other Hydro1yses.-The significance of enzyme systems capable of converting nitriles to carboxylic acids under neutral conditions seems to be becoming more widely appreciated. Although nitrilase activity (catalyzing a direct conversion) is sometimes available evidence seems to suggest that most conversions proceed by a two step process where a nitrile hydratase catalyzes a conversion of the nitrile to an amide which is in turn hydrolyzed to the corresponding carboxylic acid by an amidase.(295% e.e.1 (89%e.e.1 Scheme 7 The micro-organism Brevibacferium imperiale has been shown to convert a range of racemic aryloxypropionitriles -e.g. (24) -into the corresponding chiral (and antipodal) acids and amides (Scheme 7).47The authors demonstrated that the nitrile hydratase was non-enantioselective and that the amidase performed the kinetic resolution. Similar results were observed in the conversion of a range of arylpropionitriles (25) by Rhodococcus butanicaM where in all instances reported amide and/or acid J. Theim and T. Wiemann Angew. Chem Znt. Ed. Engl. 1991 30 1163. 45 D. P. Dumas Y. Ichikawa C.-H. Wong J. B. Lowe and R. P. Nair Bioorg. Med. Chem. Lett. 1991 1 425.46 H. Kakeya N. Sakai T. Sugai and H. Ohta Tetrahedron Lett. 1991 32 1343. 47 D. Bianchi A. Basetti P. Cesti G. Franzosi and S. Spezia Biotechnol. Lett. 1991 13 241. A. G.Sutherland could be obtained in near optical purity. Time-course studies revealed that both amidase and (to a lesser extent) nitrile hydratase systems showed some discrimination between enantiomers in this organism. The mildness of reaction condition required for these processes was illustrated by the conversion of a wide range of acid and base sensitive nitriles -e.g. (26) -to the corresponding acids by an isolated enzyme system derived from an unidentified Rhodococcus species.48 Rhodococcus equi was shown to hydrolyse the racemic p-lactam (27) with kinetic res~lution.~~ The recovered unreacted lactam (40% >99% enantiomeric excess) was converted to the low-toxicity anti-Cundida ulbicans agent (-)-Cispentacin (28).The investigation of the kinetic resolution of a series of terminal epoxides by the action of an epoxide hydrolase from a rabbit liver preparation met with mixed success.so The selectivity varied dramatically according to the alkyl substituent from nil (29 R = n-C,H,,) to apparently complete (29 R = Bu‘). It may be that the epoxide hydrolase activity currently being unearthed in fungal sourcess1 may prove more useful. A curious and possibly related report involves the selective microbial degradation of (S)-and (R)-3-chloro-l,2-propanediol by Pseudomonas and Alcaligenes bacteria respe~tively.~~ In both cases the unreacted enantiomer is recovered in high yield and enantiomeric excess (Scheme 8).The metabolized enantiomer is converted to glycidol then glycerol which infers the presence of an enzyme system capable of enantioselective halohydrin ring closure in both organisms. ‘OH OH Y Y Cl-H ClyOH I OH OH (>40% 99.5%e.e.) (>40°% 99.4% e.e.) Reagents i Pseudomonas sp.; ii Alcaligenes sp. Scheme 8 48 H. Klempier A. de Raadt K. Faber and H. Griengl Tetrahedron Lett. 1991 32 341. 49 C. Evans R. McCague S. M. Roberts A. G. Sutherland and R. Wisdom J. Chem. SOC. Perkin Trans. 1 1991 2276. 50 G. Belluci C. Chiappe F. Marioni and M. Benetti J. Chem. SOC. Perkin. Trans. 1 1991 361. 51 X. M. Zhang A. Archelas and R.Furstoss J. Org. Chem. 1991 56 3814. ’* T. Suzuki and N. Kasai Bioorg. Med. Chem. Lett. 1991 1 343. Enzyme Chemistry 3 Reduction Reactions The emphasis of research in this area continues to be on the reduction of ketones to chiral alcohols. The use of whole cell systems predominates although the utiliz- ation of isolated enzyme systems -of greater expense but often more selective and higher yielding -remains an area of note. Whole Cell Systems.-The bakers yeast (Saccharumyces cerevisiae)6 reduction of P-ketoesters remains a popular area of study. Thus the reduction of the viny- lacetoacetate (30) provides access to enantiomerically enriched compac-tin/mevinolin analogues,53 while optically pure diethyl (S)-malate was provided by conversion of sodium diethyl oxalacetate (3 1).54 An interesting variation of this theme was demonstrated by Simpson et aL55who found that when the reduction of P-ketoesters was performed in D20 almost complete di-deuteration at C-2 occured (with some additional incorporation at C-3 also observed).The reactions which could also be performed in conventional mode in water were also high yielding and highly enantioselective (Scheme 9). (75% 85% e.e.) (95% >95% e.e.) Reagents i Saccharomyces cereuisiae glucose D,O 30 "C Scheme 9 Bakers' yeast reductions are often marred by low or poorly reproducible yields and stereoselectivities -often a consequence of competing dehydrogenase activity or metabolism of the substrate or product. A dramatic approach to avoiding this problem has been proposed in the use of benzene as reaction solvent.56 Under these 53 F.D. Bennett D. W. Knight and G. Fenton J. Chem. Soc. Perkin Trans. 1 1991 133 and 519. 54 E. Santaniello P. Ferraboschi P. Grisenti F. Aragozzini and E. Maconi J. Chem. SOC.,Perkin Trans. I 1991 601. 55 M. P. Dillon M. A. Hayes T. J. Simpson and J. B. Sweeney Bioorg. Med. Chem. Lett. 1991 1 223. 56 K. Nakamura S. Kondo Y. Kawai and A. Ohno Tetrahedron Lett. 1991 32 7075. A. G. Sutherland conditions in the presence of a small amount of buffer to allow enzyme activity reductions of a range of a-ketoesters (32) were able to proceed with enhanced (R)-selectivity. This was interpreted in terms of the reaction conditions suppressing the metabolic and (S)-selective dehydrogenase activity.x CS,$CH3 N R CO2Et (32) R = CH3,(CH,),CH,n-C5H, (33) An ample demonstration that bakers’ yeast is not the only organism capable of synthetically useful reductions was given in a study of the reduction of 2-acetylthiazole (33).57No less than thirty eight yeast and mould strains capable of a highly selective reduction were identified. While some -though not all -strains of bakers’ yeast gave the (S)-alcohol in high yield (>70%) and optical purity (>95% e.e.) similar transformations were also accomplished with strains of Candida Rhizopus and Pichiu species. Furthermore two strains of Yarrowia lypolytica capable of enantioselective production of the (R)-alcohol were also found. Traditionally the regeneration of the cofactor (NADH or NADPH) required for the reduction is accomplished in whole cell systems by the metabolism of a carbohy- drate -typically glucose.The micro-organism Profeus vulgaris however has viologen-dependent molybdenum containing dehydrogenase systems which mitigate for cofactor recycling protocols more akin to palladium catalysed hydrogenation reactions than biotransformations. Thus resting cells of P. vulgaris catalyze the conversion of a range of a-ketoacids to the corresponding alcohols in the presence of formate or even hydrogen gas.58 The yields and selectivity are excellent as illustrated by the conversion of (34). P. oulgaris F &yo2 H or HCO; I 0 OH (34) (90%’>97%.e.e.) Isolated Enzyme Systems.-The commercially available D-laCtate dehydrogenase from Staphylococcus epiderrnidis has been shown to reduce a range of a-ketoacids to the corresponding (R)-2-hydroxyacids in high yield with essentially complete stereoselectivity (Scheme Given that enantiocomplementary activity has already been demonstrated using L-lactate dehydrogenase from rabbit it would appear that the synthesis of either enantiomer of many a-hydroxy acids and their derivatives -notably terminal epoxides -is possible by this approach with apparently complete and predictable enantioselectivity.57 G. Fantin M. Fogagnolo A. Medici P. Pedrini S. Poli and M. E. Guerzoni Tetrahedron Asymmetry 1991 2 243. 58 A. Schummer H. Yu,and H. Simon Tetrahedron 1991 47 9019. 59 M.-J.Kim and J. Y. Kim J. Chem. SOC.,Chem. Commun. 1991 326. 60 M.-J. Kim and G. M. Whitesides J. Am. Chem. SOC.,1988 110 2959. A-1 275 Enzyme Chemistry Staphylococcus epidermis R CO2H D-lactate R CO2H dehydrogenase R Yield YO e.e.,YO Et 86 >99 C-Pr 86 >99 n-Pr 92 >99 PhCH 80 >99 Scheme 10 4 Oxidation Reactions The use of cis-cyclohexadiene-l,2-diols(35) obtained by the microbial oxidation of arenes by mutant strains of Pseudomonas putida in organic synthesis is now well established. To some extent it might be argued tht these compounds are now full members of the ‘chiral pool’ and hence fall outside the remit of this discussion. However recent important developments in the field suggests their inclusion here.OMTPA OMTPA One major problem was that an accurate assessment of the optical purity of the diols was not predicated because of the non-availability of the racemic material. Boyd6’ has solved this problem by investigating the ‘H and I9F NMR spectra of the di-MTPA (a-methoxy-a-trifl,uoromethyl-phenylacetic) esters of the 4-phenyl- 1,2,4-triazoline-3,5-dione cycloadducts (36). The spectra of the ‘racemic’ adducts could be mimicked by making diesters with both (R)-and (S)-MTPA allowing the enantiomeric excess to be determined. In this way the diols from toluene ethylben- zene chlorobenzene trifluoromethylbenzene and benzyl acetate were all shown to be >98% e.e. while that from fluorobenzene was 60% e.e.. The diesters were all crystalline allowing confirmation of absolute configuration by X-ray crystallogra- phy.The absolute configuration of the diols from chlorobenzene toluene and anisole has also been confirmed by correlation of the CD spectra of their iron tricarbonyl complexes.62 The current major class of synthetic targets from these systems are the conduritols (1,2,3,4-tetrahydroxycyclohex-5-enes), the various stereoisomers of which display a wide range of biological activity. The strategies employed generally commence from the diol derived from fluoro chloro or bromobenzene when a suitable sequence of regioselective dihydroxylation or epoxidation and hydrolysis with expeditious D. R. Boyd M. R. J. Dorrity M. V. Hand J. F. Malone N. D. Sharma H. Dalton D. J. Gray and G. N. Sheldrake J.Am. Chem. SOC.,1991 113 666. 62 G. R. Stephenson P. W. Howard and S. C. Taylor J. Chem. SOC., Chem. Commun. 1991 126. A. G. Sutherland I HO .OH Conduritol E iv Conduritol F 0- Reagents i oso, 0-N' ; ii Bu3SnH AIBN; iii AcOH THF H,O; iv MCPBA /-J 'Me v KOH DMSO H,O Scheme 11 removal of the halogen lead to a wide selection of the series. Representative sequences are depicted in Scheme 11.63 It remains to be seen just how wide the synthetic potential of these diols is. With the current level of understanding of the chemistry of the system it would seem that any polyhydroxy/ amino functionalized system of the inositol/ pinitol/ con- duritol/ conduramine class should be readily preparable from this starting point.Whether other less 'tailor made' target systems will be readily accessible by this approach is not yet clear. Perhaps in response to this a number of groups have examined the possibility of functionalizing the ring system by carbon-carbon bond forming reactions. Thus the bromine in the acetonide derivative (37) can be successfully replaced by vinyl alkenyl and aryl groups via palladium mediated transmetalation approaches (Scheme 12);64 while similar chemistry on the unprotected bromo or iodo diols additionally yields alkyl allyl and nitrile derivative^.^^ These transformations have the effect of formally increasing the range of arenes that can be converted to the cyclohexadienediols without the need to develop new and potentially difficult biotransformations.A number of cycloadditions to the diene system have also been The acetonide derivatives were found to react conventionally in [4 + 21 manner with dimethyl acetylenedicarboxylate to give addition from the least hindered face (Scheme 13). However the reaction with diphenylketene proved less predictable 63 T. Hudlicky H. I.una H. F. Olivo C. Andersen T. Nugent and J. D. Price J. Chem. SOC.,Perkin Trans. 1 1991 2907. 64 S. V. Ley A. J. Redgrave S. C. Taylor S. Ahmed and D. W. Ribbons SYNLEm 1991 741. 65 D. R. Boyd M. V. Hand N. D. Sharma J. Chima H. Dalton and G. N. Sheldrake J. Chem. Soc. Chem. Commun. 1991 1630. 66 M. F. Mahon K. Molloy C. A. Pittol R. J. Pryce S. M. Roberts G. Ryback V. Sik J. 0. Williams and J. Winders J. Chem. Soc.Perkin Trans. 1 1991 1255. Enzyme Chemistry Scheme 12 R Scheme 13 R Ph R Scheme 14 with the expected [2 + 21 cycloaddition occuring in competition with a Diels-Alder reaction involving the ketene carbonyl (Scheme 14). Interestingly this latter path-way entirely absent in the reaction with 1,3-~yclohexadiene became predominant in the case of the fluoro derivative. The use of the enzymatic Baeyer-Villiger reaction continues to receive much attention. Whole cells of Acinetobacter calocaceticus were used to oxidize the meso- substrate (38) selectively and in high yield allowing rapid access to a key subunit for the synthesis of the polyether antibiotic ionomycin (Scheme 15).67 Two other groups have examined the use of this organism in the context of the oxidation of racemic bicyclic ketones.Roberts and co-workers68 observed two distinct types of kinetic resolution in action dependant on the substrate under examination. The bromohydrin (39) was resolved in the more typical sense in that only one enantiomer reacted so that both product lactone and recovered ketone were obtained in high optical purity (Scheme 16). Both enantiomers of the simpler 67 M. J. Taschner and Q. Z. Chen Bioorg. Med. Chem. Lett. 1991 1 535. 68 A. J. Carnell S. M. Roberts V. Sik and A. J. Willetts J. Chem. Soc. Perkin Trans. 1 1991 2385. A. G. Sutheriand Me**Qd*Me __*i ii Me0,CVOH Me Me 0 (38) (82%)1iii iv Ho-OTBDPS , I Me Me Reagents i Acinetobacter; ii CH,N,; iii Bu‘Ph,SiCI base; iv LiAlH Scheme 15 1 A I I I OH OH OH (*)(39) Scheme 16 ketone (40) reacted but resolution still occurred as the regioselectivity of the oxygen insertion was different for each enantiomer (Scheme 16).The authors interpreted these and other results in terms of only one enzyme being involved where steric interactions affected the stereochemical mode of attack of the enzyme bound hydro- peroxide moiety resulting in selective migrations in each enantiomer. Furstoss et aZ?9 observed a third distinct mode of resolution in the transformation of the r2.2.11 ketone (41) (Scheme 17). In this case only one enantiomer underwent Baeyer-Villiger oxidation (with an unexpected rearrangement to yield the [3.3.0] system (42)) while the other enantiomer was actually reduced to both the correspond- ing endo- and exo-alcohols all three products being formed in high optical purity.Leaving the rearrangement aside as an artefact of this particular substrate this distribution of products may represent some form of dynamic balance of cofactors during the course of the reaction. The relationship of the cofactors required for the interconversion between alcohol and ketone and ketone and lactone has been elegantly exploited by Roberts et aZ.” 69 K. Konigsberger V. Alphand R. Furstoss and H. Griengl Tetrahedron Lett. 1991 32 499. 70 A. J. Willetts C. J. Knowles M. S. Levitt S. M. Roberts H. Sandey and N. F. Shipton J. Chem. Soc. Perkin Trans. 1 1991 1608. Enzyme Chemistry h ,OCH2Ph Scheme 17 The realization that the cofactor generated by an alcohol dehydrogenase mediated oxidation of an alcohol to a ketone namely NADPH was that required for the monooxygenase catalyzed oxidation to the lactone prompted the investigation of a coupled enzyme system.Thus the use of the isolated enzymes Thermoanaerobium brockii alcohol dehydrogenase and A. caloaceticus monooxygenase in tandem con- verted the alcohol (43)to the corresponding lactones (44and 45) in the presence of only catalytic amounts of NADP+ (Scheme 18). HO Therrnoanaerohium brockii dehydrogenase (43) 0 Acinetobacter calcoaceticus monooxygenase (44) (45) Scheme 18 The monooxygenase catalyzed epoxidation of alkenes is likely to be an important and rewarding area of study in the near future.That high optical purities are obtainable by these processes was illustrated by Wong and co-workers in a study of the oxidation of allylic alcohol derivative^.^' Although the parent alcohol did not react usefully a number of other derivatives (e.g. 46) could be oxidized with high enantiomeric excess by growing cells of Pseudomonas oleovoruns. H.Fu M.Newcomb and C.-H. Wong J. Am. Chern. Soc. 1991,113 5878. A. G. Sutherland 5 Carbon-Carbon Bond Forming Reactions The use of fructose 1,6-diphosphate aldolase (FruA) from rabbit muscle72 or E. ~oli~~ as a catalyst for the aldol reaction of dihydroxyacetone phosphate (DHAP) with a wide range of aldehydes is well documented. The reaction reliably gives products with (3S 4R)stereochemistry (Scheme 19).0 Scheme 19 The use of two new aldolases from E. coli namely L-rhamnulose and L-fuculose 1-phosphate aldolases (RhuA and FucA) has now been reported.74 These enzymes are important in that they catalyze the formation of diastereomerically complemen- tary products. Thus RhuA and FucA produce (3R 4s)and (3R 4R)products respectively (Scheme 19). Both these enzymes were shown to accept a wide range of aldehyde substrates including aliphatic and aromatic species. The development of a fourth enzyme D-tagatose 1,6-bisphosphate aldolase (TagA) capable of produc- ing (3S 4s)products is understandably noted as an area of current investigation by this group. The increased interest in aza-sugars and glycoproteins has prompted the investiga- tion of the use of aldolases in synthetic routes to these materials.This approach had been hampered by the fact that many aminoaldehyde equivalents had transpired to be poor substrates for these enzymes. However this obstruction has now been circumvented by the discovery that azidoaldehydes participate readily in the process as illustrated in the high yielding synthesis of the azido-xylulose (47).75 CHO 1) DHAP FruA W O H N3-2) Phosphatase N3 OH (47) (78%) 72 (a) M. D. Bednarski E. S. Simon N. Bischofberger W. D. Fessner M.-J. Kim W. Lees T. Saito H. Waldmann and G. M. Whitesides J. Am. Chem. Soc. 1989 111 62; (b) E. J. Toone E. S. Simon M. D. Bednarski and G. M. Whitesides Tetrahedron 1989 45 5365. 73 C. H. van der Osten A.J. Sinskey C. F. Barbas 111 R. L. Pederson Y. F. Wang and C.-H. Wong J. Am. Chem. SOC.,1989 111 3924. 74 W. D. Fessner G. Sinerius A. Schneider M. Dreyer G. E. Schultz J. Badia and J. Aguilar Angew. Chem. Int. Ed. Engl. 1991 30 555. 75 R. R. Hung J. A. Straub and G. M. Whitesides J. Org. Chem. 1991 56 3851. Enzyme Chemistry 281 This discovery together with the increased realization that in many instances aldolases only utilize one enantiomer of a racemic aldehyde has led to the rapid synthesis of a wider range of aza-sugars for evaluation as glycosidase inhibitors through the use of all three available aldolases (Scheme 20).76*77 i DHAP FruA N3JCH0 ii Phosphatase i DHAP RhuA N3+OH & H6 HO OH *OH *How ii Phosphatase N3 HO HO OH Scheme 20 The use of the aldolase-like enzyme transketolase (TK) is likely to attract much attention in coming years.This commercially available thiamin pyrophosphate dependant enzyme readily catalyzes the irreversible decarboxylative coupling of hydroxypyruvate with aldehydes (Scheme 21). The range of potential 'acceptor' aldehydes has been shown to be very wide,78 including aliphatic aromatic heterocyc- lic and a,P-unsaturated systems. 0 OH R1 H + HOzC &OHZ/-e_OH R Scheme 21 The enzyme has also been shown to accept only one enantiomer of racemic 2-hydroxyaldehyde substrates to give a resultant vicinal diol with D-threo configur- ation (and recovered L-hydroxyaldehyde in high enantiomeric excess) -as utilized by Whitesides in a synthesis of (+)-exo-brevicomin (Scheme 22).79 A rather more distinct carbon-carbon bond forming enzyme is oxynitrilase.This enzyme (also known as mandelonitrile lyase) catalyses the stereospecific reversible addition of HCN to aldehydes (whilst some ketones have also been shown to be substrates"). The process is not without its problems apart from the notional 76 T. Kajimoto K. K. C. Liu R. L. Pederson Z. Zhong Y. Ichikawa J. A. Porco Jr. and C.-H. Wong J. Am. Chem. SOC.,1991 113 6187. 77 K. K. C. Liu T. Kajimoto L. Chen. Z. Zhong Y. Ichikawa and C.-H. Wong J. Org. Chem.,1991,56,6280. 78 C. Demuynck J. Bolte L. Hecquet and V. Dalmas Tetrahedron Lett. 1991 32 5085. 79 D. C. Myles P. J. Andrulis 111 and G. M. Whitesides Tetrahedron Lett.1991 32 4835. 80 F.Effenberger B. Horsch F. Weingart T. Ziegler and S. Kuhner Tetrahedron Lett. 1991 32 2605. A. G. Sutherland Me Scheme 22 hazards involved as the potential for 'background' non-enzymic addition of cyanide together with some racemization of the product cyanohydrin under reaction condi- tions has meant that the consistent achievment of high optical purity has proved difficult. HO CN A ENZ [ENZ . HCN] R "OxHCN R H Scheme 23 An elegant solution to these problems has been revealed.** The use of acetone cyanohydrin as a donor of HCN in a transcyanation process (Scheme 23) means that the level of HCN is kept low (possibly in enzyme bound form) and hence background reaction is kept to a minimum.Product racemization is also reduced by performing the reaction in an ether-buffer two phase system. A stark illustration of the power of this procedure is in the formation of phenylacetaldehyde cyanohydrin (48) where the enantiomeric excess of the product is more than doubled (from 40% to 88%) by adopting this new procedure. It should be noted that this technique is enantiocomplementary to the lipase-mediated route to (S)-cyanohydrin acetates delineated earlier. (48) (83'10 88% e.e.) V. I. Ognyanov V. K. Datcheva and K. S. Kyler J. Am. Cfiem.Soc. 1991 113 6992.

ISSN:0069-3030    

DOI:10.1039/OC9918800263

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

11 Biological Chemistry Biosynthesis By R. A. HILL Department of Chemistry University of Glasgow G12 800 1 Introduction The previous Report' on biosynthetic studies of secondary metabolites and related work covered the period 1986-88. This Report will cover the period 1989-91. The study of biosynthetic pathways continues to be a highly active area. Genetic approaches to biosynthetic work are still making a huge impact. Improvements in the instruments and techniques of NMR and mass spectrometry are allowing rapid advances in the sophistication of biosynthetic studies. Several reviews have appeared dealing with general aspects of biosynthetic tech- niques,2 mechanisms of enzymic glycosyl transfer,6 enzyme-catalysed allylic rearrangement^,^ and enzyme-catalysed carbon-carbon bond formation.' Comprehensive reviews of biosynthesis of the major groups of natural products appear regularly in Natural Product Reports.The papers presented at an international symposium on bioorganic processes have been published.' This report must be highly selective and aims to highlight some important advances in biosynthetic studies. 2 Fatty Acid and Polyketide Biosynthesis An excellent book covering all aspects of fatty acid and polyketide biosynthesis has been published." One of the most important advances in this area is the use of Electrospray Mass Spectrometry (ESMS) to determine the mass of proteins with high accuracy." This technique allows study of sequential steps of a biosynthetic pathway in which the intermediates remain bound to a protein.ESMS has been used to observe previously well-characterized enzyme bound intermediates12 and to T. J. Simpson Annu. Rep. Bog. Chem. Sect. E 1988 85 321. E. Leete Latinoamer. Quim. Supplement 1 1990 37. H. G. Floss and J. M. Beale Angew. Chem. Int. Ed. Engl. 1989 28 146. R. B. Herbert 'The Biosynthesis of Secondary Metabolites' 2nd Edition Chapman and Hall London 1989. ' J. A. Robinson Chem. SOC.Rev. 1988 17 383. M. L. Sinnott Chem. Rev. 1990 90 1171. 'J. M. Schwab and B. S. Henderson Chem. Rev. 1990 90 1203. R. Kluger Chem. Rev. 1990,90 1151. 'Molecular Mechanisms in Bioorganic Processes' ed. C. Bleasdale and B. T. Golding Royal Society of Chemistry Cambridge 1990. 10 D. O'Hagan 'The Polyketide Metabolites' Prentice-Hall London 1991.'' J. B. Fenn M. Mann C. K. Meng S. F. Wong and C. M. Whitehouse Science 1989 246 64. 12 R. T. Aplin J. E. Baldwin C. J. Schofield and S. G. Waley FEES Lett. 1990 277 212. 283 284 R. A. Hill monitor active site-directed inhibition of an enzyme.13 The acyl carrier protein (ACP) involved in fatty acid biosynthesis in Succhuropolysporu erythreu was used to establish that reactions could be monitored using the ESMS te~hnique’~ and a chemically prepared acyl derivative of the ACP was prepared and acylated intermediates produced by the action of fatty acid synthase were detected by ESMS.” This technique has great potential for the study of biosynthetic pathways. The degradation of linoleic acid (1) and linolenic acid in plants is an important factor that influences the flavour of fruit and vegetables.The action of lipoxygenases on linoleic acid (1) to give 9-hydroperoxyoctadeca-lO,l2-dienoic acid (2) has been well established. The hydroperoxydienoic acid (2)is transformed into colneleic acid (4) which itself can be degraded into short chain aldehydes. Studies16 using deuterium labelling have shown that the 8-(pro-R)-hydrogen of the hydroperoxydienoic acid (2) is lost in its transformation into colneleic acid (4). The divinyl ether oxygen of colneleic acid (4) was shown to be derived from oxygen not water.” These results are consistent with the intervention of an epoxy-carbonium ion intermediate (3). -COOH -0 13 P. Caffrey B. Green L. C. Packman B. J. Rawlings J.Staunton and P. F. Leadlay Eur. J. Biochem 1991 195 823. 14 A. M. Bridges P. F. Leadlay W. P. Revill and J. Staunton J. Chem Soc. Chem. Commun. 1991 776. l5 A. M. Bridges P. F. Leadlay W. P. Revill and J. Staunton J. Chem. Soc. Chem. Commun. 1991 778. 16 P. Fahlstadius and M. Hamberg J. Chem. Soc. Perkin 1 1990 2027. 17 L. Crombie D. 0.Morgan and E. H. Smith J. Chem. SOC.,Perkin 1 1991 567. Biological Chemistry Biosynthesis 285 Isotopic labelling studies" are consistent with the hypothesis that 13-hydroperoxy- linoleic acid (5) is converted into 13-hydroxy-12-oxooctadec-9-enoic acid (7) and 9-hydroxy- 12-oxooctadec-10-enoic acid (8) by nucleophilic attack by water on an allene epoxide intermediate (6) at carbons 13 and 9 respectively., HOO COOH J COOH OH J COOH 0 (7) OH COOH 13-Hydroperoxylinolenic acid (9) is converted in a similar manner to the corres- ponding a-and P-ketols and 12-oxophytodienoic acid (1 1).Isotopic labelling results are consistent with a route via antarafacial ring closure of a zwitterion (10) derived from an allene epoxide." 12-Oxophytodienoic acid (11) is further degraded to produce cyclopentanones such as jasmonic acid (12) that have plant growth regulatory properties. Many plants and insects are able to produce terminally unsaturated hydrocarbons from saturated fatty acids the elimination proceeds via an anti-elimination of the carboxyl group and the 3-(pro-S)-hydrogen of the precursor acid in the plant Carthamus tinctorius" and the insect Tribolium consusum.21 These results have been used to investigate the stereochemistry of the reduction of the enoyl system during fatty acid biosynthesis in the same organisms.Feeding experiments (Scheme 1) indicated that an anti-Re,Re addition of hydrogen occurs.22 This stereochemistry of addition is different from those observed in other organisms.23 8-Decanolide (13) and y-dodecanolide (14) are flavour components in fruit milk products and fermented foods. Their biosynthesis in plants is thought to be by 18 L. Crombie D. 0. Morgan and E. H. Smith J. Chem. SOC. Perkin 1 1991 577. 19 L. Crombie D. 0. Morgan and E. H. Smith J. Chem. SOC. Perkin 1 1991 581. 20 G. Gorgen and,W. Boland Eur. J. Biochem. 1989 185 237. 21 G.Gorgen C. Frossl and W. Boland Experientiu 1990 46 700. 22 C. Frossl and W. Boland J. Chem. SOC. Chem. Commun. 1991. 1731. S. A. Benner A. Glasfeld and J. A. Piccirilli Topics in Stereochem. 1989 19 193. 286 R. A. Hill OOH COOH 0- COOH Scheme 1 degradation of fatty acids. It was found that micro-organisms can be used to produce these flavour component^.^^ Thus Cludosporium suuueolens converted 13-hydroxy- octadeca-9,11 -dienoic acid (1 5) into 8-decanolide (13) and Yurrowiu lipolyticu con-verted 10-hydroxyoctadec-8-enoicacid (16) into y-dodecanolide ( 14). Labelling studiesz5 have shown that the addition of hydrogens to the diene system of 13- hydroxyoctadeca-9,ll-dienoicacid (15) in the biosynthesis of the 8-lactone (13) 24 R.Cardillo G. Fronza C. Fuganti P. Grassieli D. Pizzi G. Allegrone M. Barbeni and A. Pisciotta J. Org. Chem. 1991 56 5237. 25 G. Fonza C. Fuganti P. Grassieli A. Mele G. Allegrone M. Barbeni and A. Pisciotta J. Chem. SOC. Perkin 1 1991 2977. Biological Chemistry Biosynthesis AoAo H 0 HO occurs on the same face of the molecule and that the addition of hydrogen in the y-lactone (14) shows the same steric course. The biosynthesis of lipoxins and related eicosanoids has been reviewed.26 The relationship between fatty acid and polyketide biosynthesis has been the subject of much research. The pathways appear to be very similar however during polyketide biosynthesis reduction of a carbonyl to give an alcohol can often occur with stereochemistry (S) opposite to that (R) thought to be general for fatty acid synthase enzymes.The stereochemistry of carbonyl reduction in fatty acid and polyketide biosynthesis in the same organism has been investigated using appropriate labelling studies. Oleic acid (17) is produced in the same organisms as cladosporin (18) from Cladosporium cladosporioide~~~ dehydrocurvularin (19) from Alternan'a cinerariae and antibiotic A26771 B (20) from Penicillium turbatum.** In each organism 26 K. C. Nicolaou J. Y. Ramphul N. A. Petasis and C. N. Serhon Angew. Chem. Int. Ed. Engl. 1991 30,1100. 21 B. J. Rawlings P. B. Reese S. E. Ramer and J. C. Vederas J. Am. Chem. SOC.,1989 111 3382. 28 K. Arai B. J. Rawlings Y. Yoshizawa and J. Vederas J. Am. Cbem. SOC,1989 111 3391.288 R. A. Hill the oleic acid biosynthesis involved placing acetate derived hydrogens in the pro-R position on the growing fatty acid chains whereas the corresponding polyketide leaves hydrogens in the pro4 position in the growing chain. Although only a small number of organisms have been studied it does appear that the stereochemistry of enoyl thiol ester reductase involved in fatty acid biosynthesis and polyketide forma- tion in fungi may be opposite. The structure and function of polyketide synthase complexes active in the produc- tion of antibiotics in Streptomyces species has been reviewed.29 The intermediates formed on the polyketide synthase from Aspergillus melleus have been studied with N-acetylcysteamine (NAC) thioesters.The intact incorporation of deuterium labelled NAC thioesters of crotonic 2,4-hexadienoic and 2,4,6-octatrienoic acids into aspyrone (21)30 support the hypothesis that aspyrone polyketide synthase resembles a fatty acid synthase in its mode of operation and that it follows a processive mode of operation. This hypothesis was further strengthened by labelling studies3* that showed that the NAC thioester of (R)-3-hydroxybutanoic acid is incorporated into aspyrone without loss of the hydrogen at C-3. The sequence of intermediates bound to the acyl carrier protein (ACP) of the aspyrone polyketide synthase is shown in Scheme 2. Dueterium labelled 3-hydroxydeca-4,6,8-trienoic acid (22) was incorporated intact into a~pyrone.~~ Studies using I7Olabelled acetate and I7O2 as precursors and 170 NMR spectroscopy to analyze the results have ACP.S 00 0 I 29 J. A. Robinson Phil. Trans. R. SOC.Land. B 1991 332 107. 30 J. Staunton and A. C. Sutkowski J. Chem. Soc, Chem. Commun. 1991 1110. 31 A. Jacobs J. Staunton and A. C. Sutkowski J. Chem. SOC.,Chem. Commun. 1991 1113. 32 J. Staunton and A. C. Sutkowski J. Chem. Soc. Chem. Commun. 1991 1108. 289 Biological Chemistry Biosynthesis .o -+.5? H HO Scheme 3 shown that aspyrone (21) asperlactone (24) and isoasperlactone (25) arise from a common diepoxide intermediate (23) (Scheme 3).33 The biosynthesis of pseudomonic acid A (26) was investigated using labelled acetate precursors and the results show that pseudomonic acid A (26) is formed from separate CI7and C9 moieties linked at the ester and that it is not formed by a Baeyer-Villiger type cleavage of a single long-chain ketone intermediate.The proposed involvement of 3-hydroxy-3-methylglutaricacid in the biosynthesis of pseudomonic acid A (26) was not verified.34135 OH The biosynthetic origins of the hydrogen atoms of the antibiotic nonactin (27) have been studied by following the incorporations of deuterium and I3C en-riched acetate propanoate and succinate using cultures of Streptomyces gri~eus.~~ 33 J. Staunton and A. C. Sutkowski J. Chem. SOC.,Chem. Commun. 1991 1106. 34 F. M. Martin and T. J. Simpson J. Chem. SOC.,Perkin 1 1989 207. 35 P. G. Mantle and K. M. Macgeorge J. Chem. SOC.,Perkin 1 1991 255.36 D. M. Ashworth C. A. Clark and J. A. Robinson J. Chem. SOC.,Perkin 1 1989 1461. 290 R. A. Hill Mechanisms are proposed to explain the formation of (+)-and (-)-nonactic acids from these precursors catalysed by a nonactin polyketide synthase multi-enzyme complex. The biosynthesis of this and other polyether ionophore antibiotics are covered in an excellent comprehensive review.37 Feeding studies with labelled precursors38 are consistent with solanapyrone A (29) from Alternaria solani being formed via an intramolecular Diels-Alder reaction of an intermediate such as (28). Further indirect evidence is provided by the isolation of solanapyrone D (30) from the same organism.39 Solanapyrone D (30) is apparently -OMe CHO H (29) I CHO H the result of an endo-Diels-Alder cycloaddition whereas solanapyrone A (29) is the result of an exo-addition.The previous proposal4' that betaenone B is biosynthe- sized via a Diels-Alder reaction is further strengthened by the isolation of probe- taenone 1 (32) from Phoma betae indicating a cyclization of an intermediate such as (31).41 Chirally labelled malonyl-CoA has been incorporated into 6-methylsalicylic acid (6-MSA)(34) using 6-MSA synthase from Penicillium patuZum?2 The results show that the hydrogen atoms removed from the two methylene groups at the 2- and 4-positions in the putative polyketide intermediate have opposite absolute stereochemistry. 37 J. A. Robinson Prog. Chem. Org. Nut. Prod. 1991 58 1. 38 H. Oikawa T.Yokota T. Abe A. Ichihara S. Sakamura Y. Yoshizawa and J. Vederas J. Chem. SOC. Chern. Commun. 1989 1282. 39 H. Oikawa T. Yokota A. Ichihara and S. Sakamura J. Chem. SOC., Chem. Commun. 1989 1284. 40 H. Oikawa A. Ichihara and S. Sakamura J. Chem. SOC.,Chem. Commun. 1988 600. 41 S. Miki Y. Sato H. Tabuchi H. Oikawa A. Ichihara and S. Sakamura J. Chern. Soc. Perkin I 1990 1228. 42 P. M. Jordan and J. B. Spencer J. Chem. SOC.,Chem. Commun. 1990 238. Biological Chemistry Biosynthesis 291 J FCOOH OH (34) An insight into the intriguing biosynthetic control of regiochemistry of intramolecular aldol reactions is provided with the molecular genetic study43 of the actinorhodin (35)gene cluster from Streptomyces coelicolor. Mutactin (36)is a shunt metabolite produced by a mutant strain.The results indicate that a polyketide aldolase specifies the correct cyclization of a complex oligoketide chain. 0 OH \ I I COOH OH (35) (36) D. H. Sherman M. J. Bibb T. J. Simpson D. Johnson F. Malpartida M. Fernandez-Moreno E. Martinez C. R. Hutchinson and D. Hopwood Tetrahedron 1991 47 6029. 292 R. A. Hill The stereochemistry of hydrogen loss on formation of the vinyl group of ravidi- mycin (37) from Streptomyces ruvidus has been investigated by incorporation experi- ments using chirally labelled [2-2H,]propionate.44 The results indicate that the pro-S hydrogen of propionic acid is retained in the biosynthesis of the vinyl group of ravidimycin (37). OH OMe Sugar 0 (37) Anthraquinones such as austrocorticin (38) isolated from a toadstool of the Dermocybe genus have been shown to be derived from a propionate starter whereas norastrocorticin (39) and other anthracene metabolites from D.sanguine^^^ are derived from an acetate starter unit. MeOM (38) R=Me (39) R=H The biosynthesis of citreamicin (40) from Micromonosporu citreu has been studied using labelled precurs0rs.4~ A complex rearrangement of a polyketide intermediate is postulated and the '80-incorporation studies indicate some surprising results. The urdamycins are an interesting group of antibiotics from Streptomyces frudiae. They have been shown to be derived from a single decaketide chain.48 A series of non-enzymatic processes has been shown to occur in the elaboration of the urdamycin nucleus.Non-enzymatic condensation of urdamycin A (41) with 4-hydroxy- phenylpyruvic acid leads to urdamycin C (43).49 Urdamycin C (43) undergoes a novel non-enzymatic ring contraction to produce urdamycin H (44).50Urdamycin 44 R. F. Keyes and D. G. I. Kingston J. Org. Chem. 1989 54 6127. 45 M. Gill and A. GimCnez J. Chem. SOC.,Perkin 1 1990 1159. 46 M. Gill and A. GimCnez J. Chem. SOC.,Perkin 1 1990 2585. 47 G. T. Carter D. B. Borders J. J. Goodman J. Ascroft M. Greenstein W. M. Maiese and C. J. Pearce J. Chem. Soc. Perkin 1 1991 2215. 48 J. Rohr J. M. Beale and H. G. Floss J. Antibiot. 1989 42 1151. 49 J. Rohr J. Chem. SOC.,Chem. Commun. 1990 113. 50 J. Rohr Angew.Chem. Int. Ed. 1990 29 1051. Biological Chemistry Biosynthesis (41) X=H (42) X=SMe (43) RO (45) R = Sugar residues E (42) is formed by a non-enzymatic Michael-type addition (followed by oxidation) to urdamycin A (41).51Involvement of non-enzymatic processes may be considered for other biosynthetic schemes especially if there is a wide range of metabolic products. The antibiotic pradimicin A (45) from Actinomadura hibisca has been shown to be biosynthetically derived from 12 acetate units. D-Alanine is efficiently incorpor-ated into the side chain.52 3 Terpenoids Severalcomprehensive reviews on the biosynthesis of terpenoids have been published including the lower terpen~ids,~~-~~ sesquiterpene lac tone^,^^ mon~terpenoids,~~~~~ se~quiterpenes,~~ gibberellins,6' diterpene phytoalexins,6' marine natural products,62 triterpenoids and carotenoids,@ and biosynthetic methods.65 51 J.Rohr J. Chem. SOC.,Chem. Commun. 1989 492. 52 M. Kakushima Y. Sawada M. Nishio T. Tsuno and T. Oki J. Org. Chern 1989 54 2536. 53 M. H. Beale Nut. Prod. Rep. 1990 7 25. " M. H. Beale Nu?. Prod. Rep. 1990 7 387. 5s M. H. Beale Nut. Prod. Rep. 1991 8 441. 56 P. A. Vatakencherry and K. N. hshpakumari J. Sci. Ind. Res. 1989 48 31. 57 J. Gershenzon and R. Croteau Rec. Ado. Phytochem. 1990 24 99. 58 N. H. Fischer Rec. Adu. Phytochem. 1990 24 161. 59 D. E. Cane Chem. Rev. 1990 90,1089. 60 B. 0. Phinney and C. R. Spray Rec. Adv. Phytochem. 1990 24 203. 61 C. A. West A. F.Lois K. A. Wickham and Y.-Y. Ren Rec. Adv. Phytochem. 1990 24 219. 62 M. J. Garson Nut. Prod. Rep. 1989 6 143. 63 W. D. Nes Rec. Adu. Phytochem. 1990 24 283. 64 D. M. Harrison Nut. Prod. Rep. 1990 7 459. 65 J. Gershenzon D. McCaskill J. Rajaonarivony C. Mihaliak F. Karp and R. Croteau Rec. Adu. Phytochem. 1991 25 347. 294 R. A. Hill Advances have been made into the enzymology and genetics of the early stages of terpenoid biosynthesis. Studies on mevalonate-5-phosphate decarboxyla~e~~~~~ have indicated that the enzyme contains sulfydryl groups that are involved in substrate binding. The gene encoding isopentenyl diphosphate isomerase has been isolated.68 An investigation of this enzyme from Saccharomyces cerevisiae using site-directed mutagenesis has shown that the active-site residue Cyst-139 is involved in the catalytic action (Scheme 4).69 I-I PPO&-PPO& Scheme 4 Analysis of kinetic isotope effects using geranyl diphosphate (46) demonstrated that a-pinene (47) and P-pinene (48) are formed by the same enzyme in sage.70 Extensive studies on the biosynthesis of fenchol (49)71 and sabinene hydrate (50)72 have been reported.The Cll-homoterpene (51) and its C16-analogue (52) are found as the major constituents of the volatile oils of many plants. It has been shown that they are derived biosynthetically by the cleavage of a C4-unit from C15 and C20 precursors re~pectively.~~’~~ The recent work on the enzyme trichodiene synthase from Trichotheciurn roseurn has been ~urnmarized.~’ This enzyme converts farnesyl diphosphate into trichodiene 66 M.Alvear A. M. Jabalquinto and E. Cardemil Biochem. Biophys. Acta 1989,994 7. 67 A. M. Jabalquinto and E. Cardemil Biochem. Biophys. Acta 1989 996 257. M. S. Anderson M. Muehlbacher I. P. Street J. Proffitt and C. D. Poulter J. Biol. Chem. 1989 264 19169. 69 I. P. Street H. R.Coffman and C. D. Poulter Tetrahedron 1991 47 5919. 70 K. C. Wagschul T. T. Savage and R. Croteau Tetrahedron 1991,47 5919. 71 R. Croteau J. H. Miyazaki and C. J. Wheeler Arch. Biochem. Biophys. 1989 269 507. 72 T. W. Hallahan and R. Croteau Arch. Biochem. Biophys. 1989 269 313. ’3 W. Boland and A. Gabler Helv. Chem. Acta 1989 72 247. 74 A. Gabler W. Boland U. Preiss and H. Simon Helv.Chim. Acta 1991 74 1773. 7s D. E. Cane Pure Appf. Chem. 1989 61 493. Biological Chemistry Biosynthesis 295 (53) the isolation and sequence of the gene coding for this enzyme has been reported.76 Trichodiene (53) is the precursor of the trichothecene family of mycotoxins. The biosynthesis of 3-acetyldeoxynivalenol (54)from Fusarium cul-morurn has been reviewed.77 Post-trichodiene intermediates in the biosynthesis of 3-acetyldeoxynivalenol (54) from Fusarium culmorum have been isolated. Isotrichodiol (55)78 and 12,13-epoxy-9-trichothecen-2-o1(56) were incorporated into 3-acetyldeoxynivalenol(54)whereas 9-trichothecene-12,13-diol(57),although it was produced from trichodiene (53) by cultures of Fusarium culmorurn treated with the inhibitor ancymidol was not incorporated into the trich~thecenes.~~ (53) (54) Aristolochene synthase which has been isolated from cell-free extracts of Aspergil-lus terreus" and Penicillium roquefortii,'l catalyses the conversion of farnesyl diphos- phate into aristolochene (58).The mechanism of this cyclization has been studied using deuterium labelled precursors.82 The mechanism of this and other enzyme- catalysed allylic addition-elimination reactions in terpenoid biosynthesis has been reviewed.83 76 T. M. Hohn and P. D. Beremand Gene 1989 79 131. 77 L. 0.Zamir Tetrahedron 1989 45 2277. 78 A. R. Hesketh L. Gledhill D. C. Marsh B. W. Bycroft P. M. Dewick and J. Gilbert J. Chem. SOC. Chem. Commun. 1990 1184. 79 L. 0. Zamir K. A. Devor N. Morin and F.Sauriol J. Chem. SOC.,Chem. Commun. 1991 1033. D. E. Cane P. C. Prabhakaran E. J. Salaski P. H. M. Harrison H. Noguchi and B. J. Rawlings J. Am. Chern. SOC.,1989 111 8914. 81 T. M. Hohn and R. D. Plattner Arch. Biochem. Biophys. 1989 272 137. 82 D. E. Cane P. C. Prabhakaran J. S. Oliver and D. B. McIlwaine J. Am. Chem. Soc. 1990 112 3209. D. E. Cane C. Abell P. H. M. Harrison B. R.Hubbard C. T. Kane R. Lattman J. S. Oliver and S. W. Weiner Phil. Trans. R SOC.Lond. 1991 332 123. 296 R. A. Hill The biosynthesis of abscisic acid (59) in higher plants has been re~iewed.'~ Abscisic acid (59) originates by breakdown of carotenoid precursors in higher plants but has been shown to be formed directly from farnesyl diphosphate in several species of fungi.Further evidepce that abscisic acid (59) is produced from carotenoids in plants has been provided by the use of 1802 incubationss5986and 2H20studies." The biosynthesis of the clerodane skeleton in Tinospora cordifoh has been investigated using labelled mevalonic acid precursors." The results indicate that two 1,2-hydrogen shifts and two 1,2-methyl shifts occur during the formation of the ring system. The order of introduction of the hydroxyl groups in aphidicolin (60) using cultures of Phoma betae has been shown to be C-18 C-17 and finally C-3.89 Austin (61)90 and terretonin (62)9' are formed by a mixed terpenoid-polyketide pathway. Incorporation studies using labelled acetates methionine and 33- dimethylorsellinate (63) have shown that the biosynthetic pathways involve C- alkylation of 3,5-dimethylorsellinate (63) with farnesyl diphosphate an insight into the mechanisms of the biosynthetic steps that follow is provided with an analysis of the labelling patterns of these complex metabolites.Views on the evolution of terpenes to sterols have been presented.92 The biosyn- thesis of squalene has been reviewed.93 The enzyme that catalyses the cyclization of oxidosqualene to lanosterol has been purified from yeast and the enzymatic 84 R. A. Creelman Physiol. Pluntarium 1989 75 131. 85 J. A. D. Zeevaart T. G. Heath and D. A. Gage Plant Physiol. 1989,91 1594. 86 D. A. Gage F. Fong and J. A. D. Zeevart Plunf Physiol. 1989 89 1039. 87 R. W. Willows and B. V. Milborrow Phytochemistry 1989 28 2641.88 A. Akhila K. Rani and R. G. Thakur Phytochemistry 1991 30 2573. 89 H. Oikawa A. Ichihara and S. Sakamura Agric. Biol. Chem. 1989 53 299. 90 S. A. Ahmed F. E. Scott D. J. Stenzel T. J. Simpson R. N. Moore L. A. Trimble K. Arai and J. C. Vederas 1. Chem. SOC.,Perkin 1 1989 807. 91 R. McIntyre F. E. Scott T. J. Simpson L. A. Trimble and J. C. Vederas Tetrahedron 1989 45 2307. 92 G. Ourisson Pure Appl. Chem. 1989 61 345. 93 M. Y. Julia Chem. SOC.Rev. 1991 20 129. Biological Chemistry Biosynthesis properties de~cribed.9~ The cyclase of the protozoon Tetruhyrnenu pyriformis which normally converts squalene into the pentacyclic tetrahymanol (64) cyclized 2,3- dihydrosqualene into euph-7-ene (65) with an unexpected tetracyclic skeleton’ and backbone rearrangement.” Incorporation studies with [1 2l3C2]acetate have shown that the 3a-hydroxylanostane ganoderic acid S (66) is produced by the fungus Gunoderrna Zucidurn from (3s) -squalene 2,3-e~oxide.~~ 94 T.Hoshino H. J. Williams Y. Chung and A. I. Scott Tetrahedron 1991 47 5925. 95 I. Abe and M. Rohmer J. Chem. SOC. Chem. Commun. 1991 902. % M. Hirotani I. Asaka and T. Furuya J. Chem. SOC.,Perkin 1 1990 2751. 298 R. A. Hill An extensive study of the biosynthesis of cholesterol and lanosterol in isolated dog hepatocytes using 13C- and *H-labelled acetates and ethanol and exacting NMR studies have verified the earlier findings on cholesterol bio~ynthesis?~ Similar studies by the same group have elucidated the biosynthetic pathways to cycloartenol (67)98 and isofucosterol (68)99using tissue cultures of Physallis peruuiana.A number of papers have appeared concerning the details of the biosynthesis of the side-chains of sterols such as dinosterol (69) from Cryptothecodinium cohnii peridinosterol from Peridinium foliaceum gorgosterol from Cassiopea xamachana,'OO 24-propy-lidenecholesterol from Crysoderma mucosa,'o' cyclopropane-containing sterols of marine originlo2 and 24-ethylster0ls.'~~~'~~ The work on 24-ethylsterols contradicted earlier work on poriferasterol (70) but the earlier work was shown to be in error due to incorrect assignments of the I3C NMR spectra these errors have subsequently been corrected.'05 Studies on the biosynthesis of cardenolides in Asclepias curassavica did not support the hypothesis that the butenolide ring is formed by the condensation I 97 S.Seo H. Saito A. Uomori Y. Yoshimura K. Tonda Y. Nishibe M. Hirata Y. Takeuchi K. Takeda H. Noguchi Y. Ebizuka U. Sankawa and H. Seto J. Chem. SOC.,Perkin 1 1991 2065. 98 S. Seo A. Uomori Y. Yoshimura K. Takeda H. Seto Y. Ebizuka H. Noguchi and U. Sankawa J. Chem. SOC.,Perkin 1 1989 261. 99 S. Seo A. Uomori Y. Yoshimura H. Seto Y. Ebizuka H. Noguchi U. Sankawa and K. Takeda J. Chem. SOC.,Perkin 1 1990 105. 100 J.-L. Giner and C. Djerassi J. Org. Chem. 1991 56 2357. 101 J.-L. Giner and C. Djerassi J. Am. Chem. SOC.,1991 113 1386. lo* C. Djerassi and G. A. Doss in 'Studies in Natural Product Chemistry' ed.Atta-ur-Rahman Elsevier Amsterdam 1991 vol. 9 15. 103 I. Horibe H. Nakai T. Sato S. Seo K. Takeda and S. Takatsuto J. Chem. SOC.,Perkin 1 1989 1957. 104 S. Seo A. Uomori Y. Yoshimura K. Takeda H. Seo Y. Ebizuka H. Noguchi and U. Sankawa J. Chem. SOC.,Perkin 1 1989 1969. 105 D. Colombo F. Ronchetti G. Russo and L. Toma J. Chem. SOC.,Perkin 1 1991 962. Biological Chemistry Biosynthesis of a pregnane derivative with one molecule of acetate.'06 A study using l80-and 2H-labelled acetate and lSO2 has determined the mechanism of the side-chain cleavage of pregnenolone (7 1) (Scheme 5).'07 Labelled glucose has been incorporated i fi+ CH,COOH Scheme 5 into the side chain of bacteriohopanetetrol (72) and the results show that a ribose derivative is a precursor."* Labelled mevalonic acid was used to show that the aromatic ring D of nic-1 (73) from Nicandra physaloides is formed by ring D expansion of a steroid precursor with oxidative inclusion of the 18-methyl group'" and that it is formed from 24(28)-methylenecholesterol,details of the pathway have been elucidated."' / 106 H.W. Groeneveld A. Binnekamp and D. Seykens Phytochemistry 1991 30,2577. 107 S. L. Miller J. N. Wright D. Corina and M.Akhtar J. Chem. SOC.,Chem. Commun. 1991 157 548 and 792 (note that there are two corrigenda to this paper). 108 M. Rohmer B. Sutter and H. Sahm J. Chem. SOC.,Chem. Comrnun. 1989 1471. 109 H. K. Gill R. W. Smith and D. A. Whiting J. Chem. SOC.,Perkin 1 1990 2989. 1LO W.Andrews-Smith H. K. Gill R. W. Smith and D. A. Whiting J. Chem. Soc. Perkin 1 1991 291. 300 R. A. Hill 4 Shikimate and Related Metabolites An extensive review covering the molecular biology and biochemistry of the shiki- mate pathway has been published."' Regular comprehensive reviews have appeared covering all aspects of shikimate metabolite^."^-^^^ Studies on the enzymes in chorismate metabolism and the enterobactin biosynthetic pathway have been detailed."' Dehydroquinate synthase catalyses the conversion of 3-deoxy-~-arabino-heptulosonate-7-phosphate (DAHP) (74) into 3-dehydroquinate (75). The enzyme has been isolated and purified to homogeneity from Streptomyces coelicolor and has been found to be extremely thermostable."6 The enzyme has also been purified from Escherichia coli and has been shown to be a monomeric metalloenzyme containing one tightly bound Co2+."' The metal-free apoenzyme is not catalytically active activity is fully restored with Co2+ and to about half this level with Zn2+.However in vivo the enzyme is believed to contain Zn2+ rather than Co2+ the latter being introduced during the purification procedure. Dehydroquinate synthase also binds one molecule of NAD+. The overall enzyme mechanism has been well studied and the findings reviewed."* _. HxoH 0-OH I OH IOH (74) (75) Shikimate-3-phosphate (76) is converted to 5-enolpyruvylshikimate 3-phosphate (EPSP) (78) by EPSP synthase. Further evidence for the existence of the tetrahedral intermediate (77) has been provided."' Synthetic analogues of this intermediate have been shown to be potent inhibitors of the enzyme from Petunia hybrida.12' An extensive review of EPSP synthase has been pubiished.121 EPSP (78) is converted into chorismate (79) by chorismate synthase.This enzyme has been isolated and purified from a cell culture of Corydalis sempervirens.'22 Debate over the mechanism of action of this enzyme continues but an anti-1,4-elimination seems to be fa~0ured.l~~ Chorismate (79) is converted into isochorismate (80) by isochorismate synthase. This enzyme has been purified and ~haracterized.'~~ The hydroxyl group 111 R. Bentley Crit. Rev. Biochem. Mol. Biol. 1990 25 307. P. M. Dewick Nut. Prod. Rep. 1989 6 263. 113 P. M. Dewick Nut. Prod.Rep. 1990 7 165. 114 P. M. Dewick Nut. Prod. Rep. 1991 8 149. C. T. Walsh J. Liu F. Rusnak and M. Sakaitani Chem. Rev. 1990 90 1105. 116 P. J. White J. Young I. S. Hunter H. G. Nimmo and J. R. Coggins Biochem J. 1990 265 735. 117 S. L. Bender S. Mehdi and J. R.Knowles Biochemistry 1989 28 7555. 118 J. R. Knowles Aldrich Actu 1989 22 59. P. N. Barlow R. J. Aplleyard B. J. 0.Wilson and J. N. S. Evans Biochemistry 1989 28 7555. 120 D.G.Alberg and P. A. Bartlett J. Am. Chem. Soc. 1989 111 2337. 121 K. S. Anderson and K. A. Johnson Chem. Rev. 1990 90 1131. 12* A. Schaller V.Windhofer and N. Amrhein Arch. Biochem. Biophys. 1990 282 437. 123 S. Balasubramanian C. Abell and J. R. Coggins J. Am Chem Soc. 1990 112 8581. 124 J. Liu N. Quin G. A.Berchtold and C. T. Walsh Biochemistry 1990 29 1417. Biological Chemistry Biosynthesis COOH COOH @o" OH I OH OH (76) (77) I COOH COOH OH OH (79) (78) \ COOH of isochorismate is labelled by H2180 indicating that a 1,5-addition/elimination sequence occurs.125 Phenylpropanoid metabolism and molecular biology associated with the biosyn- thesis of flavonoids lignans and coumarins have been reviewed.'26 Simple coumarins from higher plants are normally derived by cyclization of a cinnamic acid precursor however 4-hydroxy-5-methylcoumarin(8 1) found as its glucoside in Gerbia jarnesonii has been shown to be of polyketide rigi in.'^' The incorporation of phenylpropanoids into cell walls including lignins has been reviewed,'** lignan biosynthesis has been covered in recent and three reviews on lignin biosynthesis have a~peared.'~'-'~~ Natural lignans are normally enantiomerically pure and arise from a stereocon- trolled coupling process.Evidence for the conversion of coniferyl alcohol (81) into 125 S. J. Could and R. L. Eisenberg Tetrahedron 1991 47 5979. 126 K. Hahlbrock and D. Scheel Annu. Rev. Plant Physiol. Plant Mol. .BioL 1989 40,347. 12' T. Inoue T. Toyonaga S. Nagumo and M. Nagai Phytochemistry 1989 28 2329. 128 E. Yamamoto G. H. Bokelmam and N. G. Lewis ACS Symp. Ser. Plant Cell Wall Polymers Biogenesis and Biodegradation 1989 399 68. 129 P. M. Dewick in 'Studies in Natural Product Chemistry' ed. Atta-ur-Rahman 1989 5 459 Elsevier Amsterdam. 130 D.C.Ayres and J. D. hike 'Lignans-Chemical Biological and Clinical Properties 1990 Cambridge University Press Cambridge. 131 N. G. Lewis and E. Yamamoto Annu. Rev. Plant Physiol. Plant Mol. Biol. 1990 41 455. 132 T.Higuchi Wood Sci. TechnoL 1990 24 23. 133 C. Haertig D. Meyer and K. Fischer 2. Chem. 1990 30,233. 302 R. A. Hill CHO 6 'OMe pinoresinol (82) in a direct stereochemically controlled coupling by a crude enzyme preparation from Forsythia intermedia has been pr0~ided.I~~ The stereospecific coupling of coniferyl alcohol (81) to produce secoisolariciresinol (83) was also demonstrated using a cell-free extract of Forsythia intermedi~.'~' The biosynthesis of flavonoids has been reviewed'36 and the biosynthesis of proanthocyanidins has been covered in a recent b00k.l~~ Chalcomoracin (84) and H Meovg HO \ H HO 1 OH OH Y (83) (84) other chalcone dimers e.g.the kuwanones have been isolated from various species of mulberry (Moms spp.). Evidence is presented that they arise by an enzymic Diels-Alder coupling of chalcone precursor^.'^^ The conversion of flavanones into isoflavanones has been well studied. It is catalysed by the enzyme isoflavone synthase which is a cytochrome P-450-dependent enzyme requiring NADPH and O2.139 Details of the mechanism of the conversion of the flavanone (85) into the 2-hydroxyisoflavanone (86) have been pre~ented.'~' The cyclization of isoprenyl side- chains in flavonoids and isoflavonoids is catalysed by cyclase enzymes. The stereochemical aspects of the cyclization of rotenoic acid (87) to deguelin (88) in Tephrosia vogellii have been in~estigated.'~' 134 T.Umezawa L. B. Davin E. Yamamoto D. G. I. Kingston and N. G. Lewis J. Chem. Soc. Chem. Commun. 1990 1405. 13' T. Umezawa L. B. Davin and N. G. Lewis Biochem. Biophys. Res. Commun. 1990 171 1008. 136 G. Hrazdina and R. A. Jensen UCLA Symp. Molecular Cellular Biol. New Series 1990 133 27. 137 'Chemistry and Significance of Condensed Tannins' ed R. W. Hemmingway and J. J. Karchesy 1989 Plenum Press New York. 138 Y. Hano T. Nomura and S. Ueda J. Chem. SOC.,Chem. Commun. 1990 610. 139 T. Hakamatsuka H. Noguchi Y. Ebizuka and U. Sankawa Chem. Pharm. Bull. 1990 38 1942. 140 T. Hakamatsuka M. F. Hashim Y. Ebizuka and U.Sankawa Tetrahedron 1991 47 5969. 141 P. Bhandari N. van Bruggen L. Crombie and D. A. Whiting J. Chem. Soc. Chem. Commun. 1989,982. Biological Chemistry Biosynthesis __* 0 (85) OMe (87) The origin of the skeleton of mangostin (89) from Garcinia mangostana has been shown to be benzoate and ma10nate.l~~ Cinnamic acid is readily incorporated into mangostin (89) but it undergoes side-chain degradation prior to incorporation. The biosynthesis of caldariellaquinone (90) from Sulfolobus acidocaldarius has been in~estigated.'~~ Both the methyl and sulfur of the methylthio group are derived from methionine but the experiments clearly show that the methylthio group was not incorporated intact. Both D-and L-tyrosine have been incorporated into caldariel- laquine (90) indicating that the cells can readily convert D-tyrosine into L-tyrosine; labelling results have shown that the C-3 pro3 hydrogen of tyrosine is retained in the biosynthesis.14 The origin of the isocyanide carbons of xanthocillin X monomethyl ether (91) from Dichotomomyces cejpii remain obscure.Recent studies have eliminated many obvious candidate^.'^^ (90) (91) 142 G. L. Bennett H.-H. Lee and N. P. Das J. Chem. SOC.,Perkin 1 1990 2671. 143 D. Zhou and R. H. White J. Chem. SOC.,Perkin 1 1990 2346. 144 D. Zhou and R. H. White J. Chem. SOC.,Perkin 1 1991 1335. 145 K. M. Cable R. B. Herbert A. R. Knaggs and J. Mann J. Chem. SOC.,Perkin 1 1991 595. 304 R. A. Hill 5 Alkaloids and other Amino-acid-derived Metabolites The range of investigations into alkaloid biosynthesis is increasing.Some excellent reviews have appeaared on alkaloid biosynthe~is,'~~~'~~ pyrrolizidine alkaloid biosyn- thesis,'48 indole and bisindole biosynthesis in plant cell cultures,'49 alkaloid biosyn- thesis in plant cell cult~tres,'~~ and antibiotic bio~ynthesis.'~' The substrate tolerance and mechanism of action of diamine oxidases from pea seedlings have been Ornithine has been symmetrically incorporated into hyoscyamine (92)in root cultures of Hyoscyarnus ~lbus'~~ in contrast to the well established unsymmetrical incorporation of ornithine into hyoscyamine (92) in Datura species. No evidence for a pathway involving 6-methylornithine could be found in Hyoscyarnus ~lbus.'~~ Further evidence for the symmetrical incorporation of ornithine into nicotine (93)in Duboisia leichhardtii has been pr~duced.'~~ The recent work on these alkaloids has been reviewed.'" Trachelanthamidine (94)rather than isoretronecanol (95)is incorporated into echinatine (96)in Cynoglossum o_tfi~inaZe'~* and emiline (97)in Erniliaflarnrne~.'~~ The involvement of the immonium ion (98)in the biosynthesis of several pyrrolizidine alkaloids has been established.16' The necic acid portion of dicrotaline (99)has been shown to be derived from isoleucine and not from acetate mevalonate or 3-hydro~y-3-methylglutarate.'~~ 146 R.B. Herbert Nut. Prod. Rep. 1990 7 105. 147 R. B. Herbert Nut. Prod. Rep. 1991 8 185. 148 D. J. Robins Chem.SOC.Rev. 1989 18 375. 149 J. P. Kutney Nu?. Prod. Rep. 1990 7 85. M. H. Zenk Rec. Adv. Phytochem. 1989 23 429. 151 H. G. Floss and J. M. Beale Angew. Chem. Znt. Edn. EngZ. 1989 28 146. 152 J. E. Craig R. B. Herbert and M. M. Kgaphola Tetrahedron Lett. 1990 31 6907. 153 A. M.Equi A. M. Brown A. Cooper S. K. Ner A. B. Watson and D. J. Robins Tetrahedron 1990 47 507. 154 Hashimoto Y. Yamada and E. Leete J. Am. Chem. Soc. 1989 111 1141. 155 T. Hashimoto Y. Yukume and Y. Yamada PZunru 1989 178 123 and 131. 156 E. Leete T. Endo and Y. Yamada Phytochernistry 1990 29 1847. 157 E. Leete PZuntu Med. 1990 56 339. 158 E. K. Hunec and D. J. Robins J. Chem. Soc. Perkin 1 1989 1437. 159 H. A. Kelly E. K. Hunec M. Rodgers and D.J. Robins J. Chem. Res. (S) 1989 358. 160 A. A. Denholm H. A. Kelly and D. J. Robins J. Chem. SOC., Perkin 1 1991 2003. 161 A. A. Denholm and D. J. Robins J. Chem. Soc. Chem. Commun. 1991 19. Biological Chemistry Biosynthesis OXNH2 Me N Anosmine (100) from Dendrobiurn parishii has been shown to be derived from two lysine units one via cadaverine and the other presumably via pipecolic acid.16* Labelling studies have shown that acetate and methionine are incorporated into harzianopyridone (101) from Trichoderma harzianurn however the biosynthetic origin of the remaining C3N unit remains A similar study on spiro- staphylotrichin A (102) from Staphylotrichum cocosporurn demonstrated that acetate and methionine are incorporated as shown and the remaining C3N unit is derived from aspartic Methionine A CH,-COOH Me0 A H (1011 A OMe %@\ (102) The previous reports that both D-and L-phenylalanine are incorporated into cytocholasine D (103) have been investigated.It now appears that D-phenylalanine is incorporated via phenylpyruvic acid and ~-phenylalanine.'~' The enzymes 162 T. Hemscheidt and I. D. Spencer J. Chem Soc. Chem. Commun. 1991,494. 163 J. M. Dickinson J. R. Hanson P. B. Hitchcock and N. Claydon J. Chem. Soc. Perkin 1 1989 1885. 162 P. Sandmeier and Ch. Tamm Helv. Chim Actq 1989 72 774. A. Hadeuer P. Roth and Ch. Tamm 2. Naturforsch. Teil C 1989 44 19. 306 R A. Hill Me0 ..MH Me0 II "PkJMe 0 catalysing the oxidative coupling of reticuline to salutaridine (104) and berbamunine have been characterized and shown to be cytochrome P-450 linked NADPH and O2 dependent microsomal bound enzymes.'66 The incorporation of C-2 of tryp- tophan into the imino carbon of spirobrassinin (105)from Brussicu carnpestris implies a molecular rearrangement (Scheme 6).'67 H 'N H H H Scheme 6 (105) Labelled acetate glycine and 1802 have been incorporated into manumycin (106) from Streptornyces p~rvulus.'~~ The C7N unit is not formed from an aromatic precursor and may be formed from dihydroxyacetone and succinate or closely 0 0 NH 166 M.H. Zenk R. Gerardy and R. Stadler J. Chem. SOC. Chem. Commun. 1989 1725. 167 K. Monde and M. Takasugi J. Chem. SOC.,Chem. Commun.1991 1582. 168 R. Thiericke A. Zeeck J. A. Robinson J. M. Beale and H. G. Floss J. Chem. SOC.,Chem Commun. 1989 402. Biological Chemistry Biosynthesis related precursors. An insight into the biosynthesis of manumycin (106) is provided by studies with unnatural precursor^.'^^ Deuterium labelling studies have shown that the proton at C-5a of roquefortine (107) from Penicillium roqueforti is derived from the 2-hydrogen of tryptophan"' contrary to an earlier rep01t.l~~ This observation implies that no 2-substituted indoles can be intermediates in the biosynthesis. Incorporation studies have shown that cyclo-(L-phenylalanyl-L-seryl) (108) is an efficient precursor of gliotoxin (109) from Gliocladium uirens and hyalodendrin (1 10) from a Hyalodendron species.'72 The cyclic dipeptide (108) is not cleaved prior to incorporation and is incorporated into epidithiodioxopiperazines with opposite sulfur bridge stereochemistry.Obaflorin (1 11) from Pseudomonasfluorescens is an interesting p-lactone antibio- tic. Earlier work has shown that p-aminophenylalanine (1 12) is incorporated into carbons 3 to 10 of obaflorin (lll).173 Carbons 1 and 2 were shown to be derived from glyoxylate (113) itself derived from glycine once the conditions for incorpor- ation were determined.'74 The labelling experiments showed interesting labelling of both carbons 1 and 2 of obaflorin (111) when [2-13C]glycine was fed this is a result of glycine metabolism producing glyoxylate (1 13) labelled at both carbons. Unlike obaflorin (1 11) in which the nitro group is derived by oxidation of an amino group 169 R.Thiericke H.-J. Langer and A. Zeeck J. Chem. SOL,Perkin I 1989 851. 170 B. Bhat D. M. Harrison and H. M. Lamont J. Chem. SOC.,Chem. Commun. 1990 1518. 171 C. R. Pulham P. T. Brain A. J. Davies D. W. H. Rankin and H. E. Robertson 1.Chem. SOC.,Chem. Commun. 1990 177. 172 M. I. Pita Boente G. W. Kirby G. L. Patrick and D. J. Robins J. Chem. SOC.,Perkin 1 1991 1283. R. B. Herbert and A. R. Knaggs Tetrahedron Lett. 1988 29 6353. 174 R. B. Herbert and A. R. Knaggs Tetrahedron Lett. 1990 31 7515. 308 R. A. Hill c1 cJg&l COOH OVO (113) the nitro group of dioxapyrrolomycin (114) is derived from direct biochemical nitration in Streptomycesfum~nus.'~~ The organism was grown on a medium contain-ing K'5N'803as the sole source of nitrogen the ratio of l80to 15Nin the dioxapyr-rolomycin (114) was found to be the same as in the nitrate precursor.The origin of the cyano group in kinamycin D (115) from Streptomyces muray-amaensis has been established as C-2 of acetate and that the cyanide carbon was originally part of the polyketide Details of the 6 steps in the biosynthesis of antibiotic LL-C10037a (1 17) from 3-hydroxyanthanilic acid (116) in a Streptomy-ces species have been e1~cidated.l~~ 0 QH Recent work on the mechanism of pyridoxal-5'-phosphate dependent decarboxy-lase and transaminase enzymes has been de~cribed.'~~ A collection of 25 papers concerned with the biosynthesis of branched chain amino acids has been pub-1i~hed.I~~ An insight into the biosynthesis of the coronamic acid (120) portion of coronatine from Pseudomonas species has been achieved.'*' Labelling studies have shown that isoleucine (1 18) is first converted into alloisoleucine (119) and that only one hydrogen is lost from the methyl group of alloisoleucine (119) when it is converted to the cyclopropyl bridge of coronamic acid (120).The hydrogen at C-3 of alloisoleucine (119) is retained during the biosynthesis and 6-hydroxyal-loisoleucine is not incorporated. These results imply that an oxidative cyclization process is probably taking place in the biosynthesis of coronamic acid (120). H2N9@tH ""\ HOOC -HOOC '-HOOC 175 G. T. Carter J. A. Nietsche J.J. Goodman M. J. Torrey T. S. Dunne M. M. Siegel and D. B. Borders J. Chem. Soc. Chem. Commun. 1989 1271. P. J. Seaton and S. J. Gould J. Antibiot. 1989 42 189. 177 S. J. Gould B. Shen and Y. G. Whittle J. Am. Chem. SOC,1989 111 7932. 178 D. Gani Phil. Trans. R. Soc. Lond. B 1991 332 131. 179 'Biosynthesis of branched chain amino acids' ed. Z. Barak D. M. Chapman and J. V. Schloss BCH New York 1990. R. J. Parry M.-T. Lin A. E. Walker and S. Mhaskar J. Am. Chem. Soc. 1991 113 1849. Biological Chemistry Biosynthesis Considerable progress continues to be made in the area of p-lactam antibiotics. Excellent reviews have appeared on the biosynthesis of penicillins and cephalo- sporins,181 mechanistic studies on isopenicillin N synthase (IPNS)18* and the molecular biology of the bio~ynthesis.'~~ The biosynthetic route to the penicillins and cephalosporins is summarized in Scheme 7.The first step in the biosynthesis involves the formation of the LLD-ACV tripeptide (121) by ACV synthase. This enzyme has been purified from Aspergillus nidulan~,'~~ Cephalosporium acremonium and Streptomyces ~lauuligerens.'~'~'~~ The nucleotide sequence of the gene in Penicil- lium chryosogenum which codes for ACV synthase has been determined.ls7 Labelling studies with [4-2H6,'802]valine have shown that both one and two valine oxygens are subject to intracellular exchange prior to formation of the ACV tripeptide (121).'88 Studies with analogues of ACV as substrates for IPNS have given more H I I Y H I COOH COOH -H2NY-q(NEA-s I H2NY-yp$ 0 0 I H H I I Scheme 7 181 J.E. Baldwin J. Heterocyclic Chem. 1990 27 71. 182 J. E. Baldwin and M. Bradley Chem. Rev. 1990,90 1079. 183 S. W. Queener Antimicrobial Agents Chemotherapy 1990 34 943. 184 J. van Liempt H. von Dohren and H. Kleinkauf J. Biol. Chem. 1989 264 3680. 185 J. E. Baldwin J. W. Bird R. A. Field N. M. O'Callaghan and C. J. Schofield J. Antibiot. 1990,43,1055. 186 J. Zhang and A. Demain Biochem Biophys. Res. Commun. 1990 169 1145. 187 D. J. Smith A. J. Earl and G. Turner EMBOJ. 1990 9 2743. 188 J. E. Baldwin R. M. Alington J. W. Bird and C. J. Schofield J. Chem. SOC.,Chem. Commun. 1989,1615. 310 R A. Hill evidence about the mechanism of a~tion.'*~-'~~ The IPNS enzyme catalyses two ring closures the P-lactam ring is formed first however synthetic (126) was not incorpor- ated into isopenicillin N (122) using enzyme extracts from Cephalosporium acremonium or Streptomyces ~Zauuligerus,'~~ similar results were obtained with syn- thetic (127) and IPNS from S.clauuligerus. These results imply that the intermediate is enzyme bound. Evidence to support an insertion-homolysis mechanism for the events leading to C-S bond formation has been pre~ented.'~~ Genes for various isoenzymes of IPNS have been expressed to a high level in soluble form in E. ~oli.'~' H COOH (126) R= L-a-aminoadipoyl (127) R= Ph CHZ-C-II The ligands coordinated to iron in IPNS have been Isopenicillin N epimerase which converts isopenicillin N (122) into penicillin N (123) has been isolated from Nocardia la~tamdurans.'~~ The epimerase gene from Streptomyces cZavuZigerus has been mapped and ~equenced.'~~ Penicillin N (123) is converted into the cephalosporins by DAOC/DAC synthase which catalyses the ring expansion to deacetoxycephalosporin C (DAOC) (124) and hydroxylation to deacetylcephalop- sporin C (DAC) (125).The stereochemistry of the ring expansion has been studied using enzymes from Cephalosporium acremonium.200 Both ring expansion and hydroxylation require a-ketoglutarate as cofactor. Labelling studies have shown that in each step the a-ketoglutarate is converted into succinate and C02 and that label from 1802 is incorporated efficiently into succinate.201 The incorporation of labelled oxygen into DAC (125) was only about 50% indicating that oxygen exchange is probably occurring at a putative iron-oxygen intermediate.When C-3 deuterated penicillin N (123) is incubated with DAOC/DAC synthase the shunt metabolite (128) is produced giving further insight into the ring expansion mechanism.202 189 J. E. Baldwin C. J. Schofield and B. D. Smith Tetrahedron 1990 46 3019. 190 J. E. Baldwin M. Bradley S. D. Abbott and R. M. Adlington J. Chem. SOC. Chem. Commun. 1990,1008. 191 J. E. Baldwin R. Adlington C. J. Schofield and H-H. Ting Tetrahedron 1990 46 6145. 192 J. E. Baldwin G. P. Lynch and C. J. Schofield J. Chem. SOC. Chem. Commun. 1991 736. 193 A. I. Scott R. Shankaranarayan and S.-K.Chung Heterocycles 1990 30,909. 194 J. E. Baldwin R. M. Adlington N. P. Crouch J. W. Keeping S. W. Leppard J. Pitlik C. J. Schofield W. J. Sobey and M. E. Wood J. Chem. SOC.,Chem. Commun. 1991,768. 195 J. E. Baldwin J. M. Blackburn J. D. Sutherland and M. C. Wright Tetrahedron 1991,47 5991. 196 L.-J. Ming L. Que Jr. A. Kriauciunas C. A. Frolik and V. J. Chen Znorg. Chem. 1990 29 1111. 197 V. J. Chen A. M. Orville M. R. Harpel C. A. Frolik K. K. Surerus E. Munck and J. D. Lipscomb J. Biol. Chem. 1989 264 21677. L. Lhiz P. Liras J. M. Castro and J. F. Martin J. Gen. Microbiol. 1990 136 663. 199 S. Kavacevic M. B. Tobin and J. P. Miller J. Bacten'ol. 1990 172 3952. 200 J. E. Baldwin R. M. Adlington N. P. Crouch N. J. Turner and C. J. Schofield J. Chem. SOC.,Chem.Commun. 1989 970. 201 J. E. Baldwin R. M. Adlington C. J. Schofield W. J. Sobey and M. E. Wood J. Chem SOC,Chem. Commun. 1989 1012. 202 J. E. Baldwin R. M. Adlington N. P. Crouch C. J. Schofield N. J. Turner and R. T. Aplin Tetrahedron 1991,47 9881. 19' Biological Chemistry Biosynthesis H RN Progress towards the understanding of the biosynthesis of clavulanic acid (132) from Streptomyces cluuuligerus continues to be made (Scheme 8). Proclavaminic acid (129) has been synthesized and its absolute stereochemistry has been deter- mined.203 The four electron oxidative cyclization of proclavaminic acid (129) to clavaminic acid (131) is carried out by an a-ketoglutarate dependent and iron containing oxygenase clavaminic acid synthase (CAS).Labelling experiments have shown that the oxygen of the hydroxyl group of proclavaminic acid (129) gives rise to the oxygen of the oxazolidine ring of clavaminic acid (131)204and that the ring closure goes with retention of configuration at C-4' of proclavaminic acid (129).205 Dihydroclavaminic acid (130) has been isolated as an intermediate in this cycliz- atioa206 Possible mechanisms for this oxidative cyclization have been dis-I COOH COOH (132) (131) Scheme 8 Labelling studies have shown that aristeromycin (133) from Streptomyces citricolor arises from a normal adenyl biosynthesis that the cyclopentane ring arises from glucose by formation of a bond between C-2 and C-ti209and that the amine (134) is an intermediate.210 Labelled forms of ATP and adenosine when administered to 203 K.H. Baggaley S. W. Elson N. H. Nicholson and J. T. Sime J. Chem. Soc. Perkin I 1990 1513 and 1520. 204 W. J. Krol A. Basak S. P. Salowe and C. A. Townsend J. Am. Chem. SOC.,1989 111 7625. 205 A. Basak S. P. Salowe and C. A. Townsend J. Am. Chem SOC.,1990 112 1654. 206 J. E. Baldwin R. M. Adlington J. S. Bryans A. 0.Bringhen J. B. Coates N. P. Crouch M. D. Lloyd C. J. Schofield S. W. Elson K. H. Baggaley R. Cassels and N. Nicholson Tetrahedron 1991,47,4089. 207 C. A. Townsend and A. Basak Tetrahedron 1991,47 2591. 208 S. P. Salowe E. N. Marsh and C. A. Townsend Biochemistry 1990 29 6499. 209 R. J. Parry V. Bornemann and R. Subramanian J. Am. Chem. Soc. 1989 111 5819. 210 R.J. Parry K. Haridas R. de Jong and C. R. Johnson J. Chem. SOC.,Chem. Commun. 1991 740. 312 R A. Hill cell-free extracts of Streptomyces griseofus produced sinefungin (135) with evidence that both precursors had been significantly degraded before incorporation.211 The ribose ring of adenosine was incorporated into sinefungin (135) intact without loss of label from C-5’. Experiments suggested that the C-C bond formation between arginine and ribose preceded attachment of the adenine ring. HOHzC rl A. HO OH HO OH HOOC NH2 6 Porphyrins A comprehensive review of biosynthetic experiments concerned with porphyrins chlorophylls and vitamin B12has appeared.212 Full details of the work that led to the discovery of the dipyrrolic cofactor essential for the action of hydroxymethyl- bilane synthase (HMBS) (or porphyrobilinogen deaminase) that converts por- phobilinogen into hydroxymethylbilane (HMB) have been p~blished.~~~,~’~ This work has also been re~iewed.~” Details of the mechanisms of HMBS and uropor- phyrinogen I11 synthase (or cosynthetase) that converts HMB into uro’gen I11 have been reviewed.216 Uro’gen I11 synthase mechanism molecular biology and bio- chemistry is covered in another review.217 Further evidence for the involvement of a spiro-intermediate between HMB and uro’gen I11 has been presented.218 The extensive investigation into the biosynthesis of vitamin B12has been covered in two The biosynthesis of vitamin B12from uro’gen I11 involves inter alia 8 C-methylation steps.Precorrins 1,2 and 3 have been identified as the first three intermediates. Recent work on the details of these steps has been pub- lished.221-223 Evidence that norcorrins are involved in the biosynthesis of cobyrinic 211 R. J. Parry and S. Ju Tetrahedron 1991 47 6069. 212 F. J. Leeper Nut. Prod. Rep. 1989 6 171. 213 A. D. Miller F. J. Leeper and A. R. Battersby J. Chem. SOC.,Perkin 1 1989 1943. 214 G. J. Hart A. D. Miller U. Beifuss F. J. Leeper and A. R. Battersby J. Chem. SOC.,Perkin 1,1990 1979. 215 P. R. Alefounder G. J. Hart A. D. Miller U. Beifuss C. Abell F. J. Leeper and A. R. Battersby Bioorganic Chem. 1989 17 121. 216 A. R. Battersby and F. J. Leeper Chem. Rev. 1990,90 1261. 217 N. Crocket P. R. Alefounder A. R. Battersby and C.Abell Tetrahedron 1991 47 6003. 218 M. A. Cassidy N. Crockett F. J. Leeper and A. R. Battersby .IChem. SOC.,Chem. Commun. 1991,384. 219 A. R. Battersby Pure AppL Chem. 1989 61 337. 220 A. I. Scott Pure Appl. Chem. 1989 61 501. 22 1 R. D. Brunt F. J. Leeper I. Grgurina and A. R. Battersby J. Chem. SOC.,Chem. Commun. 1989,428. 222 C. L. Gibson and A. R. Battersby J. Chem. SOC.,Chem. Commun. 1989 1223. 223 G. W. Weaver F. Blanche D. Thibaut L. Debussche F. J. Leeper and A. R. Battersby J. Chem. Soc. Chem. Commun. 1990 1125. Biological Chemistry Biosynthesis acid has not been A new intermediate has been isolated and named precorrin 6x.226 The site of reduction of precorrin 6x by NADPH has been determined.227 7 Miscellaneous Metabolites The mechanism of oxidative reactions catalysed by P-450and related iron-containing enzymes has been reviewed.228 A generally valuable and sensitive method for determining the configuration of chiral methyl groups has been developed.The method depends on the observation that the diastereotopic protons on C-7 of (136) have different NMR chemical shifts.229 (138) R= NH2 (139) R=OH (140) Incorporation studies have shown that label from 1802 does not appear in the oxirane oxygen of fosmycine (137) from Streptomyces fradi~e.~~' Both (2-aminoethy1)phosphonic acid (138)231 and (2-hydroxyethy1)phosphonicacid( 139)232 are incorporated into fosmycin (137). The methyl carbon is derived from the methyl of methionine (S)-(2-hydroxypropyl)phosphonic acid (140) was efficiently incor- porated into fosmycin (137).233 224 J.Kulka C. Nussbaumer and D. Arigoni J. Chem. SOC. Chem. Commun. 1990 1512. 225 I. Grgurina S. Handa G. Weaver P.A. Cole and A. R.Battersby J. Chem. SOC.,Chem. Commun. 1990 1514. 226 D. Thibaut L. Debussche and F. Blanche Proc. Natl. Acad. Sci. USA 1990 87 8795. 227 G. W. Weaver F. J. Leeper A. R. Battersby F. Blanche D. Thibaut and L. Debussche J. Chem. SOC. Chem. Commun. 1991 976. 228 M. Akhtar and J. N. Wright Chem Rev. 1990 90 1079. 229 F. A. L. Anet D. J. O'Leary J. M. Beale and H. G. Floss J. Am. Chem. SOC., 1989 111 8935. 230 F. Hammerschmidt G. Bovermann and K. Bayer Liebigs Ann. Chem. 1990 1055. 23 1 F. Hammerschmidt H. Kahlig and N. Muller J.Chem. SOC. Perkin 1 1991 365. 232 F. Hammerschmidt and H. Kahlig J. Org. Chem. 1991 56 2364. 233 F. Hammerschmidt J. Chem. Soc. Perkin 1 1991 1993.

ISSN:0069-3030    

DOI:10.1039/OC9918800283

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

Author Index Aarts G.M. 71 Abbott S.D. 310 Abboud J.L. 45 Abdali A. 209 Abdel-Baky S. 26 Abe I. 297 Abe N. 148 Abe T. 290 Abell C. 33 295 300 312 Aben R.W.M. 246 Abiko T. 203 Abramovitch D.A. 260 Abramovitch R.A. 260 Abramson F.P. 32 Abu-Soud H. 78 Achari B. 256 Acheson K.M. 260 Achiwa K. 264 Adachi T. 136 Adam W. 150 153 168 245 246 253 Adams J. 35 104 240 Adams J.P. 250 267 Adger B.M. 159 253 Adiwidjaja G. 140 Adlington R.M. 88 95 96 100 309 310 311 Afarinkia K. 124 Affolter M. 21 Afonso C.A.M. 170 Agback P. 11 12 Agnel G. 117 199 Agosta W.C. 244 Agoston G.E. 204 Agren H. 45 Agris P.F. 14 Aguilar J. 280 Aguyen K.A. 50 Ahlberg P. 147 Ahlrichs R.42 Ahmed S.A. 276 296 Ahuja J.R. 122 Aiba H. 21 Aird B.A. 76 Ajie H. 32 Akadegawa N. 124 246 Akasaka T. 244 Akhila A. 296 Akhtar M. 299 313 Akita H. 263 Akkerman O.S. 136 234 235 Akutagawa S. 249 Akutsu H. 21 Alajarin M. 261 Alam T.M. 6 Alami M. 191 Alberg D.G. 300 Albert R.,245 246 Albizati K.F. 256 Albrecht O. 153 Alderdice D.S. 29 Alefounder P.R. 312 Alexakis A. 105 236 Alexander A.J. 33 Alexander J. 147 Alexander J.E. 33 Al-Husaini A.H. 241 Ali S.A. 241 Allaf A.W. 103 146 221 Allegri G. 31 Allegrone G. 286 Allemand P.-M. 103 222 Allen A.D. 78 Allen B.H. 222 Allen M.P. 45 Allen T. 110 Allgood C. 25 Allmang G. 194 Allured V.S.41 Almena C.M. 256 Almlof J. 223 Almstead N.G. 239 Alo B.I. 138 Alonso F. 141 Alper H. 194 209 Alphand V. 278 Altamura A. 142 Altenbach H.J. 219 Alvarez C. 197 Alvarez M. 163 172 222 Alvarez M.M. 32 Alvear M. 294 Amano N. 133 Amatore C. 189 Amberg W. 250 Amiens C. 88 Amino Y. 194 Ammanamanchi R. 229 Amos R.D. 40 Amougay A. 258 Amrhein N. 300 Amster I.J. 26 Amurrio D. 213 Amyes T.L. 66 69 Anantanarayan A. 255 Anders E. 49 Andersen C. 276 Andersen K.K. 166 Anderso C.B. 125 Anderson K.S. 300 Anderson L.G. 200 Anderson M.S. 294 Anderson P.G. 217 Anderson S.W. 80 Anderson W.F. 21 Andersson P.G. 157 164 206 217 Ando A.244 Ando K. 124 246 Ando T. 259 Andrks J.L. 48 Andrews J.S. 40 Andrews L. 43 Andrews P.C. 235 Andrews-Smith W. 299 Andrievsky A.A. 258 Andrulis P.J. 11 281 Andrus M.B. 255 Anet F.A.L. 313 Angers P. 235 Angoh A.G. 257 Aniss K. 213 Aniszfeld R. 103 146 222 Anjeh T.E.N. 258 Annan R.S. 28 33 Annunziata R. 228 Anthonsen T. 270 Anz S.J. 32 222 Aoki S. 120 192 217 Aonuma S. 133 Aoyama H. 156 Aoyama Y. 253 Aplin R.T. 283 310 Appleyard R.J. 300 Aragozzini F. 273 Arai K. 245 287 296 Arai M. 51 Araki S. 141 238 Arbogast J.W. 223 Arcadi A. 189 191 206 315 316 Archelas A. 272 Archer C.M. 230 Arduengo A.J. 111 239 240 Arevalo A.R. 197 Arif A.M.203 204 212 Ariga M. 148 Arigoni D. 313 Arkle S.R. 78 Armentrout P.B. 249 Armstrong D.R. 235 Armstrong F.B. 3 Amett E.M. 64 75 231 Arrowsmith C.H. 78 Artaud I. 142 Asaka I. 297 Asami Y. 171 Asao T. 64 147 148 190 Ashare R. 149 Ashcroft J. 292 Ashwell M. 149 Ashworth D.M. 289 Asmus K.D. 102 Aubert C. 196 Auge J. 244 Aumann R. 203 Auner N. 153 Austin D.J. 142 Austin R.E. 11 1 202 240 Avenoza A. 53 Avent A.G. 146 222 Avila L.Z. 101 Awwal A. 78 Ayres D.C. 301 Aziza K.B. 142 Azzabi M. 189 Babudri F. 238 Bacaloglu R. 140 Baceiredo A. 151 Bach R.D. 42 48 253 Badia J. 280 Bae Y.K. 103 146 222 Baeckstrom P. 169 Backvall J.-E. 157 164 206 217 Baggaley K.H.254 311 Baghurst D.R. 260 Bagno A. 73 Bai X. 229 Bailey M. 110 Bailey P.D. 170 Bailey W.F. 75 232 233 Baillargeon M. 150 Baker K.V. 234 Baker M.J. 194 Baker R.W. 133 Baker T.M. 133 Bakhmutov V.I. 205 Bakke J.M. 249 Balasubramanian K.K. 141 Balasubramanian S. 300 Balavoine G. 88 193 Balbi A. 174 Balcerzak P. 241 Balch A.L. 222 Balci M. 144 Baldino C.M. 162 Baldoli C. 213 Balducci D. 85 Baldwin J.E. 61,88,95,96,100 283 309 310 311 Baldwin M.A. 25 29 33 Baleja J.D. 7 21 Balgobin N. 12 Ball J.C. 42 Ballester P. 91 110 Balm S.P. 103 146 221 Balme G. 119 203 Balogh D.W. 242 Baltas M. 109 Bambridge K. 214 Banait N.S.64 68 Banciu M.D. 147 Bandy R.E. 34 Banerjee A.K. 256 Banerji A. 144 259 Banik B.K. 260 Banki G. 52 Banks M.R. 150 Banks R.E. 136 Banno H. 58 Bansal R.K. 167 Banville D.L. 18 Banwell M.G. 127 146 147 148 190 Bao J.. 125 248 Barakat K.J. 260 Baranski A. 52 Barbas C.F. 111 263 280 Barbeaux P. 231 Barbeni M. 286 Barbieri G. 158 244 Barco A. 125 Bari S.S. 260 Barinaga C.J. 29 Barlow P.N. 300 Barlow S.J. 134 Barluenga J. 171 179 180 230 Barnett N.D.R. 235 Barr D. 236 Barrett A.G.M. 104 110 Barrett C. 159 253 Barros M.T. 170 Barrows L.R. 179 Bartha E. 256 Bartholomew D. 152 Bartl J. 64 Bartlett P.A. 300 Bartlett P.D. 48 Bartlett R.J. 43 Bartoletti M.76 Bartoli C. 73 Barton D.H.R. 139 249 Basak A. 311 Basch H. 43 47 80 Basetti A. 271 Basha A. 138 Basilevski M.V. 53 Author Index Basolo F. 212 Bassfield R.L. 131 Bassin J.P. 136 Basu B. 115 Basu K. 10 Basu M.K. 259 Batal D.J. 253 Baternan A. 32 Bates R.W. 115 186 Batey R.A. 89 119 Batlaw R. 234 Battaglia L.P. 196 Battersby A.R. 162 312 313 Bauchat P. 259 Baudy-Floc’h M. 166 Bauer D. 203 Bauer L. 234 Baum M.W. 255 Baumgarten M. 147 Bausch J.W. 103 146 222 Bauschlicher C.W. jun. 42 Bayer K. 313 Beak P. 71 229 253 Beale J.M. 18 283 292 304 306 313 Beale M.H. 293 Bean M.F. 30 Beauchamp J.L. 26 249 Beaucourt J.-P. 209 Beavis R.C.28 Beck R. 32 222 Beck W. 211 Becke A.D. 41 Becker D. 243 Becker J.Y. 222 Beckwith A.L.J. 85 86 94 95 110 Bednarski M.D. 280 Behal S. 222 Behrendt L. 237 Beifuss U. 312 Beigersbergen J.H.M. 37 Beller M. 107 250 Bellier H.S. 122 Bellina F. 189 Bellucci G. 71 72 272 Ben-Amotz D. 223 Bencheqroun M. 214 Bender S.L. 300 Benesi A.J. 230 Benetti M. 272 Benetti S. 125 Benkovic P.A. 220 Benkovic S.J. 219 220 Benner S.A. 285 Bennet A.J. 71 Bennett F.D. 273 Bennett G.L. 303 Bennett H.P.J. 32 Bennich H. 26 Benninghoven A. 26 Bensimon M. 26 Bentley R.,300 Bentley T.W. 80 81 Author Index Benz G.A. 116 Berchtold G.A. 300 Beremand P.D.295 Berg U. 73 Bergbreiter D.E. 202 240 Bergens S.H. 75 217 Berger B. 267 Berger R.L. 18 Bergmann T. 31 Bergmark W.R. 146 Bergstrom D.T. 204 Berkowitz D.R. 267 Berlan J. 259 Berlin S.C. 33 Berman S.S. 25 Bermudez M.D. 138 Bernadelli G. 124 Bernardi A. 229 Bernardi F. 46 Bernardinelli G. 109 212 214 Bernaus C. 169 Berndt W.G. 204 Bernier P.P. 221 Bernocchi E. 206 Bernstein E.R. 131 Bernstein M.P. 236 Berrios-Pena N.G. 189 Berrisford D.J. 236 Berson J.A. 60 61 Bertran J. 45 46 51 Bertrand G. 151 Bertrand M. 33 236 Bertz S.H. 236 Besbes R. 174 Beslin P. 58 Bessard Y. 241 Bestmann H.J. 267 Bethune D.S. 221 Betz P. 209 216 Beugelmans R.139 Bewersdorf M. 230 Bhalerao U.T. 268 Bhamare N.K. 125 Bhamidapaty K. 150 Bhandari P. 302 Bhat B. 307 Bhat N.G. 105 Bhatarah P. 195 Bhawal B.M. 144 Bhupathy M. 231 Bianchi D. 270 271 Bianchini C. 195 204 Bianchini R. 71 72 Bianucci A.M. 6 Bibb M.J. 291 Bibbs J.A. 219 Biccierini N. 141 Bickelhaupt F. 136 230 234 Biehl E.R. 144 Biemann K. 28 Bienz S. 229 Bigi F. 141 Billeter M. 21 Billups W.E. 144 258 Bilodean M.T. 108 Binnekamp A, 299 Bird J.W. 309 Birgeson C. 108 Birkbeck A.A. 133 Birkel M. 151 Bischofberger N. 280 Bishop K.D. 22 Bishop P.A. 101 Blackburn J.M. 310 Blacklock T.J. 255 Blades A.T. 34 Blake A.J. 161 162 Blake J.F.53 245 258 Blanche F. 312 313 Blanchfield J.T. 238 Blanda M.T. 220 Blandamer M.J. 53 80 244 Blaney J.M. 220 Blankenship J.N. 78 Blase D. 227 Blaser D. 260 Blaser H.-U. 254 Blasko A. 140 Blechert S. 247 Bleeke J.R. 131 212 Blokzijl W. 53 80 244 Blomberg M.R.A. 49 249 Blommers M.J.J. 7 8 Bloodworth A.J. 169 Bloomfield V.A. 17 Blount J.F. 145 Blum J. 254 Bochmann M. 237 Bodansky M. 259 Boden N. 102 Bodepudi V. 10 Bodner G.S. 204 Bodwell G.J. 215 Boeckman R.K. 129 Boehler M.A. 56 Boehme D.K. 32 Boelens R. 5 7 22 Boernsen K.O. 29 34 Boese R. 196 209 Boese W.T. 193 Boesl U. 29 Boger D.L. 55 162 182 183 246 Bohme D.K. 223 Boivin J. 85 244 Bokelman G.H.301 Boland W. 103 263 285 294 Bolm C. 103 251 Bolte J. 281 Bolton P.H. 10 Bombrun A. 116 207 Bonaccorsi R. 44 Bond D. 42 Bond G. 260 Bondarenko P.V. 26 Bonde B.D. 229 Bondiou J.C. 261 Bonner M.D. 108 Bonvalet C. 254 Booth S.E. 120 Borcic S. 65 Bordas-Nagy J. 36 Bordeleau L. 257 Borden D.B. 103 Borden W.T. 42 46 51 242 Borders D.B. 292 308 Bordwell F.G. 74 95 139 Borer B.C. 242 Borer P.N. 22 Borgias B. 6 Bornemann V. 31 1 Borner R. 102 Borst J.P. 230 Bos M.E. 196 Bosco M. 73 Bose A.K. 260 Bosnich B. 75 217 Bothmer V. 220 Bottle S.E. 253 Bottoni A. 46 Bouaziz R. 261 Bouchoux G. 35 Boulanger R. 235 Bourelle F. 254 Bourgogne J.P.261 Bouyssi D. 119 Bovara R. 267 Bovermann G. 313 Bowden K. 75 Bowden M.C. 157 Bowen R.D. 35 Bowie J.H.J. 38 Bowman W.R. 84 Bowry V.W. 95 Bowsers M.T. 249 Box V.G.S. 154 Boy P. 139 Boyd D.R. 141 250 275 276 Boyd R.J. 47 48 Boyd R.K. 29 33 Bradley C.D. 36 Bradley M. 309 310 Bradshaw J.S. 235 Brady J.W. 45 Brady W.T. 241 Braenden J.U. 249 270 Brain P.T. 307 Branchadell V. 46 51 246 Brande A. 119 Brandes A. 188 Brandes D.A. 209 Brandl P. 194 Brands M. 214 Brandsma L. 233 236 Brandstetter T. 128 204 Brandvold T.A. 196 197 Brauman J.I. 36 Braun M.,219 Braunlin W.H. 17 22 Bray D.D. 166 Breimair J. 21 1 Breitmaier E. 183 Brembilla D.149 Bremner J.B. 182 Brennan J. 159 253 Breslauer K.J. 9 18 Breslow R. 54 63 68 244 245 Breternitz H.-J. 140 Bretimaier E. 142 Breyer R. 110 Briant C.E. 222 Bridges A.M. 33 284 Briel D. 172 Briki F. 45 Bringhen A.O. 3 11 Brinker U.H. 51 Brittain H.G. 228 Brocard J. 213 214 Brodbelt J. 249 Brodbelt J.S. 31 Broen R.D. 144 Broka C.A. 143 Brookhart M. 203 Brophy J.E. 60 Brosch D. 67 Brouillard-Poichet A. 57 Brown A.M. 304 Brown B.B. 56 Brown C.S. 162 Brown D.A. 212 Brown D.J.S. 9 Brown G.R. 170 Brown H.C. 105 Brown J.M. 103 189 234 Brown M.F. 198 Brown M.J. 256 Brown R.E. 43 Brown R.S. 71 Brown S.H. 83 Brown T. 9 Bruckner R.191 Bruggink A. 261 Bruhn P.R. 139 Bruice T.C. 251 Brunelle A. 30 Brunet M.L. 110 Brunner H. 194 Brunt R.D. 312 Bryans J.S. 311 Bryant G.L. 140 Bryant J.A. 220 Buback M. 260 Buchholz R. 155 Buchwald S.L. 143 164 Buckman B.O. 87 Bucsi I. 146 222 Buchi G. 174 Buhanjuk S.M. 200 Buhl M. 230 Buist G.J. 78 Bulli M. 110 Bulliard M. 92 Buncel E. 70 Bunton C.A. 63 140 Bur D. 56 Burdisso M. 250 Burger H. 241 Burgess K. 103 267 Burk M.J. 254 Burkholder C.R. 61 133 Burlingame A.L. 29 33 Burn I. 103 Burn P.L. 183 225 Burnell D.J. 55 Burton D.J. 191 Burton G.W. 265 Burton N.A. 133 Bush D.M. 225 Bushby R.J. 102 Bushman D.R. 250 Butenschon H.214 Butler I.S. 217 Butsugan Y. 141 238 Bycroft B.W. 295 Bykovetz N. 222 Byrne N.E. 176 Cabal M.-P. 129 204 238 Cabbidu S. 137 233 Cable K.M. 303 Cabri W. 192 Cacchi S. 189 191 206 Cadogan J.I.G. 150 Caffrey P. 284 Caglioti L. 206 Calabrese J.C. 222 240 Caldwell K.A. 223 Calhorda M.J. 189 Cambie R.C. 212 214 Cameron J.M. 148 190 Camilleri P. 227 Cammi R. 44 Camper D.L. 216 251 Campestrini S. 251 Campos Neves A.S. 259 Camps F. 139 213 254 Camus P.P. 31 Canary J.W. 68 Candiani I. 192 Candlin J.P. 260 Cane D.E. 293 294 295 Canonne P. 235 Cantin M. 257 Cantrell W.R. 111 126 Capelli A.M. 229 Caple R. 11 5 200 Capon B. 76 Capps N. 244 Carbonnaux C.9 Cardemil E. 294 Cardillo R. 286 Cardinsux F. 245 Carey P.R. 43 Carfagna C. 192 206 207 Carilla J. 134 Carless H.A.J. 141 250 Carlbn R.P. 171 179 Carlson R. 229 Carlstedt-Duke J. 22 Author Index Carlstrom A.-S. 189 Carmen Villaverde M. 139 Carnell A.J. 277 Caro B. 215 Caron G. 266 Caron M. 261 Caronne S. 162 Carpentier J.-F. 213 Carpita A, 189 Carr S.A. 30 Carrea G. 267 Carrol P.J. 252 Carry J.-C. 258 Carter G.T. 292 308 Caruso A.J. 140 Casas J. 253 Case-Green S.C. 69 215 Casella L. 142 Casnati G. 141 Cassady C.J. 223 Cassels R. 3 11 Cassidei L. 254 Cassidy F. 211 Cassidy M.A. 312 Castan F. 151 Castaner J. 134 Castanet Y.213 Castedo L. 139 191 Castilho P.C.M.F. 73 Castro J.M. 310 Castro P.P. 148 Catalano V.J. 222 Catinella S. 31 Cativiela C. 53 Cauley J.P. jun. 222 Caulton K.G. 195 Cava M.P. 160 Cavazza M. 141 Cazes B. 106 Celadon D. 74 Cere V. 232 Cerezo A. 30 Cesti P. 271 Chaari M. 212 Chahma M. 139 Chait B.T. 27 28 33 Chakraborty R. 239 Chaloner P. 237 Chamberlin S. 196 Chami Z. 139 Chan C. 118 188 Chan D.M.T. 119 206 Chan T.-H. 253 Chan T.W.D. 28 Chang C.-T. 109 Chang K. 211 Chao I. 223 Chapeaurouge A. 229 Chapman J.R. 27 Chapuzet J.-M. 141 Chardon C. 195 Charelle A.B. 112 Charles M.J. 36 Chase D.B. 222 Author Index Chastanet J. 139 Chatani N.162 194 Chatterjee G. 198 Chatterjee K. 32 146 221 Chattopadhyaya J. 11 12 Chaudhary A.G. 260 Chaudhuri C. 256 Chaudret B. 134 214 Chauhan K. 245 Chazin W.J. 4 Che C.-M. 249 Chelain E. 198 Chen B. 202 240 Chen B.-C. 126 252 Chen C. 238 Chen C.-P. 107 Chen H. 107 250 Chen J. 247 Chen L. 242 281 Chen Q.Z. 277 Chen S.-M. 4 Chen V.J. 310 Chen X. 229 Chen Y,-Q. 134 Cheng J.-P. 139 Cheng M.-H. 208 Cheng X.-M. 107 255 Cheong C. 13 Cherkaoui H. 209 Cherng C.-D. 120 Chew S.S. 183 225 Chiacchio U. 142 202 Chianelli D. 85 Chiappe C. 72 272 Chickos J.S. 254 Chiesi-Villa A. 134 215 Chima J. 141 250 276 Chinn R.L. 202 Chino K. 170 Chioccara F.142 Chiusoli G.P. 196 Cho B.R. 70 Cho H. 217 267 Cho I.-S. 137 Cho K.Y. 171 Cho Y.H. 225 Choe S.-B. 259 Choi S. 110 Choi S.-C. 95 Choi Y.K. 217 267 Choi Y.M. 152 Cholewka E. 52 Chong J.M. 267 Chopard C. 142 Chorlton A.P. 159 Chottard J.-C. 18 Chou S.-H. 10 Chou T. 259 Chou W.N. 254 Chowdhury S.K. 27 33 Christiaens L. 167 Christie W.W. 34 Christl M. 81 Christner D.F. 98 Chu F.Y. 269 Chumpradit S. 166 Chung K.H. 171 Chung S.-K. 310 Chung Y. 297 Chung Y.K. 115 199 200 Churakov A.M. 176 Church K.M. 244 Ciattini P.G. 191 192 Cichowlas A.A. 259 Cimetiere B. 253 Cimprich K.A. 107 255 Cinquini M. 154 Cioranescu E. 147 Cioslowski J.52 145 223 Ciufolini M.A. 176 Ciula J.C. 74 Claereboudt J. 32 Claeys M. 32 Claramunt R.M. 228 Clark A.B. 258 Clark A.J. 139 Clark C.A. 289 Clark D.L. 254 Clark D.N. 84 Clark J.D. 59 245 Clark J.E. 268 Clark J.H. 134 Clark R.D. 137 Clark T.J. 146 202 Clarke M.E. 166 Claussen R.C. 144 Claydon N. 305 Clegg W. 149 235 Cleland W.W. 81 Clements J. 102 Clery M. 79 Cliffe I.A. 181 Clifton A.A. 139 259 Clinet J.-C. 193 261 Clive D.L.J. 257 258 Clore G.M. 4 Clough J.M. 213 Coates J.B. 3 11 Coburn C.A. 134 178 Cockayne E. 146 Coe J.V. 32 Coffman H.R. 294 Coggins J.R. 300 Cohen H. 259 Cohen N. 112 Cohen R.B. 30 Cohen T. 152 231 232 Colburn A.W.28 Coldham I. 126 Cole P.A. 313 Coleman C.A. 76 Coleman R.S. 129 143 Coley T.R. 40 Collet C. 245 Colley A.M. 140 Collins J.R. 216 251 Collins M.P. 244 Collins S. 164 Collis M.P. 127 147 148 190 Collum D.B. 235 236 Colombo D. 269 298 Colon D.F. 227 Colson P.-J. 209 211 Comasseto J.V. 135 Combellas C. 139 Combrink K.D. 60 Commenges G. 151 Comotti A. 229 Concellon J.M. 230 Conesa J. 200 Consolandi E. 154 Contado M.J. 35 Contini L. 137 233 Cook J.M. 244 Cooke R.J. 245 Cooks R.G. 31 Cooley N.A. 189 Cooper A. 304 Cooper D.L. 40 Cooper J. 58 Cooper K. 261 Cooper N.J. 242 Copar A. 175 Copeland J.N. 162 Coppert D.M. 142 253 Coquerel G.261 Corbett W.L. 55 Corcoran R.C. 245 Cordier C. 205 Corey E.J. 57 58 103 107 110 123 129 219 245 255 Corina D. 299 Corley E.G. 173 Cormier J.F. 258 Cornelis A. 134 Cornett D.S. 26 Correa A. 247 Cortez C. 144 Cosset C. 198 Costa A. 137 233 Costa M. 196 Cote B. 112 Coulson S.A. 212 Court J.J. 137 Courtemanche G. 117 238 Coustel N. 222 Covey T.E. 31 Cowan J.A. 17 Cowen K.A. 32 Cox C.A. 31 Cox D.M. 222 223 Cox P.J. 103 Coxon J.M. 46 55 Cozzi F. 154 Cozzi P.G. 154 Crabtree R.H. 83 Crackett P.H. 156 Craig A.G. 26 Craig J.E. 304 Cram D.J. 103 220 Cramer C.J. 45 Crampton M.R. 73 Author Index Crandall J.K. 142 253 Crandall R.L.261 Creary X. 63 256 Creaser C.S. 218 Creegan K.M. 222 Creelman R.A. 296 Cremer D. 57 147 Cremlyn R.J. 136 Crepon E. 85 Crich D. 238 Crisp G.T. 148 190 Cristofoli W.A. 192 Critchley P. 250 Criton M. 259 Crocker L.S. 204 Crocket N. 312 Crockett J.S. 34 Crombie L. 170 284 285 302 Crosby J. 227 Crossley M.J. 183 225 Croteau R. 293 294 Crouch N.P. 310 311 Crout D.H.G. 250 Csizmadia I.G. 41 Csuk R. 103 219 263 Cuccia L.A. 265 Cumps F. 116 Cunningham D. 208 Cunningham I.D. 78 Curan D.P. 97 Curci R. 142 253 254 Curran D.P. 87 90 91 103 110 172 Curran T.T. 55 Currie J. 169 Curtis J.M. 33 Cuttance F.B. 183 225 Dabbagh G. 146 236 Dabdoub M.J.135 D’Accolti L. 142 Dad M.M. 241 Dahlman K. 22 Dai H. 258 Dai W. 167 Dai W.-M. 103 128 133 Dailey W.P. 54 202 245 Dale J. 228 256 Dallemagne P. 165 Dalley N.K. 235 Dalmas V. 281 Dalpozzo R. 73 Dalton D.M. 204 Dalton H. 101 141 250 275 Damm W. 91 110 Dance I.G. 32 d’Angelo J. 46 246 Danishefsky S.J. 129 220 238 266 267 Dannenberg J.J. 46 50 51 Dannoue Y. 98 Danon T. 220 D’Anrea S.V. 144 Daran J.C. 197 198 Darby M.R. 134 Daruwala K.P. 214 Das N.P. 303 Dasaradhi L. 268 Datcheva V.K. 282 Davey A.E. 122 David W.I.F. 222 Davidson B.S. 179 Davidson E.R. 46 60 Davidson F. 240 Davidson I.G.E. 85 Davidson K. 225 Davies A.J. 307 Davies H.G.180 Davies H.M.L. 111 126 146 202 Davies M. 128 204 Davies M.J. 203 Davies S.G. 203 213 214 215 Davin L.B. 302 Davis D.R. 5 14 Davis F.A. 126 252 Davis J.M. 68 Davis P. 173 Davis R.J.H. 250 Davis S.R. 49 Dawson B.T. 214 236 Day C.S. 222 Day V.W. 222 Dean C. 65 Dearden D.V. 249 DeBernardinis S. 192 Debussche L. 313 De Cian A, 151 Dedov A.G. 142 Defoin A. 57 Degl’Innocenti A. 238 Dehmlow E.V. 240 Deighton N. 101 de Jong R. 311 Deka R. 33 Delacroix A. 261 de la Torre B. 232 Del Buttero P. 213 Delepierre M. 18 Delgado F. 197 Della-Negra S. 30 Delmastro M. 189 191 Delogu G. 194 de 10s Santos C. 9 10 Demain A, 309 de March P. 169 Dembach P.238 de Meijere A. 148 195 207 Demuynck C. 281 Denenstein A.M. 222 Deng L. 149 251 Denholm A.A. 304 Denis J.-N. 247 Denise B. 197 Denmark S.E. 150 239 240 Denney D.B. 140 Denney D.Z. 140 Dennis T.J. 146 222 Depauw J. 30 de Raadt A. 272 Derien S. 261 Derrick P.J. 28 29 35 36 Dervan P.B. 23 Desai R.C. 137 De Santis M. 189 Desimoni G. 53 245 Desper J.M. 131 Devasagayaraj A. 201 Devine P.N. 123 De Vita R.J. 188 Devor K.A. 295 DeVozz J.J. 238 DeVries K.M. 226 de Waard P. 5 Dewan J.C. 244 Dewar M.J.S. 47 Dewick P.M. 295 300 301 Dews T. 168 Dewynther G. 259 Dhanak D. 110 Dhanalekshmi S. 141 Dhawan B. 144 234 Dickens M.J. 139 213 259 Dickhaut J.91 110 Dickinson J.M. 305 Diederich F. 32 103 144 146 221 222 223 Di Gennaro P. 142 Dillon M.P. 273 Din L.B. 140 Dingle T.W. 147 Dinh T.H. 18 Dinsmore C.J. 122 202 Dinterman L.M. 219 Di Raddo P. 144 Disko M. 222 Dixneuf P.H. 198 Dixon R.E. 74 DiZio J.P. 136 Djerassi C. 298 Djukic J.-P. 213 Dobashi A. 227 Dobashi Y. 227 Dhling A. 148 Dorges C. 177 Dotz K.H. 196 198 Dolbier W.R. jun. 61 133 Doller D. 249 Dombrowski M.A. 87 Donaldson W.A. 209 211 Donnelly D.M.X. 139 Donohoe T.J. 214 Dony C. 134 Dordick J.S. 219 Dorrity M.R.J. 250 275 Dorwin E. 140 Doss C. 298 Doss G. 234 Dougherty R.C. 261 Dowd P.M. 95 126 Dowdy D.D. 72 143 Author Index 321 Dowling J.74 Doxsee K.M. 215 Egan C. 79 Eguchi M. 236 Faiti G. 245 Falick A.M. 29 30 Doyama K. 201 Doyle M.P. 111 202 240 Draghici C. 147 Dragisich V. 125 248 Drake A.F. 12 Drakenberg T. 22 Drewlies R. 110 Eguchi S. 161 Ehle M. 151 Ehrig M. 42 Eichjnger P.C.H. 38 Einhorn C. 77 230 Einhorn J. 31 77 105 230 Eisenberg M. 10 Fafianas J. 180 Fang C.-L. 129 237 Fang Y.-R. 81 Fantin G. 274 Farina V. 138 190 191 192 Farnsworth A.P.H. 29 Farooq O. 135 Dreyer M. 280 Drinkwater D.E. 37 Eisenberg R.L. 301 Eisenstein O. 195 Fattuoni C. 137 233 Faucher A.-M. 150 Drobny G.P. 6 Drueckhammer D.G. 263 Eiser V. 146 El Amouri H. 214 Faul M.M. 11 1 240 Fausto R. 43 D’Souza V.T. 134 Eldin S. 75 Fava A. 232 Du W.-Q. 134 Elemes Y. 47 Fazakerley G.V. 9 Duah C.K. 75 Elguero J.228 261 Fedorynski M. 241 Du Bay W.J. 159 Dubbert R.A. 116 199 Dubenskii B.M. 30 Dubois D. 223 Dubost P. 197 Eliel E.L. 229 Ellenberger T. 22 Eller K. 249 Ellinger F. 225 Ellstad G.A. 103 Feeney J. 21 Feigenbaum A. 254 Feigon J. 5 8 18 Feineis E. 153 Feld H. 26 Dubussche L. 312 Ellwood C. 95 Feldman D. 140 Diirst D. 139 Elmore S.W. 60 Felix D. 237 Duffault J.-M. 105 Elmorsy S.S. 133 Fellga F. 244 Dull D.L. 228 El-Sayad M.A. 34 Fenn J.B. 283 Dumas D.P. 269 271 Elson S.W. 311 Fennessey P.V. 32 Dumke S. 172 Empfield J.R. 226 Fenton G. 273 Dunach E. 261 Endo T. 166 304 Ferguson R.R. 83 Dunbar R.C. 37 Engberts J.B.F.N. 53 80 244 Fernandez-Baeza J. 134 214 Dunigan J. 252 Engelbrecht G.J. 118 Fernandez-Moreno M. 291 Dunlap R.B. 227 Enger T.A. 245 Fernandez-Moro R.186 Dunn J.A. 204 Epiotis N.D. 63 Fernandez-Moyorales A. 219 Dunne T.S. 308 Dupuis M. 46 60 Epsztajn J. 234 Equi A.M. 304 Ferraboschi P. 149 273 Ferrara L. 267 Duran M. 45 Eriksen O. 160 Femge A.G. 27 Durandetti S. 240 Erker G. 216 Fessner W.-D. 131 280 280 Durucasu I. 144 Ernst R.D. 212 Feuerstein B.G. 18 Dushenko G.A. 60 Ervin M.H. 26 Fevig T.L. 103 Dutt M. 232 Eschavarren A.M. 190 Feyereisen M.W. 223 Dutta P.K. 256 Escribano J. 138 Fiandanese V. 238 Dutter R. 42 Escudier J.M. 109 Field R.A. 309 Dutton P.J. 265 Esker J.L. 84 Fielding S. 139 Dyker G. 145 Esmans E.L. 32 Filardo G. 162 261 Earl A.J. 309 Esquivel R.O. 212 Essigmann J. 10 Finch H. 211 244 Finet J.-P. 139 Eaton P.E. 74 Estevez J.C. 139 Finkelman M.A.J. 219 Ebata E.245 Estevez R.-J. 139 Finn M.G. 216 252 Ebata K. 132 230 Etemand G. 259 Fiorani T. 192 Eberbach W. 178 Etter J.B. 90 Fiorentino M. 254 Eberson L. 145 Ettl R. 222 223 Firment L.E. 222 Ebert G.W. 236 Euser B.A. 78 Fisch K. 194 Ebina Y. 238 Evans C. 31 272 Fischer D.R. 78 Ebizuka Y. 298 302 Evans D.A. 108 111 226 240 Fischer E.R. 249 Ebright R.H. 23 Echavarren A.M. 193 Evans J.N.S. 300 Evans P.A. 180 Fischer J. 151 Fischer J.E. 222 Ecker J.R. 149 251 Evans S. 29 Fischer K. 301 Edgecombe K.E. 41 Eyler J.R. 26 Fischer N.H. 293 Edmonds C.G. 30 Fischer W. 139 Edmonds C.J. 29 Faber K. 267 272 Fisher K.J. 32 Edwards A.J. 215 Fadnavis N.W. 268 Fisher P.A. 268 Edwards D. 261 Fagan P. 7 18 222 Fitzpatrick P.A. 219 Edwards G.L. 108 215 Fahlstadius P.284 Flad J. 41 Edwards J.P. 240 Faigl F. 137 Flanagan S. 223 Effenberger F. 140 281 Faita G. 53 Fleischer U. 230 322 Fleischmann E.D. 145 223 Fleming B.G. 154 Fleming R.M. 222 Flentge E. 161 Fletcher M.T. 238 Fleury J.-P. 137 Flippin L.A. 137 Florea C. 147 Floriani C. 134 215 Floris C. 137 233 Floss H.G. 283 292 304 306 313 Flygare J.A. 104 Flynn P. 10 Foces-Foces C. 261 Fodor S.P.A. 259 Fogagnolo M. 274 Fokkens R.H. 35 Folkers J.P. 254 Folting K. 195 Fong F. 296 Font J. 46 51 169 Fontana L.P. 227 Foote C.S. 223 Forbes R.M. 68 Ford G.P. 49 Forkner M.W. 214 Forman M.A. 54 245 Fortt S.M. 204 Fossatelli M. 233 Foster D.O. 265 Fostiropoulos F.32 Foubelo F. 180 Foucaud F. 259 Fouquet E. 85 Fournet G. 203 Fowler P.W. 223 Foxman B.M. 87 Francalanci F. 192 Francisco W.A. 78 Franck R.W. 145 Franck-Neumann M. 209 21 1 Frank B.L. 98 Frankfurter A. 33 Franzosi G. 271 Fraschio F.-X. 41 Fraser-Reid B. 86 Fredrich D. 58 Fredriksen S.B. 256 Freeman J.P. 144 Freeman J.W. 212 Freeman S. 68 Freidrich E.C. 240 Freiser B.S. 223 Freitas J.E. 34 Frejd T. 189 Frenette R. 255 Frenking G. 41 111 131 Fresenius J. 28 Fried C.A. 189 Fried H.E. 74 Friesner R.A. 40 Frim R. 146 Frisch M.J. 44 Frissen A E. 52 Frossl C. 103 263 285 Frolik C.A. 310 Frontera A, 137 233 Fronza G. 286 Fronzek F.R.54 Frost J.W. 101 Fr~ystein,N.A. 17 Fruetel J.A. 216 251 Fry J.L. 131 Frye S.V. 229 Fu H. 279 Fu J.M. 5 Fu X. 244 Fuchikami T. 138 Fiirstner A. 159 Fugami K. 190 Fuganti C. 286 Fuji K. 108 110 Fujii M. 140 Fujii S. 18 259 Fujimori T. 225 Fujita M. 259 Fujita T. 156 Fujita Y. 228 Fujitani T. 176 Fujiwara K. 128 201 Fujiwara T. 135 Fukazawa Y. 148 Fukuhara T. 136 140 Fukui E. 133 Fukui H. 249 Fukui M. 226 Fukumoto F. 125 Fukunishi H. 134 Fukushima T. 228 Fukuyama Y. 146 Fuller C.E. 138 192 Fuller D.J. 235 236 Funakoshi K. 263 Funkai I. 231 Furata T. 260 Furlong M.T. 237 Furstoss R. 272 278 Furuki Y. 146 Furusawa T. 134 Furuya S.98 Furuya T. 297 Fusco C. 142 254 Futrell J.H. 36 Gable K.P. 116 Gable R.W. 148 190 Gabler A. 294 Gaeumann T. 26 Gaffney B.L. 9 Gage D.A. 296 Gais H.-J. 230 Gajewski J.J. 60 61 79 Galakhov M.V. 205 Galarini R. 206 Galiano-Roth A.S. 235 236 Galindo J. 174 Gallagher D.J. 229 Author Index Gallagher P.T. 27 58 Gallagher T. 95 Galland B. 71 Galli C. 73 77 136 Gallo M.M. 133 Gambino S. 162 261 Gandolfi R. 250 Gandour R.D. 76 Ganem B. 33 Ganesh K.N. 12 Ganesh S. 214 Gani D. 308 Ganz K.-T. 194 Gao C. 133 Gao J. 45 Gao X. 5 9 20 194 Garcia E. 138 Garcia G. 195 Garcia J. 195 Garcia J.G. 54 Garcia J.I. 53 Gardner M. 229 Gardossi L.270 Gareau Y. 202 Gareil M. 139 Garrett A.W. 34 Carson M.J. 293 Garst J.F. 234 Garvey J.F. 34 Gaskell S.J. 30 Gassman P.G. 64 74 Gassmann E. 29 Gaudin J.-M. 189 206 Gautheron C.M. 263 Gautheron-Le Narvor C. 269 270 Gauthier V. 106 Gavaskar K. 75 232 Gawley R.E. 227 Gedridge R.W. 212 Gee K.R. 60 79 Gehring W.J. 21 Geib S.J. 242 Gelli G. 137 233 Genest D. 45 Gennari C. 76 Gennari G. 229 Centric D. 215 Geoffroy G.L. 217 George M. 37 Georgens U. 267 Gerardy R. 306 Gerber H.-D. 190 Gerber P. 200 Gerlt J.A. 10 74 Germanas J. 196 Germann M.W. 7 Gerratt J. 40 Gershenzon J. 293 Gertner B.J. 48 Gervay J. 53 246 Getty S.J. 46 51 60 242 Geysermans P.213 Ghatlia N.D. 61 Author Index Gheorgiu M.D. 256 Ghosez L. 53 242 Ghosh M. 260 Gibbs R.A. 220 Gibin AS. 115 Giblin D.E. 223 Gibson B.W. 29 33 Gibson C.L. 312 Giese B. 47 91 92 93 110 Giese R.W. 26 33 Gigou A. 209 Gilbert B.A. 79 Gilbert D.E. 8 18 Gilbert J. 295 Gilchrist J.H. 235 236 Gilday J.P. 139 213 Giles R.G.F. 133 Gill H.K. 299 Gill M. 292 Gillece-Castro B.L. 29 Gillespie W.R. 76 Gillies C.W. 57 Gillies J.Z. 57 Gilow H.M. 162 GimCnez A. 292 Giner J.-L. 298 Giordano C. 228 Girault J.-P. 18 Gladiali S. 194 Gladysz J.A. 203 204 Glanzer B.I. 103 219 263 Glarum S.H. 146 Glasfeld A, 285 Glass W.K. 212 Gledhill L.295 Gleiter R. 147 Glemarec C. 11 12 Glish G.L. 27 Gloeckler G. 31 Gobbi A. 131 Goddard W.A. 111 40 Goddinho L.S. 170 Goehlich H. 31 Gorgen G. 285 Goergens U. 263 Goggins J.R. 33 Gogoll A. 164 217 Gokel G.W. 219 Goldberg I.H. 18 98 103 Goldberg M. 47 80 Goldman AS. 193 Goldman E.W. 203 Goldschmidt Z. 208 Goldsmith D. 260 Gollnick K. 153 Golsch D. 168 253 Gomez-Pardo D. 46 246 Gomibuchi T. 128 Gong L. 137 241 Gonsalves A.M.d’A.R. 183 Gonzalez C. 48 253 Gonzilez F.J. 171 179 Gonzalez J. 138 Gonzalez R. 180 256 Gonzalez-Trueba G. 73 140 Goodman J.J. 292 308 Goodman J.M. 229 Gopalakrishnan V. 12 Cord J.R. 34 Gordon M.S. 43 50 Gore J. 106 119 203 Gore P.H.72 143 Gorenstein D.G. 5 6 7 Gorman G.S. 26 Gorrichon L. 109 Gorun S.M. 222 Gosney I. 150 Goto M. 131 Goto T. 191 194 Gotoh T. 51 241 Gottarelli G. 143 Gottlieb H.E. 208 Could I.R. 146 Could S.J. 301 308 Goumont R. 197 Grabowski E.J.J. 133 173 255 Graf E. 194 Graham H.C. 22 Graille J. 267 Granger T. 125 Grant E.B. 143 Grass F. 194 Grassieli P. 286 Grau N.D. 245 Gray D.J. 250 275 Gray M. 137 Greaney M. 222 Greco F. 35 GrCe R. 209 Green B. 284 Green D.L.C. 104 Green D.P. 233 Green D.V.S. 45 Green J.V. 258 Green K. 137 Green R.H. 180 Greene A.E. 247 Greene T.W. 229 Greengrass C.W. 156 Greenhill J.V. 166 Greenstein M.292 Greenwood P.F. 32 Greico P.A. 245 Grennberg H. 217 Grese T.A. 119 205 206 Gretler E.A. 241 Grgurina I. 312 313 Grieco P.A. 59 Griengl H. 272 278 Griffin L.L. 35 Grigg R. 138 189 Gringas M. 258 Grinstaff M.W. 259 Grisenti P. 149 273 Grix R. 30 Groeneveld H.W. 299 Grollman A.P. 10 Gronenborn A.M. 4 Gronowitz S. 160 225 Grose A. 35 Groski D.M. 222 Gross M.L. 34 35 36 223 Gross P.J. 143 Grosselin J.M. 194 Grotjakn D.B. 196 Gruen D.M. 32 103 146 221 223 Gruetzmacher H.F. 36 Gruselle M. 205 214 Grushin V.V. 194 Gu M.-M. 194 Guastini C. 215 Guerchais V. 203 Guertin K.R. 253 Guerzoni M.E. 274 Guevremont R. 25 Guha S.N. 102 Guibe F. 88 Guidugli F.31 Guignant A. 46 246 Guillemet M. 166 Guindon Y. 92 110 Guinn D.E. 226 Guiry P.J. 139 Guittet E. 18 Gullotti M. 142 Gung B. 238 Gunjal A. 12 Guo H. 133 Guo Y. 133 Gupta A.K. 244 Gupta N. 167 Gupta R.B. 145 Guram A.S. 216 Guschlbauer W. 9 Gustafsson J.-A. 22 Guthrie J.P. 76 79 Gutman A.L. 219 Gybin A.S. 200 Gysel U. 227 Ha C. 84 Ha S. 45 Habaue S. 238 Habgood G.J. 166 Hachem A. 209 Haddad N. 243 Hadden S.K. 143 Haddon R.C. 146 222 Hadjiarapoglou L. 150 168 253 Hadeuer A. 305 Harter P. 203 Haertig C. 301 Haewood L.M. 103 Hagan G. 64 239 Haggerty B.S. 217 Hagiwara A. 144 Hahlbrock K. 301 Hahn Y.-S.P. 134 Haino T.148 Author Index Haire D.L. 33 Hakamatsuka T. 302 Hale K.J. 226 Haley M.M. 144 258 Hall C.D. 69 Hall H.K. jun. 51 241 Hall K.B. 10 14 Hallahan T.W. 294 Hallberg A. 160 227 Hallinan N.C. 212 Halterman R.L. 251 Hamada Y. 108 Hamann P.R. 29 Hamberg M. 284 Hamel E. 148 190 Hamilton A.D. 54 Hamilton D.C. 31 Hamilton L. 250 Haming L. 52 Hammerschmidt F. 313 Hammock B.D. 253 Hamon D.P.G. 110 Hampton C. 223 Hanafusa T. 162 234 Hand M.V. 141 250 275 276 Handa S. 313 Handke G. 227 Handy N.C. 40 Hanessian S. 110 Hanida O. 146 Hanna I. 114 Hano Y. 302 Hansch C. 63 Hansen A. 22 Hansen D. 194 Hanson R.M. 104 253 Hanson R.R. 305 Hara S.190 227 Harada N. 225 Harakaland M.E. 252 Hard T. 22 Harden D.B. 173 Hardin C.C. 15 Hare J.P. 146 221 222 Hargitai T. 227 Haridas K. 311 Harlow R.L. 240 Harman W.D. 138 Harms K. 110 Haroutounian S.A. 136 Harp J.J. 198 Harpel M.R. 310 Harring L.S. 90 Harrington P.M. 128 Harris N.J. 233 Hams P.A. 149 Harrison A.T. 235 236 Harrison D.M. 293 307 Harrison L.M. 32 Harrison P.H.M. 295 Harrison S.C. 22 Harrison T. 256 Harrowven D.C. 88 Hart D.J. 139 Hart G.J. 312 Hart H. 145 255 Hartke K. 190 Hartmann K. 209 210 Hartung J. 250 Harvey D.F. 112 113 198 Harvey J. 126 Harvey R.G. 144 Harwood L.M. 127 246 Hase T.A. 230 Hasegawa M. 97 Haselline J.N.129 Hasemann L. 245 246 Hasemi M.M. 225 Hashemi M.M. 144 Hashim M.F. 302 Hashimoto T. 304 Hashimoto Y. 133 Hashizume T. 30 Hassan M.E. 190 191 Hassner A. 104 Hatakeydima S. 124 Hatanaka K. 141 Hatanaka T. 237 Hatanaka Y. 104 238 Hatton W.G. 204 Hattori T. 136 232 Hauck S.I. 190 191 Havinger E.E. 225 Hawker C.J. 162 Hawkins J.M. 221 222 245 Hay B.P. 86 Hayakawa T. 141 Hayasaki T. 255 Hayashi K. 108 Hayashi M. 237 Hayashi T. 109 194 206 Hayashi Y. 214 215 Hayes M.A. 273 Hayes R.N. 36 Hazen K.H. 133 He G.-X. 251 He J. 47 93 He L. 14 Headley A.D. 80 Heath J.R. 222 Heath T.G. 296 Heatherington K. 181 Hebel D. 171 Heckendom D.K.129 Hecquet L. 281 Hedard A.F. 222 Hedge S.G. 257 Hedgecock C.J.R. 215 Heerma W. 33 Heffron F. 4 Hefter G.T. 258 Hegarty A.F. 50 74 79 Hegedus L.S. 56 115 182 189 198 242 Heibel G.E. 243 Heimgartner H. 181 Heinis D. 236 Heinze J. 148 Hellmann T. 214 Helmchen G. 194 Hemberger P.H. 31 Hemminger J.C. 32 103 134 146 221 Hemscheidt T. 305 Henderson B.S. 283 Henderson E. 15 Hengge A.C. 81 Henion J.D. 31 33 Henk P. 147 Hennen W.J. 263 Henry K.D. 27 36 Henry K.J. 245 Henshilwood J.A. 248 Heravi M.M. 188 Herbert R.B. 283,303,304,307 Hercules D.M. 28 Herdtweck E. 153 203 Herges R. 131 Herman F. 18 Hermoso J.A. 195 Hernandez A.E. 236 Herndon J.W.198 Herrington P.M. 256 Hersperger R. 110 Hertel R. 242 Herunsalee A. 194 Hesketh A.R. 295 Hesse H. 242 Hettrick C.M. 189 192 Heumann A. 189 Heus H.A. 3 4 13 Hewgill F.R. 142 Hidai M. 133 Hidaka A. 194 Hideshima C. 134 159 Hiemstra H. 239 Higashi M. 147 Higuchi H. 148 Higuchi T. 301 Hikage S. 167 Hilbers C.W. 4 5 7 8 Hilhorst R. 220 Hill D.H. 189 Hill J.A. 28 Hill J.M. 104 Hill L. 209 Hillenkamp F. 28 29 Hillier I.H. 45 Hinck A.P. 22 Hinds M.G. 21 Hinman L. 29 Hinman M.M. 111 240 Hirama M. 128 Hirao T. 134 Hirata M. 298 Hirate J. 268 Hirooka S. 146 Hirosawa C. 133 Hirotani M. 297 Hirsch A, 222 Hirst S.C. 54 Hitchcock P.B.305 Author Index 325 Hiyama T. 104 238 Hlasta D.J. 137 Howard P.W. 208 210 211 275 Ihmeis H. 254 Iimori T. 193 Ho G.-J. 240 Howell J.A.S. 208 Ikawa A. 187 Ho Y.-H. 208 Hoye T.R. 122 202 Ikeda A. 228 Hodgson P.K.G. 150 Horsch B. 281 Hoz S. 47 80 Hrazdina G. 302 Ikeda S. 220 Ikehara M. 9 Hoffman E. 22 Hmciar P. 213 Ikonornou M.G. 34 Hoffmann H.M.R. 155 Hrubowchak D.M. 26 Ikushima Y. 51 Hoffmann J. 151 Hrusak J. 223 Illas F. 40 Hoffmann R. 39 Hsaio C.-N. 155 203 Im H.-S. 131 Hoffmann R.W. 92 230 Hsu C.S. 222 223 Imai N. 57 123 245 Hofrneister G.E. 30 Hsu J. 103 Imbroisi D.O. 173 Hohn T.M. 295 Hu H.-A. 45 Inagaki M. 141 268 Hojo M. 70 176 186 193 Huang E.C. 31 Inage M. 212 Holand S. 177 Huang J.-T. 131 143 Ingendoh A. 28 29 Holbrook J.J.45 Huang X. 50 206 Ingold K.U. 265 Hollander F.J. 222 Huang Y. 223 Ino A. 191 Hollander I.J. 29 Huang Y.-Q. 22 Ino Y. 178 Holler E.R. 222 Hubbard B.R. 295 Inokawa H. 131 Holloway J.H. 146 222 Holm T. 234 Hubbard C.D. 166 Hubel M. 110 Inone S. 163 Inoue N. 148 190 Holman R.T. 34 Hudecek M. 213 Inoue T. 301 Holmes A.B. 180 Hudlicky T. 124 158 244 276 Inoue Y. 131 259 Holmes J.L. 37 Hudson C.E. 35 Inubushi T. 120 Holubka J.W. 42 Huffman D.R. 32 Ioffe S.L. 176 Holzapfel C.W. 118 Huffman M.A. 133 195 Ipavich F.M. 31 Homberger G. 240 Hughes A.B. 133 Iqbal J. 135 256 Honert D. 258 Hughes N. 234 Ire R. 251 Hong C.Y. 129 Hong Y.-P. 128 Hui R.C. 230 Hummer W. 254 Ireland C.M. 179 Ireland R.E. 58 236 Hongwen H. 140 Hoogsteen K. 255 Humski K. 65 Hunec E.K.304 hie R. 216 Irwin W.J. 68 Hop C.E.C.A. 34 Hung R.R. 280 Isaacs N.S. 63 260 Hope E.G. 146 222 Hung S.-H. 259 Isaksson R. 227 Hopf H. 220 Hungerbuehler H. 102 Ishibashi T. 135 Hopkins M.H. 158 256 Hunt D.F. 33 36 Ishida A. 131 Hoppilliard Y. 35 Hunt I. 53 244 Ishiguru S. 22 Hopwood D. 291 Hunt J.E. 32 146 221 Ishii Y. 133 Horbuckle S.F. 103 Hunter G.A. 161 162 Ishikawa A. 253 Horeau A. 33 Hunter IS. 300 Ishikawa S. 147 Hori K. 177 Hurley L.H. 18 Ishikawa T. 127 246 Horibe I. 298 Horikoshi Y. 243 Hursthouse M.B. 237 Husa R.K. 110 Ishiyama T. 104 Isobe M. 191 194 Horino H. 148 190 Hutchinson C.R. 291 Ito M. 249 Horiuchi C.A. 134 Hutchinson J. 226 Ito S. 64 147 Horn E. 136 234 Hutchinson K.D. 256 Ito Y. 216 217 251 Horn H. 42 Hutsoj A.C.249 Itoh M. 95 Hornbuckle S.F. 202 Hutzinger M.W. 236 Itoh N. 228 Horne S. 164 Huval C.C. 244 Itoh T. 176 265 Homer G. 92 110 Huynh-Dinh T. 18 Iwabuchi Y. 216 252 Hortelano E.R. 229 Hwang C.-K. 128 226 Iwaki D. 225 Hoshino T. 297 Hwang J.C. 47 Iwaoka T. 124 Hosmane R.S. 131 HWU C.-C. 208 Iwasaki M. 133 Hosoi S. 110 Hwu J.R. 79 Iwasaki T. 138 Hosokawa T. 217 Hynes J.T. 48 Iwasawa N. 129 Hosomi A. 193 Hosoya N. 216 Hosoya T. 133 192 Ibberson R.M. 222 Ibbotson A. 209 Iyanar K. 260 lyer R.R. 105 Iyoda T. 225 Hossain M.A. 211 Ichihara A. 290 296 Izatt R.M. 235 Houk K.N. 46 47 54 61 93 Ichikawa Y. 269 271 281 Izawa K. 194 111 245 Idziak S.H.J. 222 Houpis I.N. 191 Hovestadr D. 31 Howard J.A. 223 Ignatenko A.V. 193 Igolen J. 18 Ihara N. 125 Jabalquinto A.M.294 Jackman L.M. 230 Jackson D.Y. 220 Jackson R.F.W. 149 Jackson R.M. 45 Jackson W.R. 194 Jacob L. 253 Jacobs A. 288 Jacobsen E.N. 149 251 Jaeger R. 110 Jager V. 253 254 Jagoe C.T. 59 245 Jahangir 137 Jaime C. 228 Jakubke H.D. 263 James J.P. 29 James T.L. 6 7 Jamie J.F. 238 Jan S.-T. 251 Janda K.D. 220 Janda L. 173 Janeczek H. 232 Jankowski A. 232 Janson S.W. 30 Janssen A.J.M. 267 Janssen S.J. 212 Janzen E.G. 33 Jaouen G. 213 214 217 218 Jaouen J. 205 Jardine D.R. 29 Jarvinen P. 68 Jarvis S. 27 Jaseja M. 11 Jaspere C.P. 103 Jastrzebski J.T.B.H. 155 Jaturonrusmee W. 182 Jayaweera P. 34 Je J.T. 70 Jean-Claude B.J. 179 Jebaratnam C.J.118 188 Jedlinski Z. 232 Jefford C.W. 169 Jeffrey T. 105 189 Jencks W.P. 68 73 Jendralla H. 136 193 Jenhi A. 212 215 Jenkins P.R. 120 Jenkins T.C. 9 Jennings J.R. 260 Jennings K.R. 36 Jennings L.D. 267 Jensen F. 47 Jensen J.H. 43 Jensen N.J. 35 Jensen R.A. 302 Jeong N. 115 199 200 Jephcote V.J. 238 Jeppsson-Wistrand U. 219 Jerina D.M. 250 Jeromin G.E. 267 Jeroncic L.O. 238 Jia X. 15 Jiang S. 204 Jimenez-Vazquez H.A. 256 Jimeno M.L. 125 Jiminez-Hugo H.A. 63 Jin R. 9 Jin S.-J. 238 Jinbu Y. 133 Jodai A. 239 Joh T. 201 Johar P.S. 238 John C.R. 125 Johnson C.D. 53 244 Johnson C.R. 250 267 31 1 Johnson D. 291 Johnson D.K. 232 Johnson E.P.114 196 Johnson F. 10 Johnson K.A. 300 Johnson M.R. 205 Johnson R.D. 221 Johnson T.J. 195 Johnston M.V. 29 Johnstone R.A.W. 216 251 Jonczyk A. 241 Jones C.R. 5 6 Jones E.T.T. 255 Jones G. 133 Jones J.B. 263 264 268 Jones K. 139 Jones P.G. 211 Jones R.A. 9 Jones R.V.H. 235 Jones S. 69 Jones T.K. 255 Jones W.M. 203 Jordan P.M. 290 Jordan R.F. 216 Joret H. 30 Jorgensen W.L. 45 53 220 245 255 258 Joseph-Nathan P. 212 Josephs J.L. 170 Josephy P.D. 138 Joule J.A. 163 172 JoulliC M.M. 163 Journet M. 110 Ju S. 312 Judice J.K. 220 Julia M. 253 Julia M.Y. 296 Juliano C.A. 116 199 Jumbam D.N. 159 Jung M.E. 53 144 152 246 Just G.179 Jutand A. 189 Kababia S. 37 Kabat M. 112 113 Kabuto C. 125 132 230 245 Kahlig H. 313 Kagan H.B. 56 Kagan J. 225 Kagechika H. 64 Kagechika K. 155 Kageyama M. 56 Kahr B. 223 Kahr M. 223 Kaiser R.E. 31 Kajimoto T. 281 Author Index Kajita M. 134 Kakeya H. 271 Kakisawa H. 228 Kakiuchi K. 148 Kakushima M. 293 Kalantar T.H. 252 Kalivretenos A. 182 Kaloustian M.K. 145 Kambe N. 97 Kamenetskaya LA. 60 Kaminski Z.J. 81 Kamitori Y. 70 176 Kammermeier B.O.T. 232 Kanagasabapathy V.M. 64 Kanamori F. 135 Kanbata Y. 146 Kandil A. 138 Kane C.T. 295 Kaneko C. 124 267 Kaneko T. 237 Kanematsu K. 242 Kang D.H. 80 Kang H.-J. 124 Kang S. 209 Kang T.W.88 Kanno H. 22 Kano ,95 Kao L.-C. 249 Kappen L.S. 98 Kaprinidis N. 244 Kaptein R. 5 7 22 Karaghiosoff K. 167 Karaman R. 131 Karas M. 28 29 Kardish K.M. 223 + Karelson M. 44 149 Karp F. 293 Karplus M. 45 Karsch H.H. 244 Karslake C. 5 Kasai N. 261 272 Kashman Y. 228 Kashyap R.P. 54 Kasper A.M. 55 Kassir J.M. 142 202 Kastler A. 21 1 Katagiri N. 124 Katahira M. 18 Katayama A. 143 Kato K. 107 Kato M. 203 244 Katritzky A.R. 44,49 136 149 166 Katsuki M. 133 192 Katsuki T. 216 251 253 Katsumura N. 141 Katta V. 33 Katz T.J. 198 Katzenellenbogen J.A. 136 167 Kaur N.P. 232 Kaur S. 29 Kavacevic S. 310 Kawabata C. 176 Author Index Kawabata T.108 Kawabata Y. 237 Kawada M. 155 187 189 Kawada Y. 203 Kawai G. 14 22 Kawai Y.,-273 Kawamoto K. 194 Kawanami Y. 250 Kawanishi S. 99 Kawano C. 140 Kawaoka M. 242 Kawasaki K. 141 Kawasaki T. 164 Kawasaki Y. 194 Kawase M. 181 Kawase Y. 9 237 Kazi A.B. 203 Kazlauskas R.J. 265 266 Kazubski A. 255 Keaffaber J.J. 61 133 Keay B.A. 123 192 Kebarle P. 27 34 Keck G.E. 255 Kee I.S. 120 Keeping J.W. 310 Keese R. 200 Kegley S.E. 204 Keiderling T.A. 254 Kellenbach E. 22 Kellett M.A. 146 Kellner D. 257 258 Kelly C.M. 41 Kelly H.A. 304 Kelly K.E. 162 Kenda B. 231 Keniry M.A. 18 Kenny C.C. 90 120 Kenttamaa H.I. 31 Kenyon G.L.74 Kerdesky F.A.J. 138 Kershaw D. 259 Kessar S.V. 232 Kevill D.N. 80 Keyes R.F. 292 Kgaphola M.M. 304 Khalifa N.A. 147 Khan F.A. 111 Khan M.A. 135 Khan N. 151 Khanapure S.P. 144 Khanolkar A.D. 232 233 Kharakhanov E.A. 142 Kharolkar A.D. 75 Khemani K.C. 103 146 221 Khodabocus A. 257 Kice J.L. 69 Kido F. 203 Kido J. 228 Kiefer J.H. 51 Kiegel J. 112 Kierzek R. 13 14 Kigoshi H. 107 Kiji S. 134 Kikuchi K. 141 Kikugawa Y. 181 Kikukawa T. 259 Kilenyi S.N. 59 Kiljunen H. 230 Kim B.M. 250 Kim J. 257 Kim J.Y. 274 Kim K. 209 Kim K.D. 191 Kim M.-J. 217 267 274 280 Kim S. 120 Kim S.K. 127 Kim Y.-J. 235 236 Kimmer G.F. 146 202 Kimura T.259 King D.J. 29 King J.D. 196 King R.W. 21 King S.M. 143 Kingston D.G.I. 292 302 Kinkel J.N. 227 Kinter C.M. 124 Kirby A.J. 71 Kirby G.W. 307 Kirio Y. 193 Kirmse W. 67 240 Kirsch R.S. 142 253 Kirshnan K. 114 Kise N. 237 Kishi K. 206 Kishi Y. 129 Kishigama S. 238 Kistemaker P.G. 37 Kita Y. 141 Kitajima N. 249 Kitamura M. 103 107 237 Kitamura T. 177 Kitano M. 225 Kitazume T. 220 Kitching W. 238 Kiyomiya H. 134 Klabunde K.-U. 147 Kleanthous C. 33 Kleijn H. 155 Klein D.P. 204 Klein W.R. 236 Kleine-Klausing A. 247 Kleinkauf H. 309 Klempier H. 272 Kleywegt G.J. 5 Klibanov A.M. 219 270 Kline M. 239 240 Kling J.K. 192 Klobukowski M. 71 Kluger R.283 Klumpp G.W. 230 232 Klunder A.J.H. 267 Klusener P.A.A. 236 Knaggs A.R. 303 307 Knaup W. 203 Kneifel H. 142 Knight D.W. 58 273 Knight J.G. 186 Knobler C.B. 220 223 Knochel P. 105 116 237 238 Knolker H.-J. 209 210 211 Knoess H.P. 237 Knops P. 228 Knowles C.J. 278 Knowles J.R. 300 Knowles P.J. 40 Knush A.N. 26 Knutzen-Mies K. 153 Kobayashi K. 95 Kobayashi S. 177 Kobiro K. 148 Koch A. 103 146 221 222 Koch M. 140 Kochi J.K. 63 143 211 Kodakek T. 22 111 Kodama A. 164 Kolmel C. 42 Koenig M. 259 Konigsberger K. 278 Koga N. 47 Koh J.S. 120 Kohler K.F. 111 Kohmoto S. 168 239 Kohno T. 22 Koike S. 110 Koizumi T. 228 Kol M. 142 Kolb H.C.124 Kollin K.B. 222 Kolmogorov Y.N. 193 Kolthof K. 232 Komatsu K. 133 Komatsu M. 179 Kompan O.E. 60 Kondo K. 138 Kondo S. 273 Konig B. 148 Koning T.M.G. 5 7 Konopelski J.P. 56 Konosu T. 156 Koo I.S. 80 Koo S.Y. 260 Koola J.D. 249 Koole L.H. 11 12 Kopach M.E. 138 Koppenhoefer B. 253 Korda A. 194 Kornak E.P. 225 Kornig S. 37 Koroniak H. 61 133 Kortan A.R. 146 Kotnis A.S. 134 Kouchakdjian M. 10 Kovalev I.P. 193 Kowalczyk J.J. 203 Kozaki M. 148 Kozarich J.W. 74 98 Kozelka J. 18 Kozhushkov S.I. 258 Kozikoeski A.P. 246 Krach T. 263 269 Kraetschmer W. 32 223 KralTt M.E. 199 201 Kraft M.E. 116 Kraka E. 57 147 Krass N. 136 Kraus W.229 Krause N. 227 Kreddan K.M. 212 Kreif A. 231 Kreiter C.G. 214 Kresge A.J. 71 78 Kriauciunas A. 310 Krieger C. 148 Krishnan K. 113 Krogh-Jespersen K. 42 132 Krohn K. 219 Krol E.S. 68 Krol W.J. 311 Kron J.A. 74 Kronja O. 65 Kroon J. 155 Kropp M.A. 150 Kroto H.W. 103 146 221 222 Krotz A. 194 Kriiger C. 203 209 216 Krumpe K.E. 202 Krusic P.J. 222 Krygsman P.H. 33 Kudryavtsev A.N. 30 Kubauch H. 195 Kiihner S. 281 Kundig E.P. 124 212 213 214 Kunzer H. 134 Kiister W. 200 Kuhn D.R. 47 Kulik W. 33 Kulka J. 313 Kulkarni D.J. 122 Kumar A. 126 252 Kumarauel G. 109 Kume S. 179 Kumobayashi H. 249 Kunishima M. 122 Kuo E.Y. 128 Kupczyk-Subotkowska L.69 Kurahashi H. 180 Kurata T. 260 Kurella M.G. 115 200 Kurihara T. 207 Kurita J. 180 Kuroda S. 146 Kuroda T. 138 Kuroda Y. 216 Kurusu Y. 207 Kusano K. 97 Kusumi T. 228 Kutney J.P. 304 Kutscher R. 30 Kutzelnigg W. 230 Kuzmierkiewicz W. 166 Kvittingen L. 270 Kwong J.-L. 250 Kybett A.P. 134 Kyler K.S. 282 Kyogoku Y. 18 21 Lai T.-F. 249 Laibinis P.E. 254 Laiz L. 310 Lakshmikantham M.V. 160 Lal G.S. 136 Lallemande J.-Y. 18 114 Lam J.N. 136 Lambert C. 103 146 167 222 Lambert J.N. 148 190 Lamerichs R.M.J.N. 22 La Monica G. 142 Lamont H.M. 307 Lampard C. 139 Lamy-Schelkens H. 53 Lan X. 136 Land D.P. 134 Landais Y. 141 Landis C.R.41 Landon P. 134 Landuyt L. 61 Lane A.N. 9 Lane M.J. 22 Langadianou E. 237 Langer H.-J. 307 Langer M. 147 Langford S.J. 225 Langley G.J. 146 Langley J. 222 Langlois B.R. 140 Langlois J.-M. 40 Lapinte C. 203 Larbig H. 196 198 Larkin J. 170 Larock R.C. 163 188 189 206 Larsen R.D. 173 Lascola R. 43 Laszlo P. 60 134 245 Lattman R. 295 Lau P.P.T. 78 Lauk U. 139 Laurent E. 140 Lautens M. 118 188 Lavallee J.-F. 92 110 Lavergne J.-P. 212 215 Lavery R. 45 Lawrence K.E. 234 Layrolle P. 259 Leadlay P.F. 33 284 Leary J.A. 30 Le Beyec Y. 30 Le Bihan J.-Y. 215 Le Blanc J.C.Y. 25 Lebold S.A. 110 Le Bozec H. 198 Lebrun A. 141 Lednicer D.229 Lee B.J. 21 Lee B.Y. 200 Lee C.W. 70 Lee D.H. 58 Lee G.-H. 207 208 217 Lee H.-H. 303 Lee I. 80 Author Index Lee J.-G. 40 Lee J.I. 106 Lee J.P. 22 Lee J.W. 222 Lee M.D. 103 Lee M.K. 33 Lee N.H. 188 206 Lee P.H. 205 Lee R. 221 Lee S. 120 Lee S.H. 199 200 Lee S.J. 21 115 199 259 Lee T.R. 254 Lee Y. 76 Leeding C.J. 69 Leeper F.J. 312 313 Lees W. 280 Leete E. 283 304 Leh T.P. 57 Lehmann R.E. 21 1 Leigh W.J. 243 Lellouche J.-P. 209 LeMaster D.M. 22 Lenardao E.J. 135 Le Noble W.J. 54 Leo A. 63 Lepine-Frenette C. 240 Lepoivre J.A. 234 Leppard S.W. 310 Leresche J. 124 214 Lerner R.A. 219 220 Letavic M.A. 245 Leue V. 196 Leupin W.4 Leusen F.J.J. 261 Leute A. 26 Levanon M. 144 Levenson C. 8 18 Levin I. 37 Levin W. 250 Levine B.H. 188 Levine R.D. 36 39 Levitt M.S. 278 Lewis D.P. 235 Lewis N.G. 139 301 302 Lewis T.A. 222 Lex J. 147 Ley S.V. 124 186 276 Leyh-Nihant B. 37 Li C. 219 Li G. 30 Li H. 54 Li L. 169 Li N.-P. 134 Li Q. 222 Li Y. 9 Li Y.T. 33 Li Z. 206 Liao Y. 124 Lichtin D.A. 30 Liebeskind L.S. 116 133 190 195 207 Liebman J.F. 131 Lifshitz A, 51 Author Index Lifshitz C. 37 222 Liguori A. 35 Likhite S.M. 12 Limbach H.-H. 258 Limbach P.A. 32 Lin C.H. 18 Lin C.R. 222 Lin F. 253 Lin J.T. 220 Lin M.-T. 308 Lin S.-H. 207 Lin S.-K.211 Lin W.-J. 207 Linden A. 181 Lindner E. 195 Lindner H.J. 230 Lindsay D.A. 33 Link J.O. 255 Link R. 258 Linstrumelle G. 191 Lionel I. 33 Liotta D.C. 229 Lipscomb J.D. 310 Lipshutz B.H. 106 107 138 Liras P. 310 Lister M.A. 214 Liu H. 97 172 Liu H.-X. 134 Liu J. 300 Liu J.L.-C. 219 Liu K.K.C. 281 Liu L. 49 Liu R. 212 213 Liu R.-S. 207 208 217 Liu Y. 203 Live D. 9 Llamas-Saiz A.L. 261 Llavona L. 230 Lledos A. 45 Llinas-Brunet M. 92 Lloyd M.D. 311 Lluch A.-M. 139 213 254 Lochmann L. 231 233 Loew G.H. 216 251 Loewenthal H.J.E. 229 Loganathan V. 189 Loh S.N. 22 Loh T.-P. 123 245 Loike J.D. 301 Lois A.F. 293 Loncharich R.J.46 Longevialle P. 35 Lonnberg H. 67 68 Loo J.A. 29 30 Look G.C. 269 Lopez C. 228 Lopez G. 195 Lopez J. 193 Loren S. 221 222 245 Lorents D.C. 103 146 222 Lorenz M. 103 263 Lorimer J.P. 259 Lorquet J.C. 37 Los J. 37 Lovas F.J. 57 Lowe C. 257 Lowe J.B. 271 Lowenthal R.E. 111 240 Lozana P. 267 Lu A.T. 259 Lu K.-L. 217 Lu X. 188 Lubben D. 107 250 Lubin M. 244 Lubineau A. 244 Lubman D.M. 28 Luche J.-L. 77 230 259 Luke G.P. 238 Lukin K.A. 258 Luna H. 276 Lund H. 132 233 Lund K.P. 112 113 198 Lund T. 132 233 Lundgren R.A. 31 Luque F.J. 40 Lusby W.R. 161 Lustig D.A. 28 Lutz F. 203 Luzhkow V. 45 Lykke K.R. 32 146 221 223 Lynch G.P.310 Lynch V. 184 Ma J. 245 Ma S. 188 Ma Y.C. 25 McAdoo D.J. 35 McAllister M.A. 41 241 McArdle P. 208 McBride J.M. 261 McCague R. 272 McCarthy C. 139 McCaskill D. 293 McCauley J.P. jun. 252 McClelland R.A. 64 76 McCloskey J.A. 30 McClung R.E.D. 71 McCullough D.W. 231 McCullough J.J. 250 McDermott M.T. 32 McDonald D.Q. 46 55 MacDonald T.L. 33 McDouall J.J.W. 42 48 253 MacDougall P.J. 131 McEachin M.D. 116 199 McElvany S.W. 32 Macfarlane E.L.A. 266 MacGeorge K.M. 289 McGhie A.R. 222 MacGregor M. 235 McGregor W.M. 143 Machi D. 120 Maciejewski L. 214 McIlwaine D.B. 295 McIntyre R. 296 McIver R.T. jun. 134 Mackay L.G. 212 214 Mackay M.F. 148 190 329 McKee B.H.252 McKervey M.A. 159 253 McLafferty F.W. 27 37 McLafferty K.D. 36 Maclagan R.G.A.R. 46 55 McLaughlin L.W. 10 McLaughlin M.L. 54 McLuckey G.L. 27 McMahon T.B. 34 MacManus D.A. 250 McMordie R.A.S. 250 McNab H. 161 162 McNally J.J. 246 MacNicol D.D. 143 Maconi E. 273 McPhail T. 110 MacWhorter S.E. 199 Maekawa K. 207 Markl G. 177 Maeshima K. 201 Maggi R. 141 Maggini M. 73 140 254 Magnus P. 126 128 204 Magomedov G.K.I. 213 Magriotis P.A. 191 Mahaux J.M. 59 Mahmoudi M. 214 Mahon M.F. 142 173 276 Maier M.E. 128 204 Maier W. 178 Maiese W.M. 292 Maiorana S. 213 Majetich G. 239 Makhija A.V. 146 222 223 Malacria M. 110 Malandra J.L.56 242 Malegiannakis G. 31 Maler B. 22 Malhotra N. 49 149 Malhotra R. 32 103 146 222 Mallinson P.R. 143 Malone B. 222 Malone J.F. 250 275 Malone S. 50 Malpartida F. 291 Maltby D.A. 29 Mandai T. 155 187 189 Mandal S.B. 256 Mander L.N. 110 Mandolini L. 77 Manhas M.S. 260 Mann IS. 213 Mann J. 244 303 Mann M. 27 283 Mannle F. 258 Manoury E. 107 250 Mansson M.-O. 219 Mansuy D. 142 Mantle P.G. 289 Mantlo N.B. 129 Mantz D.S. 81 Mar E.K. 267 Maran F. 74 Marbury G.D. 36 Marcelis A.T.M. 52 March R.E. 31 Marchand A.P. 259 Marco-Contelles J. 125 Margaretha P. 244 Mariani L. 207 Marinella F. 189 191 Marinelli F. 206 Marinovic N. 154 Marioni F.272 Markies P.R. 235 Markley J.L. 22 Marko I.E. 110 239 251 Marmon R.J. 84 Maroux J.F. 112 Marples B.A. 254 Marquess D.A. 100 Marr J. 236 Marsais F. 234 Marsh D.C. 295 Marsh E.N. 311 Marshall A.G. 15 32 Marshall J.A. 159 238 239 Martelli J. 209 Martin F.M. 289 Martin J.F. 310 Martin K. 134 Martin N. 168 Martin S.F. 111 124 202 240 Martin T.P. 31 Martin V.A. 256 Martinez E. 291 Martinez J.R. 124 Martinez L. 125 Martinez R.I. 30 Martinez-Grau A. 125 Martinez-Ripoll M. 195 Maruki I. 245 Marumoto R. 98 Maruoka K. 58 253 Marx J.N. 134 Marziano N.C. 72 Marzilli L.G. 15 18 Marzouk H. 139 Masaki Y. 107 Masamune S. 11 1 240 Mascarenas J.L.191 244 Maskill H. 68 Mason T.J. 259 Massy-Westropp R. 110 Masuda G. 163 Masuda H. 22 Masuda R. 70 176 Masuyarna Y. 207 Matasi J.J. 198 Mateos A.F. 256 Mathey F. 177 Mathre D.J. 226 255 Matsuda T. 228 Matsuda Y. 167 Matsugo S. 99 Matsui J. 237 255 Matsumoto K. 260 Matsurnoto T. 133 192 Matsumoto Y. 194 Matsumura Y. 123 245 Matsumuyo H. 237 Matsuo H. 21 Matsuo J. 260 Matsuo M. 227 Matsusita H. 135 Matsuura H. 231 Matsuura T. 99 Mattay J. 242 Matthewman J.C. 222 Maycock C.D. 170 Maynard G.D. 59 254 Mayoral J.A. 53 Mayr H. 64 239 Mazid M. 237 Mazumderiand A. 10 Mazzei M. 174 Meadows R. 7 Medich J. 236 Medici A. 274 Medina J.C. 219 Medzihradszky K.F.29 30 Meegan M.J. 154 Meerholz K. 148 Meffert A. 253 Megard P. 200 Mehdi S. 300 Meijer E.W. 225 Meijer G. 221 Meissner R.S. 236 Mekhalfia A. 239 Mele A. 286 Meli A. 195 Mello R. 142 253 254 Melmed A.J. 31 Mendez L. 236 MCndez N.Q. 204 Meng C.K. 283 Menger F.M. 68 220 Meot-Ner M. 35 Mercier C. 194 Merlic C.A. 89 196 Merritt J.E. 86 87 Merz A. 225 Meschwitz S.M. 18 Mesh J.C. 174 Messeguer A. 139 213 253 254 Messmer R.P. 41 Metha G. 111 Meth-Cohn O. 140 Metiver P. 255 Metz J.T. 5 Meunier B. 251 Meyer A. 221 222 Meyer D.T. 144 225 301 Meyer F.E. 195 Meyer S.D. 232 Meyers A.I. 137 230 Meyerstein D. 259 Mhaskar S.308 Micheda C.J. 49 Michel H. 33 Author Index Middleton D.S. 257 Midland M.M. 255 Miehlich B. 41 Mignon L. 212 Mihaliak C. 293 Mihle C. 18 Mikami K. 245 Mikhailov I.E. 60 Miki K. 261 Miki S. 290 Mikkelsen K.V. 45 Milborrow B.V. 296 Mildvan A.S. 22 Millar J. 222 Miller A.D. 312 Miller D.B. 115 Miller J.P. 310 Miller J.R.,198 Miller J.S. 221 Miller M.J. 155 203 Miller M.K. 30 Miller R.A. 196 Miller S.L. 299 Mills N.S. 232 Min B.K. 70 Minami T. 215 Ming L.-J. 310 Mingos D.M.P. 260 Minkin V.I. 60 Minniear J.C. 142 Minuti L. 246 Minyaev R.M. 60 Miravitlles C. 134 Mirkin C.A. 217 Mirza S. 126 Misiolek A. 232 Mistra P. 256 Misumi S.148 Mitamura S. 143 Mitchell M.B. 95 137 190 Mitchell R.H. 147 148 Mitscher L.A. 229 Mitsudo T. 193 Mixon S.T. 223 Miyaji K. 245 Miyake R. 214 Miyano N. 234 Miyano S. 110 136 232 Miyata M. 261 Miyaura N. 104 Miyazaki J.H. 294 Miyazawa T. 14 22 Mizokami T. 136 Mizuchi M. 110 Mizukami F. 143 Mizuno K. 243 Moberg C. 189 Moe K.D. 75 231 Mofaddel N. 261 Mohan J.J. 255 Mohialdin-Khaffat S.N. 136 Mohri M. 179 Molander G.A. 90 120 Molina P. 261 Author Index 331 Molinari F. 76 Muegge K. 60 Nakanishi K. 154 243 Molins E. 134 Muehlbacher M. 294 Nakata T. 189 Molinski T.F. 179 Miillen K. 147 Nakayama A. 135 Molloy K. 142 276 Monahan L.C. 161 162 Muller N. 313 Miiller P.111 202 240 Nakayama J. 225 Nally J. 110 Monde K. 306 Mueller T. 118 188 Namane A. 18 Monette M. 255 Mueller W.T. 219 Naota T. 249 Montero J.-L. 259 Munck E. 310 Narasaka K. 103 244 Montgomery J. 56 242 Mujsce A.M. 146 236 Narasimhan N.S. 229 Montoya J. 193 Mukaiyama T. 216 Nardelli M. 196 Moodie R.B. 72 Mukerjee A.K. 149 Narin S.Y. 142 Moody A. 221 Mukundan S. jun. 18 Narukawa Y. 56 242 Moody C.J. 203 Mullen G.P. 22 Naruse Y. 52 Mooiweer H.H. 239 Muller A.J. 146 Nasielski J. 193 Moore H.W. 242 Muller D. 137 Nasielski-Hinkens R. 193 Moore J.A. 77 Muller G. 244 Naso F. 238 Moore R.N. 296 Muller J. 230 Nassimbeni L.R. 261 Mooren M.M.W. 5 8 Muller M. 21 56 Nativi C. 238 Morales M. 168 Muller P.M. 235 Nayak S.K. 144 259 Mordini A, 238 Muller R.P.40 Naylor A. 173 Moren C.M. 261 Mulvey R.E. 235 Nayyar N.K. 135 Moreno M.J.S.M. 259 Mulzer J. 219 Neelakatan P. 268 Morera E. 191 192 Munakata H. 168 Negishi E.-i. 104 117,186,199 Moreto J.M. 116 Munson B. 25 216 233 Morey J. 137 233 Muqtar M. 241 Negri J.T. 67 256 Morgan B. 267 Murahashi S.-i. 217 249 Neibecker D. 194 Morgan D.O. 284 285 Murai S. 194 Neil D.A. 113 198 Morgan T.M. 87 Murai Y. 163 Nelsen S.F. 131 Mori M. 134 155 Murakami M. 217 Nelson C.C. 30 Mori S. 178 Murakami T. 187 Nelson R.W. 28 Moriarty K.J. 56 Muramatsu T. 14 22 Nelson T.D. 124 Morimoto K. 165 Murashima T. 135 136 Nemerof N.H. 163 Morin N. 295 Murata M. 264 Nemeth G.A. 239 Morishima N. 161 Murayama H. 189 Ner S.K. 304 Morishima T. 184 Murphy D.W. 222 223 Nes W.D.293 Morita H. 34 Murphy J.A. 139 Nestler B. 245 246 Morita N. 64 147 Murray C. 46 60 Nevalainen V. 107 Moriya M. 165 Murray C.J. 76 Newaz S.N. 260 Moriya O. 166 Murray R.W. 159 253 Newcomb M. 84 85 279 Morokuma K. 47 Murray W.V. 143 Newsom I.A. 183 225 Moro-oka Y. 249 Musco A. 192 206 207 Newton M.G. 239 Morris K.G. 209 Musunari T. 193 Nguyen M.T. 50 61 Morris T.H. 151 Muto Y. 22 Nguyen T. 216 233 Morrison D.L. 189 Mutti S. 236 Nibbering N.M.M. 35 Morrow G.W. 261 Muxworthy J.P. 254 Nicholas K.M. 204 206 Mortlock A.A. 215 Myers A.G. 128 Nichols M.A. 235 Mortreux A, 213 Myles D.C. 281 Nicholson N.H. 31 1 Morvant M. 202 240 Nicolaides A. 42 Mosandl T. 150 253 Nagai M. 301 Nicolaou D.C. 98 Mosbach K. 219 Nagao M. 193 Nicolaou K.C.98 103 128 Mosher H.S. 228 Nagao Y. 122 133 226 287 Moss R.A. 240 Nagaoka H. 89 Niemer B. 211 Motallebi S. 71 Nagaoka M. 45 Niessen W.M.A. 31 Motherwell W.B. 89 108 119 Nagashima U. 49 249 Nietsche J.A. 308 205 2 15 Nagler M. 243 Niimi T. 22 Mourino A. 191 259 Nagumo S. 301 Nikishin G.I. 193 Mouser J.K.M. 215 Nair R.P. 271 Nikitidis G. 160 Mowlem T.J. 139 213 Nakahashi K. 152 Nikonenkov N.V. 30 Moyes R.B. 260 Nakahira T. 217 Nikonowicz E.P. 5 7 Muchowski J.M. 137 Nakai H. 298 Nilsson K. 227 Muci A.R. 149 251 Nakai T. 60 245 Nimmo H.G. 300 Mudd C.P. 18 Nakamura E. 103 120 192 Nishi S. 194 Mudryk B. 152 232 Nakamura K.,227 265 273 Nishi T. 228 Muedas C.A. 83 Nakamura T. 148 Nishibe Y. 298 Nishida S. 55 124 Nishide K. 150 Nishide T.164 Nishigaichi Y. 239 Nishiguchi H. 136 Nishikawa T. 191 Nishimura A. 133 195 Nishimura H. 215 Nishimura J. 243 Nishimura Y. 140 Nishio M. 293 Nishioka T. 268 Nishiwaki T. 225 Nishiyama S. 265 Nitta M. 178 Nitti P. 244 Niven M.L. 261 Niwa S. 143 237 Niyati-Shirkhodaee F. 240 Noda Y. 216 Noguchi H. 295 298 302 Nomura T. 302 Noordik J.H. 261 Nordahl A. 229 Nordenskioeld L. 22 Norman S.J. 80 81 Normant J.-F. 117 236 238 Note H. 228 Nouaille A. 33 Nourse B.D. 31 Novak B.M. 137 Novoa J.J. 232 Noyori R. 103 107 237 Nozoe T. 147 Nsunda K.M. 134 Nucci L. 141 Nugent T. 276 Nugent W.A. 89 Nunez M.E.G. 253 Nudist R. 221 Nureki O.22 Nuss J.M. 188 Nussbaumer C. 313 Oak O.Z. 141 250 Oalmann C.J. 111 202 240 O’Bannon P.E. 202 O’Callaghan N.M. 309 Ochai M. 107 122 O’Connor P.B. 145 Oda J. 268 Oda M. 131 Oda Y. 9 O’Doherty B. 265 Odom J.D. 227 Oehlschlager A.C. 236 267 Ogasawara K. 165 216 252 Ogawa A. 97 Ogawa M. 133 189 Ogawa T. 129 237 Ogawa Y. 193 Ogiku T. 138 Ogilvie W.W. 226 Ogino Y. 107 250 Ognyanov V.I. 282 Ogoshi H. 216 Oguni N. 237 Ogura A. 110 Ogura H. 131 Oh C.H. 258 Oh S.M.N.Y.F. 72 Oh T. 123 O’Hagan D. 283 Ohara Y. 245 Ohe K. 194 Ohfune Y. 154 Ohira E. 265 Ohkita M. 55 124 Ohkuma T. 107 Ohmeyer M.J. 103 Ohmizu H. 138 Ohno A. 140 273 Ohrai S.-i.158 Ohsawa A. 176 Ohshiro Y. 134 179 Ohta H. 271 Ohta K. 98 Ohtake T. 98 Ohtani I. 228 Ohtsuka E. 9 Ohwada T. 135 Oi R. 251 Oida S. 156 Oikawa H. 290 296 Oishi T. 263 Oivanen M. 67 68 Ojima I. 152 194 Okada E. 70 Okada K. 131 Okafo G.N. 227 Okamoto M. 237 Okamoto Y. 228 Okano T. 161 Okazaki E. 237 Okazaki R. 234 Oki T. 293 Okira A. 22 Okuda K. 261 Okuda Y. 160 Okudo M. 237 Okumoto H. 133 195 Okuno Y. 45 Olah G.A. 65 103 134 135 136 146 159 222 O’Leary D.J. 313 O’Leary M.H. 81 Oliva A. 46 51 246 Olivares de Valle F.J. 44 Olivella S. 50 Oliver J.E. 161 Oliver J.S. 295 Olivo H.F. 124 276 Olivucci M. 46 Olk B. 172 Ollis W.D.110 Olmstead M.M. 222 Olsen R.S. 142 Olsher U. 235 Author Index Olson L.P. 61 O’Malley S. 111 Omote Y. 156 O’Neil M.P. 223 O’Neil P.A. 235 Ono H. 225 Onwood D.P. 78 Ooka T. 225 Oppolzer W. 109 186 188 Orban J. 6 Orita H. 141 Orlovic M. 65 Orozco M. 40 Ortar G. 191 192 Ortega F. 140 Orti J. 46 51 Ortiz F.L. 179 Ortiz de Montellano P.R. 216 251 Ortufio R.M. 46 51 246 Orville A.M. 310 Osawa T. 259 Osella D. 218 O’Shea M.G. 238 Oshima K. 107 190 Oshima M. 206 Oshio A. 237 Otsujii Y. 243 Otting G. 21 Otto C. 183 Ourisson G. 296 Ovaska T.V. 75 232 Overman L.E. 158 256 Overton W.M. 142 Owczarczyk Z. 104 Owen D.A. 211 Owensby A.L.42 48 253 Ozawa F. 206 Ozment J.L. 49 Pacelli K.A. 220 Packman L.C. 284 Paderes G.D. 255 Padias A.B. 51 241 Padilla A. 5 Padwa A. 103 142 202 Pak C.S. 127 Pakrashi S.C. 256 Palin M.G. 208 Palio G. 238 Palmieri G. 73 Palotai I.M. 211 Pan J. 114 Panek J.S. 157 Paneth P. 81 Pang L.S.K. 32 Pankowski J. 201 Pannek J.-B. 211 Paolucci C. 232 Paquette L.A. 58 59 60 67 124 127 254 256 Parasuk V. 223 Parchment O.G. 45 Pardi A. 3 4 5 13 Author Index Paredes M.C. 190 Parida S. 219 Park B.-S. 243 Park C.Y. 250 Park J. 209 Park J.C. 201 Park K.M. 150 Parker D. 227 Parker D.H. 32 103 146 221 Parker K.A. 134 178 Parkin S.R.222 Parlier A, 197 198 Parry R.J. 308 311 312 Parsons P.J. 137 Partali V. 270 Parziale P.A. 61 Passudetti M. 73 140 Pasto D.J. 56 60 242 Pataki J. 144 Patel D.J. 5 9 10 20 Patel P. 157 198 Paterson I. 229 Patil P.A. 138 Patney H.K. 145 Patonay T. 253 Patrick G.L. 307 Pattenden G. 87 88 95 157 Patterson C.H. 41 Pauson P.L. 204 Paz-Sandoval M.A. 212 Pearce C.J. 292 Pearlman D.A. 7 Pearson A.J. 116 139 199,211 Peat A.J. 238 Pederson R.L. 263 280 281 Peel M.R. 205 Pegram J.J. 125 Peifer W.R. 34 Peiters R.J. 240 Pelin M.J. 223 Pelinski L. 214 Pelizzi C. 196 Peller R.C. 109 Pellin M.J. 32 146 221 Pellin W.J. 103 Pelter A. 133 Penco S. 192 Peng J.227 Peng M.-L. 259 Peng S.-M. 207 208 217 Penicaud A. 103 Percec V. 191 Peregrina J.M. 53 Pereira M.M. 183 216 251 Perera S.A.R. 237 Peres T. 222 Pereyre M. 191 Pergola F. 141 Periasamy M. 201 Perichon J. 240 261 Perlmutter P. 194 Perrine D.M. 225 Perrio S. 58 Perron-Sierra F. 256 Perry R.J. 165 Peruzzini M. 195 204 Petasis N.A. 287 Pete J.-P. 258 Peters E.-M. 245 246 Peters K. 245 246 Peterson M.R. 41 Petillo P.A. 131 Petit F. 213 Petit M.N. 261 Petranek J. 231 Petride A. 147 Petrini M. 73 Petruso S. 162 Pettiette-Hall C.L. 134 Pettitt B.M. 45 Pfleiderer W. 67 Philipp U.C. 267 Philippides A. 162 Phillipo C.M.G. 127 Phillips H. 127 246 Phillips N.H.233 Phinney B.O. 293 Phipps A. 29 Phipps J. 265 Piarulli U. 76 Piccirilli J.A. 285 Piccolino E. 231 Pickard S.T. 227 Pieters R.J. 111 202 Pietra F. 141 Pikul S. 123 245 Pilch D.S. 8 Pinhey J.T. 139 Pinna L. 194 Pinson J. 139 Pioch D. 267 Piorko A. 212 Piotto M.E. 5 Pirkle W. 221 Pirrung M.C. 259 Pisciotta A. 286 Pita Boente M.I. 307 Pitacco G. 244 Pitlik J. 310 Pitt A.R. 100 Pitterna T. 204 Pittol C.A. 142 276 Piva O. 258 Pizzi D. 286 Plattner R.D. 295 PIC P.A. 250 267 Pochat F. 142 Podmore I.D. 101 Polborn K. 211 Polec I. 169 Poli S. 274 Pollack R.M. 75 Pollard J.E. 30 Pollicino P. 232 Pollington S.D. 260 Pollini G.P.125 Polniaszek R.P. 226 Pornerantz M. 144 Pomerantz S.C. 30 Ponec R. 51 Pople J.A. 40 Porco J.A. jun. 281 Porte C. 261 Porter H.P. 250 Porter N.A. 110 Porter W.H. 227 Posner G.H. 124 258 Poszich-Buscher C. 142 Potenza D. 76 Potier P. 217 Poulter C.D. 14 81 294 Powell D.M. 108 215 Powell D.R. 131 235 Powers D.G. 109 Powers R. 5 6 Pozuelo C. 125 Prabhakaran P.C. 295 Prachayasittikul S. 234 Pradhan J. 61 110 133 Prakash G.K.S. 103 134 136 146 159 222 Prasad C.V.C. 226 Prasad K. 107 Prassides K. 222 Prato M. 73 140 254 Prechtl F. 245 246 Predieri G. 196 Pregel M.J. 70 Preiss U. 294 Prencipe T. 142 Press J.B. 246 Price G.J. 139 259 Price J.D.276 Priestley E.S. 244 Pringle P.G. 194 Proffitt J. 294 Promo M.A. 256 Prosperio D.M. 39 Prosser J.K. 15 Pruesse T. 33 Prusiner S.B. 33 Pryce R.J. 142 276 Przeslawski R.M. 252 Pugh C. 191 Puglisi J.D. 15 Pulham C.R. 307 Pulleyblank D.E. 8 Purrington S.T. 136 Pushpakumari K.N. 293 Pyke S.M. 225 Pyun S.Y. 70 Qian K. 36 Qian Y.Q. 21 Quan M.L.C. 220 Quayle P. 196 Que L. jun. 310 Queener S.W. 309 Queguiner G. 234 Quelch G.E. 133 Quin N. 300 Quinn J.P. 27 Quintilly U. 73 140 Ra C.S. 124 Rabideau P.W. 230 Rabinovitz M. 140 146 Radaelli R. 142 Radhakrishnan I. 5 9 Radner F. 145 146 Raghavachari K. 146 Rahm A. 181 Raifel’d Y.E.252 Raimondi M. 40 Rajagopal P. 8 RajanBabu T.V. 89 103 Rajaonarivony J. 293 Raju V.S. 260 Rakiewicz E.F. 230 Ramaswamy S. 267 Ramer S.E. 287 Ramirez A.P. 222 223 Ramon D.J. 230 Ramphul J.Y. 287 Ramstein J. 45 Rancourt J. 92 110 Rani K. 296 Rankin D.W.H. 307 Ranson R.J. 75 Ranu B.C. 259 Rao B.G. 45 45 Rao K.S. 129 Rao S.A. 116 201 237 238 Rappaport A.T. 265 Rappoport Z. 47 80 Rastelli A. 250 Rathjen H.-J. 244 Rau A. 198 Rauk A. 42 Rault S. 165 Rauscher D.J. 195 Raushel F.M. 78 Rautenstrauch V. 200 Ravasio N. 254 Ravishankar R. 127 Rawlings B.J. 284 287 295 Rawson D.J. 137 230 Raychaudhuri S.R. 115 Razus A.C. 256 Razzino P.110 Read J.L. 259 Reamer R.A. 173 255 Reau R. 194 Rebek J. jun. 91 110 Rebhun L.I. 33 Reddy G.M. 259 Reddy J.P. 245 Reddy N.K. 128 Redgrave A.J. 276 Redmore D. 144 234 Reed C.A. 103 Reese P.B. 287 Reetz M.T. 103 110 111 Regitz M. 151 239 Reich H.J. 230 233 Reichardt C. 244 Reichel F. 147 Reid B. 10 Reid B.R. 4 Reid M.D. 198 Reid S.S. 17 Reider P.J. 173 Reilly M.H. 30 Rein K.S. 227 Rein T. 124 Reinders L.G. 33 Reinholdsson P. 227 Reissig H.U. 219 Reliquet A. 174 Reliquet F. 174 Remaud G. 12 Remeta D.P. 18 Ren Y.-Y. 293 Renaud P. 110 Rennels R.A. 188 Repic O. 107 Rescifina A. 142 Restelli A, 228 Retherford C. 238 Reum M.E. 148 190 Reuter K.H.133 Reuther I. 153 Reux D. 142 Revill W.P. 33 284 Reynolds S.J. 87 Rhee C.K. 228 Rheingold A.L. 204 217 Rhode O. 216 Ribbons D.W. 276 Ricard L. 177 Ricart S. 116 Ricci A. 238 Richard J.P. 66 69 Richardson G.D. 169 Richardson P.F. 251 Ridd J.H. 63 143 Rieger D.L. 108 Rieke R.D. 214 234 235 236 237 Riera J. 134 Riesinger S.W. 190 Rifqui M. 259 Rigby J.H. 248 Righetti P.P. 53 245 Rindone B. 142 Rinehart K.L. 33 Ringnalda M.N. 40 Ringold C. 239 Rinkel L.J. 8 Ripa A. 212 213 Ripka W.C. 220 Rishton G.M. 158 256 Rittich S. 142 Riva R. 56 Riva S. 267 Rivero R.A. 226 Rizzo C.J. 54 245 Rizzoli C. 134 Robb M.A.. 46 Author Index Robba M.165 Robbins J. 222 Robbins W. 222 Robert A. 134 166 251 Roberts F.E. 255 Roberts R.M.G. 214 Roberts S.M. 142 263 266 272 276 277 278 Robertson C.D. 143 Robertson H.E. 307 Robertson J. 95,96 Robin J.-P. 141 Robins D.J. 304 307 Robinson E.D. 121 Robinson J.A. 226 283 288 289 290 306 Rocco V.P. 266 Rocha Gonsalves A.M.d’A. 216 Roddick D.M. 249 Rodin W.A. 144 Rodrigo R. 164 Rodriguez I. 109 Rodriguez J. 196 Roesrath U. 190 Roger C. 204 Rogers C. 123 Rogers M. 304 Rogers R.D. 58 60 256 Rohmer M. 297 299 Rohr J. 292 293 Roidot N. 140 Rollence M.L. 219 Romanow W.J. 222 Romberg F.E. 236 Rorner D.R. 255 Ronan B. 56 Ronchetti F.269 298 Rong D. 134 Roongta V.A. 5 Roques B.P. 18 Rose E. 213 Rose-Munch F. 212 213 Ross D.S. 32 Ross W.J. 21 1 Rosseinsky M.J. 146 222 223 Rossi K. 75 232 Rossi M. 254 Rossi R. 189 Rosier J.-C. 169 Rossiter B.E. 236 Roth G.P. 138 192 Roth L.M. 223 Roth P. 305 Rotter H. 258 Roush W.R. 56 201 Rowley E.G. 201 Roy M.A. 53 Roy S. 115 Rozema M.J. 237 Rozen S. 142 171 Rozynov B.V. 26 Ruasse M.-F. 71 Rubin Y. 32 222 223 Author Index Rubio E. 219 Rubio J. 40 Rudler H. 197 198 Rudler M. 197 Rueterjans H. 22 Riither G. 188 Ruguero M. 46 Ruhland R.W. 230 Ruiz J. 195 Runnels J.B. 232 Runsink J. 242 Rusnak F. 300 Russell A.T. 100 Russo G.298 Russu I.M. 22 Rutledge P.S. 212 214 Ruud C.C. 232 Ruzziconi R. 52 Ryaboi V.M. 53 Ryabov A.D. 217 219 263 Ryback G. 142 276 Rychnovsky S.D. 257 Ryoden K. 155 187 Ryu I. 97 Rzema M.J. 105 Rzepa H.S. 44 52 228 Saa J.M. 137 233 Saberi S.P. 209 Sachinauala N.D. 115 Saeki T. 227 Sa e Melo M.L. 259 Safi M. 206 Sahali Y. 243 Saha-Moiler C.R. 150,153,253 Sahaue N. 134 Sahm H. 299 Saikali E. 202 Saimoto H. 158 Sainsbury M. 173 St.John P. 32 Saitho Y. 225 Saito H. 298 Saito I. 98 99 Saito K. 56 148 Saito N. 51 Saito T. 22 280 Sakaguchi R. 18 Sakai J. 267 Sakai K. 129 237 263 Sakai N. 271 Sakairi M. 25 Sakaitani M. 300 Sakamoto M.156 Sakamura S. 290 296 Sakoda H. 267 Sakurai H. 132 230 245 Sakya S.M. 182 Salas M. 163 172 Salaski E.J. 295 Salaun J. 207 Salem J.R. 221 Salgado V.O.N. 246 Sallese G. 192 207 Salmain M. 217 Salomon R.G. 114 Salowe S.P. 311 Sampoli M. 72 Sampon J.R. 14 Sanchez G. 195 Sinchez-Baeza F. 139 213 253 254 Sanderson A.J. 72 Sanderson I. 69 Sandey H. 278 Sandham D.A. 108 215 Sandmeier P. 305 Sandri E. 232 Sandstrom A. 11 12 Sandstrom J. 227 Sanford D.G. 22 Sankararaman S. 143 Sankawa U. 298 302 Santa Lucia J. jun. 13 14 Santaniello E. 149 273 Santasiero B.D. 71 Santhakumar V. 189 Santi R. 192 206 207 Santini R. 5 Santos A. 193 Saracoglu N.144 Sarandeses L.A. 191 259 Sargent M.V. 133 Sarkar A. 214 Sarshar S. 107 255 Sartori G. 141 Sasai H. 93 155 Sasaki A. 95 217 Sasaki M. 158 Sashida H. 180 Sashiwa H. 158 Sasson Y. 254 Sato A. 261 Sato F. 253 Sato J. 253 Sato K. 163 Sato M. 243 267 Sato R. 170 Sato T. 165 249 298 Sato Y. 290 Satoh S. 93 Sauer G. 134 Saunders M. 63 256 Saunders W.H. jun. 81 Sauriol F. 295 Savage T.T. 294 Savtant J.-M. 139 Savignac M. 217 Sawada Y. 293 Sawyer J.S. 258 Sayer P. 156 Saykally R.J. 222 Schaber H. 31 Schaefer H.F. 111 46 52 133 24 1 Schaeffer M.J. 122 Schaer M. 29 Schaller A. 300 Schaumann E. 140 Scheel D. 301 Scheeren H.W. 246 Scheidt A.267 Schellenberger V. 263 Schiedekamp A.M. 49 Schindler M. 131 Schlag E.W. 34 Schlegel H.B. 42 48 253 Schleimer M. 227 Schleyer P.von R. 131 230 Schloeder D.M. 220 Schlosser M. 52 137 241 Schmalsteig L. 147 Schmalzing D. 227 Schmid W. 238 Schmidpeter A, 167 Schmidt B. 237 Schmidt J. 22 Schmidt T. 209 Schmittling E.A. 258 Schmitz U. 7 Schneemeyer L.F. 146 Schneider A. 280 Schneider M.P. 263 267 Schneider P. 189 Schnell R. 67 Schniesser C.H. 95 Schofield C.J. 283 309 310 311 Scholler D. 254 Schore N.E. 199 201 Schriver K.E. 32 Schroeder S.A. 5 Schroter D. 253 Schulte G.K. 129 266 Schulte G.M. 238 Schultz G.E. 280 Schultz P.A. 41 Schultz P.G.219 220 Schultz-Merkel L.A. 49 Schumacher D.P. 268 Schummer A. 274 Schurig V. 227 Schuster D.I. 243 244 Schuster G.B. 150 Schwab J.M. 77 283 Schwalbe C.H. 68 Schwartz C.E. 87 Schwarz H. 32 33 223 249 Schweikhard L. 32 Schwendlr J.T. 223 Schwesinger R. 258 Schwindt M.A. 198 Scoble J.A. 148 190 Scopes D.I.C. 173 Scorrano G. 73 140 254 Scott A.I. 297 310 312 Scott F.E. 296 Scott I.L. 116 199 Scott L.T. 144 225 Scott M.E. 191 Scott W.J. 133 136 189 192 Searle M.S. 18 Author Index Seaton P.J. 308 Sebastian J.F. 233 Sebastiano R. 142 Sebestra D.P. 253 Seconi G. 238 Secor H.V. 131 Seddon M.J. 27 Sedrati M. 209 Seebach D. 227 237 245 260 Seeman J.I.131 Segal-Lew D. 140 Segura J.L. 168 Seidenschwartz C. 153 Seidl E.T. 46 52 241 Seki Y. 194 Sekiguchi A. 132 230 245 Selig H. 222 Sellers S.F. 61 133 Selzle H.L. 34 Sen A. 249 SCnCchal D. 215 SCnCchal-Tocquer M.-C. 2 15 Senn D.R. 164 Sensharma D. 32 222 Sensharma D.K. 103 146 Seo S. 298 Seoane C. 168 Sera T. 98 Serhon C.N. 287 Serikawa K. 21 Sessler J.L. 184 Seto H. 298 Seufert-Baumbach P. 153 Severance D.L. 45 Severin M.G. 74 Sexton A. 234 Seyden-Penne J. 255 Seyferth D. 230 Seykens D. 299 Shabanowitz F.W. 36 Shabanowitz J. 33 Shafer R.H. 8 18 Shah A. 169 Shah M. 260 Shahlai K. 145 Shankaranarayan R. 310 Shapka M. 219 Sharif I. 136 Sharkey A.G. 28 Sharma N.D.141,250,275,276 Sharma R.R. 115 Sharma S. 236 Sharp M.J. 138 Sharpless K.B. 107 216 250 251 252 Shashkov A.S. 200 Shaw J. 216 251 Shaw J.E. 140 Shay W.R. 194 Shea K.J. 125 Sheldon R.B. 31 Sheldrake G.N. 141 250 275 Shen B. 308 Shen Y.-S. 134 Sherman D.H. 291 Sherman J.C. 220 Sherrick J.M. 142 Sherwood R.D. 222 Shi Y. 118 248 Shi Z. 47 48 Shiang D.L. 253 Shibakami M. 261 Shibasaki M. 93 155 193 217 Shibata K. 234 Shibata T. 107 250 Shibutani S. 10 Shibuya K. 89 Shiea J. 25 Shigemasa Y. 158 Shimada K. 167 Shimao I. 146 Shimidzu T. 225 Shimizu I. 206 Shimizu K. 135 136 164 Shimizu M. 141 Shimizu T. 238 Shimoyama I. 186 Shin H.A. 191 Shin J.A. 23 Shindo K. 147 Shinkai I.173 Shinkai S. 228 Shiori T. 108 Shipman M. 205 Shipton M.R. 213 215 Shipton N.F. 278 Shirai H. 133 Shirakawa E. 237 Shirakawa M. 21 Shiratori S. 180 Shiro M. 214 242 Shmikk D.V. 30 Shneier A. 33 Shoberu K.A. 263 Shono T. 237 261 Shorter J. 63 Shudo K. 135 Shukla A.K. 36 Shulman-Roskes E.M. 258 Sianipar H. 133 Sibille S. 240 Sicking W. 53 Siddiqui M.A. 138 Sidhu S.S. 51 Sieburth S.McN. 247 Sieck L.W. 35 Siegbahn P.E.M. 49 249 Siegel M.M. 29 308 Siegmann K. 138 Siegrist T. 223 Sierzputowska-Gracz H. 14 Sik V. 142 276 277 Silks L.A. 111 227 Silveira C.C. 135 Silver J.E. 54 Silverberg L.J. 107 194 Silvestri G. 162 261 Sime J.T. 3 11 Simig G. 137 Simon E.S.280 Simon H. 274 294 Simon J. 22 Simonet J. 141 Simonet-Gueguen N. 141 Simonyan S.O. 200 Simpkins N.S. 103 173 239 Simpson T.J. 273 283 289 291 296 Sindona G. 35 Sinerius G. 280 Singer R.D. 236 Singh K.N. 232 Singh M. 253 Singh P. 232 Singh U.C. 45 45 Singleton D.A. 64 124 244 Sinnott M.L. 283 Sinou D. 206 Sinskey A.J. 280 Siu K.W.M.,25 Siverberg L.J. 121 Skarnulis A.J. 234 Skelton B.W. 133 Sklenar V. 5 Skokotas G. 98 Skramstad J. 160 Slamet R. 142 Slawin A.M.Z.,209 228 236 Sletten E. 17 Slot H.J.B. 261 Smadja W. 110 Smallbridge A.J. 203 Smart T.A.M. 265 Smeets W.J.J. 235 Smit W.A. 115 200 Smith A.B. 111 222 226 Smith A.C. 128 Smith B.D. 310 Smith B.J. 29 Smith D.A.54 245 Smith D.J. 309 Smith D.T. 238 Smith E.H. 151 195 284 285 Smith H.D. 202 Smith H.E. 227 Smith K. 133 Smith P.E. 45 Smith P.J. 244 Smith R.D. 29 30 Smith R.H. jun. 49 Smith R.W. 299 Snaith R. 236 Snead T.E. 217 Snider B.B. 60 86 87 Snieckus V. 138 234 Snook B.M. 238 Snustad D.C. 56 242 Soai K. 237 255 Sobey W.J. 310 Sodeoka M. 93 193 217 Soderberg B. 115 Author Index Sodupe M. 42 46 246 Sohar P. 255 Sohmiya H. 259 Sokolov V.I. 205 Sola M. 45 Solari E. 134 Solas D. 259 Sole A. 50 Solladie-Cavallo A. 214 Solomon S. 32 Somayajula K.V. 28 Somei M. 164 Sommer S. 241 Sonawane H.R. 122 Song J.-S. 239 Sonoda N. 97 194 Soose D.J. 244 S~rensen P.E. 76 Sorensen T.S.42 Soria J.J. 260 Sosna F. 216 Soto J.L. 168 Sottofattori E. 174 Souchez J.P. 212 Spada G.P. 143 Spalluto G. 125 Spears G.W. 154 Speckamp W.N. 239 Speir J.P. 26 Spek A.L. 136 155 234 235 Spencer I.D. 305 Spencer J.B. 290 Spero D.M. 104 240 Spezia S. 271 Spindler C. 167 Spray C.R. 293 Squibb A.D. 208 Srdanov G. 222 Sridharan V. 138 189 Srikrishna A. 113 114 Srinivasan K. 211 Srivastava R.R. 256 Staab A.J. 125 Staab H.A. 148 Stack D.E. 236 Stack J.G. 91 110 Stadler R. 306 Stafford G.C. jun. 31 Stahl B. 29 Stahl M. 219 Stahl N. 33 Stam C.H. 52 Standaert A. 193 Stanescu M.D. 147 Stang P.J. 63 78 104 107 Stanger A. 131 Stanovik B. 175 244 Stark A.G. 225 Starkemann C.109 Staunton J. 33 284 288 289 Steel P.J. 46 55 Steenken S. 64 Stein E. 218 Stein S.E. 145 Steiner V. 29 Stenzel D.J. 296 Stephenson G.R. 208 210 211 218 275 Sternbach D.D. 205 Steup M. 29 Stevens J.A. 73 Stevens W.J. 43 Stevenson P.J. 189 250 Stewart J.M. 142 Stille J.K. 182 189 Stock L.M. 32 103 146 221 Stocks M.J. 152 Stoddart J.F. 221 236 Stokes T.M. 267 Stollar B.D. 22 Stolle A. 207 Stolle W.A.W. 52 Stolowich W.J. 76 Stone C. 186 Stone G.B. 164 Stoodley R.J. 156 Storey J.M.D. 139 Stoven V. 18 Stratakis M. 47 Straub J.A. 280 Street I.P. 294 Streib W.E. 195 Streicher W. 140 Streith J. 56 57 Streitweiser A. 74 Strekowski L. 173 Strelenko Y.A. 193 Strnad M.51 Struchkov Yu.T. 60 200 Struhl K. 22 Strul G. 208 Stryer L. 259 Stryker J.M. 206 Stuart J.G. 204 Stubbe J. 98 Stucky G.D. 232 Stutten J. 240 Su H. 189 Su T.-L. 143 Suarez M. 168 Subramanian R. 3 11 Subramanyam D. 243 Suehiro K. 159 Suemune H. 98 129 237 263 Suenram R.D. 57 Suerig T. 36 Suffert J. 191 Sugai T. 271 Sugawara K. 124 Sugi K.D. 56 242 Sugimoto N. 242 Sugimura T. 259 Suginome H. 95 Suginome M. 217 Sugita Y. 267 Sugiura Y. 128 Sugiyama H. 98 99 Sugiyama J. 142 Suh G.-H. 194 Sukegawa K. 176 Sumi K. 110 Sumi T. 146 Sun D. 18 Sun M.L. 211 Sun S. 91 110 Sundberg R.J. 33 Sunder N.M. 229 Sundqvist B.U.R. 26 Suner G. 137 233 Sunner J. 25 Surerus K.K.310 Suslick K.S. 259 259 Sustman R. 53 Sutherland A.G. 272 Sutherland J.D. 3 10 Sutherland R.G. 212 Sutkowski A.C. 288 289 Sutter B. 299 Sutton D. 204 Suzuki A. 104 136 140 190 Suzuki H. 135 136 231 237 255 Suzuki K. 133 192 Suzuki S. 125 147 187 Suzuki T. 136 232 272 Suzuki Y. 216 Svensson P. 147 Swain C.J. 120 Swann E. 110 Swanson D.R. 216 Swanson S. 211 Sweeney J.B. 273 Swenton J.S. 261 Swinbourne E.J. 136 Swindell C.S. 127 Sygula A. 230 Syka J.E.P. 31 Sykes B.D. 7 21 Symons M.C.R. 101 Synder J.P. 244 Syvret R.G. 136 Szmuszkovicz J. 144 Tabahashi T. 245 Tabei K. 260 Taber D.F. 107 121 194 Tabuchi H. 290 Tacconi G. 245 Taddei M. 238 Taft R.W. 63 Tai A. 131 259 Tailhan C.244 Taillepied I. 141 Takagawa H. 124 Takagi Y. 135 265 Takahashi H. 243 Takahashi K. 56 148 Takahashi M. 138 Takahashi N. 171 Takahashi S. 201 Takahashi T. 148 Takai T. 216 338 Author Index Takamuku S. 131 Takano J. 148 Takano M. 217 Tebbe F.N. 222 Teixeira-Dias J.J.C. 43 Tembo O.N. 165 Tokitoh N. 234 Tokunaga M. 107 Toma L. 269 298 Takano S. 124 165 216 252 Temperini A. 85 Toma S. 213 Takasugi M. 306 Takatsuto S. 298 Takayama H. 246 Takayanagi H. 131 Takeda H. 146 ten Hoeve W. 225 Teniou A. 209 Terada M. 245 Tercel M. 214 Teresa J.de P. 256 Tomasi J.J. 44 Tomietto M. 223 Tominaga Y. 193 Tomooka K. 60 Tonda K. 298 Takeda K. 298 Terrier F. 73 140 Toone E.J. 264 268 280 Takeda M. 220 Takeda T. 135 Teston-Henry M. 60 Thakur R.G.296 Top S. 213 Torii S. 133 195 Takehira K. 141 Takeishi Y. 167 Thaler A. 245 260 Thatcher G.R.J. 68 Torrey M.J. 308 Torssell K.B.G. 136 Takemoto K. 261 Theim J. 271 Tortato C. 72 Takenaka H. 166 Takeuchi G. 143 Thibault P. 33 Thibaut D. 312 313 Toscano R.A. 197 Toshima K. 98 Takeuchi H. 136 Takeuchi K. 133 ThiCbault A. 139 Thiel F.A. 146 Toth K. 112 Tottie L. 189 Takeuchi Y. 228 298 Thiel Y. 75 232 Toubai Y. 131 Takeyama Y. 190 Takikawa Y. 167 Thiele G. 74 258 Thiericke R. 306 307 Toupet L. 209 Townsend C.A. 31 1 Takimoto M. 21 Takizawa Y. 142 Takuwa A, 239 ThimmaReddy R. 252 Thomas E.J. 129 238 Thomas R. 103 220 Toyonaga T. 301 Toyota K. 151 Tozer S.W. 222 Tamamura K. 140 Tamareselvy K. 260 Thomas R.D. 211 Thornas R.M. 28 Traeger J.C. 35 Traldi P.31 Tamaru Y. 186 Thomas S.E. 209 Trentmann B. 203 Tamayo N. 190 Thomrnen M. 200 Trimble L.A. 296 Tamburu C. 51 Tami Y. 110 Tamm Ch. 305 Thompson C.M. 104 Thompson M.J. 135 Thompson R.L. 242 Trivedi N.J. 103 146 222 Troitskaya L.L. 205 Tropsch J.G. 49 Tan R.P. 235 Tanaka K. 110 231 237 238 Thompson T.R. 163 Thomsen I. 136 Trost B.M. 118 119 188 189 205 206 242 248 255 Thomson D.E. 150 Trost M.K. 189 242 Tanaka M. 189 Thorel P.-J. 90 Truhlar D.G. 45 50 Tanaka S. 147 Thorne G.C. 30 Tsai Y.M. 120 Tang L. 27 Thornton E.R. 108 Tsang W. 51 Tang W.-T. 249 Thornton-Pett M. 189 Tsay S.-C. 128 Tang Y.C. 78 Tidor B. 45 Tschamber T. 56 Tani K. 148 Tidwell J.H. 164 Tse D.S. 103 146 222 Tani S. 122 Tidwell T.T. 41 78 241 Tsuchida T. 146 Taniguchi H. 177 Tiecco M.85 Tsuchiya T. 180 Taniguchi M. 190 Taniguchi N. 125 Tildesley D.J. 45 Timmers D.A. 203 Tsuji J. 155 187 189 Tsuji R. 133 Tanner D. 108 Tindall P. 222 Tsuji T. 55 124 Tanner M.E. 220 Tao C. 209 Tao Y. 257 Tapia O. 63 Ting H.-H. 310 Tinga M.A.G.M. 136 234 Tingoli M. 85 Tinoco I. jun. 8 13 15 Tsukamoto K. 135 136 Tsunetsugu J. 147 Tsuno T. 293 Tsuruda T. 245 Tartakowski V.A. 176 Tip L. 236 Tucker A. 111 Taschner M.J. 277 Tirvengadum M.-C. 208 Tuckmantel W. 246 Tasdeler E.E. 194 TiSler M. 175 Tudoret M.-J. 203 Tashiro M. 134 159 Tasker A.S. 119 188 Tateishi A. 142 Tateno M. 22 Tius M.A. 128 Tivakornpannarai S. 203 Tjaden U.R. 31 Toba M. 143 Tully J.C. 223 Tupper D.E. 211 Turecek F. 37 Turner D.H. 13 14 Taticchi A. 246 Tobe Y. 148 Turner G. 309 Tatsuta K.98 Tobin M.B. 310 Turner M.E. 103 Taylor N. 164 Toda F. 238 261 Turner N.J. 263 266 310 Taylor R. 146 222 Todd J.F.J. 31 Turner S.R. 165 Taylor R.J. 122 203 Tohda Y. 148 Turner S.U. 198 Taylor. S.C.. 208. 210. 275. 276 Tohma H. 141 Turos E. 204 Teasdale A 138 189 . Toisawa Y. 128 Turro N. 259 Author Index 339 Turvill M.W. 159 van Leusen D. 161 Wagschul K.C. 294 Tustin G.J. 209 van Liempt J. 309 Wakabayashi H. 147 Tycko R. 146 223 van Mier G.P.M. 155 Wakefield J.B. 206 Vanquickenborne L.G. 61 Waldmann H. 54 245 280 Uang J.Y.-J. 254 Van Setten D. 33 Waldron R.F. 78 Uccella N. 35 Varani G. 13 Waley S.G. 283 Uda H. 225 Varej50 J.M.T.B. 183 Walker A.E. 308 Udaya Kumar M. 85 Vasnike S. 180 Walker J.A. 51 Udseth H.R. 29 Vatakencherry P.A.293 Wallace E.M. 104 Ueda S. 302 Vaughan G. 222 Wallbank P.J. 137 190 Uekawa T. 161 Veale A.C. 226 Wallow T.I. 137 Uemura M. 214 215 Vederas J.C. 287 290 296 Walls F.C. 29 30 Uenishi K. 148 Vegas A. 195 Walsh C.T. 300 Uesugi S. 9 Veillard A. 40 Walsh O.M. 154 Uesugi T. 151 Venimadhavan S. 64 Walsh R. 151 Uggerud E. 36 Venkatachalam C.S. 141 Walshe N.D.A. 140 Ugrak B.I. 258 Veretnov A.L. 115 200 Walter A.E. 14 Ukita T. 250 Verheij E.R. 31 Walter K. 29 Umezawa T. 302 Verhoeven T.R. 255 Walton D.R.M. 146 222 Underiner G.E. 235 Verlhac J.-B. 191 Walton G. 208 Unelius R. 169 Vernon P.G. 257 Walton R. 86 Ungvary F. 234 Vessieres A. 217 Wan B.Y.-F. 87 Uomori A. 298 Vesugi M. 128 Wang A, 10 Uozumi Y. 206 Vettori U. 31 Wang E. 8 Upton R.M.222 Veya P. 215 Wang F. 110 Urabe H. 253 Vial J.M. 12 Wang J. 22 Urata H. 138 Viallefont P. 212 215 Wang K.T. 269 Urata Y. 166 Vianello E. 74 Wang L.-F. 194 Urbanczyk-Lipowska Z. 260 Vicens J. 220 Wang Q. 136 Urbanos F. 134 214 Vicente J. 138 Wang W. 144 Urpi F. 108 Vichard D. 214 Wang W.-L. 230 Ushio H. 237 Vickers D. 236 Wang X. 124 138 228 239 Uskovic M.R. 112 Vidal A, 261 245 253 Usui S. 148 Villa M. 228 Wang Y. 9 52 Utimoto K. 190 Villarreal N.Z. 212 Wang Y.F. 280 Vinas J.M. 116 Wang Z. 206 Vaccaro H. 226 Vincent B.R. 181 Ward D.E. 228 Vaisman A.M. 252 Vincenti M. 220 Warmus J.S. 56 Vaissermann J. 197 198 213 Vinogradov M.G. 193 Warren H.B. 144 Valenta Z. 55 Virgili A. 228 Warren H.P. 225 Valentin E. 244 Vizza F. 195 Warren S.219 Vanberkel G.J. 27 Vo N.H. 127 Warshel A. 45 van Boom J.H. 5 7 8 9 22 Vogel E. 147 Wasielewski M.R. 222 Van Bramer S.E. 29 Vogtle F. 220 228 Wasserman E. 222 van Bruggen N. 302 Vohra R. 232 Waszczak J.V. 146 Van den Eeckhout E.G. 32 Volhardt J. 230 Watanabe A, 237 Van der Greef J.J. 31 Vollhardt K.P.C. 114 196 Watanabe K.A. 143 van der Haest A.D. 261 Volmer M. 229 Watanabe S. 156 van der Marel G.A. 5,7,8,9,22 von Dohren H. 309 Watanabe Y. 141 193 van der Osten C.H. 280 Vong W.-J. 207 Waters D.N. 72 143 Van der Plas H.C. 52 von Kiederowski G. 259 Waters R.M. 161 VanderRoest J.M. 245 von Schnering H.G. 245 246 Watkin D. 127 246 van der Steen F.H. 155 Vorontsova L.G. 11 5 200 Watson A.B. 304 van de Sande J.H. 7 Vos M. 232 Watson C.H. 26 van de Ven F.J.M.4 7 8 Vouros P. 33 Watson T. 15 Van Durme E. 59 van Eikema Hommes N.J.R. Voyle M. 211 Vuister G.W. 5 Watson W.H. 54 Weaver G.W. 312 313 230 Weaver J.H. 222 van Eldik R. 259 Wada Y. 243 Webb K.J. 237 van Hoorn M. 69 Waegell B. 236 Webb M.L. 228 Van Hoy M. 22 Wagner B. 211 Weber D.J. 22 van Koppen P.A.M. 249 Wagner G. 172 Wehmeyer R.M. 237 van Koten G. 155 Wagner O. 151 Wei S.Y. 60 van Leusen A.M. 161 Wagner P.J. 243 Weickhardt. C.. 29 340 Weidmann H. 159 Weigel L.O. 252 Weiland T. 259 Weinberg N.N. 53 Weiner H. 254 Weiner S.W. 295 Weingart F. 281 Weinhouse M.I. 220 Weinkauf A. 211 Weinkauf R. 29 Weinstein R.M. 230 Weipert P.D. 110 Weiske T. 32 223 Weiss E.P. 204 Weiss M.A. 22 Weissfloch A.N.E.265 Welch A.J. 79 Welch C.J. 221 Welmaker G.S. 238 Wemmer D.E. 18 Wender P.A. 244 Wenderborn S.V. 128 Wendt M.D. 60 Wenglowsky S. 125 248 Wennerberg J. 49 249 Werner H. 203 Werner S. 216 Werth M.J. 264 West C.A. 293 West R. 235 Westaway K.C. 81 Weston J.B. 170 Wetterich F. 91 110 Wey H.G. 214 Whalen D.L. 75 Whan D.A. 260 Whang D. 209 Whangbo M.-H. 232 Wheeler C.J. 294 Wheller R.L. 103 Whetten R.L. 32 146,221,222 223 Whitby R.J. 235 White A.C. 181 White A.H. 133 White J.B. 254 White J.M. 110 White P.J. 300 White R.H. 303 Whiteford J.A. 200 Whitehead A.J. 21 1 Whitehouse C.M. 283 Whitesides G.M. 238,254,274 280 281 Whiting D.A. 299 302 Whitlow M. 219 Whitman C.P.76 Whitnell R.M. 48 Whittaker D. 65 Whitten D.G. 146 Whittle Y.G. 308 Whitworth S.M. 42 Wiberg K. 232 Wiberg K.B. 44,75 78 Wicha J. 113 Wickham G. 18 Wickham K.A. 293 Wickham P.P. 133 Widdowson D.A. 139 213 Widner H.M. 29 Wiechert R. 134 Wiemann T. 271 Wight C.A. 26 Wijmenga S.S. 5 8 Wilcox C.S. 244 Wild D. 150 153 253 Wilde J.A. 10 Wilen S.H. 229 Wilkins C.L. 223 Wilkins P.C. 101 Wilkinson D.A. 223 Willet G.D. 32 Willetts A.J. 277 278 Williams C.S. 173 Williams D.J. 209 228 236 Williams D.L.H. 72 Williams E.R. 36 Williams G.D. 203 Williams H.J. 297 Williams I.H. 50 Williams J.D. 31 Williams J.O. 142 276 Williams M.A. 155 203 Williams N.H. 71 Williams P.28 Williams P.G. 74 Williams R.J.P. 22 Williams R.V. 245 Williams S. 211 Williard P.G. 235 236 Willmer R. 72 Willows R.W. 296 Wilmes O. 147 Wilson B.J.O. 300 Wilson K.R. 48 Wilson L.J. 223 Wilson R.D. 170 Wilson S.R. 240 Wilson W.D. 9 Wimalasiri W.R. 169 Wincel H. 35 Winders J. 142 276 Windhofer V. 300 Wink D.J. 244 Winkler J.D. 241 Winograd N. 26 Wipf P. 58 Wisdom R. 272 Withka J.M. 10 Wittenbrink R.J. 212 Wobbe C.R. 22 Woerpel K.A. 11 1 240 Wojciechowski K. 165 Wolf M.A. 238 Wolff J.J. 131 WoliT S. 244 Wolin R.L. 90 Wolk J.L. 47 80 Author Index Wollnik H. 30 31 Won Y. 40 Wong C.-H. 219,263,269,270 271 279 280 281 Wong K.-Y. 249 Wong M.W. 44 Wong S.F. 283 Wong W.-T.249 Woning J. 243 Wood K.W. 253 Wood M.E. 310 Woodard D.L. 136 Woodard S.S. 216 252 Woodgate P.D. 212 214 Woodling R.E. 255 Woods K.W. 71 Worakun T. 189 Worth L. jun. 98 Worthy W. 259 Wovkulich P.M. 112 Wright A.W. 35 Wright C. 116 199 Wright D.S. 236 Wright J.N. 299 313 Wright M.C. 310 Wu A. 65 WU A.-H. 135 WU C.-P. 147 Wu G. 186 WU G.-Y. 206 Wu J. 15 Wu M. 134 Wu S.C. 139 Wu S.H. 269 wu w.-x. 110 Wu Y.D. 61 111 Wudl F. 103 146 221 222 Wiithrich K. 4 21 Wulff W.D. 125 196 197 248 Wurz P. 32 103 146 221 Wuster H. 51 Wuts P.G.M. 229 Wyatt J.R. 15 Wydra R.L. 173 Wylie W.A. 52 Wynberg H. 225 261 Xavier L.C. 255 Xia H. 242 Xiang J.N. 58 Xie L. 81 Xie Z.-F.103 263 Xiong H. 234 235 Xu D. 89 196 Xu J.E. 186 Xu S.L. 142 202 242 xu Y. 18 Yadav J.S. 127 Yahiro K. 108 Yakura T. 141 Yamabe T. 45 Yamada H. 217 Yamada K. 168 239 Author Index Yamada M. 146 Yamada T. 216 Yamada Y. 89 304 Yamagata N. 135 Yamaguchi A. 134 Yamaguchi H. 147 Yamaguchi J.-i. 135 Yamaguchi K. 176 228 Yamaguchi S.-I. 131 Yamamoto A. 206 Yamamoto E. 301 302 Yamamoto H. 58 238 253 Yamamoto K. 99 225 Yamamoto K.R. 22 Yamamoto M. 168 239 Yamamoto S. 165 Yamamoto Y. 260 Yamaoki H.,189 Yamasaki N. 131 Yamashita D.S. 129 266 Yamataka H.,234 Yamato T. 152 159 Yamauchi O. 22 Yamazaki H. 97 Yamazaki T. 220 Yamoto M. 124 Yamoto T. 134 Yanagisawa A.238 Yanase T. 156 Yang C.X. 144 Yang G.-M. 207 217 Yang G.X.-Q. 198 Yang M. 157 Yang P.-W. 147 Yang S.S. 214 Yang Z.-Y. 191 Yannoni C.S. 221 Yanovsky A.I. 200 Yardov A. 45 Yarema K. 10 Yarwood J. 73 Yashunsky D.V. 238 Yasui M. 158 Yasui S. 140 Yates P. 125 Yato M. 135 Ye H.,134 Yeh M.-C.P. 208 211 Yeo S. 242 Yergey A.L. 25 Yi M. 44 Yi P. 140 Yiannikouros G.P. 154 Yin Y. 71 Yohannes D. 1242 18371057 Yokota T. 290 Yokoyama S. 14 22 255 Yokoyama T. 131 Yoneda N. 136 140 Yong W. 140 Yoo S.-E. 115 199 200 Yoon S.K. 129 Yoshida H. 142 Yoshida S. 171 Yoshida Y. 217 Yoshida Z.-i. 186 Yoshifuji M. 151 Yoshihara N. 142 Yoshikoshi A. 203 Yoshimura H. 151 Yoshimura Y.298 Yoshino A. 56 Yoshitake M. 239 Yoshizawa Y. 287 290 Yost R.A. 29 Young B.A. 217 Young E.C. 78 Young J. 300 Young K.M. 166 Young M.A. 131 Young R.N. 255 Young W.B. 202 Yu H. 274 Yuan K. 136 Yuan W. 219 Yudelevich I.A. 60 Yukume Y. 304 Yum E.K. 163 Yus M. 141 180 230 Zahalka H.A. 265 Zahouily M. 110 Zahra J.P. 236 Zahurak S.M. 146 222 223 Zamir L.O. 295 Zandi K.S. 125 Zanello P. 218 Zanirato V. 125 Zanobini F. 204 Zarcone L.M.J. 75 233 Zard S.Z. 85 244 Zare R.N. 36 Zdrojewski T. 240 Zeeck A. 306 307 Zeegers P.J. 135 Zeevaart J.A.D. 296 Zefirov N.S. 258 Zeiss H.-J. 254 Zeitz H.-G. 92 110 Zellner K. 244 Zenk M.H. 304 306 Zerner M.C. 44 Zha Q. 33 Zhang C.212 Zhang H. 144 Zhang H.-Y. 57 123 245 Zhang J. 309 Zhang M. 225 246 Zhang P. 206 Zhang Q. 43 60 Zhang S.-W. 193 Zhang S.-Y. 194 Zhang T. 206 Zhang W. 126 149 206 251 Zhang X. 95 Zhang X.M. 272 Zhang Z.J. 202 Zhao B. 138 Zhao G. 26 Zhao M. 152 Zhao S. 28 Zhdankia V.V. 107 Zheng K. 243 Zhong Z. 219 281 Zhou D. 303 Zhou N. 6 Zhou O. 222 Zhou P. 148 Zhou W. 206 Zhou x.-x. 12 Zhou Z. 30 196 Zhu L. 237 Zhu Q. 222 Zhuang J.-M. 204 Zhuangyu Z. 140 Ziegler T. 40 281 Zilber G. 146 Zimmerman J.A. 26 Zimmerrnann J. 94 Zipse H.,47 93 Zon G. 9 15 18 Zongshan D.X. 28 Zschunke A. 60 Zubarev R.A. 26 Zucco C. 140 Zucco M. 142 253 Zuerker J. 134 Zurmuehlen R. 26 Zwanenberg B.267 Zwettler R. 216 Zwier T.S. 34

ISSN:0069-3030    

DOI:10.1039/OC9918800315

出版商:RSC    

年代:1991

数据来源: RSC