摘要:

7 Aromatic Compounds By R. McCAGUE Drug Development Section Institute of Cancer Research Sutton Surrey SM2 5NG 1 General and Theoretical Studies Benzene and the Phenyl Ring.-Amidst the continuing debate relating to an operable definition of aromaticity amenable to calculation a kinetic interpretation has been emphasized wherein by MNDO-SCF and ab initio calculations a molecule is considered aromatic if its protonated form loses a proton to 'revert to type' rather than undergo addition.' An alternative test for aromaticity is to determine the energy profile upon deviation of the ring system from planarity when not unexpectedly the distortion is endothermic for aromatic compounds and exothermic for antiaro- matic ones.* On the origin of the symmetric structure of benzene Stanger and Vollhardt have in an ab initio study examined the effect of distortion by closing in adjacent pairs of ring hydrogen atoms.At the point where the C-C-H bond angle was go" the .rr-system was stabilized by 4.5 kcal mol-' although the total energy was raised considerably. The results are therefore entirely consistent with postulates that the symmetrical .rr-structure of benzene is imposed by the CT-frarnew~rk.~ A further consequence is that the bond fixation in angular phenylenes must originate at least partly from bond angle distortions. In this regard an elegant experimental determination of the aromatic character of the central ring of bent-terphenylene was to examine the barrier to rotation of the tricarbonylchromium group in the complex ( l).4If the ring were completely delocalized the energy barrier for rotation would be virtually zero but would reach 19.4 kcal mol-' for localized bonding.The observed barrier to rotation of 9.4 * 0.5 kcal mol-' determined by carbon-13 dynamic n.m.r. is entirely consistent with the degree of bond localization predicted by theory. However bond alternation in benzocyclobutene is not revealed by X-ray crystallographic analysis probably because the distortions cause a shift of electron density in the aromatic ring away from the line of the n~clei.~ All aspects of the chemistry of cycloproparenes have appeared in a review.6 The benzene ring has been shown to be capable of forming several complexes with for instance the electropositive hydrogen of hydrogen fluoride' and various other simple molecules.8 An unusual interaction is that proposed between an ' J.M. Bofill J. Castells S. Olivella and A. Sole J. Org. Chem. 1988 53 5148. * B. L. Podlogar W. A. Glauser W. R. Rodriguez and D. J. Raber J. Org. Chem. 1988 53 2127. A. Stanger and K. P. C. Vollhardt J. Org. Chem. 1988 53 4889. M. Nambu and J. S. Siege] J. Am. Chem. SOC.,1988 110 3675. R. Boese and D. Blaser Angew. Chem. Znt. Edn. Engl. 1988 27 304. W. E. Billups W. A. Rodin and M. M. Haley Tetrahedron 1988 44 1305. J. L. Bredas and G. B. Street J. Am. Chern. SOC.,1988 110 7001. B. V. Cheney M. W. Schulz J. Cheney and W. G. Richards J. Am. Chem. SOC.,1988 110 4195. 163 164 R. McCague 0 aromatic ring and a methyl group to explain why the 2-isomer (shown) of the 5-arylmethylenehydantoin(2) is preferred over the E-isomer.An electron-rich aro- matic ring is necessary for an appreciable interaction and replacement of the methyl groups on the aromatic ring by hydrogen results in the E-isomer being preferred.' The weak interactions of aromatic compounds in gas-liquid chromatography have been shown to be essentially shape-specific." The pentafluorophenyl ring has been shown to form an attractive interaction with enolate oxygen," and when incorporated into an iron-acyl complex high stereodiff erentiation in aldol condensations is achieved which interestingly is opposite to that in the corresponding phenyl complex. When a phenyl ring is present a to a ketone group the stability of the enol form is increased.This stabilization is exceptionally large in 2-indanone where the phenyl ring and ketone group are forced into co-planarity and its methylene protons are 106-fold more acidic than in simple ketones.12-14 @-Aromaticity and Homoaromaticity.-A relatively new concept is that of a-aroma- ticity when there is a stable closed shell of delocalized electrons in a-orbitals requiring the need to cast aside the assumption that electrons in a-orbitals are necessarily localized. This concept has been discussed by Minkin and co-worker~,~~ and its pros and cons by Cremer.16 In this latter work cyclopropane has been ascribed some degree of cT-aromaticity by virtue of its containing two- and four- electron three-centre bonding orbitals representing normal and Mobius aromatic systems and this accounts for the relatively low strain energy for its high degree of torsion.An interesting dication described as a-aromatic is that of hexaiodobenzene (3) which gives a stable isolable triflate salt. The in-plane p-orbitals of the iodine atoms form a closed ten-electron shell. A consequence is an aromatic ring current causing a 42.6 ppm upjield shift of the carbon-13 n.m.r. signal relative to the neutral compound. The stabilization is destroyed if one iodine is replaced by fl~orine.'~ Presumably those species termed 'homoazomatic' will incorporate a degree of a-aromatic character as consideration of bonding in the structures discussed below will reveal. S.-F. Tan K.-P. Ang and G.-F.How J. Chem. Soc. Perkin Trans. I 1988 2045. 10 M. M. Ito J.4. Kato S. Takagi E. Nakashiro T. Sato Y. Yamada H. Saito T. Namiki I. Takamura K. Wakatsuki T. Suzuki and T. Endo J. Am. Chem. SOC.,1988 110 5147. I' I. Ojima and H. B. Kwon J. Am. Chem. SOC.,1988 110 5617. l2 A. M. Ross D. L. Whalen S. Eldin and R. M. Pollack J. Am. Chem. SOC.,1988 110 1981. l3 J. R. Keeffe A. J. Kresge and Y. Yin J. Am. Chem. SOC.,1988 110 1982. 14 J. R. Keeffe A. J. Kresge and Y. Yin J. Am. Chem. SOC.,1988 110 8201. V. I. Minkin M. N. Glukhovtsev and B. Y. Simkin J. Org. Chem. USSR (Engl. Transl.) 1988 24 1. 16 D. Cremer Tetrahedron 1988 44 7427. D. J. Sag1 and J. C. Martin J. Am. Chem. SOC.,1988 110 5827. Aromatic Compounds 12+ Haddon's POAV-3D HMO treatment where .rr-orbitals are treated as hybrids locally orthogonal to the a-system has been applied to homoaromatic systems.In the homotropylium cation the homoconjugate resonance integral is calculated to be of similar strength to a normal rr-bond so that the homotropylium ion emerges as an excellent approximation to the ideal homoaromatic species. l8?l9 Despite this the potential energy surface is rather flat and the stabilization amounts to only a few kcal mol-'. Whereas homoaromaticity in cationic systems is well established such a descrip- tion of neutral and anionic species is somewhat controversial. In the case of the cyclic polyacetylene (4) heat of hydrogenation measurements in comparison with related open-chain polyalkynes have led to the conclusion of a homoaromatic stabilization in (4) amounting to 8.3 kcal mo1-1.20 This result reinforces claims of a 4.5 kcal mol-' stabilization in triquinacene (5) but ab initio calculations on (5) failed to give any indication of homoaromatic stabilization.21 Probably the most convincing evidence yet for aromaticity in an anionic species has been produced from comparisons of the rate of base-catalysed exchange in the diene (6) bearing the electron-rich anisyl groups with that in the corresponding diphenyl compound.When the non-conjugated double bond is absent the dianisyl species is less acidic than the diphenyl species as expected but when present the dianisyl species is the more acidic as a result of homoaromaticity in the anion (7).22 Thus when the formally localized resonance forms of the anion are destabilized homoaromaticity becomes more important.In Haddon's POAV-3D HMO treatment the parent bicyclo[3.2.l]octadienyl anion is considered to have a transannular interaction of similar magnitude to that in 1,5-methano[ lO]annulene (see section 7).19 R. C. Haddon J. Am. Chem. SOC.,1988 110 1108. 19 R. C. Haddon Acc. Chem. Rex 1988 21 243. 20 L. T. Scott M. J. Cooney D. W. Rogers and K. Dejroongruang J. Am. Chem. SOC.,1988 110 7244. 21 M. A. Miller J. M. Schulman and R. L. Disch J. Am. Chem. SOC. 1988 110 7681. 22 A. Tuncay M. A. Carroll L. A. Labeots and J. M. Pawlak J. Chem. SOC.,Chem. Commun. 1988 1590. 166 R. McCague OMe OMe Me0 Me0 (6) (7) 2 Formation of the Benzene Ring from Non-aromatic Precursors via Diels-Alder Cyc1oaddition.-New 2~r-components for use in the synthesis of benzene derivatives are P-sulphinylnitroethylene,which reacts as a nitroacetylene equivalent with appropriate dienes to give aromatic nitro compounds (Scheme 1),23 and trialkoxysiloxyalkynes (e.g.HCGC-OSiBuiMe) prepared by dehydro-bromination of (2)-2-bromovinyl silyl ethers.24 The latter have been found to be outstanding 27-components in the reactions with the ketenes obtained from thermal ring-opening of cyclobutenones leading to a new synthesis of resorcinols. OMe Scheme 1 There is continued popularity in the use of a-pyrones as 47-components; a recent application is a synthesis of a benzo-fused tr~pane.~* Effective regio-control in the addition is achievable by the presence of a 6-alkylthio substituent in the a-pyrone (Scheme 2) this being attributed to secondary orbital interactions between orbitals C02Et fix Py2"' HC = C -CO,Et + @ X X=H 52 48 X=SMe 90 10 Scheme 2 23 N.Ono A. Kamimura and A. Kaji J. Org. Chem. 1988 53 251. 24 R. L. Danheiser A. Nishida S.Savariar and M. P. Trova Tetrahedron Lett. 1988 29 4917. 25 G. L. Grunewald D. J. Sall and J. A. Monn J. Med. Chem. 1988 31 433. Aromatic Compounds on the sulphur and the carbonyl group of the 2.rr-comp0nent.~~ Intramolecular coupling of an a-pyrone to an acetylene has led to a benzo~ycloalkane.~~ The versatility of a-pyrones for the synthesis of benzene derivatives is dependent upon approaches for their preparation and some new methods have emerged.28-30 A curious synthesis of pentasubstituted benzenes from 3-halogeno-2,5-dialkylthiophene 1,l-dioxides proceeds by dimerization followed by ring opening (Scheme 3).31 Scheme 3 uia Cyc1ocondensation.-Nearly all the cyclocondensation procedures for the con- struction of a benzene ring give rise to phenols by virtue of the final step being tautomerization of a cyclohexadienone.This is not a limitation for the synthesis of aromatic natural products since these are generally themselves phenolic owing to a cyclocondensation process in their biosynthesis. The biomimetic polyketide con- densations have been largely applied to polycyclic systems (see Section 5) but are also useful for monocyclic phenols.By the choice of an appropriate metal salt to promote the condensation the cyclization can frequently be controlled to give the aromatic product.32 For the total synthesis of aromatic natural products having the pterocarpan framework the 1,3-Michael-Claisen [3C + 3C] annulation has been shown to be eff e~tive.~~ The process is a combination of a sulphur-directed Robinson annulation and thermolytic sulphoxide elimination to introduce the necessafy unsaturation (Scheme 4). Enynones have been demonstrated to be versatile acyclic precursors to alkylated phenols. Especially useful is that the mode of cyclization can be controlled by the choice of conditions (Scheme 5).34 26 R. K. Dieter W. H. Balke and J. R. Fishpaugh Tetrahedron 1988 44 1915.27 C. J. Moody P. Shah and P. Knowles J. Chem. SOC.,Perkin Trans. 1 1988 3249. 28 S. A. Ahrned E. Bardshiri and T. J. Simpson Tetrahedron Lett. 1988 29 1595. 29 R. K. Deiter and J. R. Fishpaugh J. Org. Chem. 1988 53 2031. 30 T. Tsuda S. Morikawa R. Surniya and T. Saegusa J. Org. Chem. 1988,53 3140. 31 S. Gronowitz G. Nikitidis A. Hallberg and R. Servin J. Org. Chem. 1988 53 3351. 32 M. Yamaguchi K. Shibato H. Nakashima and T. Minarni Tetrahedron 1988 44 4767 33 Y. Ozaki K. Mochida and S.-W. Kim J. Chem. SOC.,Chem. Commun. 1988 374. 34 P. A. Jacobi and J. 1. Kravitz Tetrahedron Lett. 1988 29 6873. 168 R. McCague PhCHzO (11) (i)NaH DME 0 + benzene 80°C' phcH202 II 'OH (2S)O/o A0 Scheme 4 OTs-@OH 482 ?\ 1 OAc TsOH PhBr 200 9C J 80O/O Scheme 5 2,6-Dialkylphenols which are difficult to prepare by conventional methods are preparable in one step from cyclohexanones and aldehydes by zirconocene-catalysed cross aromatization.The zirconocene promotes both the aldol condensation and subsequent redistribution of the un~aturation.~~ Metal-promoted Benzene Ring Formation.-A review of transition metal mediated cycloaddition reactions of alkynes has been published.36 A new application of the rhodium-catalysed [2 + 2 + 21 cycloaddition is an efficient regiospecific route to the sesquiterpene calomelanolactone (Scheme 6).37 Wulff has extended the utility of carbene complexes of Group VI transition metals to give a phenol synthesis by an intramolecular-intermolecular two-acetylene addi- tion pro~ess.~' An example is shown in Scheme 7.Enediyne Cyc1ization.-The creation of the aromatic ring is the driving force for the formation of a high-energy DNA-damaging benzene-l,4-diyl biradical in the action of antibiotics of the calicheamicin and esperamicin class which contain the enediyne substructure. In model compounds closely related to the natural products (see 35 T. Nakano H. Shirai H. Tamagawa Y. Ishii and M. Ogawa J. Org. Chem. 1988,43 5181. 36 N. E. Schore Chem. Reu. 1988 88 1081. 37 S. J. Neeson and P. J. Stevenson Tetrahedron Lett. 1988 29 813. 38 W. D. Wulff and Y.-C. Xu,Terruhedron Lert. 1988 29 415. Aromatic Compounds 0 1''3 P HO i J+ HO 86% 0 Calomelanolactone Reagents i 2 mol RhCI(PPh,), EtOH 25 "C 12 h Scheme 6 PhC-CH MeCN 45-85 "c 3648 h Me 43% Scheme 7 0 0 0 11 H sugar sugar ms sugar Nu-' SMe Scheme 8 Scheme 8 for the presumed mode of action) Nicolaou et al.have shown that cyclization takes place when the termini of the enediyne are brought closer than about 3.20 and this becomes so when nucleophile cleavage of the trisulphide linkage and attack by sulphur on the enone causes a change in hybridization of the bridgehead carbon from sp2 to sp3.39,40The spontaneous cyclization of enediynes for the synthesis of aromatics has yet to be effectively exploited though the condensa- tion of (2)-dilithiohex-3-ene-l,Sdiyne with benzaldehyde does give a low yield of 1,2-diben~oylbenzene.~~ 3 Substitution in the Benzene Ring Eiectrophilic Substitution-The presence of the nitrosonium ion (NO+) in nitrating mixtures can have a profound influence on the course of reaction since it is an efflcient electron acceptor causing formation of arene radical cations.A consequence 39 K. C. Nicolaou G. Zuccarello Y. Ogawa E. J. Schweiger and T. Kumazawa J. Am. Chem. SOC.,1988 110,4866. 40 P. Magnus R. T. Lewis and J. C. Huffman J. Am. Chem. SOC.,1988 110 6921. 41 S. J. Danishefsky D. S. Yamashita and N. B. Mantlo Tetrahedron Lett. 1988 29 4681. 170 R. McCague is biaryl by-product formation and for arenes more readily oxidized than mesitylene a method for removal of lower oxides of nitrogen from the nitrating mixture is ~ecommended.~~ The importance of such purification has been demonstrated in the synthesis of 4,6-dinitroresorcinoI (8) which can be obtained in up to 60% yield by nitration of resorcinol if purified nitric acid is used containing large quantities of urea to remove nitrous acid.If these measures are not taken nitration takes place at the 2-position via nitr~sation.~~ A difference in the positional selectivity of electrophilic attack is also seen for dibenzofuran .(9) which undergoes acetylation at C2 via immediate u-complex formation but nitration at C3 due to the reaction proceeding via initial electron transfer to NO+.44A further consequence of the presence of NO+ is the formation of benzoquinones as well as nitrophenols in the two-phase nitration of phenols.This reaction has an induction period during which the transfer agent NO+ builds up and so addition of large amounts of urea to suppress nitrous acid lengthens the latent period.45 Seemingly at odds with the above weight of evidence in favour of alternative mechanisms in electrophilic substitution Kochi has asserted that all such reactions can be described in terms of electron transfer. Spin densities at the various positions in the radical cation are considered to determine the orientation of attack an approach which predicts correctly the preferred attack para to halogen in halogenoben~enes.~~ Nevertheless one of the principal problems in aromatic halogenation is achieving sufficient positional selectivity.Regioselective p-halogena- tion of activated arenes takes place with benzeneseleninyl chloride and aluminium chloride or bromide.47 Chlorination by N-chloroamines in acidic solution leads to very high selectivity for para isomers for those substrates with strong .rr-donors (e.g. OH or NH2). A consequence of the selectivity is that if the 4-position is blocked then yields of ortho products are generally In complete contrast when phenols are treated with N-chlorodialkylamines in the presence of silica there is high ortho-~electivity.~~ Fluorine is probably the most difficult halogen to introduce directly with positional selectivity and consequently indirect methods are used the most popular of which is nitration reduction to the aniline and then to carry out the Balz-Schiemann reaction.A valuable new alternative is first to mercurate with mercury bis(trifluoroacetate) and then to replace the metal by fluorine using acetyl 42 F. Radner J. Org. Chem. 1988 53 702. 43 R. J. Schmitt D. S. Ross J. R. Hardee and J. F. Wolfe J. Org. Chem. 1988 53 5568. 44 T. Keumi K. Hamanaka H. Hasegawa N. Minamide Y. Inoue and H. Kitajima Chem. Left. 1988,1285. 45 M. J. Thompson and P. J. Zeegers Tetrahedron Left. 1988 29 2471. 46 J. K. Kochi Angew. Chem. Znt. Edn. Engl. 1988 27 1227. 41 N. Kamigata T. Satoh M. Yoshida H. Matsuyama and M. Kaymeyama Bull. Chem. SOC.Jpn. 1988 61 2226. 48 J. R. Lindsay Smith L. C. McKeer and J. M. Taylor J. Chem. Soc. Perkin Trans. 2 1988 385. 49 K. Smith M. Butters and B.Nay Tetrahedron Lett. 1988 29 1319. Aromatic Compounds 171 hyp~fluorite.~' A second problem in aromatic halogenation is to achieve reaction on deactivated arenes. Bromination of deactivated rings is possible with a combina- tion of bromine mercuric oxide and sulphuric acid,51 but a particularly useful development is the discovery that bromine monofluoride prepared by combination of the elements in fluorotrichloromethane allows the rapid brominatioh of deacti- vated arenes without a catalyst. Examples are meta-bromination of acetophenone in 92% yield after 5 minutes at -40 "C,the quantitative conversion of bromobenzene into 1,4-dibromobenzene and the meta -bromination of benzaldehyde in 95 YO yield this last example demonstrating that the reagent is non-~xidizing.~~ Similarly iodine monofluoride (prepared from the elements) is useful for iodinating moderately deactivated substrates ethyl benzoate giving 85 '/o of the m-iodo derivative; however nitrobenzene did not react and anisole gave only tars.53 Iodination of aromatic ethers in good yields takes place with benzyltrimethylammonium dichl~roiodate.~~ A review on the synthesis and uses of aryl iodides has been p~blished.~~ For the introduction of radiolabelled iodine or bromine direct halogenation is only efficient with activated rings otherwise a recommended procedure is to employ ipso-substitu- tion of trimethylgermyl by the halide and in situ generated peracetic acid.56 Numerous papers continue to be published on the hydroxylation of arenes by electrophilic attack of the hydroxyl radical generated by various rnean~,~'-~~ a process important in metabolism.It has been suggested that the high proportion of NIH shift (1,2-shift of the hydrogen from the site of hydroxylation to the adjacent position) seen in microbial oxidation is due to an efficient one-electron oxidation of the dienyl radical to a cation which rearranges and that it is not necessary to invoke an arene oxide intermediate.60 Trifluoromethylation of arenes can be accomplished either by reaction with trifluoroacetic acid in the presence of xenon difluoride in which case a tri-fluoromethyl radical is the active electrophile,61 or photochemically with bromotri- fluoromethane in which case the reaction proceeds via electron transfer from the excited singlet state of the arene to the reagent; a consequence of this mechanism is unusual selectivity anisole giving the ortho-substituted product.62 A photochemically induced intramolecular electron transfer from an arene to an imine followed by radical combination gives a useful cyclization reaction (Scheme 9).63 Similar cyclization of a silylmethylarene on to an iminium salt where coupling 50 A.Luxen and J. R. Barrio Tetrahedron Lett. 1988 29 1501. '' S. A. Kahn M. A. Munawar and M. Siddiq J. Org. Chem. 1988 53 1799. s2 S. Rozen M. Brand :md R. Lidor J. Org. Chem. 1988 53 5545. 53 S. Rozen D. Zamir Y. Menachem and M. Brand J. Org. Chem. 1988 53 1123. 54 S. Kajigaeshi T. Takinami M. Moriwaki M. Watanabe S. Fujisaki and T.Okamoto Chem. Lett. 1988 795. 55 E. B. Merkushev Synthesis 1988 923. 56 S. M. Moerlein W. Beyer and G. Stocklin J. Chem. Soc. Perkin Trans. 1 1988 779. 57 S. Ito T. Yamasaki H. Okada S. Okino and K. Sasaki J. Chem. Soc. Perkin Trans. 2 1988 285. s8 H. M. Chawla S. K. Sharma K. Chakrabarty and S. Bhanumati J. Chem. Soc. Chem. Commun. 1988 128. 59 M. Blanchard C. Bouchoule G. Bjaneye-Boundjou and P. Canesson Tetrahedron Left. 1988,29 2177. 60 T. Kurata Y. Watanabe M. Katoh and Y. Sawaki J. Am. Chem. SOC.,1988 110 7472. 61 Y. Tanabe N. Matsuo and N. Ohno J. Org. Chem. 1988,53,4582. T. Ariyama K. Kato M. Kajitani Y. Sakaguchi J. Nakamura H. Hayashi and A. Sugimori Bull. 62 Chem. SOC.Jpn. 1988 61 3531. 63 1.4. Cho and P.S. Mariano J. Org. Chem. 1988 53 1590. 172 R. McCague Me 58% Me Scheme 9 takes place at the benzylic position has been applied to a synthesis of the alkaloid pr~toberberine.~~ Aromatic carboxamides can be prepared by the use of biscarbamoyl diselenides as carbamoylating agents.65 An attractive acylmethyiation procedure for the prepar- ation of wary1 ketones is from nitro-olefins in the presence of titanium tetrachloride followed by hydrolysis. An example is shown in Scheme N-OTiC1 0 94% Scheme 10 For the electrophilic substitution of deactivated benzenes the nature of the catalyst can be important. Trifluoromethanesulphonic acid is an efficient catalyst of methanesulphonylation with methanesulphonyl chloride by assisting formation of the methanesulphonium ion.If aluminium chloride is the catalyst then products of chlorination and methanesulphination can exceed that of the wanted Boron aluminium and gallium triflates are effective Friedel-Crafts catalysts in alkylation acylation and isomerization.68 Although deuteration is normally carried out on aromatic hydrocarbons by acid catalysis it is useful to know that di- and trihalogenobenzenes have sufficiently acidic ring protons to enable deuteration under the effectively strong basic conditions of phase-transfer catalysis with 60% sodium deuteroxide in deuterium oxide and tetrabutylammonium hydrogen ~ulphate.~~ .rr-Complexation of an arene with tricarbonylchromium is well known to activate the aromatic ring to nucleophilic attack.It has now been shown by Leong and Cooper that upon reduction of the complex to the dianion with potassium naph- thalenide the ring becomes strongly activated to electrophilic attack; for instance benzylation to give a monoanionic dienylium a-complex takes place with benzyl ~hloride.’~ 64 G. Dai-Ho and P. S. Mariano J. Org. Chem. 1988 53 5113. 65 S.4. Fujiwara A. Ogawa N. Kambe 1. Ryu and N. Sonoda Tetrahedron Lett. 1988 29 6121. 66 K. Lee and D. Y. Oh Tetrahedron Lett. 1988 29 2977. 67 M. Ono Y. Nakamura S. Sato and I. Itoh Chem. Lett. 1988 395. 68 G. A. Olah 0. Farooq S. M. F. Farnia and J. A. Olah J. Am. Chem. Soc. 1988 110 2560. 69 D. Feldman and M. Rabinovitz J. Org. Chern. 1988 53 3779. 70 V. S. Leong and N.J. Cooper J. Am. Chem. SOC.,1988 110 2644. Aromatic Compounds 173 Nucleophilic Substitution.-MNDO calculations have led to the proposal of the formation of a charge transfer complex (CTC) on the pathway to the Meisenheimer complex (MC) and also that if the CTC is stable an increased activation energy for formation of the MC can lead to a retardation of the reaction rate -thus the propensity of fluoride to act as a leaving group (moreso than the other halogens) is attributed to its disfavouring the CTC. Similarly activation of the ring by a nitro group is explained by it stabilizing the MC more than the CTC.7' The effect of CTC formation on reaction rate has also been recognized for the reactions of hydroxide ion with l-halogen0-2,4-dinitronaphthalenes~~ and l-substituted-2,4,6-trinitroben-~enes,~~ where the high reactivities when the 1-substituent is fluorine nitro or arylsulphonate are hard to explain in terms of inductive effects.Evidence for the CTC is the occurrence of proton exchange and n.m.r. line broadening which occur least when the MC formation is rapid.74 Formation of electron donor-acceptor complexes with benzene makes this not an inert solvent in aromatic nucleophilic substit~tion.'~ Electron transfer to 4-nitrocumyl systems leads to substitution at the benzylic position.76 Advances have been made in the vicarious nucleophilic substitution of hydrogen by expansion of the range of capable nucleophiles although substrates tend to be restricted to nitroarenes. The reaction takes place para to this nitro substituent unless the 4-position is blocked or a 3-trifluoromethyl group is present.77 New nucleophiles include anions from 4-(chlorophenoxy)acetonitrile78 leading to arylacetonitriles and 4-(alkylamino)-l,2,4-triazolesleading to the alkylamino-substituted a~ene.~~ Overall substitution of hydrogen also takes place when tricar- bonylchromium-complexed oestradiol ethers are treated with the lithium salt of dithiirane followed by oxidation.However with the lithium salt of acetonitrile methoxide is displaced to give a 3-substituted oestratriene (Scheme 1 l)." 7r-Complexes with a cationic iron complex [Are -.(C5H5)Fe+PF,] are also activated strongly to nucleophilic substitution on the ring.*' A group of miscellaneous reactions that do not proceed via a Meisenheimer complex and do not belong to any of the forthcoming sections are included here as the overall conversions resemble a nucleophilic substitution.Substitution of hydrogen is the overall reaction when phenylnitrenium ions generated from phenyl azide and trifluoroacetic acid are treated with alkyl sulphides. The initially formed sulphonium ion resulting from attack on the nitrogen rearranges to the ortho-position and an alkyl group is finally lost (Scheme 12).'* 7' S. K. Dotterer and R. L. Harris J. Org. Chem. 1988 53 777. 72 R. Bacaloglu C. A. Bunton and F. Ortega J. Am. Chem. SOC.,1988 110 3512. 73 R. Bacaloglu C. A. Bunton and F. Ortega J. Am. Chem. Soc. 1988 110 3503. 74 R. Bacaloglu C. A. Bunton G.Cerichelli and F. Ortega J. Am. Chern. Soc. 1988 110 3495. 75 S. M. Chiacchiera J. 0.Singh J. D. Anunziata and J. J. Silber J. Chem. SOC.,Perkin Trans. 2 1988 1585. 16 N. Kornblum P. Ackermann J. W. Manthey M. T. Musser H. W. Pinnick S. Singaram and P. A. Wade J. Org. Chem. 1988 53 1475. 71 B. Mudryk and M. Makosza Tetrahedron 1988,44 209. 78 M. Makosza W. Danikiewicz and K. Wojciechowski Liebigs Ann. Chem. 1988 203. 19 A. R. Katritzky and K. S. Laurenzo J. Org. Chem. 1988 53 3978. 80 H. Kiinzer and M. Thiel Tetrahedron Lett. 1988 29 1135. A. S. Abd-El-Aziz C. C. Lee A. Piorko and R. G. Sutherland Synth. Commun. 1988 18 291. 82 H. Takeuchi S. Hirayarna M. Mitani and K. Koyama J. Chem. SOC.,Perkin Trans. I 1988 521. 174 R. McCague OSiMezBut OSiMe,But &p >Meo OSi M e B ut Me0@ Cr(CO)3 -Y dP NCCHZ Reagents i [:)-Li+; ii oxidation; iii Li+-CH,CN; iv oxidation Scheme 11 H +,Me N-S.Scheme 12 One route for nucleophilic substitution in aryldiazonium ions takes place by dissociation to nitrogen and the reactive aryl cation. On the pathway is a cationic pair [Ar+.-.N,] in which the nitrogen can be exchanged with the isoelectronic carbon monoxide at high pressure (1000 bar) to give a benzoyl cation which if trapped with water gives the benzoic The hindered diary1 ether framework of thyroid hormone analogues has been efficiently constructed by the coupling of phenyls with iodonium salts (Ar21+X-).84 A procedure for the preparation of specific chloroarenes is chlorodenitration with phenyltetrachlorophosphorane ( PhPC14) at 170 “C.The reagent will convert 2,3-dichloronitrobenzeneinto 1,2,3-trichlorobenzene in 94% yield and can be used as an alternative to the Sandmeyer approach. The suggested mechanism (Scheme 13) involves substantial modification of the nitro Substitution uia Aryl a-Radicals.-Reviews have been published covering the gener- ation of aryl radicals from arenediazonium ionsB6 and the electrochemically catalysed SRNlreaction where the aryl radical is initially generated by cleavage of a halogenobenzene radical anion at the ~athode.~’ Aryl radicals formed electrochemi- 83 M. D. Ravenscroft P. Skrabal B. Weiss and H. Zollinger Helv. Chim. Acra 1988 71 515. 84 D. M. B. Hickey P.D. Leeson R. Novelli V. P. Shah B. E. Burpitt L. P. Crawford B. J. Davies M. B. Mitchell K. D. Pancholi D. Tuddenham N. J. Lewis and C. O’Farrell J. Chem. SOC.,Perkin Trans. I 1988 3103. 85 E. Bay P. E. Timony and A. Leone-Bay J. Org. Chem. 1988 53 2858. 86 C. Galli Chem. Rev. 1988 88 765. *’ J.-M. Saveant. Bull. SOC.Chim. Fr. 1988 225. Aromatic Compounds Ph -PhPOCI P -NOCl + .?/ ArCl -Ar-N=O c1-Ar-N 0-c1 I c1 ‘C1 Scheme 13 cally add cleanly to styrene provided isopropanol is added to inhibit polymeriz- ation,” to carbon dioxide to give arylcarboxylic acids,89 and to phenoxide ions to give biphenyls.” The photochemical SRNlreaction is particularly useful for the synthesis of various biaryl~.~’-~~ Intramolecular cyclization of an aryl radical gener- ated from the halogenobenzene by tributyltin radical abstraction has been used in a synthesis of retinoids where conveniently the stereochemistry obtained is that required for maximum insecticidal activity (Scheme 14).94 62% Scheme 14 Electron transfer from aryl Grignard reagents to 2,3-dichloropropene is also thought to lead to aryl radicals; these dimerize to yield symmetrical biaryl~.’~ Halogenonitrobenzenes are generally unreactive in the electron transfer SRNl reaction since the nitro group stabilizes the v* orbital bearing the extra electron in the radical anion so preventing the transfer to a u* orbital necessary for the fragmentation.However 2-iodonitrobenzene does undergo the SR,l reaction pre- sumably because of steric inhibition of conjugation of the nitro group by the bulky iodine atom.96 For 4-bromonitrobenzene the acid-catalysed nucleophilic substitu- tion by chloride is thought to proceed via electron transfer from chloride ion to the 88 Z.Chami M. Gareil J. Pinson J.-M. Saveant and A. Thiebault Tetrahedron Lett. 1988 29 639. 89 M. Heintz 0. Sock C. Saboureau J. Perichon and M.Troupel Tetrahedron 1988 44,1631. 90 C. Amatore C. Combellas J. Pinson J.-M. Saveant and A. Thiebault J. Chem. SOC.,Chern. Commun. 1988 7. 91 R. Beugelrnans M. Bois-Choussy and Q. Tang Tetrahedron Lett. 1988 29 1705. 92 R. Beugelrnans and M. Bois-Choussy Tetrahedron Lett. 1988 29 1289. 93 A. B. Pierini M. T. Baumgartner and R. A. Rossi Tetrahedron Lett. 1988 29 3429.94 S. A. Ahmad-Junan and D. A. Whiting J. Chem. SOC.,Chem. Commun. 1988 1160. 95 J.-W. Cheng and F.-T. Luo Tetrahedron Lett. 1988 29 1293. 96 C. Galli Tetrahedron 1988 44,5205. 176 R. McCugue 3n,7r* state of the arene and then coupling of the intact radical anion with the chlorine radi~al,~' whereas for 3-bromonitrobenzene substitution is a classical nucleophilic attack on the photoexcited arene in an SN23Ar* reaction the acid catalysis being due to protonation of the 3n,u* state.98 Substitution viu Arynes.-Advances in the utility of arynes in organic synthesis arise from gaining regioselectivity in the addition of the nucleophile and in harnessing the reactivity of the resulting aryl anion. The aryne derived from 2-bromo-4-methyl- anisole is attacked at the 3-position by the anion of acetonitrile and the aryl anion formed then abstracts cyanide intramolecularly (Scheme 15).99 W O M e t- $-n)$/ / \ 83 % 'OMe OMe Scheme 15 Other useful aryne traps are vinylsilyl Grignard reagents leading to o-alkyl- substituted aryl magnesium halides,'" and 0-silyl enolates of esters leading to o-alkylbenzoic acids via hydrolysis of bicyclic compounds."' An excellent control of aryne reactivity has been reported by Meyers and co-workers starting with the oxazoline (10) (Scheme 16).'02 The o-chloroaryl anion formed by deprotonation with butyllithium is exceptionally stable losing hydrogen chloride only above -10 "C and allowing the inclusion of various nucleophiles.Moreover the regiochemistry of addition is controlled by the choice of reagent alkyllithiums add at the 2-position by virtue of chelation with the oxazoline whereas alkylcuprates add at the 3-position.97 G. G. Wubbels E. J. Snyder and E. B. Coughlin J. Am. Chem. SOC.,1988 110 2543. 98 G. G. Wubbels D. P. Susens and E. B. Coughlin J. Am. Chem. SOC.,1988 110 2538. 99 S. P. Khanapure L. Crenshaw R. T. Reddy and E. R. Biehl J. Org. Chem. 1988 53 4915. 100 T. K. Vinod and H. Hart Tetrahedron Lett. 1988 29 885. 101 S. Masarrat Ali and S. Tanimoto J. Chem. Soc. Chem. Commun. 1988 1465. 102 P. D. Pansegrau W. F. Rieker and A. I. Meyers J. Am. Chem. Soc. 1988 110 7178. Aromatic Compounds 0d wN Reagents i Bu"Li -78 "C; ii -10 to 0 "C; iii RLi; iv E+; v R,CuLi; vi E+ Scheme 16 Substitution uia Aryl-Metal a-Complexes.-Activation of the C-H Bonds of Ben-zene.Various transition metal complexes have been found to be capable of under- going oxidative addition of benzene to give an aryl-metal a-complex. There are reports of such activation with complexes of platinum,'03~'04 iridi~rn,''~ rhodium,'06 and zir~onium.''~ Hopefully some of these adducts will find use in the synthesis of substituted benzenes. In a reaction which is thought to proceed uia formation of an aryl-rhodium complex benzene has been shown to react under photocatalysis with methyl acrylate in the presence of RhCl(CO)(PMe3)2 to give methyl (E )-cinnamate."* Aryl- Metal u-Complex US the Electrophile. A review of some of the newer methods of arylation with emphasis on the use of organobismuth and organolead reagents has been p~blished.'~~ Aromatic substitution reactions uia aryl-metal intermediates due to mediation by catalytic amounts of transition metal complexes most commonly of palladium are now well established in vast variety for aryl bromides iodides and trifluoromethanesulphonates (triflates).By using a nickel complex catalyst containing a chiral ferrocenylphosphine ligand an asymmetric synthesis of 1,l'-binaphthyls by cross coupling in 95% ee has been reported."' Methods are emerging for the inclusion of aryl chlorides into this area of chemistry they can be activated at 140 "C with a bimetallic nickel-palladium system comprising sodium iodide nickel bromide and a palladium(0) complex whereby the nickel salts mediate halogen exchange to generate kinetic amounts of aryl iodide into which the palladium complex can insert.The coupling between 4-chlorotoluene and ethyl acrylate by 103 M. Hackett J. A. Ibers and G. M. Whitesides J Am. Chem. SOC.,1988 110 1436. 104 M. Hackett and G. M. Whitesides J. Am. Chem. SOC.,1988 110 1449. 10s W. D. McGhee and R. G. Bergman J. Am. Chem. SOC.,1988 110 4246. 106 C. K. Ghosh D. P. S. Rodgers and W. A. G. Graham J. Chem. SOC.,Chem. Commun. 1988 1511. 107 C. C. Cummins S. M. Baxter and P. T. Wolczanski J. Am. Chem. SOC. 1988 110 8731. 108 K. Sasaki T. Sakakura Y. Tokunaga K. Wada and M. Tanaka Chem. Lett. 1988 685. 109 R. A. Abramovitch D. H. R. Barton and J.-P.Finet Tetrahedron 1988 44 3039. 110 T. Hayashi K. Hayashizaki T. Kiyoi and Y. Ito J. Am. Chem. SOC.,1988 44 8153. 178 R. McCague this method proceeds in 73% yield."' Also n-complexation of the arene with tricarbonylchromium activates the oxidative addition and allows in the case of the chlorobenzene complex a palladium-catalysed carbonylative coupling at 170 "C to give methyl benzoate in 80% yield."2 Nickel or palladium complexes have also been shown to insert in a synthetically useful manner into tetraalkylarnmonium salts,' l3 aryldiazonium tetrafluoroborates,' l4 and 5-( 1-phenyltetrazolyl) ethers.' l5 The last type represent an alternative to triflates and have the advantage of being (generally) crystalline. Intramolecular palladium-complex-catalysed cyclizations of aryl iodides are finding increasing use for the synthesis of the polycyclic frameworks of natural products.Cyclization on to a soft enolate has been used in an approach to fredericamycin,'16 and cyclization on to the double bonds of cycloalkenes for the formation of tricycles with a cis-fused ring j~nction.~"~"~ Aryl-Metal a-Complex as the Nucleophile. Although boron is not a metal arylboronic acids in the presence of base deliver an aryl nucleophile allowing coupling to aryl or vinyl halides in the presence of palladium catalysts. This coupling method has been applied in a simple synthesis of i~oflavones'~~ and of agylcones of benzonaph- thapyrone antibiotics.12' Buchwald and Nielsen have reviewed the zirconocene/ titanium complexes of benzyne which behave with electrophiles as benzene- 1,2-dianion~.'~' Stabilization of 1,2,4,Stetrahydrobenzenehas also been achieved by complexation at two nickel(0) centres.'22 Substitution via Lithiation.An especially useful example of lithiation directed by an oxazoline has been described above. The area of directed ortho-lithiation has been reviewed (in French).lZ3 An iterative directed lithiation whereby the substituent introduced is then used to direct a further lithiation has been employed to build the pentasubstituted benzene ring in a total synthesis of fredericamycin For substitution on both sides of a directing group use of lithium tetramethylpiperidide as base with mercuric chloride as an in situ trap gives bis(ch1oromercury)arenes from which the mercury can then be exchanged with other f~ncti0ns.l~~ The lithiation of fluoranisoles has revealed unexpected regioselectivity.Whereas methoxide was formerly reported to be a better director of lithiation than fluorine this may be Ill J. J. Bozell and C. E. Vogt J. Am. Chem. SOC.,1988 110 2655. R. Mutin C. Lucas J. Thivolle-Cazat V. Dufaud F. Dany and J. M. Basset J. Chem. SOC.,Chem. Commun. 1988 896. 113 E. Wenkert A.-L. Han C.-J. Jenny J. Chem. SOC. Chem. Commun. 1988 975. 114 K. Ikenaga S. Matsumoto K. Kikukawa and T. Matsuda Chem. Lett. 1988 873. R. A. W. Johnstone and W. N. Mclean Tetrahedron Lett. 1988 29 5553. 1 I6 M. A. Ciufolini H.-B. Qi and M. E. Browne J. Org. Chem. 1988 53 4151. 117 R.C. Larock H. Song B. E. Baker and W. H. Gong Tetrahedron Lett. 1988 29 2919. 118 Y. Zhang B. O'Connor and E.4 Negichi J. Org. Chem. 1988 53 5588. 1 I9 Y. Hosino N. Miyaura and A. Suzuki Bull. Chem. SOC.Jpn. 1988 61 3008. 120 M. E. Jung and Y. H. Jung Tetrahedron Lett. 1988 29 2517. I21 S. L. Buchwald and R. B. Nielsen Chem. Reu. 1988 88 1047. 122 M. A. Bennett J. S. Drage K. D. Griffiths N. K. Roberts G. B. Robertson and W. A. Wickramasunghe Angew. Chem. Int. Edn. Engl. 1988 27 941. 123 V. Snieckus Bull. SOC.Chim. Fr. 1988 67. I24 T. R. Kelly S. H. Bell N. Ohashi and R. J. Armstrong-Chong J. Am. Chem. Soc. 1988 110 6471. 125 P. E. Eaton and R. M. Martin J. Org. Chem. 1988. 53 2728. Aromatic Compounds because the o-fluoroaryllithio species readily degrade to benzyne.It has now been found that fluorine competes effectively and if the aryl-oxygen bears t-butyldimethyl- silyl instead of methyl the lithiation ortho to fluorine is exclusive (Scheme 17).'26 OSiMe2Bu' ?H (i) Bu'Li. -78 "C (iij DMF' 9 (iii) BU,N+F-I F F Scheme 17 Whereas metallation of benzylamine derivatives has not been reported previously their N-pivaloyl derivatives upon treatment with two-equivalents of alkyllithium do metallate.12' o-Hydroxylation of aromatic aldehydes is also possible with sonically generated s-butyllithium in the presence of tri-n-butylborate and hydrogen peroxide to trap the aryllithium and oxidize the boronate.'28 Lastly a titanium-nitrogen complex has been found which will allow direct conversion of an aryllithium into an ary~amine.'~~ 4 Benzene Derivatives for the Synthesis of Non-aromatic Compounds Reductions.-The disruption of the aromaticity of benzene by q2-complexation with pentaammineosmium(II)'~','~' enables the selective reduction to the cyclohexene complex from which cyclohexene itself can be liberated and the metal centre re~yc1ed.l~~ The cyclohexadienes formed from the Birch reduction-alkylation of aryl ketones and carboxylates are proving increasingly valuable as precursors of a range of natural products such as the antimicrobial fatty acid tetrahydrodicranenone B'33 and functionalized perhydroindanes which are substructures of the antibiotics pleurotin and gibberellic acid.'34 By using L-prolinol as a chiral auxiliary in its amide with 2-methoxybenzoic acid very high diastereoselectivity in the reductive alkylation (260 1) has been obtained,'35 which should provide a new entry to optically pure natural products.Photochemical Processes.-In an exceedingly complex example of the arene-olefin meta-photocycloaddition that produces in one step three contiguous stereocentres I26 D. C. Furlano S. N. Calderon G. Chen and K. L. Kirk J. Org. Chem. 1988 53 3145. I27 G. Simig and M. Schlosser Tetrahedron Lett. 1988 29 4277. 128 J. Einhorn J.-L. Luche and P. Demerseman J. Chem. SOC.,Chem. Commun. 1988 1350. 129 V. B. Shur E. G. Berkovich S. Lenenko L. I. Vyshinskaya G. A. Vasil'eva and M. E. Vol'pin Bull. Acad. Sci. USSR (Engl. Transl.) 1987 36 2220.130 W. D. Harman and H. Taube J. Am. Chem. SOC.,1988 110 7555. 131 W. D. Harman M. Sekine and H. Taube J. Am. Chem. SOC.,1988 110 5725. 132 W. D. Harman and H. Taube J. Am. Chem. Soc. 1988 110 7906. 133 C. J. Moody S. M. Roberts and J. Toczek J. Chem. SOC.,Perkin Trans. 1 1988 1401. 134 C.-P. Chuang J. C. Gallucci and D. J. Hart J. Org. Chem. 1988 53,3210. 135 A. G. Schultz M. Macielag P. Sundararaman A. G. Taveras and M. Welch J. Am. Chem. SOC.,1988 110,7828. 180 R. McCague A *-(*)-laurenene Scheme 18 Wender and co-workers have compiled a synthesis of (*)-laurenene in 5% overall yield (Scheme 18).'36 Upon performing the photocycloaddition in a dihydroxycyclophane derivative only one of two conformers (11) is reactive the other requiring conformational inversion.The result is explainable by Frontier MO consideration^,'^' and a similar situation is found in the rneta-photocycloaddition of ethenes to cyanoanisoles where the methoxy group directs cycloaddition to the 2-and 6-po~itions.'~~ Oxidations.-The cis-1,2-dihydrocatechols obtained from the microbial oxidation of arenes with Pseudornonasputidu have been used for the synthesis of the hexasub- stituted cyclohexane inositol 1,4,5-tripho~phate'~~ and for precursors of terpenes and pro~tanoids.'~' Osmium tetroxide has been found to add to benzenoid hydrocarbons in the presence of light and added pyridine to give a 2 1 c~mplex'~' having the structure 13' P. A. Wender T. W. von Geldern and B.H. Levine J. Am. Chem. SOC.,1988 110 4858. 137 M. Miyake T. Tsuji and S. Nishida Chem. Lett. 1988 1395. 138 N. Al-Jalal A. Gilbert and P. Heath Tetrahedron 1988 44 1449. 139 S. V. Ley and F. Sternfeld Tetrahedron Lett. 1988 29 5305. 140 T. Hudlicky H. Luna G. Barbieri and L. D. Kwart J. Am. Chem. SOC.,1988 110 4735. 141 J. M. Wallis and J. K. Kochi J. Org. Chem. 1988 53 1679. Aromatic Compounds 181 (12) as found in the The first addition is thought to be due to photoactiva- tion of the donor-acceptor complex between the arene and osmium tetroxide and the second takes place thermall~.'~~ 5 Condensed Polycyclic Aromatic Compounds Theoretical Considerations and Reactivity.-The difference in energy between a six-electron .rr-system (benzene) and a benzannelated four-electron system (as in naphthalene) of 6 f 1kcal mol-' is reflected in a difference in acidity of the ring thereby demonstrating an ionic probe of aromaticity.This reduced aromaticity of a given ring of naphthalene makes possible the addition of strong nucleophiles to give a dihydro species.'44 When a chiral oxazoline is a substituent in the 2-position the high diastereoselectivity of aryllithium addition has enabled an efficient total synthesis of (+)-~hyltetralin'~' and (-)-podophyllotoxin (Scheme 19).'46 ,(0) SiMezBu' Me0 c / -Me OMeOMe Ar N3-Me Me0 Me0 1 1 ?* OMe Scheme 19 Strong peri-interactions in 1,8-disubstituted naphthalenes confers unusual reac- tivity both on the substituents and on the Hence the isolated double bond in l-methoxy-8-(2-propenyl)naphthalenecannot be reduced by catalytic hydro- genation without also reducing one of the benzene rings to give a tetralin.142 J. M. Wallis and J. K. Kochi J. Am. Chem. SOC.,1988 110 8207. 143 M. Moet-Ner J. F. Liebman and S. A. Kafafi J. Am. Chem. SOC.,1988 110 5937. 144 A. I. Meyers K. A. Lutomski and D. Laucher Tetrahedron 1988 44 3107. 145 A. 1. Meyers G. P. Roth D. Hoyer B. A. Barner and D. Lacher J. Am. Chem. Soc. 1988 110 4611. 146 R. C. Andrews S. J. Teague and A. 1. Meyers J. Am. Chem. Soc. 1988 110 7854. 147 A. J. Kirby and J. M. Percy Tetrahedron 1988 44 6903. A. J. Kirby and J. M. Percy Tetrahedron 1988 44 6911. 14' 182 R. McCague An interesting enzymatic conversion in the anthraquinone natural product emodin is the removal of one of the phenolic hydroxy groups.Studies in detuerium oxide reveal that this reduction proceeds through reduction of the carbonyl of the keto tautomer followed by deh~drati0n.l~~ In cycloarene systems molecular mechanics calculations predict that these will not exhibit superaromatic delocalization by virtue of inner and outer (4n + 2)T-electron circuits but rather will localize to those resonance forms containing the maximum number of Clar sextet^.'^' The thermal automerization of acenaphthy- lene whereby a carbon-13 label is redistributed to other periphery carbons has been explained by a benzene ring contraction mechanism."' A review on conjugated dianions of polycyclic systems has been ~ublished.'~~ For these systems the charges are predicted to alternate around the ring system in order to maximize donor-acceptor interactions whether they are diatropic or para- tropi~."~ The dianion of naphthalene is a strongly paratropic 4n system as evidenced by a 30.4 p.p.m.downfield shift of the quaternary carbon atoms.ls4 Synthesis.-The anthracyclinone antibiotic 11-deoxydaunomycinone is currently a popular synthetic target. Syntheses using chromium carbene complexes have been reported by the groups of dot^'^^ and Wulff The latter synthesis which involves a one-pot tandem benzannulation for construction of the ring system is shown in Scheme 20. i-v -// Bu'0,C' & OMe OMe 0 vi vii I 1 1 -deoxydaunomycinone 61 Yo Reagents i C,H, 75 "C;ii air; iii TFAA NaOAc; iv TFA; v OH-; vi Ag20 HN03 acetone; vii 02 DMF Scheme 20 149 J.A. Anderson B.-K. Lin H. J. Williams and A. I. Scott J. Am. Chem. SOC.,1988 110 1623. 150 P. M. Lahti J. Org. Chem. 1988 53 4590. 15' L. T. Scott and N. H. Roelofs Tetrahedron Lett. 1988 29 6857. 152 M. Rabinovitz and Y. Cohen Tetrahedron 1988 44 6957. 153 Y. Cohen J. Klein and M. Rabinovitz J. Am. Chem. SOC.,1988 110 4634. 154 R. Benken and H. Gunther Helv. Chim. Acta 1988 71 694. 155 K. H. Dotz and M. Popall Chem. Ber. 1988 121 665. 156 W. D. Wulff and Y.-C. Yu,J. Am. Chem. SOC.,1988 110 2312. Aroma tic Compounds A total synthesis of 1 1-deoxydaunomycinone using a [4C + 2C] condensation for c-ring construction has also been rep~rted,'~' and related compounds have been prepared by a Diels- Alder approach with an isobenzofuran where a sulphone substituent allows introduction of the necessary regiosele~tivity.'~~ The chemistry of isobenzofurans has been reviewed;'59 as well as for the synthesis of natural products they are well suited as precursors to polycyclic hydrocarbons.A novel strategy for the preparation of isobenzofurans uses the retro-Diels- Alder reaction to ex.cise a two-carbon unit from the benzyne-furan cycloadduct,'60 but probably the simplest preparation of the parent compound has been made possible by careful control in the formation of benzyne from aminobenzotriazole and lead tetraacetate allowing the 1 :1 oxazoline adduct (13) to be obtained in quantitative yield.This adduct loses benzonitrile cleanly on mild thermolysis (k= 2 x s-' at 40 "C) to give isobenzofuran16' (Scheme 21). Ph (13) Scheme 21 Regioselectivity is attained if 3-fluorobenzyne (from 1,3-difluorobenzene and butyllithium) undergoes cycloaddition with a 2-substituted furan where the syn-adduct is preferred owing to the concerted addition being non-synchronous so that the first bond formed is to the 3-position leading to a build up of negative charge at the 2-position in the transition state where it is stabilized by the fluorine atom.16* For the synthesis of angular condensed polycyclic systems a one-pot cyclocon- densation procedure has been developed; a synthesis of chrysene is shown in Scheme 22.'63 A comparable coupling between an enamine salt and a naphthylethyl iodide has been used for a synthesis of cyclopenta[ alphenanthrene and its carcinogenic methyl derivatives.164*165 A method that is gaining increasing popularity for the synthesis of anthracyclinone natural products is the biomimetic polyketide condensation. In a [SC + SC] con-densation regioselectivity has been gained because of the greater reactivity of a ketal than an acetal (Scheme 23).'66 157 E. Ghera and Y. Ben-David J. Org. Chem. 1988 53 2972. 158 F. M. Hauser and P. Hewawasam and D. Mal J. Am. Chem. SOC.,1988 110 2919. 159 R.Rodrigo Tetrahedron 1988 44,2093. 160 J. Moursounidis and D. Wege Ausr. J. Chem. 1988,41 235. 161 S. E. Whitney and B.Rickborn J. Org. Chem. 1988 53 5595. 162 G. W. Gribble D. J. Keavy S. E. Branz W. J. Kelly and M. A. Pals Tetrahedron Lett. 1988 29 6227. 163 P. Di Raddo and R.G. Harvey Tetrahedron Lett. 1988. 29 3885. 164 H. Lee and R. G. Harvey Tetrahedron Lett. 1988 29 3207. 165 H. Lee and R.G. Harvey J. Org. Chem. 1988 53 4253. I66 D. Stossel and T. H. Chan J. Org. Chem. 1988 53 4901. 184 R. McCague rCHO -&- TiCI, -78 "C to r.t. // ~ MesSiO I 7 7 '/o 65 % Scheme 22 TMS TMS TMS Ill 000 OH OH 0 UOMe TMS-OTf CH,CI * OMe jyy -80 "C Me0 nOMe Me MeowOMe (regioisomeric purity at least 95% ) Me Scheme 23 Various combinations of 1,3-dicarbonyl-containingcomponents have been conver- ted into the pretetramides which contain a polyhydroxylated naphthacene n~cleus.'~~-'~~ Lastly an ingenious synthesis of anthraquinones (Scheme 24) employs in its key step a nucleophilic substitution of a methoxy group activated by an ortho-oxazoline substit~ent.'~~ Carcinogenicity of Polycyclic Aromatic Hydrocarbons (PAH).-For the synthesis of the carcinogenic diol epoxide metabolites directly from the hydrocarbons ceric ammonium nitrate has been shown to convert benzo[ klfluoranthene into a mixture of quinones one of which has been converted into a diol ep~xide.'~' Direct oxidation of polycyclic arenes to the arene oxides took place with the 2-nitrobenzyl peroxysul- phonate generated from the sulphonyl chloride.'72 167 S.G.Gilbreath C. M. Harris and T.M. Harris J. Am. Chem. SOC.,1988 110 6172. 168 T. M. Hams C. M. Harris T. A. Oster L. E. Brown jun. and J. Y.-C. Lee J. Am. Chem. Soc 1988 110 6180. 169 T. M. Hams C. M. Hams P. C. Kuzma J.Y.-C. Lee S. Mahalingam and S. G.Gilbreath J. Am. Chem. SOC 1988 110,6186. 170 T. M. Nicoletti C. L.Raston and M. V. Sargent J. Chem. SOC.,Chem. Commun. 1988 1491. 171 G.Balanikas N. Hussain S. Amin and S. S. Hecht J. Org. Chem. 1988 53 1007. Aromatic Compounds 185 OMe MebcH2Mgc1 OMe Me OMe OMe OMe OMe 0 CrO, AcOH 85% 86'/o I OMe 0 OMe 0 Scheme 24 Biological data on synthesized diol epoxides of derivatives of dibenz[ a jlanthracene support the generalization that carcinogenic potency is enhanced by methyl substituents in the bay region.'73 7-and 12-Methyl substituents in benz[ a]anthracene-3,4-dione cause distortions from planar geometry that lead to a reordering of the electronic energy 1e~els.l~~ An account of the binding of such PAH metabolites to nucleic acids has been pre~ented.'~~ Covalent binding of a dihydrodiol epoxide to poly( dG-dC) has been shown to involve excimer formation attributed to interactions between the pyrene and guanine chromophores in the DNA minor grooves.'76 Whereas the diol epoxide of benzo[ alpyrene itself forms a guanosine adduct when single electron electrochemical oxidation is catalysed by I72 H.K. Lee K. S. Kim J. C. Kim and Y. H. Kim Chem. Lett. 1988 561. 173 R. G. Harvey C. Cortez T. W. Sawyer and J. DiGiovanni J.Med. Chem. 1988 31 1308. I74 R. S. Becker L. V. Natarajan C. Lenoble and R. G. Harvey J. Am. Chem. Soc. 1988 110 7163. 175 R. G. Harvey and N. E. Geacintov Acc. Chem. Rex 1988 21 66. 176 M. Eriksson B. Norden B. Jernstrom A. Graslund and P.-0. Lycksell J. Chem. Soc. Chem. Commun. 1988 211. 186 R. McCague horse-radish peroxidase a carbon-carbon bond is formed between the C8 of guanine and C6 of the hydr~carbon.'~~ Novel Polycyclic Structures.-Stoddart has discussed approaches to the synthesis of [12lcyclacene (14) an intriguing belt-shaped hydrocarbon which may be considered to be an infinite acene and thereby to have high reactivity. So far the carbon framework has been constructed by Diels-Alder cyclizations between anthraquinone endoxides as bisdienophile components and bisdienes and the adduct converted into the hydrocarbon (15).'787'79 [7]Circulene (16) has been prepared X-ray analysis reveals that it adopts a saddle-shaped structure.'80 _---_ / ../ \ I \ Schmalz et al. have calculated that spherical hydrocarbons comprising fused aromatic rings containing as many as 240 carbon atoms should be stable.'" Whereas hydrocarbon free radicals are normally thought of as transient reactive species peri-naphthenyl radicals have been observed naturally in flints by e.s.r. Their stability results from the immobilization by their entrapment within disc-shaped cavities. 182 6 Cyclophanes A strongly bent naphthalene unit has been observed in the cyclophane (17). The two rings of the naphthalene are twisted dihedrally by 33" but the compound is ~tab1e.I'~ This is a good indication for the stability of spherical clusters and belt- shaped hydrocarbons which suffer similar deformation.The rates of flipping of the p-phenylene ring in dibenzo[2.2]metaparacyclophane the cyclophanediene (1 8) and derivatives having benzo-fused bridges as measured by dynamic n.m.r. curiously increase as the bridging bonds lengthen [e.g. compound (18) has a barrier of 35 kcal mol-' whereas the corresponding cyclophane with saturated linkages has 177 E. G. Rogan E. L. Cavalieri S. R. Tibbels P. Cremonesi C. D. Warner D. L. Nagel K. B. Tomer R. L. Cerny and M. L. Gross J. Am. Chem. Soc. 1988 110. 4023. 178 P. R. Ashton N. S. Isaacs F.H. Kohnke A. M. Z. Slawin C. M. Spencer J. F. Stoddart and D. J. Williams Angew Chem. Int. Edn. Engl. 1988 27 966. I79 J. F. Stoddart Chem. Br. 1988 1203. 1no K. Yamamoto T. Harada Y. Okamoto H. Chikamatsu M. Nakazaki Y. Kai T. Nakoo M. Tanaka S. Harada and N. Kasai J. Am. Chem. SOC.,1988 110 3578. 181 T. G. Schmalz W. A. Seitz D. J. Klein and G. E. Hite J. Am. Chem. Soc. 1988 110 1113. in2 H. Chandra M. C. R. Symons and D. R. Griffiths Nature (London) 1988 332 526. 183 N. E. Blank M. W. Haenel C. Kruger Y.-H. Tsay and H. Wintges Angew. Chem. Int. Edn. Engl. 1988 27 1064. Aromatic Compounds a barrier of 87 kcal mol-'I. This is explainable since the longer bridging coincides with a decrease in the bond angles drawing the aromatic rings closer together.'84 Through-space interactions in [n-nlcyclophanes bring about several curious properties.In the cyclophane (19) the through-space shielding influence of the ring causes the proton shown to resonate at the upfield position of S 3.36 in the 'H n.m.r. The interactions also complicate the analysis of circular dichroism spectra if the cyclophanes are chiral.'86 When 5-amino[3.3]paracyclophanes are diazotized cyclization to a barrelene takes place causing loss of aromaticity of one of the rings.'87 Syn-[2.2]metacyclophane is an elusive compound. In a route to a derivative where one bridge was fused to a phenanthrene to block ring rotation isolation of the cyclophane was unsuccessful owing to valence tautomerization to the dihydropyran which oxidizes to the pyran (in this case a tetrabenzanthracene).lg8The difluorocyc- lophane (20) prepared from its bis( tricarbonylchromium) c( mplex is somewhat more stable yet it cyclizes similarly above 35 "C to a dihydropyrene[ 14lannulene.Cis-trans-isomerization in (20) is however prevented by strong fluorine-fluorine repulsions this interaction being stronger than the steric repulsion between two methyl groups.'89 Macrocyclophanes in great variety are proving valuable for the construction of host-guest complexes where cavities are built by the suitable linking of aromatic 184 T. Wong S. S. Cheung and H. N. C. Wong Angew. Chem. Int. Edn. Engl, 1988 27 705. 185 T. K. Vinod and H. Hart J. Am. Chem. SOC.,1988 110 6574. 186 V. Buss and M.Klein Chern. Ber. 1988 121 89. 187 N. Mori T. Takemura and K. Tsuchiya J. Chem. SOC.,Chem. Commun. 1988 575. 188 Y.-H. Lai and S.-M. Lee J. Org. Chem. 1988 53 4472. 189 R. H. Mitchell G. J. Bodwell T. K. Vinod and K. S. Weerawarna Tetrahedron Lett. 1988 29 3287. 188 R. McCague rings. These include carcerands which have spherical ca~ities’’~ and ~alixarenes.‘’~ When arenes are bound to such hosts binding is stronger if internal substituents are positively rather than negatively charged indicating a favourable interaction between benzene rings and positively charged gr~ups.’’~ In artificial receptors for thymine of the type (21) the thymine forms a hydrogen-bonded complex to the substituted pyridine moiety and interacts favourably with the naphthalene ring.This interaction can be face-face or face-edge. The former is favoured only if the substituents R allow electrostatic complementarity with the 1iga11d.l’~ 7 Non-benzenoid Aromatic Systems The synthesis and crystal structure of the 14~-hydrocarbon (22) has been rep~rted.’’~ It is planar shows substantial bond length equivalence around the periphery and gives downfield shifts in its n.m.r. spectra so it therefore represents a new aromatic system. The annelated tropylium ion (23) is extraordinarily stable (pKR+ = 13.0). It is compatable with various basic counter-anions such as phenylthiolate and carbonate.”’ For all aspects of annulene chemistry a comprehensive survey in three volumes has been p~blished.’~~ For 1$methano[ lOIannulene more evidence has arisen for the presence of appreciable transannular interaction and the consequent description of this compound as homonaphthalene.For instance the interaction causes only weak relay between substituents in the positions 2 and 7 (either side of the bridge),’” and double benzannulation leading to (24) results in forfeiture of the aromaticity revealing the fragility of its extended conjugati~n.’~~ The dianion of 1,5-methano[ l01annulene has been generated by reduction of the hydrocarbon with lithium sand. It is thermally stable and paratropic the bridgehead protons resonate at S 11.4 but in keeping with the homonaphthalene descfiption the chemical shifts of the periphery protons are very similar to those of the naphthalene dianion.‘” A 190 D.J. Cram S. Karbach Y. H. Kim L. Barczynskyj K. Tarti R. M. Sampson and G. W. Kalleymeyn J. Am. Chem. Soc. 1988 110 2554. 191 C. D. Gutsche and I. Alam Tetrahedron 1988,44 4689. 192 H.-J. Schneider and T. Blatter Angew. Chem. Int. Edn. Engl. 1988 27 1163. 193 A. V. Muehldorf D. Van Engen J. C. Warner and H. D. Hamilton J. Am. Chem. SOC.,1988,110,6560. 194 K. Hafner G. F. Thiele and C. Mink Angew. Chem. Znt. Edn. Engl. 1988 27 1191. 195 K. Komatsu H. Akamatsu Y. Jinbu and K. Okamoto J. Am. Chem. Soc. 1988 110 633. 196 A. T. Balaban M. Banciu and V. Ciorbe ‘Annulenes Benzo- Hetero- Homo-Derivatives and their Valance Isomers. Volumes 1 2 and 3’ CRC Press Boca Raton Florida 1987. 197 T. Suzuki K. Takase K. Takahashi A.P. Laws and R. Taylor J. Chem. Soc. Perkin Trans. 2,1988,697. 198 R. K. Hill C. B. Giberson and J. V. Silverton J. Am. Chem. Soc. 1988 110 497. 199 D. Schmalz and H. Giinther Angew. Chem. Int. Edn. Engl. 1988 27 1692. Aromatic Compounds particularly interesting higher annulene is the extended porphyrin (25). Despite the large size (347r)of the ring n.m.r. spectroscopy reveals a high ring current the difference between chemical shifts of the inner (8 -14.3) and outer (8 +16.2-17.2) olefinic protons being greater than in the corresponding [26]annulene or in [18]annulene. The flattening of the ring system by the pyrrole units probably contributes to the high degree of aromaticity.200 Et Et Et Et G. Knubel and B. Franck Angew.Chem. Int. Edn. EngL 1988 27 1179.

ISSN:0069-3030    

DOI:10.1039/OC9888500163

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

8 Heterocyclic Compounds By D. E. AMES Department of Chemistry Queen Mary College London Mile End Road London El 4NS 1 Introduction The review on heterocyclic compounds for 1988 is again highly selective and emphasizes developments in synthetic methods. A hint of the future is perhaps provided by a paper on CAMEO (Computer- Assisted Mechanistic Evaluation of Organic Reactions). This computer program has been expanded to treat and organize the major types of heterocycle-forming reactions.’ Useful reviews have been published on substitution reactions of aromatic N-heterocycles’ and on the synthesis of condensed heteroaromatic compounds by palladium-catalysed reaction^.^ Reviews on reactions of acetoa~etamides~ and azides’ also cover many heterocyclic syntheses.2 Three-membered Rings A synthesis of chiral epoxides6 involves asymmetric induction in the condensation of (-)-chloromethyl p-tolyl sulphoxide with carbonyl compounds (Scheme 1). RN~m 0 i ii -iii II -0 Ar&HRCi ArSII H Reagents i LiNPr; cyclohexanone; ii base; iii Bu”Li Scheme 1 Methyl(trifluoromethy1)dioxiranehas been generated by oxidation of methyl trifluoromethyl ketone with potassium peroxymonosulphate (‘oxone’).’ It is stable enough to be isolated stored and characterized but is much more reactive than dimethyldioxirane in oxygen-transfer reactions such as the stereospecific conversion of cis-oct-2-ene into the cis-epoxide. ’ M. G. Bures and W. L. Jorgensen J. Org. Chem. 1988 53 2504. ’ H. Vorbriiggen and M.Maas Heterocycles 1988 27 2659. T. Sakamoto Y. Kondo and H. Yamanaka Heterocycles 1988 27 2225. S. M. Hussain and A. M. El-Reedy J. Heterocycl. Chem. 1988 25 9. E. F. V. Scriven and K. Turnbull Chem. Rev. 1988 88 297. T. Satoh T. Oohara and K. Yamakawa, Tetrahedron Lett. 1988 29 2851. ’ R. Mello M. Fiorentino 0. Sciacovelli and R. Curci J. Org. Chem. 1988 53 3890. 191 192 D. E. Ames Selective oxidation of aflatoxin Bl with dimethyldioxirane' has given the 8,9-epoxide (l) which is regarded as the ultimate carcinogenic species. It is sufficiently stable for manipulation and storage. An efficient preparation of 2,3-epithio-alcohols (2) is based on a titanium-catalysed reaction of the epoxide (3) with thiourea.' 00 R3eOH 0 R' S,S-Diphenylsulphilimine reacts with sulphones (4) to form aziridines (5).1° N-Alkoxyaziridines (6) can be obtained by intramolecular cycloaddition to an oxime C=N bond when the sodium salt (7) of a tosylhydrazone is heated (Scheme 2)." (7) (6) Reagents i NaH; ii A PhCl Yield 73% Scheme 2 Dialkylaminoazirines (8) react with trimethylsilyl isocyanate (or isothiocyanate) to give imidazolinones (9) (or the thione).I2 Phenylmethyldiazirine (10) forms a stable solid complex with P-cy~lodextrin.'~ Pyrolysis or irradiation of the complex gives isomers of 1,2-diphenyl- 1 -methylcyclopropane.Selectivity in the formation of the trans-isomer (11) is ten times greater for the complex than for neat diazirine and this is attributed to generation of carbene inside the cyclodextrin.' S. W. Baertschi K. D. Raney M. P:Stone and T. M. Harris J. Am. Chem. SOC.,1988 110 7929. Y. Gao and K. B. Sharpless J. Org. Chem. 1988 53 4114. K. Buggle and B. Fullon J. Chem. Rex (S) 1988 49. I' G. B. Jones and C. J. Moody J. Chem. SOC.,Chem. Commun. 1988 1009. I* I. Handke E. Schaumann and R. Ketcham J. Org. Chem. 1988 53 5298. l3 C. J. Abelt and J. M. Pleier J. Org Chem.. 1988 53 2159. Heterocyclic Compounds Sulphonylimines ( 12) are efficiently oxidized to 2-sulphonyloxaziridines (13) by '~xone'.'~ These oxaziridines are useful selective aprotic oxidizing agents e.g. for epoxidation and for sulphide to sulphoxide reactions. 0 /\ RS02N=CHAr RS02N-CHAr (12) (13) Phosphirenes (14) have been obtained by a cycloaddition reaction of iminophos-phorane and a1k~ne.I~ The phosphatricyclo[2.1 .0.02*5]pentane ring system (1 5) has been formed by phosphaalkyne dimerization with carbon monoxide incorporation in the presence of a titanium catalyst.I6 R NAr 0 RP=NAr+ PhCECPh + \p&APh -Ph Bu'C + -P co CP*Ti(CO) ,,.&But P-P (14) (15) 3 Four-membered Rings The oxetane ( 16) is formed regiospecifically in boron trifluoride-catalysed ring opening-recyclization of epoxide (17).17 Among the cyclic peroxides (1,2-dioxetanes) prepared during the review year are the products (18; X = 0,S) obtained from 2,3-dimethyl-4,5-dihydrofuran(19; X = 0) and the corresponding thiophene." OCH2Ph OAc OAc I sensitizer 0 Me (19) (18) l4 F.A. Davis S.Chattopadhyay J. C. Towson S. Lal and T. Reddy J. Org. Chem. 1988 53 2087. Is E. Niecke and M. Lysek Tetrahedron Lett. 1988 29 605. A. R. Barron A. H. Cowley S. W. Hall and C. M. Nunn Angew. Chem. Int. Ed. En& 1988 27 837. '' S. Hatakeyama K. Sakurai H. Numata N. Ochi and S. Takano J. Am. Chem. SOC.,1988 110 5201. W. Adam A. G. Griesbeck K. Gollnick and K. Kutzen-Mies J. Org. Chem. 1988 53 1492. 194 D. E. Ames R2 Me R2 LIAIH t-- :j-fRYe KOBu (23) Scheme 3 P-Chloroimines (20) can be converted into azetidines (21) cyanoazetidines (22) and 1 -aryl-2-methyleneazetidines (23) (see Scheme 3).19 Reactions of the kinetically stabilized tri-t-butylazete (24) have been studied." Sterically non-demanding cycloaddition reagents attack at C2-C3 whereas reagents with bulky groups attack at Nl-C4 (see Scheme 4).B u' Bu' Buir302Me 4rTf' MeO2CC=CCO,Me b (1.4-addition) B u' B u' C02Me Bu' (24) Scheme 4 Li$e __+ R4 HO ClCHZ Roe 3-Hydroxyselenetanes (25) have been prepared2' from chloromethyloxiranes (26). The parent compound (25; R = H) could not be oxidized to 3-oxoselenetane which is presumably too unstable to be isolated. Insertion of a phosphorus electrophile into cyclopropanes provides an efficient synthesis of phosphetanes (Scheme 5).22 19 (a) P. Sulrnon N. de Kimpe N. Scharnp B. Tinant and J.-P. Declerq Tetrahedron 1988 44 3653; (b) P. Sulrnon N. de Kimpe and N. Scharnp J. Org. Chem. 1988 53 4462. U. J. Vogelbacher M. Ledermann T.Schach G. Michels U. Hees and M. Regitz Angew. Chem. Inr. 20 Ed. Engl, 1988 27 272. 2' G. Polson and D. C. Dittrner J. Org. Chem. 1988 53 791. 22 S. A. Weissman and S. G. Baxter Tetrahedron Lett. 1988 29 1219. Heterocyclic Compounds Both 3- and 4-alkylidene- 1,2-0xasiletanes can be obtained regiospecifically from alkylidenesilacyclopropanesby oxygen-insertion reactions (Scheme 6).23The prod- ucts are thermally stable and do not undergo retro [2 + 21 reactions. 0- Ar3i-O M~~+c,H, Butfl!'z Ph,SO 0-SiArz Bu'P-/ Scheme 6 p-Lactams.-Intense activity continues in this very specialized field and a short section such as this can only attempt to indicate some reactions of general interest. Nickel carbonyl has been used24 for a one-pot conversion of an aziridine into a p-lactam by carbonyl insertion (Scheme 7).Reactions of organometallic carbene complexes (27) with methyl isocyanide and an aminoalkyne lead to an azetidinone (Scheme 8).25 Me Me H I-NI CO Ni(CO) 0BIHzPh CH2Ph Scheme 7 MeNC (CO),M=C(OEt)Ph -(CO),M[MeN=C=C(OEt)Ph] (27) M = Co or W 1MeCrCNEt Scheme 8 A review26 of applications of organometallic reagents in p-lactam chemistry concentrates on the construction and ring system rearrangements of p-lactams. An efficient diastereoselective conversion (Scheme 9) of methyl 3( S)-hydroxy- butanoate into (3S,4S)-3-[(1S)-1-hydroxyethyl]-4-benzoylazetidin-2-one has been de~cribed.~' It is based on the addition of ketene (28) to an imine of phenylglyoxal to give (29) as the major product.Desilylation is then accompanied by epimerization at C4 to give the truns-3,4-disubstituted P-lactam (30). 23 H. Saso H. Yoshida and W. Ando Tetrahedron Lett. 1988 29 4747. 24 W. Chamchaang and A. R. Pinhas J. Chem. Soc. Chem. Comrnun. 1988 710. 25 R. Aumann E. Kuckert C. Kruger R. Goddard and K. Angermund Chem. Eer. 1988 121 1475. 26 A. G. M. Barrett and M. A. Sturgess Tetrahedron 1988 44,5615. '' D. M. Tschaen L. M. Fuentes J. E. Lynch W. L. Laswell R. P. Volante and I. Shinkai Tetrahedron Lett. 1988 29 2779. 196 D. E. Ames /1 + several EtNPri C02Me steps COCl C ArN=CHCOPh I HO OSiPrl 'HH 'HH *COPh BU,6F-/\F_S-COPh -&-NAr &NAr 0 0 Scheme 9 A highly stereoselective preparation of carbapenem intermediates (3 1) has been reported.28 (3S,4R)-4-Acetoxy-3-[ (1R)-1-t-butyldimethylsilyloxyethyl]azetidin-2-one (32) and 0-silyl enol ethers of thiopropanoate esters (33) undergo a Lewis-acid- mediated reaction in which the acetoxy-group is displaced by the propanoate unit to give the thioester (31).M = Bu'SiMe A palladium( 11) catalyst induces nucleophilic ring closure of an allene unit on to an azetidinone nitrogen in a synthesis29 of 2-functionalized carbapenems (Scheme 10). M = Bu'SiMe Scheme 10 The use of tributyltin hydride with a,a'-azobisisobutanonitrile (AIBN) has been widely applied during the year to effect radical cyclization processes in heterocyclic synthesis. 1,6-Bond couplings of this type provide routes to carbacepham and carbacephem systems (Scheme 1 l).30 28 A.Martel J.-P. Daris C. Bachand J. Corbeil and M. Menard Can. J. Chem. 1988 66 1537. 29 J. S. Prasad and L. S. Liebekind Tetrahedron Lett. 1988 29 257. 30 T. Kametani S. Chu A. Itoh S. Maeda and T. Honda J. Org. Chem. 1988 53 2683. 197 Heterocyclic Compounds SPh R I oev C02Me 0 C02Me C02Me Reagents i CH,=CHCH,Br base; ii Bu3SnH AIBN Scheme 11 3-Substituted cephems (34; R = alkenyl) have been obtained efficiently3' by coupling 3-triflyloxycephems with alkenyltributylstannanes in the presence of a palladium catalyst. The process is also of interest for introducing tri-(2-furyl)phos- phine as the ligand. PhCH2CONH R~CONHH H xx 0 0 R3 COzCHPhz C02R4 (34) (35) Cephalosporins (35; R' = H) can be converted into the 2-methoxy derivatives (35; R' = OMe) by electrolysis with tetraethylammonium tosylate in methanol- tetrahydrofuran or by oxidation with ceric ammonium nitrate in the same ~oIvents.~* 4 Five-membered Rings A shows that furans pyrroles and indoles can act as dienophiles in Diels- Alder reactions provided that there are electron-withdrawing groups in the &position and also as N-substituents in the nitrogen-compounds.For example 3-acetyl-l- benzenesulphonylpyrrole and isoprene give a 1 1 mixture of isomeric adducts in 51% yield (Scheme 12). PhS02 PhSOz PhSOz Scheme 12 A stereoselective synthesis of substituted tetrahydrofuran-2,5-dicarboxylateesters has been developed34 (Scheme 13) as part of a synthesis of the diacid unit of the pyrrolizidine alkaloid jacobine.An w-allenic p-keto-ester can be cyclized (Scheme 14) by the combined catalytic actions of a Lewis acid and a Brgjnsted acid3' to form 3' (a)V. Farina S. R. Baker and C. Sapino Terruhedron Leu. 1988 29,6043; (b) V. Farina S. R. Baker D. A. Benigni and C. Sapino ibid. p. 5739. 32 G. Pattenden A. Stapleton D. C. Humber and S. M. Roberts J. Chem. Soc. Perkin Trans. 1 1988,1685. 33 E. Wenkert P. D. R. Moeller and S. R. Piettre J. Am. Chem. SOC.,1988 110 7188. 34 L. L. KIein and M. S. Shanklin J. Org. Chem. 1988 53 5202.. 35 T. Delair A. Doutheau and J. Gore Bull. SOC.Chim. Fr. 1988. 125. 198 D. E. Ames c1 Me02C C02Me c1 c1 I iii C02Me Reagents i A; ii 0,-MeOH; iii Raney Ni Scheme 13 Scheme 14 a reduced furan with an enol-ether structure.3-Acyl- and 3-alkoxycarbonylfurans can be prepared by cerium( iv) ammonium nitrate-promoted addition of 1,3-dicar- bony1 compounds to vinyl acetate (Scheme 15).36 Condensation of enolate dianions with cyclohexadiene cobalt(tricarbony1) tetrafluoroborate (Scheme 16) gives fused- ring dihydr~furans.~' The chemistry of isobenzofurans has been reviewed38 and cycloaddition routes to fused heterocycles have been For example in Scheme 17 the 1,2,4- triazine ring acts as the diene component in an internal Diels-Alder reaction with the acetylene unit. Loss of nitrogen gives a fused-ring system with the trimethylsilyl group available for methathesis.Scheme 15 + -0$OR Q M' M2 = Li Na or SiMe (CO)&o+BF; Scheme 16 36 E. Baciocchi and R. Ruzziconi Synth. Commun. 1988 18 1841. 37 L. S. Barinelli and K. M. Nicholas J. Org. Chem. 1988 53 2114. 38 R. Rodrigo Tetrahedron 1988 44 2093. 39 E. C. Taylor Bull. SOC.Chim. Belg. 1988 97 599. Heterocyclic Compounds %Me3 5ime3 -RA-0 y-tJ-l=-J R NO Scheme 17 Radical cyclization processes using tributyltin hydride mentioned above have been particularly useful in syntheses of hydrofuran ring systems as shown in Schemes 1840and 19.4' An aryl radical generated by the tin reagent initiates a tandem radical cyclization process (Scheme 20) to convert the aromatic ether (36) into a furano- phenanthrene (37).42 OCH,(CH,),CH,SePh Bu,SnH ___+ 0 Scheme 18 Scheme 19 (37) Scheme 20 Furano[3,4-b]furans having a new diheteropentalene system have been pre- pared43 by thermal isomerization of an oxirane-alkyne system (38).Like related fused furans the products (39) show high reactivity in Diels-Alder additions across the diene unit in ring B. 40 D. S. Middleton and N. S. Simpkins Tetrahedron Left. 1988 29 1315. 41 A. Gopalsamy and K. K. Subramanian J. Chem. SOC.,Chem. Commwn. 1988 28. 42 K. A. Parker D. M. Spero and J. Van Epp J. Org. Chem. 1988 53 4628. 43 W. Eberbach H. Fritz and N. Laber Angew. Chem. Inf. Ed. Engl. 1988 27 568. 200 D. E. Ames An enantioselective synthesis of (+)-biotin in twelve steps from L-cystine dimethyl ester has been reported.44 The sterically overcrowded 3,4-di-t-butylthiophene (40) has been prepared45 by internal reductive coupling of diketone (41).X-Ray analysis showed the diol intermediate to be the cis-isorner (42). Thiophene (40) can be nitrated and halogen- ated but with aluminium chloride it rearranges to the 2,4-di-t-butyl-isomer. OH OH Iodine-induced cyclization of ?,&unsaturated secondary thioamides (43)46 pro- ceeds regio- and chemoselectively to form imine salt (44). Dehydroiodination and acetylation then complete a general route (Scheme 21) to alkyl-substituted 2- acetamidothiophenes (45). ,R2 ,R2 R5& NHR’ i R4 R3 S (43) (44) (45) Reagents i I ;ii DBU (=1,8-diazabicyclo[ 5,4,0]undec-7-ene); iii MeCOCI DBU Scheme 21 2,3-Dimethylenethiophene(46) has been generated as a transient species (Scheme 22) which can be trapped to form a ben~othiophene.~’ Michael addition of 2- mercaptothiophene to a$-unsaturated acids (rather than the esters) gives acid (47) (Scheme 23).Cyclization of the acid chloride provides an efficient synthesis of thieno[ 2,341 thiopyrans (48) .48 44 E. J. Corey and M. M. Mehrotra Tetrahedron Left. 1988 29 57. 45 J. Nakayama S. Yamaoka and M. Hoshino Tetrahedron Lett. 1988 29 1161. 46 H. Takahata T. Suzuki M. Maruyama K. Moriyama M. Mozumi T. Takamatsu and T. Yamazaki Tetrahedron 1988 44,4777. 47 A. M. van Lensen and K. J. van den Berg Tetrahedron Lett. 1988 29 2689. 48 G. S. Ponticello M. B. Freedman C. N. Habecker M. K.Holloway J. S. Amato R. S. Conn and J. J. Baldwin J. Org. Chem. 1988 53 9. Heterocyclic Compounds (46) Reagents i F-; ii MeO2CCH=CHCO2Me Scheme 22 0 (47) Reagents i I ISH; ii (COCI),; iii SnCl, LJ Scheme 23 In a general synthesis of substituted pyrr~lidines:~ transmetallation of the stannyl- imine (49) with butyllithium is used to generate 2-azaallyl anions (50) which readily undergo cycloaddition with alkenes (Scheme 24). Pyrrolidine (51) is obtained in 62% yield as a 1 :1 mixture of isomers. The process can also be applied to effect stereospecific intramolecular condensation (Scheme 25). BuLi PhCH ICH Ph PrCH=NCH,SnR -flG-b Pr (49) (50) Scheme 24 BuLi+ & 'n N SnBu3 HH Scheme 25 The preparation of lactam acetals and their uses in heterocyclic synthesis have been re~iewed.~' Regio- and stereospecific cycloaddition of the imine (52) of an amino-ester to a dipolarophile has been rep~rted.~' The reaction which probably proceeds uia a 4Y W.H. Pearson D. P. Szura and W. G. Harter Tetrahedron Lett. 1988 29 761. so N. Anand and J. Singh Tetrahedron 1988 44 5975. 51 D. A. Barr R. Grigg H. Q. N. Gunaratne J. Kemp P. McMeekin and V. Sridharan Tetrahedron 1988 44 551. 202 D. E. Ames ,co,~t Et02C --<-ArCH= NCHRC0,Me Ar (52) (53) metallo-l,3-dipole is catalysed by silver acetate and triethylamine and yields pyr- rolidines (53). A promising approach to cyclic systems from open-chain diynes5’ has been used mainly for carbocycles but also for a pyrrole synthesis (Scheme 26).The diynylamine (54)is condensed with benzaldehyde in the presence of nickel(0) biscyclooctadiene and tricyclohexylphosphine to form nickel complex (55) and thence pyrrole (56) in 97% yield. Another synthesis of pyrrole~~~ is based on a [4+11 annelation reaction of 2,3-di(phenylsulphonyl)buta-l,3-dienewith primary amines (Scheme 27). Conju- gate addition and then 5-endo-trig cyclization of amine on to the adjacent vinyl COPh Et I Et I I 1 N Pr Pr (54) (55) Reagents i PhCHO Ni(cod) Scheme 26 pho2y-J SOzPh ii SOzPh [=jSOzPh --+ 4 N N N R R R SOzPh (57) (58) (59) Reagents i RNH,; ii NaOMe; iii DDQ Scheme 27 sulphone unit produces di(phenylsulphony1)pyrrolidine (57).Base-catalysed elimin- ation of benzenesulphinic acid to form pyrroline (58) is followed by dehydrogenation to pyrrole (59). The phenylsulphonyl group facilitates 2-lithiation so that reaction with electrophiles then leads to various 2-substituted pyrroles from which the phenylsulphonyl group can be removed. A synthesis of the red pigment pr~digiosin~~ introduces an elegant route to 2,2’-bipyrrolyls. A polymer-supported palladium catalyst is used to promote intramolecular dehydrogenative cyclization of the dipyrrolylimide (60). Removal of 52 T. Tsuda T. Kiyoi T. Mujane and T. Saegusa J. Am. Chem. Soc. 1988 110 8570. 53 A. Padwa and B. H. Norman Tetrahedron Lett. 1988 29 3041. s4 D. L. Boger and M. Patel J. Org. Chem. 1988 53 1405.Heterocyclic Compounds 203 the carbonyl group from cyclic imide (61) gives unsymmetrical 2,2’-bipyrrolyl (62) in high yield (Scheme 28). Two useful reviews have been published covering aspects of recent work on synthesis of substituted in dole^.^^ Tributyltin hydride has been used again for cyclization reactions in indoline syntheses (Scheme 29). Unsaturated amides (63) of alkylbromoaniline give indolines (64),56 whereas reaction in the presence of ethyl acrylate leads to ester (65).57 R R N -NH PCO2Me I pC02Me &C02Me I1 N\ \ 4 -co co Reagents i,@-Pd(OAc),; ii LiOMe Scheme 28 R2 R2 Ac Ac (65) Reagents i Bu3SnH AIBN; ii CH,=CHCO,Et Scheme 29 A tandem cyclization- hydride capture process provides a general approach to carbocyclic and heterocyclic syntheses.’* The method is illustrated by the conversion of acetylenic iodoamide (66) into 1-acetyl-3-methyleneindoline(67)by reaction with pyrrolidine and formic acid (hydride ion source) in the presence of palladium(I1) acetate and triphenylphosphine.55 (a) U. Pindur and R.Adam J. Hererocycl. Chem. 1988 25 1; (b) L. S. Hegedus Angew. Chem. Znr. Ed. Engl. 1988 27 1113. 56 J. P. Dittami and H. Ramanathan Tetrahedron Lerr. 1988 29 45. 57 H. Togo and 0. Kikuchi Tetrahedron Lett. 1988 29 4133. 58 B. Burns R. Grigg V.Sridharan and T. Worakun Tetrahedron Lett. 1988 29 4325. 204 D. E. Ames Ac (67) Palladium catalysis is also employed in both steps of a valuable new synthesis of 4-substituted indoles (Scheme 30)59from the 3-substituted 2-bromoaniline derivative (68).Condensation with tributylvinylstannane gives a rather unstable vinyl com- pound (69) which is cyclized directly by an oxidative process to 4-substituted-l- tosylindole (70). Yields range from 49 to 87% for C02Me OAc CH(OAc), OMe and Me groups as the 4-substituent. R R R Reagents i Bu3SnCH=CH2 (Ph,P),Pd; ii PdCI2( MeCN) ,LiCI benzoquinone Scheme 30 2-Vinylindole has been synthesized for the first time6’ by an intramolecular Wittig reaction of phosphonium salt (71). The vinylindole reacts with dienophiles; for example dimethyl acetylenedicarboxylate gives dihydrocarbazole (72) by [4 + 21 addition followed by [1,3]-H shift (Scheme 31). (71) Reagents i PhMe A; ii MeO,CC=CCO,Me Scheme 31 It has been shown6’ by n.m.r.and X-ray studies that chlorosulphonation of l-acetyl-5-bromoindoline occurs at the 6-position and not C7 as previously reported. 7-Aminosulphonyl-derivatives of indoline and indole have now been prepared61 from indoline with a C(0)NHS02CI unit attached to the ring nitrogen by an intramolecular suphonation. 59 M. E. Krolski A. F. Renaldo D. E. Rudisill and J. K. Stille J. Org. Chem. 1988 53 1170. U. Pindur and M. Eitel Helu. Chim. Acra 1988 71 1060. A. L. Borror E. Chinoporos M. P. Filosa S. R. Herchen C. P. Petersen and C. A. Stern J. 0%.Chem. 60 61 1988 53 2047. Heterocyclic Compounds Reduction of phthalimide with borane in tetrahydrofuran6* provides an improved synthesis of isoindoline (50% yield by a ‘one-pot’ process).Condensation of 2-ethylindole with methyl vinyl ketone in the presence of pal-ladium charcoal and molecular sieves63 yields 1,2-dimethylcarbazole (73) in 8 l ‘/o yield. It has been that lithiation of N-[(dialkylamino)methyl] carbazoles with t-butyllithium occurs exclusively at the protonated carbon adjacent to the ring nitrogen atom (74). Reactions with electrophiles give C-substitution products and removal of the N-protecting group then affords 1 -substituted carbazoles. R2 (73) (74) An ingenious synthesis of 1,8-diarnino~arbazole~~ has been developed (Scheme 32). The rather unstable product was isolated as its diacetyl derivative. A general chiral synthesis (Scheme 33) of bicyclic systems with a nitrogen atom at the ring junction has been reported.66 An o-chloroacyl unit is attached at N3 of an auxiliary 4-(S)-isopropyl-l,3-thiazolidine-2-thione as in (75; rn = 1 or 2).Reac- tion with tin( 11) trifluoromethylsulphonate gives complex (76) which is stereo- specifically condensed with a 2-acetoxy-lactam (77; n = 1 or 2) to form (78). Reagents i S4N4;ii Sn HCI H20; iii H3P04 Scheme 32 62 R. E. Gawley S. R. Chemburkar A. L. Smith and T. V. Anklekar J. Org. Chern. 1988 53 5381. J. Bergman and B. Pelcman Tetrahedron,1988 44 5215. 64 A. R. Katritzky G. W. Rewcastle and L. M. V. de Miguel J. Org. Chern. 1988 53 794. 65 K. Takahashi H. Eguchi S. Shiwaku T. Hatta E. Kyoya T. Yonemitsu S. Mataka and M. Tashiro J.Chem. SOC.,Perkin Trans. 1 1988 1869. 66 Y. Nagao W.-M. Dai M. Ochiai. S. Tsukagoshi and E. Fujita J. Am. Chern. SOC.,1988 110 289. 206 D. E. Ames Sn-OS02CF3 f c1 / U (79) (78) (77) iv v T Reagents i Sn(OS02CF,)2 base; ii LiAIH (small excess); iii (Bu,Sn), EtI hv;iv EtC0,Cs; v LiAIH Scheme 33 Cyclization and reduction with lithium aluminium hydride remove the auxiliary unit to give bicyclic system (79) in good yield. Each ring in (79) may be five- or six-membered. Alkaloid (-)-trachelamanthamidine (79; m = n = 1) has also been synthesized stereo~electively~~ by atom-transfer annulation of iodo-amide (80). The ratio of cis (81) to trans (82) isomers was 30 1. Caesium propanoate was used to displace iodine by propanoate in the mixed isomers and then lithium aluminium hydride reduction gave the alcohols.After chromatography cis-isomer (79; rn = n = 1) was obtained in 46% overall yield. A convergent biomimetically patterned synthesis of indolizidines6' is shown in Scheme 34. The bis-acetal (83) is hydrolysed at pH5.5 to the pyrrolinium salt (84) the aldehyde group of which condenses with a P-keto-ester and cyclizes to 67 R. S. Jolly and T. Livinghouse J. Am. Chem. Soc. 1988 110 7536. 68 G. W. Gribble F. L. Switzer and R. M. SOH,J. Org. Chem. 1988 53 3164. Heterocyclic Compounds OMe (86) Reagents i 1.4MHCI; ii PrCOCH,CO,CH,Ph; iii 8M HCI Scheme 34 indolizidine (85). In strongly acidic conditions elimination of water ester hydrolysis and decarboxylation occur to produce (*)-elaeokanine A (86) (56%).Tributyltin hydride is used in both steps of an efficient synthesis69 of benzo[f]in-dolizidin-1-ones (87) (Scheme 35). Reductive acylation of an isoquinoline gives iodo-amide (88) which is converted by a radical cyclization process into (87) (55% yield from the isoquinoline). 3,6-Di-t-butyl-l,4-diazapentalene (89) has been obtained by oxidation of the dihydro-derivative (90). It is only inductively stabilized. The spectra and MNDO calculations show that KekulC structure (89) dominates i.e. the bonds are fixed.” Reagents i I(CH,),COCI. Bu,SnH; ii Bu,SnH AIBN Scheme 35 NiOz @ hydroquinone BU‘ H But Scheme 36 69 R. Yamaguchi T. Hamasaki and K. Utimoto Chem. Lett. 1988 913.70 S. Tanaka K. Satake A. Kiyomine T. Kumagi and T. Mukai Angew. Chern. Inr. Ed. Engl. 1988 27 1061. 208 D. E. Ames A tetra-donor-substituted 2,5-diazapentalene has been synthesized (Scheme 37).71 The double bonds of (91) are delocalized even though the system contains eight welectrons (antiaromatic). A series of cross-conjugated mesomeric betaines have been prepared (Scheme 38)72 and their properties studied (dipole moments as well as n.m.r. and X-ray methods). Me2N Me2N 0 NMe2 EtO NMe2 (911 Reagents i NaH; ii Et,O+ BF4-Scheme 37 Reagents i O=C=C=C=O; ii CICOCPh=C=O (phenyl chlorocarbonyl ketene) Scheme 38 X- Me c0r2 R‘ H R2 Me02C C02Me Reagents i PhSiH, CsF; ii MeO2CC=CCO2Me Scheme 39 The [3 + 23 nitrone-olefin cycloaddition reaction to form isoxazolidines has been reviewed.73 Treatment of oxazolium salts (92) with phenylsilane and caesium fluoride gener- ates 4-oxazolines (93).74Ring-opening occurs spontaneously to form azomethine ylides (94) which form [2 + 31 cycloadducts e.g.(95) with dipolarophiles. Stereoselective contra-steric conversion of epoxides into cis-4,5-disubstituted oxazolidin-2-ones (96) has been achieved7’ by an ingenious use of 2-methoxynaphth-l-yl isocyanate (Scheme 40). The bulky naphthyl unit is subsequently removed by oxidation with cerium(rv) ammonium nitrate. At least 89% of the product is the ” F. Closs R. Gompper H. Noth and H.-U. Wagner Angew. Cheh. Int. Ed. Engl. 1988 27 842. 72 (a) K. T. Potts P. M. Murphy and W. R.Kuehnling J. Org. Chem. 1988 53 2889; (6) K. T. Potts P. M. Murphy M. R. De Luca and W. R. Kuehnling ibid. p. 2898. 73 P. N. Confalone and E. M. Huie Org. React. (N.Y.) 1988 36 1. 74 E. Vedejs and J. W. Grissom J. Am. Chem. SOC.,1988 110 3238. ’’ B. M. Trost and A. R. Sudhakar J. Am. Chem. SOC.,1988 ii0 7933. Heterocyclic Compounds 0-c0 0-c0 R I 2R1* ~ Ar +ii R1* H \ 'H RZ \ 'H R2 ' (96) Reagents i ArNCO Pd,(dba) P(OPr'),; ii (NH4),Ce(N03) Scheme 40 cis-isomer (96) whether the epoxide used is cis or trans and this is attributed to the rapid interconversion of two diastereoisomeric .rr-ally1 palladium complexes. Treatment of azlactones with o-aminobenzenethiol in acetic acid gives benzo- thiazoles efficiently (Scheme 41).76 The oximes of 2-acylthioanisoles are converted into benzisothiazoles (Scheme 42)77 by heating with acetic anhydride and pyridine.Scheme 41 Scheme 42 Chlorine dioxide a gaseous free radical that can easily be generated and stored has been used7' to effect oxidative cyclization of amino-alcohols via an iminium ion (Scheme 43). Another convenient synthesis of similar 0,N-heterocycles is based on the reaction of proline with an aldehyde in dimethyl ~ulphoxide.~~ The azomethine ylide generated undergoes a 1,3-dipolar cycloaddition to a second molecule of aldehyde to form a 1-oxapyrrolizidine (Scheme 44). n = lor2 Scheme 43 76 A. R. Katritzky K. Sakizadeh J. Swinson S. M. Heilmann L. R. Krepski and S. V. Pathre Synth. Commun. 1988 18 651. 77 D.M. McKinnon and K. R. Lee Can. J. Chem. 1988 66 1405. 78 C.-K. Chen A. G. Hortmann and M. R. Marzabadi J. Am. Chem. Soc. 1988 110 4829. 79 F. Orsini F. Pelizzoni M. Forte R. Destro and P. Gariboldi Tetrahedron 1988 44 519. 210 D. E. Ames ArCHO -co, -n -k" N (--Qcoi Arc HO 0CO.H II ArCH '. H I Arc H Ar Scheme 44 Work on rings with less common heteroatoms includes the preparation of a stable dihydro-1,3-diborofulvene80 as shown in Scheme 45. The organic chemistry of phospholes has been reviewed.81 Novel phosphorus- containing heterocycles (97),82 (98),83 and (99)84 have been synthesized. Compound (99) is a 10 .rr-electron planar heterocycle which exhibits stable 3pT-3p bonding between phosphorus and sulphur.An efficient synthesis of selenophenes (Scheme 46) is based on reductive coupling of diketones (100) to form cis-diols (101) which are dehydrated to give the aromatic R' R' I -I BC1 (Me,Sn),C=CMe 'X>C=CMe2 n2 =-I I R' R' Scheme 45 P\,-J C02Me I OH OH R1xooxR1 i_ R'Q-R2 Se R2 R2 Reagents i TiCI, Zn; ii TsOH A Scheme 46 80 V. Schafer H. Pritzkow and W. Siebert Angew. Chem. Int. Ed. Engl. 1988 27 299. 81 F. Mathey Chem. Rev. 1988 88 429. 82 N. Maigrot L. Ricard C. Charrier and F. Mathey Angew. Chem. Int. Ed. Engl 1988 27 950. 83 G. Markl S. Dietl M. L. Ziegler and 9. Nuber Tetrahedron Lett. 1988 29 5867. h4 N. Burford B. W. Royan A. Linden and T. S. Cameron. J. Chem. Soc. Chem. Commun. 1988 842. Heterocyclic Compounds 211 structures (102).s5 Thermal reactions of the sterically protected 1,2,3-~elenadiazole (103) with elemental sulphur and seleniums6 produce 1,2,3-trithiole (104) and 1,2,3-triselenole (105) structures respectively.5 Six-membered Rings The chromanochromanol acetate (106) the core structure of a rotenoid alcohol has been synthesized (Scheme 47).” The cis-arrangement of all three hydrogens at the contiguous chiral centres is obtained by an intramolecular 6-ex0 aryl radical addition. A synthesis of the elusive fungal metabolite patulin (107) has been achieved via Scheme 48.” Ketone (108; X = 0),from arabinose gave (108; X = CHC0,Me) by a Wittig reaction. Ketal cleavage and cyclization produced a mixture (109; R = H and CH,Ph) which was debenzylated.Dehydration of (109; R = H) then gave patulin (107). I 9% I I -Iq.lla i”p&J 0 / i,ii,iii 0 / + 0 / 0 0 0 Reagents i NaBH,; ii pyridinium chlorochromate; iii CH,=CMe(OAc); iv Bu3SnH AIBN Scheme 47 OR w 1 + -ko zPh Obo ~ HO Reagents i HCIO,; ii CF,CO,H Et3N Scheme 48 n5 J. Nakayama F. Murai and M. Hoshino Tetrahedron Lett. 1988 29 1399. 86 N. Tokitoh H. Ishizuka and W. Ando Chem. Lett. 1988 657. 87 S. A. Ahmad-Junan and D. A. Whiting J. Chem. SOC.,Chem. Commun. 1988 1160. an G. B. Gill G. Pattenden and A. Stapleton Tetrahedron Lett. 1988 29 2875. 212 D. E. Ames New syntheses of 2-pyranones have been reported and are summarized in Schemes 49,8950,’’ and 51.’l Interesting visible laser photochemical reactions of 4,4-dimethylpyran-2-one have been described.’* In the presence of benzoquinone oxetanes (110) and (111) are formed but in the presence of dioxygen the intermediate biradical (112) gives trioxanes (1 13) and (1 14).New syntheses of thiopyrans (Scheme 53)93 and benzothiopyrans (Scheme 54)94 have been reported. The sulphoxide (115) has been converted via (116) into (117) which has a new heterocyclic skeleton 2,6-epithi0-3-benzazocine.~~ Reagents i LiCH2C02Li; ii (CF,C0)20 Scheme 49 4 CO,H R’ R’ R’ R’ 0 Reagents i R2CH2N02 Et3N; ii NaBH,; iii HZSO, MeOH; iv Ac20 H+ Scheme 50 Reagents i C02 bis-( 1,5-cyclooctadiene)nickel(0) Scheme 51 89 R. K. Dieter and J. R. Fishpaugh J. Org.Chem. 1988 53,2031. 90 F.M.Hauser and V. M. Baghdanov J. Org. Chem. 1988 53,4676. 91 T.Tsuda S. Morikawa R.Sumiya and T. Saegusa J. Org. Chem. 1988 53,3140. 92 W. Adam U. Kliem T. Mosandl E.-M. Peters K. Peters and H. G. von Schnering 1. Org. Chem. 1988 53,4986. 93 K.R. Lawson B. P.McDonald 0. S. Mills R. W. Steele J. K. Sutherland T. J. Wear A. Brewster and P. R. Marsham J. Chem. SOC.,Perkin Trans. 1 1988 663. 94 A. Arnoldi and M. Carughi Synthesis 1988 155. 95 M. Hori T. Kataoka H. Shimizu E. Imai N. Iwata N. Kawamura and M. Kurono Heterocycles 1988 27 2091. Heterocyclic Compounds 213 (112) (113) (114) Reagents i hv (visible laser) benzoquinone; ii O2 Scheme 52 Scheme 53 NaOMe aR2 R1 Scheme 54 Scheme 55 There has been continued interest in directed metallation of pyridines as synthetic intermediates.1-Methylpyrid-4-one gives the 2-lithio-derivativeg6 while 2-methoxy- pyridineg7 and 2-fluoropyridine9* both give 3-lithio-compounds. These intermediates provide an attractive approach to functionalization of the pyridine ring. 96 P. Meghani and J. A. Joule J. Chem. SOC.,Perkin Trans. I 1988 1. 97 F. TrCcourt M. Mallet F. Marsais and G. Queguiner J. Org. Chem. 1988 53 1367. 98 L. Estel F. Marsais and G. QuCguiner J. Org. Chem. 1988 53 2740. 214 D. E. Ames A mixture of titanium( IV) and tin( 11) chlorides deoxygenates heteroaromatic N-oxides effi~iently.~~ Oxidation of N-alkylpiperidines and other cyclic tertiary amines with mer-cury( 11)-ethylenediamine tetracetic acid complex gives lactams.lOO For example 1-methyl-4-t-butylpiperidine gives the corresponding piperid-2-one in 90% yield.Thermal 6~-electrocyclic rearrangement of o-vinyl anils with air oxidation of dihydro-intermediates provides a synthesis of quinolines under non-acidic condi- tions (Scheme 56)."' R' R' R' Scheme 56 The skeleton of 1,2-~ecoergolinehas been constructed in eight steps starting from /?-naphthol."* The heterocycle-forming process is shown in Scheme 57. A Beckmann rearrangement of oxime (118) provides an improved ~ynthesis"~ of benzomorphan (I19). Steric factors preclude the usual formation of isoxazole from diketone monoxime. Me Me Me I I I fNCOCF3 rNCOCF3 rNCOCF3 CH2NO2 CHzNO2 Reagents i MeNO, base; ii CF3S03H Scheme 57 Reagents i Polyphosphoric acid A Scheme 58 99 L.Kaczmarek M. Malinowski and R. Balicki Bull. Soc. Chim. Belg. 1988 97 787. I00 E. Wenkert and E. C. Angell Synrh. Commun. 1988 18 1331. 101 L. G. Qiang and N. H. Baine J. Org. Chem. 1988 53,4218. 102 D. H. R. Barton A. Fekih and X. Lusinchi Bull. SOC.Chim. Fr. 1988 681. I03 C. W. Bird and K. Naidoo Svnth. Commun. 1988 18 1119. Heterocyclic Compounds Reduction of isoquinoline with sodium triethylborohydride gives the boron- activated enamine ( 120) which has been usedlo4 to prepare 4-substituted isoquino- lines (Scheme 59). In a palladium( 11)-silver fluoroborate-catalysed process,lo5 ben- zaldimines and alkynes are converted into isoquinolinium salts (Scheme 60).r 1 L _J Scheme 59 H I Reagents i PdCI, AgBF,; ii R2CzCR2 Scheme 60 A convenient synthesis of pyrido[ 3,4-g]isoquinoline has been effected by a novel ortho-metallation-dimerization reaction of N,N-diethylnicotinamide (Scheme 61).lo6 0 Reagents i LiNR2; ii HI; iii Pd/C A Scheme 61 A definitive monograph entitled 'Fused Pyrimidines Pteridines' has been pub- 1i~hed.l'~ Thionation of pyrimidine-2,4( 1 H,3 H)-dione derivatives with the Lawesson reagent is highly regioselective and occurs at the 4-po~ition.l~~ 5-Bromopyrimidines have been converted into the 5-lithio and 5-stannyl derivatives; palladium-mediated condensation with alkenylstannane then gives the 5-alkenylpyrimidine.'09 In another 104 D.E. Minter and M. A. Re J. Org. Chem. 1988 53 2653. 10s G. Wu S. J. Geib A. L. Rheingold and R. F. Heck J. Org. Chem. 1988 53 3238. 106 V. Bolitt C. Mioskowski S. P. Reddy and J. R. Falck Synthesis 1988 388. 107 D. Brown 'Fused Pyrimidines Pteridines' Wiley New York 1988. 108 K. Kaneko H. Katayama T. Wakabayashi and T. Kurnonaka Synthesis 1988 153. I09 J. Sandosham T. Benneche B. S. Mbller and K. Undheirn Acta Chem. Scand. Ser. B,1988 42 455. 216 D. E. Ames palladium-catalysed process"o an alkenylurea (121) is converted into a hydro- pyrimidone (122) by reaction with carbon monoxide and methanol in the presence of palladium( 11) and copper(I1) chlorides. VO2Me PhCH2NKNHMe 0 0 PhCH2NKNMe (121) (122) Reagents i CO MeOH WCI, CuCI Scheme 62 An annelation approach to the synthesis of fused-ring pyrimidines'" is based on electrocyclic ring closure of a conjugated heterocumulene (Scheme 63).Aroylpyrazines are conveniently prepared by a homolytic substitution process,' l2 as shown in Scheme 64. Ph Reagents i CS,; ii R'NCO Ph Scheme 63 HO2C N, Ho2cx) lNACoAr-QOA Reagents i ArCHO Bu'02H FeSO, H,SO,; ii. Cu A Scheme 64 Recent progress in quinoxaline chemistry has been reviewed113 and in a new synthesis of cinnoline~,"~ diazo-compound (123; X = N2) has been condensed with tributylphosphine to form iminophosphorane (123; X = N-N=PBu3) and thence cinnoline (124). Pyrrolo[ 1,2-b]cinnolines (125) have been prepared' l5 by fluoride ion displacement to close the central ring (Scheme 65).I10 Y. Tamaru M. Hojo H. Higashimura and Z. Yoshida J. Am. Chem. Soc. 1988 110 3994. Ill P. Molina A. Arques M. V. Vinader J. Becher and K. Brondum J. Org. Chem. 1988 53 4654. 112 G. Heinisch and G. Lotsch Synthesis 1988 119. 113 G.Sakata K. Makino and Y. Kurasawa Heterocycles 1988 27 2481. I14 T. Miyamoto and J.-I. Matsumoto Chem. Fharm. Bull. 1988 36 1321. I15 R. R. L. Hamer D. Sekerak R.C. Effland and J. T. Klein J. Heterocycl. Chem. 1988 25 991. Heterocyclic Compounds 0 0 N/ ' N' 1 R (125) Reagents i KOH H20;ii HCI H20 Scheme 65 Reaction of 2-alkylaminobenzonitrilewith chlorosulphonyl isocyanate provides an efficient one-pot synthesis of l-alkyl-4-amino-2( 1 H)-quinazolinone.1'6 Silylation of pteridines makes efficient hydrogenation of the pyrazine ring possible (Scheme 66)."' Yield 85% Reagents i H2-Pt; ii HCI H,O Scheme 66 Protection of the ring nitrogen as =NCO,Li during lithiation allows C1 metallation for the preparation of 1-substituted phenothiazines."* Phenothiazines and 1,4-benzothiazines are the subjects of a book."' 3,6-Dichloro-4-pyridazinecarbonyl chloride can be converted into a wide variety of condensed heterocycles (Scheme 67).I2O 6 Seven-membered Rings The synthesis of seven-membered-ring heterocycles via pericyclic reactions has been reviewed.121A stereoselective route to oxepanes by Lewis-acid-mediated condensa- tion of aldehydes with alkenols (Scheme 68) has been described.'** An enzymatic I16 A.V. N. Reddy A. Kamal and P. B. Saltur Synth. Commun. 1988 18 525. 117 P. H. Boyle and M. F. Kelly Tetrahedron 1988 44 5179. 118 A. R. Katritzky L. M. V. de Miguel and G. W. Rewcastle Synthesis 1988 215. 1 I9 R. R. Gupta 'Phenothiazines and 1,4-Benzothiazines' Elsevier Amsterdam 1388. 120 W. Ried and T. A. Eichorn Chem. Ber. 1988 121 2049. ''I K. Hassenruck and H. D. Martin Synfhesis 1988 569. I22 L. Coppi A. Ricci and M. Taddei J. Org. Chern. 1988 53 911. 218 D. E. Ames c1acl COCl c1 0 0 NHOH Reagents i NH3; ii 2-H2NC,H4C02Me; iii R-C / 'NH Scheme 67 Yield 51% Reagents i Me,CHCHO AIC13; ii H20 Scheme 68 Baeyer-Villiger ~xidation'~~ of cyclic ketones is highly enantioselective in producing seven- (as well as five- and six-) membered-ring lactones.A palladium-catalysed cy~lization'~~ of the tin complex of unsaturated trio1 derivative (126) gives both diastereoisomers of hydroxyoxepane ( 127) (Scheme 69). HOk OC02Me (26) HO Reagents; i Bu2SnO; ii (dba),Pd,CHCI Scheme 69 (127) 123 M. J. Taschner and D. J. Black J. Am. Chern. Soc. 1988 110 6892. 124 B. M. Trost and A. Tenaglia Tetrahedron Lett. 1988 29 2927. Heterocyclic Compounds Irradiation of dithiono-esters (128) involves cyclizati~n'~~ with loss of S2to form enol-ether (129) and thence ketone (130) a fused-ring oxepane. In another photolytic process'26 the 0-bridge compound (131) gives 8H-3-oxaheptalen-8-one (132) an oxepine condensed with tropone.Reagents i hv; ii Bu,N+ F- H20 Scheme 70 N-Substituted azepines have been obtained'27 by reductive condensation of adipaldehyde with primary amine using tetracarbonylhydridoferrate as selective reducing agent. Photolysis of 3,6-di-t-butyl-l-methoxycarbonylazepine (133)12* produces cyclo- butapyrrole (134) a 'Dewar azepine'. Hydrolysis and thermolysis lead to 3,6-di-t- butyl-3 H-azepine (135) (Scheme 71). Azepino[3,4,5-cd]indoles (136) have been ~btained"~ by intramolecular photocyclization of chloro-amide (137). u Bu' C02Me C02Me (133) (134) (135) Reagents; i hv; ii KOH; iii A Scheme 71 A remarkably stable 1O.n- aromatic system 1,3,5-2,4,6-trithiatriazepine is formed13' by action of sulphur nitride on dimethyl acetylenedicarboxylate.The product ester (138; R = CO,Me) on hydrolysis and decarboxylation gives the parent compound (138; R = H). 125 K. C. Nicolaou C.-K. Hwang and D. A. Nugiel Angew. Chem. Znt. Ed. Engl. 1988 27 1362. 126 T. Nakazawa M. Ishihara M. Jinguji M. Yamaguchi H. Yamochi and I. Murata Chem. Lerr. 1988 1647. 127 S. C. Shim C. H. Doh T. J. Kim and H. K. Lee J. Heterocycl Chem. 1988 25 1383. 128 K. Satake H. Saitoh M. Kimura and S. Morosawa J. Chem. Soc. Chem. Commun. 1988 1121. 129 S. E. Klohr and J. M. Cassady Synth. Commun. 1988 18 671. 130 P. J. Dunn J. L. Morris and C. W. Rees J. Chem. SOC.,Perkin Trans. I 1988 1745. 220 D. E. Ames 7 Larger Rings A flexible and efficient synthesis of 9- lo- and 1 1-membered-ring unsaturated macrolides has been de~eloped'~' and is illustrated by Scheme 72.An intramolecular Nozaki coupling reaction has been used'32 to prepare 4-epibrefeldin C (139) (Scheme 73). (+)-Brefeldin C the epimer at C4 is also formed as the minor product (4 1 ratio). . .. ... aCoEt I II 111 Reagents i LiSnBu3; ii CH,=CHCOEt; iii MeCHO; iv Pb(OAc) Scheme 72 Reagents i CrCI, Ni(acac) Scheme 73 New natural large-ring compounds reported during the year include two cytotoxic macrolide~'~~ and the first 20-membered-ring lac tone^,'^^ all isolated from marine sponges. In a Wittig reaction the phsophorane-ketene (140) yielded'35 20% of the 'dimer' (141) which was converted into (-)-pyrenophorin (142) (Scheme 74). 131 G.H. Posner K. S. Webb E. Asirvatham S. Jew and A. Degl'Innocenti J. Am. Chem. SOC.,1988,110 4754. 132 S. L. Schreiber and H. V. Meyers J. Am. Chem. Soc. 1988 110 5198. 133 D. G. Corley R. Herb R. E. Moore P. J. Scheuer and V. J. Paul J. Org. Chem. 1988 53 3644. 134 E. Quiiioi Y. Kakou and P. Crews J. Org. Chem. 1988 53 3642. I35 M. Yoshida N. Harada H. Nakamura and K. Kanematsu Tetrahedron Lett. 1988 29 6129. Heterocyclic Compounds 221 H ii iii 0 0 H (142) Reagents i DIBAH MeCu; ii m-CIC,H4C03H; iii Cr03 Scheme 74 Yield 36% Reagents i (BU~S~)~S, CsF 18-crown-6 MeCN Scheme 75 R' R' R2 R3 Reagents i R2C( N2)COR3 Rh(OAc) Scheme 76 Two interesting syntheses of sulphur-containing macrocycles are summarized in Schemes 75i36and 76.13' A reviewi3* of azadienes covers the synthesis of eight- (as well as five- and six-) membered rings.Rings with eight nine and ten members including nitrogen and two oxygens have been prepared (Scheme 77).'39 Meisenheimer rearrangement of N-oxides (143;n = 2) of 5-aryl-4-methyl-2,3,4,5-tetrahydro-l,4-benzoxazepines has given the 2H,6H-1,5,4-benzodioxazocine(144;n = 2).14* A nine-membered ring I36 R. Gleiter and S. Rittinger Tetrahedron Lett. 1988 29 4529. 137 0. Meth-Cohn and E. Vuorinen J. Chem. Soc. Chem. Commun. 1988 138. 138 J. Barluenga Bull. SOC.Chim. Belg. 1988 97 545. I39 K. E. Krakowiak B. Kotelko J. S. Bradshaw and N. K. Dalley X Heterocycl. Chem. 1988 25 1327. 140 J. B. Bremner E. J. Browne L.M. Engelhardt I. W. K. Gunawardana and A. H. White Aust. J. Chem. 1988 41 293. 222 D. E. Ames (CH,),,OH /(CHz),?,-o\ I -RIN R d CHR' \ \ / (C Hz) n0H (CH2)n-O m,n = 2or3 Reagents i R'CHO or BrCH,Br Scheme 77 system (n = 3) was prepared similarly. Another nine-membered ring structure pyrrolo[ 1,2-~][3,1,6]benzothiadiazanonine,has also been synthesized (Scheme 78).I4l In the very active host-guest chemistry and porphyrin areas it is only possible to draw attention to a few papers. Crown thioethers have been reviewed'42 and crown ether structures incorporating ~yran'~~ and indazole'44 units have been reported. 0 Reagents i Cu(CNS),; ii NaBH Scheme 78 The synthesis chemical reactivity and electrochemical behaviour of porphyrins with metal-carbon bonds have been reviewed.145 Tripyrrin macrocycles related to proposed intermediates in porphyrin biosynthesis have been ~ynthesized.'~~ Caesium fluoroxysulphate has been used14' to fluorinate the -CH= ring-linking groups of octaethylporphyrin.The main product is the 5-fluoro-derivative (-CF= link) but di- tri- and tetrafluoro-compounds are also formed. Much attention has 141 G. W. H. Cheeseman and G. Varvonnis J. Heferocycl. Chem. 1988 25 431. 142 S. R. Cooper Acc. Chem. Res. 1988 21 141. I43 P. J. Dijkstra H. J. den Hertog J. van Eerden S. Harkema and D. N. Reinhoudt J. Org. Chem. 1988 53,374. 144 J. C. Cuevas J. de Mendoza and P. Prados J. Org. Chem. 1988 53 2055. 145 R. Guilard and K. M. Kadish Chem.Rev. 1988 88 1121. 146 W. M. Stark M. G. Baker F. J. Leeper P. R. Raithby and A. R. Battersby J. Chem. SOC. Perkin Trans. I 1988 1187. 147 L. E. Andrews R. Bonnett A. N. Kozyrev and E. H. Appelman J. Chem. SOC. Perkin Trans. I 1988 1735. Heterocyclic Compounds 223 been given to bridged porphyrin systems both to study distortion of the macr~cycle'~~ and to influence the properties by forming cavities in structures with or two'50 porphyrin units. I 48 T. P. Wijesekera J. B. Paine and D. Dolphin J. Org. Chem. 1988 53 1345. 149 T. P. Wijesekera S. David J. B. Paine B. R. James and D. Dolphin Can. J. Chem. 1988 66 2063. 150 (a) C. A. Hunter M. N. Meah and J. K. M. Sanders J. Chem. Soc. Chem. Commun. 1988 692; (b) ibid.p. 694.

ISSN:0069-3030    

DOI:10.1039/OC9888500191

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

9 Organometallic Chemistry Part (i) The Transition Elements By S. G. DAVIES and I. M. DORDOR-HEDGECOCK The Dyson Perrins Laboratory University of Oxford South Parks Road Oxford OX1 3QY 1 Introduction The number of applications of organotransition-metal reactions to organic synthesis continues to increase. Of necessity therefore this report is restricted to new advances in the area rather than to new applications of previously reported methodology. A number of useful reviews have been published this year including organozir- conium compounds in organic synthesis,’ contributions to organonickel chemistry,2 enantioselective synthesis of organic compounds with optically active transition- metal catalysts in substoicheiometric q~antities,~ enantioselective synthesis with optically active transition-metal catalyst^,^ carbonylation catalysed by transition metal^,^ carbonylation of organic compounds catalysed by palladium complexes,6 the versatility of palladium compounds in organic chemistry,’ olefin synthesis via organometallic coupling reactions of enol triflates,* applications of organometallic reagents to p-lactam chemistry,’ reductions promoted by low-valent transition-metal complexes in organic synthesis,” and carbon dioxide as an alternative C1synthetic unit -activation by transition-metal complexes.” The selectivity imposed by a transition-metal template during organic synthetic transformations has led to the development of many synthetically useful reagents and reactions.Some of the more recent advances in the applications of stoicheiometric and catalytic reactions are described in the book entitled ‘Organometallic Chemistry and Organic Synthesis’ which records the proceedings of a Royal Society Discussion Meeting held in February 1988.12 ’ E.Negishi and T. Takahashi Synthesis 1988 1. G. Wilke Angew. Chem. Inr. Ed. Engl. 1988 27 186. H. Brunner Top. Stereochem. 1988 18 129. H. Brunner Synthesis 1988 645. I. Ojima Chem. Rev. 1988 88 1011. Y. U. Gulevich Russ. Chem. Rev. 1988 57 299. L. S. Hegedus Angew. Chem. In?. Ed. Engl 1988 27 1113. W. J. Scott and J. E. McMurray Acc. Chem. Res. 1988 21 47. A. G. M. Barrett and M. A. Sturgess Tetrahedron 1988 44 5615. J. M. Pons and M. Santelli Tetrahedron 1988 44 4295. I‘ A. Behr Angew. Chem. Int.Ed. Engl. 1988 27 661. I2 ‘Organometallic Chemistry and Organic Synthesis’ eds. S. G. Davies and M. L. H. Green The Royal Society London 1988. 225 S. G. Davies and I. M. Dordor-Hedgecock 2 Organometallics as Nucleophiles The stereoselective aldol reaction between the aluminium enolate derived from (R)-($-C5HS)Fe(CO)(PPh3)COMe (R)-(1) and Boc-L-prolinal (2) gives after deprotection and decomplexation (1S,8S)-1 -hydroxypyrrolizidin-3 -one (1S,8S)-(3) (Scheme l) whilst its epimer (1R,8S)-(3) is obtained in the same way from Boc 75% liv v (1S,8 S)-(3) 40% Reagents i BuLi; ii Et,AICI; iii Boc-L-prolinal (2); iv p-MeC,H,S03H; v Br Scheme 1 (S)-(l).13 In the former case the inherent stereocontrol of (2) is overpowered by the iron chiral auxiliary.The stereoselective aldol reaction between the aluminium enolate derived from (S)-(~5-CSH5)Fe(CO)(PPh,)COEt (S)-(4) and 4-pentenal formed the key step in the asymmetric synthesis of (2R,3S)-2-methyl-6-oxohepta-1,3-diacetate (S) which unambiguously established the absolute configuration of a marine cyclic peroxide (Scheme 2).14The final step in the synthesis of (5) involved the palladium-catalysed oxidation of the terminal double bond of (6) to a methyl ketone. The iron succinoyl complex (S)-(7)undergoes deprotonation a to the ester rather than a to the iron acyl; however the iron chiral auxiliary still controls the stereochemistry of the alkylation reaction with pentyl iodide to yield (S,R)-(8) (Scheme 3).15 Decomplexation of (8) in the presence of 0,N-dibenzylhydroxylamine gives the protected hydroxamic acid group directly.Coupling and deprotection gave (-)-actinonin in an overall yield of 41%. The very high stereocontrol observed in reactions at benzylic centres of arene chromium tricarbonyl complexes has been put to good effect by Uemura et all6 For example complexation of (9) directed by the hydroxy group predominantly to one face of the arene yielded (10) (Scheme 4). 1,3-Chirality transfer was achieved I3 R. P. Beckett and S. G. Davies J. Chem. Soc. Chem. Commun. 1988 160. 14 R. J. Capon J. K. MacLeod S. G. Davies G. L. Gravatt I. M. Dordor-Hedgecock and M. Whittaker Tetrahedron 1988 44 1637. 15 G. Bashiardes and S. G. Davies Tetrahedron Lett. 1988 29 6509. 16 M.Uemura T. Minami and Y. Hayashi Tetrahedron Lett. 1988 29 6271. Organometallic Chemistry -Part (i) The Transition Elements Reagents i BuLi; ii Et,AICI; iii CHO ; iv O, PdCI ,CuCI Scheme 2 (S)-(7) (S,R)-(8) 82% 1iii Y - 0 CH2PhI 1 + HO%NocH2ph I CsH11 C5Hll \OH 82% (S,S,R)-(-)-actinonin Reagents i BuLi; ii CSH,,I;iii Br, PhCH20N(CH2Ph)H Scheme 3 in the conversion of (10) into (1 1) via palladium catalysis. Stereoselective reduction directed by the proximate methoxy group gave (12) which was converted into (13). The retention of configuration in the substitution of the hydroxy group in (12) for the methyl group in (13) is due to the intermediacy of a chromium-stabilized configurationally stable benzylic carbonium ion.Decomplexation and further trans- formations gave (14) a side-chain precursor of a-tocopherol. The aminodeoxyhex-5-enopyranoside ( 15) is converted under palladium catalysis into the carbocycle (16) (Scheme 5).17 The reaction mechanism is unknown but ” S. Adam Tetrahedron Lett. 1988 29 6589. S. G. Davies and I. M. Dordor-Hedgecock b QH C~(CO) (9) (10) 78% 84% d.e. lii-iv &C H( C02Me)2 ii vi 1 I I I I wCH(C02Me)2 - - Me02C -. Reagents i (C,,H,)Cr(CO),; ii Ac20 py; iii NaCH(C02Me)2 [(C3HS)PdC1l2 dppe; iv Ph3CBF4;v NaBH4; vi Me3AI Scheme 4 0 (i) HP (ii) PdC1,,60"C AcNCHzPh AcNCHzPh (15) ( 16) 60-8O% Scheme 5 Organometallic Chemistry -Part (i) The Transition Elements presumably involves palladium-mediated deprotection of the acetal.The mild condi- tions make this potentially a very useful reaction. Allylic alcohols acetates and carbonates behave as synthetic equivalents of ally1 carbanions under the influence of catalytic amounts of PdC12( PhCN)2 and SnC12 reacting as nucleophiles with aldehydes.'8-20 The reactions presumably proceed through an intermediate allyltin species. 3 Organornetallics as Electrophiles Palladium-catalysed allylations of tetronic acid and triacetic acid lactone occur at carbon rather than at oxygen (Scheme 6).21 The enantioselective palladium-catalysed OH OH 83 Yo Scheme 6 cyclization of (17) in the presence of homochiral diphosphines gives the ergoline synthon (18) in up to 70% e.e. (Scheme 7).22The cyclization of carbamates derived Reagents Pd(dba), ( -)-chiraphos K2C0 Scheme 7 from but-2-ene- 1,4-diol to 4-vinyl-2-oxazolidones is catalysed by palladium (Scheme 8).23 In the presence of homochiral ferrocenyl diphosphines the product is formed in up to 73% e.e.An asymmetric synthesis of quaternary chiral centres is achieved in the palladium-catalysed allylation of the sodium enolates of P-diketones in the presence of homochiral ferrocenyl diphosphines (Scheme 9).24The hydroxy group on the ferrocenyl ligand is associated with the high enantioselectivities observed. '' Y. Masuyama R. Hayashi K. Otake and Y. Kurusu J. Chem. SOC. Chem. Commun. 1988 44. 19 Y. Masuyama K. Otake and Y. Kurusu Tetrahedron Lett. 1988 29 3563. 20 Y. Masuyama J.P. Takahara and Y. Kurusu J. Am. Chem. SOC. 1988 110 4473. 21 M. Moreno-Manas M. Prat J. Ribas and A. Virgili Tetrahedron Lett. 1988 29 581. 22 J. P. Genet and S. Grisoni Tetrahedron Lett. 1988 29 4543. 23 T. Hayashi A. Yamamoto and Y. Ito Tetrahedron Lett. 1988 29 99. 24 T. Hayashi K. Kanehira T. Hagihara and M. Kumada J. Org. Chem. 1988 53 113. S. G. Davies and I. M. Dordor-Hedgecock PhNHCOz 0 -OCONHPh PhN< 0 8O% 73% e.e. Reagents Pd2(dba),CHCI, PPhi Scheme 8 81% e.e. Reagents i NaH; ii [(C3H5)PdCI12 CH2=CHCH20Ac PPh2 Scheme 9 The double electrophilic character of diene cobalt tricarbonyl cations has been utilized in a novel synthesis of dihydrofurans from enolate dianion equivalents (Scheme Similar behaviour of diene molybdenum cations has also been observed although reactivation of the intermediate ally1 complex is necessary (Scheme 1 1).26 0 I cO+ BF; 76% (C0)3 0 I 0+ TMxs-co+ BF; H0 68% Scheme 10 25 L.S. Barinelli and K. M. Nicholas J. Org. Chem. 1988 53 2114. 26 A. J. Pearson and V. D. Khetani J. Org. Chem. 1988 53 3395. Organometallic Chemistry -Part (i) The Transition Elements 231 . COzH ii iii a* BF; H0 Reagents i MeCH=C(OLi)OTMS; ii NOPF, Et,N; ii air Scheme 11 The first examples of nucleophilic addition to iron tricarbonyl complexes of azadienes have been reported.*’ Nucleophilic attack occurs at a carbonyl ligand which after migration of the thus-formed acyl to the azadiene leads to pyrrole formation (Scheme 12).PhaNPh I 70% Reagents i Fe,(CO),; ii MeLi; iii Bu‘Br Scheme 12 The stereoselective addition of lithioiodomethane to the chiral crotonyl complex (19) results in the asymmetric synthesis of trans-cyclopropanecarboxylicacid deriva- tives (Scheme 13).28 ii iii H -0=t$ (19) 85% >98% d.e. Ph Reagents i CH212 MeLi; ii Br,; iii H2N< Scheme 13 1,CDichlorobenzene chromium tricarbonyl undergoes sequential substitution by phenoxide and methoxide leading to a potentially versatile synthesis of substituted diary1 ethers (Scheme 14).29Complexation of a protected 3-0-methyl oestradiol 27 T. N. Danks and S. E. Thomas Tetrahedron Lett. 1988 29 1425. 28 P. W. Ambler and S. G. Davies Tetrahedron Lett.1988 29 6983. 29 F. Hossner and M. Voyle J. Organomer. Chem. 1988 347 365. S. G. Davies and I. M. Dordor-Hedgecock c+3 .- i_ I Cr(C0)3 59O/o Reagents i NaOPh DMSO 20°C; ii NaOMe DMSO Scheme 14 OTBDMS@ -(i) (ii) LiCH,CNair \ OTBDMS Me0 Cr(CO)s CN 46% Scheme 15 Acid-promoted cyclization of the chromium tricarbonyl complex of derivative to chromium tricarbonyl promoted substitution of the 3-methoxy group (Scheme 15).30 9 N-(3,4-dimethoxybenzyl)ephedrine gave after decomplexation exclusively cis-2,3-dimethyl-4-phenyl-6,7-dimethoxytetrahydroisoquinoline via a double inver- sion mechanism (Scheme 16).31 (i) H+ -(ii) air Me0 Me0 75% Scheme 16 Two chiral Lewis acids have been reported for asymmetric additions to aldehydes.A chiral ferrocenyl diphosphine gold complex catalyses aldol and related reactions (Scheme 17).32-34Stereoselective reduction of ketones occurs after coordination to a chiral rhenium Lewis acid (Scheme 18).35 30 H. Kunzer and M. Thiel Tetrahedron Lett. 1988 29 1135. 31 S. J. Coote and S. G. Davies J. Chem. Soc. Chem. Commun. 1988 648. 32 Y. Ito M. Sawamura E. Shirakawa K. Hayashizaki and T. Hayashi Tetrahedron Lett. 1988 29 235. 33 Y. Ito M. Sawamura M. Kobayashi and T. Hayashi Tetrahedron Lett. 1988 29 6321. 34 Y. Ito M. Sawamura and T. Hayashi Tetrahedron Lett. 1988 29 239. 35 J. M. Fernandez K. Emmerson R. D. Larsen and J. A. Gladysz J. Chem. Soc. Chem. Commun. 1988 37. Organometallic Chemistry -Part (i) The Transition Elements jo2Me MeCHO + A 0vN CN 84% 96% e.e.96% 81% e.e. Reagents i (C6H,,NC)*AuBF4 PPhi PPh2 Scheme 17 0 .-'\ + pPh3 I,. II.. ?H 8' -' Re'. Me*Ph PF6-A0 'Tph 39% >99'/0 e.e. Me Reagents i (v5-C,H,)Re( NO)( PPh,)CHO; ii CF3C02H Scheme 18 4 Coupling and Cyclization Reactions The palladium-catalysed couplings of vinyltin derivatives with ally1 acetates36 and vinyl triflates3' have been applied to the synthesis of 3-substituted cephems (Scheme 19). The former reaction involves regioselective coupling at the y-position of an a$-unsaturated ester. The complementary approach involving coupling of a tin dienolate to an aryl bromide has also been described (Scheme 20).38 A solution to the problem of preparing 4-substituted indoles is provided by a series of palladium-catalysed reactions (Scheme 21).39 Vinylation of the triflate of 2-bromo-3-nitrophenol was chemoselective for replacement of the bromo substituent.Oxidative cyclization of the protected o-vinylaniline (20) to the indole was achieved with a palladium(r1) catalyst in the presence of p-benzoquinone as reoxidant. Coupling of the 4-indole triflate thus generated gave the 4-substituted indoles. 2,5-Dibromopyridine undergoes regioselective coupling reactions at the 2-position with terminal acetylenes and arylzinc derivatives (Scheme 22).40 A second coupling involving the remaining 5-bromo substituent can be achieved. 36 V. Farina S. R. Baker D. A. Benigni and C.Sapino Tetrahedron Lett. 1988 29 5739. 37 V. Farina S. R. Baker and C. Sapino Tetrahedron Lett. 1988 29 6043. 38 Y. Yamamoto S. Hatsuya and J. Yamada J. Chem SOC.,Chem. Commun. 1988 86. 39 M. E. Krolski A. F. Renaldo D. E. Rudisill and J. K. Stille J. Org. Chem. 1988 53 1170. 40 J. W. Tilley and S. Zawoiski J. Org. Chem. 1988 53 386. S. G. Davies and I. M. Dordor-Hedgecock The Wenkert reaction for the stereoselective synthesis of trisubstituted alkenes via the nickel-catalysed coupling of non-reducing Grignards to dihydrofurans has been extended to dihydropyrans (Scheme 23).41These coupling reactions have been applied to the synthesis of zoapatano14’ and a fragment of premonensin B.43 The coupling of homoenolate equivalents with aryl triflates has also been described (Scheme 24).44 A large number of transformations related to the Heck reaction involving the coupling of an aryl iodide with an alkene or acetylene have been described.Bromo- and iodopyrimidines have been used as s~bstrates.~~ A modification of the reaction conditions allows chloroarenes to be used.46 Very good yields under very mild reaction conditions are obtained with cyclic alkene~.~’ Intramolecular versions have I C02CHPh2 I COzCHPhz 82% 0 0 ph4H I,. 11 .. 0DL COzCHPhz C02CHPhz 79‘/o Reagents i Pd(dba), op; ii fiSnBu3 Scheme 19 Br Pco2, POzEt \ SnBu3 0 60% Scheme 20 41 P. Kocienski N. J. Dixon and S. Wadman Tetrahedron Lett. 1988 29 2353. 42 P.Kocienski C. Love R. Whitby and D. A. Roberts Tetrahedron Lett. 1988 29 2867. 43 P. Kocienski S. Wadman and K. Cooper Tetrahedron Lett. 1988 29 2357. 44 S. Aoki T. Fujimura E. Nakamura and I. Kuwajima J. Am. Chem. Soc. 1988 110 3296. 4s A. Wada H. Yasuda and S. Kanatomo Synthesis 1988 771. 46 J. J. Bozell and C. E. Vogt J. Am. Chem. Soc. 1988 110 2655. 47 R. C. Larock and B. E. Baker Tetrahedron Lerr. 1988 29 905. 235 Organometallic Chemistry -Part (i) The Transition Elements OTf OTf OTf &J I I 91O/O Tos Tos (20) 52% 88% 1. 6 \ I Tos 8 8O/o Reagents i Bu3SnA Pd(PPh3)4;ii Fe AcOH; iii TosCI Py; iv (MeCN),PdCI, 3; I -COzEt v Bu,Sn Pd(PPh314 0 9 Scheme 21 . .. flBr ii iii OH N TMs *MS.74% 86Yo Reagents i Me,SiCzCH; ii (Ph3P),PdCl, CuI Et,N; iii HC=CCH,CH(OH)Me Scheme 22 MeMgBr ( Ph3P),NiCI HO 85% Scheme 23 ,% 85 Yo Scheme 24 S. G. Davies and I. M. Dordor-Hedgecock produced benzof~rans~~ and indole The benzylation of the appropri- ate dienolates generates cyclohexenone derivatives which cyclize under the influence of Pdo (Scheme 25).5’ 71% Scheme 25 The palladium-catalysed coupling of a vinyl bromide with an enone has been used in a short synthesis of 15-dehydroprostaglandin B methyl ester (Scheme 26).’* Treatment of the diazoacetoacetamide derivative (21) with rhodium acetate results in the clean formation of a p-lactam (Scheme 27).53The efficiency of this C-H I 80% Reagent (Ph3P),Pd(OAc) Scheme 26 4n R.C. Larock and D. E. Stinn Tetrahedron Lett. 1988 29 4687. 49 B. Burns R. Grigg V. Sridharan and T. Worakun Tetrahedron Lett. 1988 29 4325. 50 B. Burns R. Grigg P. Ratananukul V. Sridharan P. Stevenson S. Sukirthalingam and T. Worakun Tetrahedron Lett. 1988 29 5565. ” Y. Zhang B. O’Connor and E. Negishi J. Org. Chem. 1988 53 5588. ’* H. Naora T. Ohnuki and A. Nakamura Chem. Lett. 1988 143. 53 M. P. Doyle M. S. Shanklin S.-M. Oon H. Q. Pho F. R. van der Heide and W. R. Veal J. Org. Chem. 1988 53 3384. Organometallic Chemistry -Part (i) The Transition Elements bond insertion reaction has been explained in terms of a locked conformation which places the carbenoid in close proximity to the C-H bond.5 Carbonylation Reactions The conversion of phenols into aryl ketones can be achieved by carbonylation of the corresponding triflate in the presence of alkyltin derivative^.^^ Thus the phenolic group can be used to direct electrophilic substitution and subsequently converted into a ketone. P-Lactams are formed from carbonylation of aziridines with nickel tetracarbonyl.” The carbon monoxide inserts into the less substituted C-N bond. In the presence of palladium acetate with 1,3-bis(diphenylpho~phino)propane allylamines can be carbonylated in good yield to @,y-unsaturated amide~.’~ In the presence of alcohols P,y-unsaturated esters are formed. Double carbonylation of the ally1 chloride (22) occurred with concomitant carbocyclization (Scheme 28) .57 (22) 90% Reagents CO Et,N MeOH (Ph,P),PdCI Scheme 28 A new route to polycyclic cyclopentenones involves the coupling of enynes with isontriles in the presence of Nio (Scheme 29).58 The stoicheiometric decarbonylation of aldehydes by chlorotris(tripheny1phos-phine)rhodium is well known.The decarbonylation of unprotected aldol sugars to the next lower alditol has now been demonstrated for example in the conversion of glucose to arabinitol in 88% yield.59 54 A. M. E. Echavarren and J. K.Stille J. Am. Chem. SOC.,1988 110 1557. 55 W. Charnchaang and A. R. Pinhas J. Chem. SOC., Chem. Commun. 1988 710. 56 S. I. Murahashi Y. Irnada and K. Nishirnura J. Chem. Soc. Chem. Commun. 1988 1578. 57 E.-I. Negishi G. Wu and J. M. Tour Tetrahedron Lett.1988 29 6745. 58 K. Tamao K. Kobayashi and Y. Ito J. Am. Chem. SOC.,1988 110 1286. 59 M. A. Andrews and S. A. Klaeren J. Chem. SOC.,Chem. Commun. 1988 1266. 238 S. G. Davies and I. M. Dordor-Hedgecock H H 92yo Reagents i Ni(cod),; ii H30+ Scheme 29 6 Oxidation and Reduction The asymmetric synthesis of phenyl alkyl sulphoxides via the non-destructive mediation of an iron chiral auxiliary has been described.60 Noyori’s ruthenium BINAP system for asymmetric hydrogenation continues to become more widely applicable. Very good stereocontrol is observed when there is an additional coordination site such as a heteroatom in the substrate. Thus the diastereoselective hydrogenation of N-protected y-amino P-keto esters provides an entry into the statine series (Scheme 30).61 Ketones with an a-heteroatom also undergo highly enantioselective reductions.62 For example the asymmetric hydro- genation of an a-chloro ketone (Scheme 30) was the key step in an asymmetric synthesis of (R)-~arnitine.~~ 1,3-Diols are formed with high diastereo- and enan- tioselectivities in the asymmetric reduction of P-diketones (Scheme 30).64 NHBoc NHBOC 99yo 97%,97% e.e.99%’ >99% e.e. Reagents i [(R)-binaplRuBr, H2;ii [(S)-binap]Ru(OAc), H,; iii [(R)-binap],Ru,Cl, H Scheme 30 60 S. G. Davies and G. L. Gravatt J. Chem. Soc. Chem. Commun. 1988 780. 61 T. Nishi M. Kitamura T. Ohkuma and R. Noyori Tetrahedron Lett. 1988 29 6327. 62 M. Kitamura T. Ohkuma S. Inoue N. Sayo H.Kumobayashi S. Akutagawa T. Ohta H. Takaya and R. Noyori J. Am. Chem. Soc. 1988 110 629. 63 M. Kitamura T. Ohkuma T. Takaya and R. Noyori Tetrahedron Lett. 1988 29 1555. 64 H. Kawano Y. Ishii M. Saburi and Y. Uchida J. Chem. Soc. Chem. Cornmun. 1988 87. Organometallic Chemistry -Part (i) The Transition Elements The asymmetric catalytic hydrogenation of P-disubstituted a-phenylacrylic acids gives carboxylic acids with two adjacent chiral centre centres in high e.e. using a rhodium catalyst in the presence of a homochiral ferrocenyl diphosphine ligand.65 The asymmetric hydrogenation of benzylamine-derived imines is improved (up to 91% e.e.) by adding iodide to the catalyst system ([Rh(nbd)Cl], (R)-Cycphos H2}.66 Chiral nitroalkanes are reduced to the corresponding amines without racemization by transfer hydrogenation using ammonium formate in the presence of palladium on ~arbon.~' The methyl dicarbonylates from 2-ene- 1,4-diols are reduced catalytically to dienes by Pd' the methanol liberated acting as the reducing agent.68 7 Miscellaneous Reactions [2 + 2 + 21 Cycloadditions of diynes with carbon dioxide69 and aldehydes7* under nickel catalysis produce a-pyrones and a-pyrans respectively (Scheme 3 1).Et Et Reagents i Ni(cod)2 ZPCyc,; ii CO,; iii Pr"CH0 Scheme 31 Two methods for the stereoselective rearrangement of a-ynones to (E,E)-2,4-dienones in high yield using ruthenium7' or palladi~rn'~ catalysts have been described (Scheme 32). Compound (23) prepared via a palladium-catalysed alkylation reac- 0 0 90% Scheme 32 65 T.Hayashi N. Kawamura and Y. Ito Tetrahedron Lett. 1988 29 5969. 66 G.-J. Kang W. R. Cullen M. D. Fryzuk,B. R. James and J. P. Kutney J. Chem. Soc. Chem Cornrnun. 1988 1466. 67 A. G. M. Barrett and C. D. Spilling Tetrahedron Lett. 1988 29 5733. B. Trost and G. B. Tometzki J. Org. Chem. 1988 53 915. 69 T. Tsuda S. Morikawa R.Sumiya and T. Saegusa J. Org. Chem. 1988 53 3140. 70 T. Tsuda T. Kiyoi T. Miyane and T. Saegusa J. Am. Chem. Soc. 1988 110 8570. 71 D. Ma Y. Lin X.Lu and Y. Yu Tetrahedron Lett. 1988 29 1045. 72 B. M. Trost and T. Schmidt J. Am. Chem. Soc. 1988 110 2301. S. G. Davies and I. M. Dordor-Hedgecock tion undergoes stereoselective palladium-catalysed rearrangement to form (24) the thermodynamically less stable cis-fused diastereoisomer (Scheme 33).73 _3 PhSOa SOaPh PhSO2 (23) 49% (24) 56% Reagents i Pdz(dba),-CHCl3 PPh3; ii 0;iii Ac20 Py;iv AcOH Scheme 33 B.M.Trost and J. I. Luengo J. Am. Chem. SOC.,1988 110 8239.

ISSN:0069-3030    

DOI:10.1039/OC9888500225

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

9 0rga nometa IIic Chemistry Part (ii) Main-Group Elements By P. D. LlCKlSS Department of Chemistry and Applied Chemistry University of Salford Salford M5 4WT This year this section covers all of the main-group metals and is therefore somewhat longer than last year. Despite this increase in length the continuing great interest in the preparation of novel main-group organometallic compounds particularly as species of potential use as precursors to new materials has meant that much of interest has been omitted. This report concentrates mainly on novel structural features and new or potentially useful reactions. 1 Group I Reviews on the structure and reactivity of lithium enolates' and the mechanistic aspects of the lithium-halogen exchange reaction have been published, as has a book 'Organolithium Methods' by B.J. Wakefield (Academic Press London 1988) giving practical details and information on a wide variety of organolithium reagents. A detailed theoretical study of methyllithium oligomers (MeLi), n = 1-4 has been carried The H3C-Li bond dissociation energy is calculated to be 11.1 f 0.6 kJ mol-' and the rotation barrier of the Me group in (MeLi) is about 0.24 kJ mol-'. The use of CH2LiC1 has been limited by its thermal instability but ultrasonic irradiation has led to its generation at -15 "C from CH,BrCl and lithium. It reacts cleanly with carbonyl compounds to give chlorohydrins and epoxides. Thermolysis of monosubstituted lithium reagents e.g. Me3SiCHRLi provides a general synthesis of 1,l -dilithio compounds containing no p-hydrogens [e.g.Me3CCHLi2 and (Me,Si),CLi,] apparently via a bimolecular reaction involving lithium-R exchange to afford the dilithium reagent (Me3Si)CRLi and Me,SiCH,R (R = H or Me,Si).' The highly elusive LiCH2CH2Li has been prepared in low yield by condensing lithium into ethylene at -196 "C. The dilithium reagent was trapped using Me3SnC1 or C02.6 ' D. Seebach Angew. Chem. Int. Ed. Engl. 1988 27 1624. ' W. F. Bailey and J. J. Patricia J. Organornet. Chem. 1988 352 1. E. Kaufmann K. Raghavachari A. E. Reed and P. von R. Schleyer Organometallics 1988 7 1597. C. Einhorn C. Allavena and J.-L. Luche J. Chem. SOC.,Chem. Commun. 1988 333. ' H. Kawa B. C. Manley and R. J. Lagow Polyhedron 1988 7 2023. N. J. R. van Eikema Hommes F.Bickelhaupt and G. W. Klumpp Angew. Chem. Int. Ed. Engl. 1988 27 1083. 241 242 P. D. Lickiss Short Li...Li distances have been found in the solid state by X-ray crystallography and coupling between 'Li nuclei in solution has been detected by n.m.r. spectroscopy for the tetramer (0-LiC6H4CH2NLiCH2CH,NMe2)4 .' This work provides more conclusive evidence for what had previously been thought to be significant interac- tions in organolithium aggregates. Evidence for Li.. CH interactions in both solid and solution has been found in [(PhCH,),NLi] where the formal coordination number of Li is 2. This low coordination number appears to promote close interac- tions with aromatic C and C-H groups.8 The solid-state structure of ( 1) has been determined by X-ray crystallography and is shown to be polymeric with the TMEDA bridging between dimeric centrosym- metric subunits.In THF solution however the compound is monomeric with the lithium apparently not bound by the TMEDA but showing close contacts to the vicinal H and to the But group.' A detailed study of the reaction of Bu"LiTMEDA with phenylacetylene" confirms that both mono- and dilithium products are formed. Both MNDO calculations and 2D n.m.r. spectroscopic data indicate a short Li...H distance suggesting an 'agostic' interaction in the monolithium product. The second lithiation site is predicted to be at this agostic hydrogen and this was confirmed by the X-ray crystal structure of (2). A unique planar quinquedentate environment has been found for Li in (3; M = Li) by X-ray Crystallography." There are no close interactions between the cations the lithium in (3; M = Li) does not exchange with that in LiCl ill solution and it does not react with hot water.The analogues (3; M = Na K Rb or Cs) have also been prepared. The first monomeric diboryldilithiomethane (4)has been prepared and structurally characterized.I2 The compound has Li-C-Li and B-C-B angles of 120.1 (3)" and 168.4(4)" respectively and the lithium atom; have a close contact (2.3 A) and with the ips0 carbons of the mesityl groups. A tetralithio compound containing both u-and .rr-bonded lithium atoms is thought to have the structure (5) and is prepared by treating benzo[b]biphenylene with 1ithi~m.I~ ' D. Barr W. Clegg S.M. Hodgson R. E. Mulvey D. Reed R. Smith and D. S. Wright J. Chem. SOC. Chem. Cornmun. 1988 367. D. R. Armstrong R. E. Mulvey G. T. Walder D. Barr R. Snaith W. Clegg and D. Reed J. Chem. SOC.,Dalton Trans. 1988 617. W. Bauer P. A. A. Klusenor S. Harder J. A. Kanters A. J. M. Duisenberg L. Brandsma and P. von R. Schleyer Organometallics 1988 7 552. 10 W. Bauer M. Feigel G. Muller and P. von R. Schleyer J. Am. Chem. Soc. 1988 110 6033. " E. C. Constable M. J. Doyle J. Healy and P. R. Raithby J. Chem. SOC.,Chem. Commun. 1988 1262. 12 M. Pilz J. Allwohn R. Hunold W. Massa and A. Berndt Angew. Chem. Int. Ed. Engl. 1988,27 1370. l3 M. Pilz J. Allwohn R. Hunold W. Massa and A. Berndt Angew. Chem. In?. Ed. Engb 1988,27 1182. 243 Organometallic Chemistry -Part (ii) The Main-Group Elements Li.Et,O Li Mesityl I ,Mesityl 8;\ B-C-B -,, " (3) (4) The X-ray crystal structure of (2,6-dimethoxyphenyl)lithiumhas been reported by two group^.'^.'^ The structure comprises two connected dimeric units with the C-Li carbons having overall five-coordination within the tetramer but having an approximate planar tetracoordinate geometry (as had previously been postulated for a compound where oxygen-lithium chelation occurs) in the dimer.The effects of silyl substitution on the structures of lithium phosphinornethanes has been investigated in {(TMEDA)Li[(Me,P)CH(SiMe,)l) and (TMEDA)-{Li[( Me,P)C( SiMe,),]} .16 Increasing the degree of silylation weakens the Li-C interactions but promotes additional bridging Lie..P interactions to the second Li atom in the dimer. Similar Li. -.P interactions are also seen in the solid-state structures of { (THF) Li[ (Me,P)*C( and { (THF) Li[ (Ph2P)2CH])2 .I7. Treatment of (E,E)-1,4-bis( trimethylstanny1)buta- 1,3-diene with excess MeLi affords (Z,Z)-1,4-dilithiobuta-l,3-diene, thus providing experimental evidence for greater stability of the (2,Z)-over the (E,E)-dilithio isomer.'* The synthesis of various 9,lO-disubstituted anthracenes (e.g. dimethyl difluoro diiodo and diacetyl) can be accomplished by treatment of 9,lO-dilithioanthracene with electr~philes.'~ An X-ray crystal structure of a lithium triorganostannate lithium tris-(a-furyl)stannate has been determined for the first time.,' The structure consists of an anion containing a lithium atom coordinated to the six oxygens from two tris-(a- fury1)stannate groups and a Li(dioxane) cation together with two free dioxane molecules.Mossbauer spectra for Ph3SnM (M = Li Na or K) have been remeasured and reinterpreted.21 The X-ray crystal structure of Ph,SnK.( 18-crown-6) shows a naked Ph,Sn- anion to be present with the K+ being >6 8 distant from the Sn. The potassium rubidium and caesium salts of the strong acid (CF3S02)3CH are readily formed in the reaction between metal carbonate and the acid.22 The X-ray crystal structure of the (CF3S02)3C- anion in the potassium salt shows the CS3 core to be planar and none of the salts react with Xe derivatives to give Xe-C containing species. The crystal structure of the widely used reagent cyclooctatetraenylpotassium I4 H.Dietrich W. Mahdi and W. Storck J. Organomer. Chem. 1988 349 1. S. Harder J. Boersma L. Brandsma A. van Heteren J. A. Kanters W. Bauer and P. von R. Schleyer J. Am. Chem. SOC.,1988 110 7802. H. H. Karsch A. Appelt B. Deubelly K. Zellmer J. Riede and G. Muller Z. Naturforsch. Teil B 1988 43 1416. 17 H. H. Karsch B. Deubelly and G. Muller J. Organomet. Chem. 1988 352 47. lg A. J. Ashe I11 and S. Mahmoud Organometallics 1988 7 1878. 19 B. F. Duerr Y.3. Chung and A. W. Czarnik J. Org. Chem. 1988 53 2120. 20 M. Veith C. Ruloff V. Huch and F. Tollner Angew. Chem. Int. Ed. EngL 1988 27 1381. T. Birchall and J. A. Ventrone J. Chem. Soc. Chem. Comrn. 1988 877. 22 L. Turowsky and K. Seppelt Inorg.Chem. 1988 27 2135. 244 P. D. Lickiss C8H8K2.(THF)3 has been determined.23 The C8H8 ring is planar and bonded to two equivalent K+ ions one on either side of the ring which are connected via bridging THF molecules to K+ ions of adjacent molecules so as to form a chain structure. A chain structure is also found in the solid state for the 2,4-dimethylpen- tadienylpotassium- TMEDA complex which contains planar U-shaped 2,4-dimethyl- pentadienyl anions. Each anion has a K+ cation on either side which is chelated by TMEDA; the cations are linked by bridging anions.24 The potassium-graphite laminate C8K cleanly and rapidly forms silyl potassium reagents R'R;SiK (e.g. R' = R2 = Me; R' = Me R2 = Ph). For some of the reagents e.g. Me,SiK this preparation is more convenient than that for the analogous lithium reagent and the potassium species are easily coverted into silyl cuprates manganates etc.which can be used for various substitution and addition reactions.2s 2 Group I1 Co-condensation of t-butyllithium with BubBe at -196 "C affords a good yield of Li[ BeBu;] which can be crystallized from pentane as a solvent-free dimer in which each lithium interacts with the beryllium atom and four carbons of one [BeBuil- anion and one carbon from the second anion in the dimer.26 Novel Grignard reagents (6;n = 0 or 1)in which there is intramolecular coordina- tion in a crown ether have been prepared by treatment of the parent aryl bromide with magnesium.27 The X-ray crystal structure of (6; n = 0) shows the magnesium coordinated to four oxygens and a carbon in the crown ether ring and the bromine giving a distorted pentagonal pyramid structure.A 0 (6) n = 0 or 1 Metal-halogen and metal-hydrogen exchange reactions while common for organolithium reagents are very rare in Grignard reagent chemistry. Such reactions will occur readily however if activation by a crown ether system is available. For example Ph,Mg will metallate both (7a) and (7b) to give (8) the structure of which has been determined crystallographically showing the magnesium to be coordinated to all of oxygens in the ring as well as two aromatic carbons.28 23 N. Hu,L. Gong Z. Jin and W. Chen J. Organornet. Chern. 1988 352 61. 24 L. Gong N. Hu Z. Jin and W. Chen J.Organornet. Chern. 1988 352 67. 25 A. Furstner and H. Weidmann J. Organornet. Chern. 1988 354 IS. 26 J. R. Wermer D. F. Gaines and H. A. Harris Organornefallics,1988 7 2421. 27 P. R. Markies 0. S. Akkerman F. Bickelhaupt W. J. J. Smeets and A. L. Spek J. Am. Chern. Soc. 1988 110 4284. 28 P. R. Markies T. Nomoto 0. S. Akkerman F. Bickelhaupt W. J. J. Smeets and A. L. Spek Angew. Chern. Int. Ed. EngL 1988 27 1084. Organometallic Chemistry -Part (ii) The Main-Group Elements n 0 /-O 4.'Ph W (7a) X = H (7b) X = Br The use of [Mg(anthracene)(THF),1 as a soluble source of magnesium has been extended to the preparation in high yield of benzylic Grignard reagents bearing 0-or p-halogeno ring substituents; for example 0-BrC,H4CH2CI affords o-BrC6H4CH2MgC1 in 90% yield.Both 0-and p-chloromethyl(methoxymethyl)-benzenes give di-Grignard reagents but the m-isomer gives a mono-Grignard only.29 The problem of removal of anthracene from product mixtures after using [Mg(anthracene)(THF),1 can be overcome by attaching the anthracene group to a polystyrene backbone via an SiMe linkage. The polymer-supported Mg( anthracene) reagent gives good yields of benzylic Grignard reagents from the corresponding halides and the spent polymer can then be removed by filtrati~n.~' Direct observation of magnesiate ions R,Mg has been achieved by studying solution and solid-state structures of RMg( 15-crown-5)+ R,Mg species derived from reaction of R,Mg with 15-crown-5.3' Crystalline MeMg( 1 5-crown-5)Me5Mg2 contains cations in which the magnesium lies close to the plane of the crown ether oxygens and is bound to all of them and to an apical Me group.A methyl group from the Me,Mg anionic polymer chain occupies the other apical position. 'H n.m.r. spectra of the neopentyl analogue in solution suggest that it adopts a structure similar to that for the Me analogue in the solid state. A series of substituted cyclopentadienyl derivatives (9) of Group I1 elements have been prepared by co-condensation of ligand solvent and metal vapour at -196 "C. X-Ray crystal structural analysis of (10; M = Ca or Sr) shows the compounds to be monomeric isomorphous and isostructural. The Sr compound appears to be the SiMe THF M[C,H,-1,3-( SiMe,),] cp heat -THF M -03 (9) M = Ca Sr or Ba / 29 M.J. Gallagher S. Harvey C. L. Raston and R. E. Sue J. Chem. SOC.,Chem. Commun. 1988 289. 30 S. Harvey and C. L. Raston J. Chem. SOC.,Chem. Commun. 1988 652. 31 A. D. Pajerski M. Parvez and H. G. Richey jun. J. Am. Chem. SOC.,1989 110 2660. 246 P. D. Lickiss first solid-state structural determination of an organostrontium compound. The Sr-ring centroid distance is 2.551 8 and the ring centroid-Sr-ring centroid angle is 134".32 The 'bent metallocene' structure was also found in the first X-ray structure determination of an organobarium compound (~'-(c,Me,),Ba.~~ It has a ring centroid-Ba-ring centroid angle of 131" and an average Ba-C distance of 2.987 (18) A. 3 Group 111 A dialane {[ (Me3Si)2CH]2A1}2 has been prepared by reduction of [(Me3Si),CHl2A1C1 with potassium.The compound has an Al-A1 bond length of 2.660( 1) A with the four CH carbons and the two A1 atoms being almost ~o-planar.~~ The first trimeric iminoalane [MeAlN(2,6-Pr;C,H3)] has been prepared from AIMe and H2N(2,6-Pr&H,).35 It has a planar six-membered ring of alternating A1 and N atoms and an average AI-N bond length of 1.78 A. N.m.r. spectroscopy of the compound does not indicate the AI,N ring to be aromatic. Treatment of AIMe with 2 equivalents of the bulky phenol 2,6-Bu\C,H30H or a deficiency of the phenol leads to formation of (2,6-Bu:C,H30),AIMe and (2,6- Bu&H,0)AlMe2 respectively. Both of the aluminium aryl oxides form complexes with PMe . The X-ray crystal structure of (2,6-Bu:C,H30)AIMe2.PMe3 shows the usual distorted tetrahedral geometry around the Al but an unusually large AI-0-C angle of 164.5 (4)" and a short A1-0 distance of 1.736 (5) A.These features are interpreted in terms of a rr-type interaction between the A1 and the 0 atoms.36 There is continuing interest in the preparation of organometallic compounds containing bonds between Group 111 and Group V elements and their use as precursors to electronic materials via Metal-Organic Chemical Vapour Deposition (MOCVD) techniq~es.~' The first aluminium-arsenido complex (Et,AIAsBu:) ,to be structurally characterized has an AI-As distance of 2.571 (2) A and is made by treatment of AIEt with BUSASH.~' This material is seen as a precursor to electroni- cally useful thin films via MOCVD techniques as is the dinuclear gallium phosphide compound [Bu\G~PHC,H~]~ .38 1 Me AIMez 32 L.M. Engelhardt P. C. Junk C. L. Raston and A. H. White J. Chem. SOC.,Chem. Commun. 1988 1500. 33 R. A. Williams T. P. Hanusa and J. C. Huffman J. Chem. Soc. Chern. Cornmun. 1988 1045. 34 W. Uhl 2. Narurjorsch. Ted B,1988 43 1113. 3s K. M. Waggoner H. Hope and P. P. Power Angew. Chem. Int. Ed. Engl 1988 27 1699. 36 M. D. Healy D. A. Wierda and A. R. Barron Organornefallics,1988 7 2543. 37 A. H. Cowley B. L. Benac J. G. Ekerdt R. A. Jones K. B. Kidd J. Y. Lee and J. E. Miller J. Am. Chem. Soc. 1988 110 6248. 38 D. E. Heaton R. A. Jones K. B. Kidd A. H. Cowley and C. M. Nunn Polyhedron 1988 7 1901.Organometallic Chemistry -Part (ii) The Main-Group Elements 247 The product (11) from the reaction between AIMe and N,N’-bis-(3-aminopropy1)ethylenediamine has a pentacoordinate aluminium atom in a trigonal- bipyramidal en~ironment.,~ This unusual coordination is thought to be preferred over the usual square-pyramidal coordination owing to the greater flexibility of the open-chain amine over the cyclic amines usually found in such complexes. Treatment of (T’-C~M~,)~Y~(THF) with aluminium alkyls AIR (R = Me Et or Bu’) gives ytterbium-organoaluminium complexes. The crystal structure of one (12) shows an unusual Yb-(p-Et)-Al linkage to be present with a Yb-C-A1 angle of 177.7’ and a Yb-CH2 distance of 2.854( 18) A. The complex polymerizes CH2=CH2 methyl methacrylate and styrene.40 The reaction between AIMe and (T’-C~M~~)~S~(THF), affords complex (131 which polymerizes ethylene and in which a pair of bent metallocene units is bridged by two tetrahedral (p-Me),AlMe groups via nearly linear Sm-( p-Me)-A1 linkage^.^' THF I .AI-Et / I Sm Et Convenient high-yield preparations of neopentyl (Np) gallium compounds GaNp ,GaNp,CI GaNp,Br GaNpCI, and GaNpI have been described with the reaction between NpMgCl and GaCI giving the synthetically useful GaNp .42 The synthesis and properties of AlMe, GaMe ,and InMe adducts with involatile phosphines such as PPh and (Ph,PCH,) have been reported.43 Such compounds are more easily handled than the free alkyls are readily purified and thermally dissociate to give free pure R3M which can be used for MOCVD purposes.Intramolecular stabilization in organogallium compounds such as ( 14) also gives compounds that are relatively easy to handle melting at 34°C and reacting only slowly with O2.44 Reaction of Me,Ga with l-hydroxymethyl-3,5-dimethylpyrazole affords ( 15).45 The novel terdentate ligand (16) forms complexes with Ni4’ and Mo.~~ Treatment of Ga[GaCI,] with hexaethylbenzene in toluene affords a complex (17) in which each Gat centre is q6-bonded to one molecule of toluene and one of C6Et, the 3’4 G. H. Robinson S. A. Sangokoya F. Moise and W. T. Pennington Organomerallics 1988 7 1887. 40 H. Yamamoto H. Yasuda K. Yodota A. Nakamura Y. Kai and N. Kasai Chem. Lerr. 1988 1963. 41 W.J. Evans L. R. Chamberlain T. A. Ulibarri and J. W. Ziller J. Am. Chem. SOC.,1988 110 6423. 42 0. T. Beachley jun. and J. C. Pad Organometallics 1988 7 1516. D. C. Bradley H. Chudzynska M. M. Faktor D. M. Frigo M. B. Hursthouse B. Hussain and L. M. 43 Smith Polyhedron 1988 7 1289. 44 H. Schumann U. Hartmann A. Dietrich and J. Pickardt Angew. Chem. Int. Ed. Engl. 1988 27 1077. 45 A. Mar S. J. Rettig A. Storr and J. Trotter Can. J. Chem. 1988 66 101. 46 S. J. Rettig A. Storr and J. Trotter Can. J. Chem. 1988 66 355. 248 P. D. Lickiss Me Me2 Me A!?! Ga-N 'OH--0 Me Me Me2 9-t rings fp-ming an angle of 38.8'. One molecule of C6Et6 is situated between each pair of molecules (17).47 New organoindium compounds Me2Sn(CH21nMe2) and Me,Sn[CH21n(OCH2- CH,NMe,),] have been prepared by treatment of Me,Sn(CH,Li) with Me,InCl and (Me2NCH2CH20)21nCI Such compounds may be useful precur- re~pectively.~' sors to metal oxides with a ratio 1n:Sn > 1.X- Ray crystallography shows that [Me,InAsMe,] contains two independent molecules in the unit cell one contains a planar In,As ring and the other a puckered ring the In-As distances being about 2.67 A."" A review of thallium n.m.r. spectroscopy including organothallium compounds has been p~blished.~' The synthetically useful reagents benzyl- and phenyl-cyclopentadienylthallium are prepared in good yields from TlOEt and benzyl- or phenyl-cyclopentadiene re~pectively.~' The X-ray crystal structure of the needle modification of pentabenzyl-cyclopentadienylthallium has been determined.52 The structure consists of a chain of monomeric molecules in which the thallium is shielded by two benzyl groups attached to the cyclopentadienyl ring to which it is bonded and three benzyl groups of the next monomer in the chain.A gas-phase electron diffraction study5 of pentamethylcyclopentadienylthallium shows that the TI-C distance r2.663 (5) %.I 47 H. Schmidbaur R. Nowak B. Huber and G. Miiller Z. Nutirrforsch. Teil B 1988 43 1447. 48 H. Schumann R. Mohtachemi and M. Schwichtenberg Z. Nuturforsch. Teil B 1988 43 1510. 49 A. H. Cowley R. A. Jones K. B. Kidd C. M. Nunn and D. L. Westmoreland J. Organornet. Chern. 1988 341 C1. 50 J. F. Hinton K. R. Metz and R.W. Briggs Bog. Nucl. Magn. Reson. Spectrosc. 1988 20 423. 5' P. Singh M. D. Rausch and T. E. Bitterwolf J. Organornet. Chern. 1988 352 273. 52 H. Schumann C. Janiak M. A. Khan and J. J. Zuckerman J. Orgunornet. Chern. 1988,354 7. 53 R. Blom H. Werner and J. Wolf J. Orgunornet. Chern. 1988 354 293. Organometallic Chemistry -Part (ii) The Main-Group Elements is shorter than that in the non-methylated compound as was found previously in the indium analogues. 4 Group IV Reviews have been published covering silyl-directed stereocontrol in organic syn- thesis,54 the characteristic reactions of allylsilane~,~~ the synthetic uses of organosilanes under nucleophilic catalysis conditions,s6 how gas-kinetic studies have aided the understanding of organosilicon reaction mechanisrn~,~~ the reactions between halogenosilanes and acetals orthoesters or their analogues," the physical and chemical properties of pyridine and quinoline derivatives of Si Ge Sn and Pb,s9 and phase transfer catalysis in organosilicon chemistry.6o A book in the 'Best Synthetic Methods' series 'Silicon Reagents in Organic Synthesis' by E.W. Colvin (Academic Press London 1988) gives details about the practical aspects of using a wide range of silicon reagents. A series of silacyclohexadienes with bulky substituents (e.g.Bur) and good leaving groups on silicon (e.g. OMe) have been prepared as precursors to silabenzenes.61 The most stable silabenzene reported so far (18),which can be observed spectroscopi- cally up to -100 "C has been prepared by photolysis of the diazo compound (19).The silabenzene has a characteristic 29Si n.m.r. shift of 26.8 p.p.m. and can be trapped by MeOH.62 BU' BU' The stable silanimine Bu\Si=NSiBu\ can be prepared by reaction of Bu\SiNa with Bu\SiCIN3 and forms adducts with donors e.g.NMe,Et and THF. The reactions of the Si=N double bond in the free compound and its adducts with a wide range of protic and unsaturated species have also been studied.63 The silene (Me3Si)2Si=CPh(OSiMe,) reacts with the azete (20) to give pyrrole (21) uia a complicated rearrangement whilst with 1,2,3,4,5-pentamethylcyclopen-tadiene and cyclohexa-1,3-diene normal Diels- Alder products are obtained.64 54 I. Fleming Pure Appl. Chem. 1988 60 71. 55 A. Hosomi Acc.Chem. Res. 1988 21 200. 56 G. G. Furin 0.A. Vyazankina B. A. Gostevsky and N. S. Vyankin Tetrahedron 1988 44 2675. 57 I. M. T. Davidson J. Organornet. Chem. 1988 341 255. 5x R. S. Musavirov E. P. Nedogrey I. N. Syraeva E. A. Kantor and D. L. Rakhmankulov J. Organomet. Chern. 1988 350 139. 5V E. Lukevics and I. D. Segal g. Organomef. Chem. Library 1988 20 69. 60 Yu. Goldberg V. Dirnens and E. Luckevics J. Organomer. Chem. Library 1988 20 21 1. 61 P. Jutzi and M. Meyer Chem. Ber. 1988 121 1393. 62 G. Mark1 and W. Schlosser Angew. Chem. In/. Ed. Engl. 1988 27 963. 63 N. Wiberg and K. Schurz Chem. Ber. 1988 121 581. 64 H. Richter S. Arenz. G. Michels J. Scheider 0. Wagner and M. Regitz Chem. Ber. 1988 121 1363. 250 P.D. Lickiss Si(SiMe3)2 I OSiMe3 (21) Pyrolysis of (22) in the presence of an alkyne affords (23) in low yield. The reaction is thought to involve extrusion of MeSiESiMe which rapidly reacts with RC=CR present to give a 1,4-disilabenzene or 1,4-disila Dewar benzene which subsequently reacts with RC=CR to give the observed 1,4-disiIabarrelene (23).65 The first compound (24) containing an q2-silene coordinated to a transition metal has been isolated and characterized by X-ray crystallography.66 The Si=C bond length is about 1.78 A and the Ru-Si=C angle about 64”. Addition of isonitriles RNC (R=Bu‘ or CMe2CH,CMe3) to a stable silene e.g. (Me,Si),Si=C(OSiMe,)-C10H15 initially gives a silacyclopropanimine which rapidly rearranges to a silaaziridine e.g.(25).These compounds are the first to be isolated and structurally characterized which contain a three-membered SiCN ring ~ystem.~’ The disilene Bu\Si=SiBu\ undergoes addition reactions with 2,2’-bipyridyf8 and a thia~ole.~~ The reactions of the first siliconocene (q5-C5Me,),Si with protic species have been compared with those of its heavier analogues (T~-C~M~,)~M (M = Ge Sn or Pb).” Unlike the derivatives of the heavier analogues HX (X = C1 Br 02CCF, 65 A. Sekiguchi G. R. Gillette and R. West Organometallics 1988 7 1226. 66 B. K. Carnpion R. H. Heyn and T. D. Tilley J. Am. Chem. SOC. 1988 110 7558. 67 A. G. Brook Y. K. Kong A. K. Saxena and J. F. Sawyer Organometallics 1988 7 2245. 68 M. Weidenbruch A. Schafer and H. Marsmann J.Organomet. Chem. 1988 354,C12. 69 M. Weidenbruch B. Flinther S. Pohl D. Haase and J. Martens J. Organomet. Chem. 1988 338 C1. 70 P. Jutzi U. Heltrnann H. Briigge and A. Muller J. Chem. SOC.,Chem. Commun. 1988 305. Organometallic Chemistry -Part (ii) The Main-Group Elements 25 1 03SCF3 etc.) attacks (q5-C5Me,),Si at the lone pair giving compounds of type (C5Me5)2SiHX although treatment with HBF affords the cyclotetrasilane (C,Me,SiF) apparently via dimerization of the unstable disilene C,Me,( F)Si=Si( F)C5Me5. A range of mono- and di-( q' -pentamethylcyclopen-tadieny1)silanes C,Me,SiX (X = F Br H etc.) and (C,Me,),SiXY (X = Y = F or H; X = H Y = C1 or NH,) have been prepared.71 Both chemical and X-ray crystallographic studies show the significant degree of steric hindrance afforded by the q1-bound ligand.Details of the convenient chemical thermal and photochemical generation of silylene Bu:Si from various of precursors should encourage further study of this and other sterically hindered ~ilylenes.~ In an argon matrix Bu',Si has A,, = 480 nm reacts with alcohols and inserts into SiH and SiOMe bonds.73 In contrast to less bulky silylenes (2,4,6-PrjC6H2),Si reacts with cis-and trans-but-2-enes non-stereospecifically giving both cis and trans silirane products. The reason for this bulk effect is not known.74 Reaction of Rh,H,(CO),(dppm) with primary silanes PhSiH or EtSiH gives fluxional products which contain silylenes bridging between Rh atoms e.g. Rh,(p-SiPhH),(CO)2(dppm)2,the crystal structure of which shows Si-Rh distances of 2.35 A and Rh-Si-Rh angles of about 73.5°.75 The stabilization energy of a carbenium ion by a p-silyl group has been measured in the gas phase for Me3Si(CH2CH,)+ and found to be 9.3 kJ mol-' relative to CH3CHi.76 The magnitude of the well-known stabilization of a carbanion by an a-silyl group has been determined via measurement of the electron affinity of the Me,SiCH; radical.The derived proton affinity of the anion Me,SiCH is 93.5 f 0.4 kJ mol-' from which a value of 4.8 kJ mol-' for a-silyl carbanion stabilization is ~alculated.~~ Further evidence for the existence of Ph,Si+ and Me,Si+ species in low concentra- tion in solution has been provided by 35Cl and ,'Cl n.m.r. studies of Ph,SiOC1O3 and Me3SiOC103.Below about 0.01M and 0.006M for Me,SiOClO and Ph,SiOC103 respectively the C1 n.m.r. signals are sharp indicating >90% ionic character but at higher concentration e.g. 0.584M for Me,SiOC10, the C1 n.m.r. signals are broad indicating predominantly covalent ~haracter.'~ Detailed evidence for the existence of silicocations (RS),Si+ (R = Me Et or Prl) in dilute solution in CH2C12 MeCN or sulpholane has been reported. The ions are prepared by hydride abstraction from (RS),SiH using Ph3COC103 and the ionic nature of (RS),Si0C1O3 at low concentration is indicated by conductance n.m.r. spectroscopy and molecular weight determination. At higher concentrations (>O.lOM) as for Ph,SiOClO and Me,SiOClO, the compounds appear to be predominantly covalent in nat~re.'~ 7' P.Jutzi D. Kanne M. Hursthouse and A. J. Howes Chem. Ber. 1988 121 1299. 72 P. Boudjouk U. Sarnaraseera R. Sooriyakumaran J. Chrusciel and K. R. Anderson Angew. Chem. Int. Ed. Engl. 1988 27 1355. 73 K. M. Welsh J. Michl and R. West J. Am. Chem. SOC.,1988 110 6689. 74 W. Ando M. Fujita H. Yoshida and A. Sekiguchi J. Am. Chem. SOC.,1988 110 3310. 75 W.-D. Wang S. I. Hornmeltoft and R. Eisenberg Organometallics 1988 7 2417. 76 D. Hajdaz and R. Squires J. Chem. SOC., Chem. Commun. 1988 1211. 77 D. M. Wetzel and J. I. Brauman J. Am. Chem. SOC.,1988 110 8333. 78 J. B. Lambert and W. Schilf J. Am. Chem. SOC.,1988 110 6364. 79 J. B. Larnbert W. J. Schulz jun. J. A. McConnell and W. Schilf J. Am. Chem. SOC.,1988 110 2201.252 I? D. Lickiss Compounds containing the new ring system 1,2-dihydro- 1,2,5-disilaborepine (26) are formed when 1,2-diethynyltetramethyldisilaneis treated with an excess of Me,B or Et3B.80 A new class of cyclic organosilicon compounds cyclopoly( silapro- pynylenes) (R,SiC=C) (where R = Me or Ph) have been prepared by treatment of dilithium derivatives R,Si(C_CLi) with the corresponding R2SiCI2. Treatment of R,Si(C_CLi) with RiSiCl leads to products in which the R2Si and the RiSi units are distributed randomly.81 The smaller strained ring system 1,2,5,6-tetrasilacyc- loocta-3,7-diyne (27) can be prepared in good yield by treatment of di-Grignard derivatives of disilanes (R,SiCrCMgBr) with ClRiSiSiRiC1.82 MelSiHg R2Si-C=C-SiR; I I Me2Si R,Si-CfC-SiR; I HR (27) R = R' = Me; R = R' = Bun; (26) R = Me or Et R = Me R' = Bun The X-ray crystal structure of decaisopropylhexasilabicyclo[2.2.0lhexane (28) has been determined (the first of such a ring system).The rings are puckered and the central Si-Si bond of 2.396 8 is similar in length to those in the periphery of the molecule (2.385-2.426 The first compound (29) containing the octasilacubane ring system has been prepared by condensation of Br,RSiSiRBr or RSiBr (R = Bu'Me2Si) with sodium giving 55 and 72% yields respectively. The compound is air-sensitive but stable in an inert atmo~phere.~ R R R2Si-Si-SiR2 RSi I. I. I R2Si-Si-SiR2 R RSi R (28) R = Pr' (29) R = Bu'Me,Si Reduction of Cl[Si(C6HI 1)2]4C1 by potassium affords octacyclohexyl-cyclotetrasilane in 89% yield.The Si ring is not planar but has a fold angle of 27.6" and the Si-Si bond lengths in the ring are 2.391 A.85The reductive oligomeriz- ation of [C1,( Bu')Si] with lithium naphthalenide gives several products among which are the first examples of the tricyclo[2.2.0.02~s]hexasilane(30) and tetracyclo[3.3.0.02~7.03~6]octasilane (31) ring systems.86 UO B. Wrackmeyer J. Chem. SOC. Chem. Commun. 1988 1623. '' R. Bortolin B. Parbhoo and S. S. D. Brown J. Chem. SOC.,Chem. Commun.,1988 1079. 82 T. Iwahara and R. West. J. Chem. SOC.,Chem. Commun.,1988 954. n3 H. Matsumoto H. Miyamoto N. Kojima Y. Nagai and M. Goto Chem. Len. 1988 629. 84 H. Matsumoto K. Higuchi Y. Hoshino H. Koike Y. Naoi and Y.Nagai J. Chem. SOC.,Chem. Commun. 1988 1083. 85 M. Weidenbruch K.-L. Thom S. Pohl and W. Saak Montash. Chem. 1988 119 65. 86 Y. Kabe M. Kuroda Y. Honda 0.Yamashita T. Kawase and S. Masamune Angew. Chem. Int. Ed. Engl. 1988 27 1725. Organometallic Chemistry -Part (ii) The Main-Group Elements Bu' B u' \ But Two new types of polysilane (PhMeSiMe,Si) and [(PhMe,Si)MeSi], have been prepared from the disilane fraction from the Direct Process via initial phenylation of C1,MeSiSiMe2C1 to give ClMePhSiSiMe,Cl and C1,MeSiSiMe2Ph with sub- sequent condensation using sodium. This reaction sequence thus turns a Direct Process residue into polysilanes which are currently of great interest as ceramic precursor^.^^ The first 'polyalkylsilyne' [(n-hexyl)Si],,,has been prepared by treat- ment of (n-hexyl)SiCl with Na/ K alloy with ultrasound irradiation.The polymer is yellow soluble in hexane more stable to photodegradation than linear polysilanes and has other properties different to simple polysilanes that should make this new class of polymer the subject of considerable interest." The condensation of dichlorosilanes R'R2SiC12 (R'= R2 = n-hexyl; R' = Ph R2 = Me) with sodium to give polysilanes has been carried out under irradiation by ultrasound. The polysilanes produced are of high molecular weight only (M,> lo5) and do not contain the usual low molecular weight (M,l -lo3)p~lyrner.'~ Group transfer polymerization of polyunsaturated esters has been achieved using silyl ketene acetals or silyl polyenolates.Better control over M,and low polydisper- sity is achieved using silyl polyenolates for initiation." The preparation of optically pure organosilanes containing chiral silicon centres has been further explored by utilizing the reaction between (R)-(1-naphthyl)phenyl-methylsilylmethyllithium (naphthPhMeSiCH,Li) and carbonyl compounds. Although the p-hydroxysilanes formed had only a 3"% diastereoisomeric excess it was possible to study the stereochemistry at silicon of p-elimination. With BF,-OEt, H2S04 or AcOH-NaOAc elimination occurred with inversion of stereochemistry but with KH retention of configuration occurred." Transfer of chirality from silicon to an a-carbon has been achieved using the chiral thioketone (R)-( -) -naphthMePhSiC( S)Ph which gives diastereoisomeric sulphides naph- thMePhSiCHPhSMe when treated with MeLi followed by MeOH and thiopyrans when treated with buta-1,3-diene with 40 and 50% d.e.re~pectively.'~ This success should prompt further work in this potentially very useful field. 87 H. Watanabe Y. Akutsu A. Shinohara S. Shinohara Y. Yamaguchi A. Ohta M. Onozuka and Y. Nagai Chem. Lett. 1988 1883. 88 P. A. Bianconi and T. W. Weidman J. Am. Chem. Soc. 1988 110 2342. 89 H. K. Kim and K. Matyjaszewski J. Am. Chem. SOC.,1988 110 3321. 90 W. R. Hertler T. V. RajanBabu D. W. Ovenall G. S. Reddy and D. Y. Sogah J. Am. Chem. Soc. 1988 110 5481. G. L. Larson A. Prieto and E. Ortiz Tetrahedron 1988 44 3781. 92 B. F. Bonini F. Mazzanti P. Zani and G.Maccagnani J. Chem. SOC. Chem. Commun. 1988 365. 254 P. D. Lickiss A new route for the preparation of alkoxysilanes by hydrosilylation of ketones using diphenyltitanocene as catalyst has been described. For example Ph2SiH, MeC(0)C5Hll and (q5-C5H5),TiPh gave Ph,HSiOCHMe(C,H,,) in 91% yield after reaction at 120"for 11 h.93 The convenient synthesis of rare trialkylsiloxyalkynes such as HC_COSiR and Me3SiC~COSiR3 (SiR3 = SiBukMe) is achieved by dehydrobromination of (2)-2-bromovinyl silyl ethers.94 The transition-metal cata- lysed reaction between R3SiH compounds and diazo esters or diazo ketones leads Aeanly to the formation of a-silyl esters and a-silyl ketones respectively providing a new and synthetically useful route to these widely used compounds:95 Both Na,SiF6 and (NH4),SiF6 have been found to be good fluorinating agents for chlorosilanes with the latter working well even for hindered chlorosilanes such as Bu\SiCl and mesity12SiC12.The ammonium salt should be particularly useful as it does not affect Si-H Si-Si or Si-0-Si bonds as do many other reagents used for the Si-C1 to Si-F conver~ion.~~ The use of NaN impregnated on an Amberlite resin converts silyl chlorides into silyl azides in good yields with short reaction times in common solvents such as CH2C12 benzene and he~ane.~~ This convenient method can also be used to prepare silyl azides containing Si-H or Si-CH=CH groups and should become a common route to this useful group of compounds. The use of silica as starting material for the preparation of R3SiX species has been demonstrated thus avoiding the need to prepare elemental silicon for use as a feedstock in the Direct Process.The method involves breakdown of Si02 by catechol in the presence of a base such as KOH to give a tricatecholate e.g. [(C6H4Oz),Sil2-2K+ and subsequent reaction of this hexacoordinate species with a Grignard or lithium reagent to give R3SiH7 &Si or 0-(R3SiO)C6H40H (R = Me Et CH,Ph Ph etc.). It will be interesting to see if this type of synthesis can be scaled up and become commercially viable.98 The first example of oxidative addition of an Si-halogen bond to a Ptocomplex has been observed in the reaction between Pt(PEt,) and Me3Si-Br to give trans-Me,SiPtBr( PEt3)2; thus Me3SiBr behaves like an organic halide in the reaction.99 The one-pot synthesis of a range of aliphatic aromatic and heteroaromatic acylsilanes can be achieved by treatment of an acid chloride with the silyl cuprate (Me Si )2CuLi.loo The use of (Me3Si),SiH as a reducing agent to replace Bu;SnH has been redis- covered"' 18 years after the initial reportlo2 of this compound's reducing ability! The reduction of alkyl chlorides bromides and iodides can be achieved using the silane alone or in the presence of a radical initiator such as benzoyl peroxide.93 T. Makano and Y. Nagai Chem. Lett. 1988 481. 94 R. L. Danheiser A. Nishida S. Savariar and M. P. Trova Tetrahedron Lett. 1988 29 4917. 9s V. Bagheri M. P. Doyle J. Taunton and E. E. Claxton J. Org. Chem. 1988 53 6158.96 R. Damrauer R. A. Simon and B. Kanner Organornetallics 1988 7 1161. 97 K. Sukata J. Org. Chem. 1988 53 4867. 98 A. Bouding G. Cerveau C. Chuit R. J. P. Corriu and C. Reye Organornetallics 1988 7 1165. 99 H. Yamashita T. Hayashi T. Kobayashi M. Tanaka and M. Goto J. Am. Chem. Soc. 1988,110,4417. 100 A. C. Copperucci A. Degl'Innocenti C. Faggi A. Ricci P. Dembech and G. Seconi J. Org. Chem. 1988 53 3612. 101 C. Chatgilialoglu D. Griller and M. Lesage J. Org. Chem. 1988 53 3641. H. Burger W. Kilian and K. Burczyck J. Organomet. Chem. 1970 21 291. Organometalfic Chemistry -Part (ii) The Main-Group Elements 255 Reduction of MeCH(SiCl,) by LiAlH, affords MeCH(SiH,), which may be a useful precursor to hydrogen-containing silicon-carbon alloys.'03 Air-stable metallocenes of Ge Sn and Pb containing tetraphenylcyclopentadienyl or (4-t-butylphenyl)tetraphenylcyclopentadienylligands can be prepared from the metal dihalide and the appropriate cyclopentadienyl alkali-metal salt.lo4 The syn- thesis and properties of the air- and moisture-stable (v5-C5Ph5)*M (M = Ge Sn or Pb) have been described together with their solid-state n.m.r.spectra.'05 The pentaphenyl tin analogue (q5-C5H5)( q5-C5Ph5)Sn is also moderately air-stable and has a ring centroid-Sn-ring centroid angle of 151.1(3)0.'06 Photolysis of Me,GeGeMe,Ph gives a range of products predominantly diger- manes e.g. Me,GeGeMe3 and hydrogermanes e.g. Me,GeH which are thought to be derived from homolysis of the Ge-Ge bond giving Me,Ge' and PhMe2Ge' and also from formation of Me2Ge:.'07~'08 The treatment of 1-alkenylsulphides R' R2C=CHSPh or 1-alkenylstannanes R'R2C=CHSnPh3 with Ph,GeH in the presence of Et,B gives good yields of 1-alkenylgermanes R'R2C=CHGePh3 (R' = R2 = Ph or Et; R' = n-CloH21 R2 = H etc.).'" The first preparation of bis(phenylseleno)germanes,R'R2Ge( SePh) ,has been achieved by reaction of PhSeNa and R'R2GeX2 (R' = R2 = Me X = C1; R' = R2 = Ph X = Br etc.).The X-ray crystal structure of 1,l-bis(phenylse1eno)-1-germacyclopentane shows a Ge-Se bond length of -2.36A and an Si-Ge-Se angle of 101.7°."0 A review of 73Ge n.m.r.spectroscopic studies of organogermanium compounds has been published,"' and ',Ge n.m.r. data for a series of germacyclohexanes have been reported.' l2 Allylic germanes and stannanes are formed in good yield when allenes are treated with Ph,GeH or Ph,SnH in the presence of Pd(PPh,),.Thus allene gave CH,=CHCH,GePh and CH,=CHCH,SnPh in 88 and 40% yields re~pectively."~ An absorption at 420 nm in the products from room-temperature laser photolysis of Me,Ge(SePh) has been attributed to Me,Ge and is the first time that its U.V. spectrum has been rep~rted."~ Laser flash photolysis of (Me3Si)2GePh2 in cyclo- hexane generates a species with A,, 445nm attributable to Ph,Ge which can be trapped by various reagents and dimerizes to give Ph2Ge=GePh2 .l15 The reactions of dimethylgermylene Me,Ge with various acetylenes to give several new germa- heterocycles have been described."6 Various diarylgermylenes e.g.Ph,Ge and 103 H. Schrnidbaur and R. Hager Z. Naturforsch Teil B 1988 43 571. 104 H. Schurnann C. Janiak and J. J. Zuckerrnan Chem. Ber. 1988 121 207. 105 C. Janiak H. Schurnann C. Stader B. Wrackrneyer and J. J. Zuckerrnan Chem. Ber. 1988 121 1745. 106 M. J. Heeg R. H. Herber C. Janiak J. J. Zuckerrnan H. Schumann and W. F. Manders J. Organomet. Chem. 1988 346 321. 107 K. Mochida M. Wakasa Y. Nakadaira Y. Sakaguchi and H. Hayashi Organometallics 1988 7 1869. 108 K. Mochida H. Kikkawa and Y. Nakadaira Chem. Lett. 1988 1089. 109 Y. Ichinose K. Oshima and K. Utimoto Chem. Lett. 1988 669. 110 S. Tornoda M. Shirnoda Y. Takeuchi and Y. Iitaka Chem. Lett. 1988 535. 111 E. LiepnS I. Zicrnane and E. Lukevics J. Organomet.Chem. 1988 341 315. 112 Y. Takeuchi Y. Ichikawa K. Tanaka and N. Kakirnoto Bull. Chem. Soc. Jpn. 1988 61 2875. I13 Y. Ichinose K. Oshirna and K. Utirnoto Bull. Chem. Soc. Jpn. 1988 61 2693. 114 S. Tomoda M. Shirnoda Y. Takeuchi Y. Kajii K. Obi I. Tanaka and K. Honda J. Chem. Soc. Chem. Commun. 1988,910. 115 S. Konieczny S. J. Jacobs J. K. Wilking and P. P. Gaspar J. Organomet. Chem. 1988 341 C17. 116 G. Billet W. P. Neurnann and G. Steinhoff Tetrahedron Lett. 1988 29 5245. 256 P. D. Lickiss mesityl,Ge form complexes with heteroatom-containing molecules such as Bu; P Et3N Me,S and PhCl that can be detected by U.V.spectroscopy in matrices at 77 K. On warming the matrix the germylenes dimerize to give digermenes Ar,Ge=GeAr .I1' Addition of germylene {(Me,Si),CH},Ge to the phosphaalkyne Bu'CrP gives the first phosphagermirene (32) in good yield as a yellow crystalline solid.l8 The chemistry of the digermene (2,6-Et,C6H3),Ge=Ce( 2,6-Et,C,H3) has been explored and the first digermirane (33) and azadigermirane (34) have been prepared by treatment of the digermene with CH,N2 and PhN, re~pectively.~'~ Reaction of (33) or (34) with pyridine N-oxide S8,or Se gives four-membered ring products in which insertion of 0 S or Se into the Ge-Ge bond has occurred. [CH(SiMe,),l cH2 Ph Cie N /\ /\ /\ // // beAr, Bu'-C=P Ar2Ge- Ge Ar Ar2Ge- GeAr (32) (33) Ar =2,6-Et2C,H (34) The photolysis of the cyclotrigermane (mesityl,Ge) produces the digermene mesityl,Ge=Ge( me~ityl)~ and the germylene mesityl,Ge which react with suphur to give (35) and (36; E =S) respectively.The digermene also reacts with selenium to give (36 E =Se).'" Digermene (2,6-Et2C6H,)2Ge=Ge(2,6-Et2c6H3)2 undergoes various cycloaddition reactions with for example CH2N2,PhCECH and acetone giving digermacyclopropane digermacyclobutene and digermaoxetane products S // E (Mesityl),Ge-Ge( Mesityl) (Mes it y 1)?G e /\Ge( Mesity 1)2 E (35) (36) E =S or Se The crystal structure of the first germaphosphene mesityl,Ge=P(2,4,6-Bu\C6H2) has been determined122and is found to have a Ge=P bond length of 2.138(3) A -8.5% shorter than a Ge-P single bond. Addition of S or Se to the germaphosphene leads to addition to the Ge=P bond and formation of the first structurally character-ized germathiaphosphirane and germaselenaphosphirane respectively.' 23 A Ge=C double bond can be stabilized by charge transfer into an aromatic system thus allowing mesityl,Ge(fluorenylidene) to be isolated as a crystalline solid with a Ge=C bond length of 1.803 (4) 117 W.Ando H. Itoh T. Tsumuraya and H. Yoshida Organometallics 1988 7 1880. I18 A. H. Cowley S. W. Hall C. M. Nunn and J. M. Power J. Chem. SOC.,Chem. Commun. 1988 753. I I9 W. Ando and T. Tsumuraya Organometallics 1988 7 1882. I20 T. Tsumuraya S. Sato and W. Ando Organometallics 1988 7 2015. 121 S. A. Batcheller and S. Masamune Tetrahedron Lett. 1988 29 3383. 122 M. Drager J. Escudik C. Couret H. Ranaivonjatovo and J. Satgk Organometallrcr 1988 7 1010.123 M. Andrianarison C. Couret J.-P. Declercq. A. Dubourg J. Escudie H. Ranaivonjatovo and J. Sat& Organometallics 1988 7 1545. I24 M. Lazraq J. Escudik C. Couret J. Satge M. Drager and R. Dammel Angew. Chem. Int. Ed. Engl. 1988 27 828. Organometallic Chemistry -Part (ii) The Main-Group Elements The first preparation of R,Ge' species (R = Me or Ph) in solution has been achieved using the same method as in the R,Si+ analogues i.e. hydride abstraction from R,GeH by trityl perchlorate. The ionic nature of R3GeOC103 predominates at low concentration e.g. 0.0015M but at higher concentrations e.g. 0.146M for R = Ph a covalent structure is preferred.12' The crystal structure of the arylgermane (o-Me2NCH2C6H4),GeH shows intramolecular coordination to the Ge atom by all three Me2N groups giving a pseudo-heptacoordinate environment.X-Ray powder data suggest that the silicon analogue has a similar structure.'26 The reaction of germanium powder with CH2CI at 350°C affords MeGeCl, CH2(GeC1,)2 and (C12GeCH2)3 as major products; these can be reduced by LiAIH4 to the corresponding hydrides which may have potential as precursors to ger- manium-carbon alloys using chemical vapour deposition technique^.'^^ Reductive dehalogenation of Bu'jGeC1 and BuSGeCl gives cyclotrigermane (BuiGe) and digermane BuiGeGeBuS respectively; the latter contains the longest Ge-Ge (2.710A) and Ge-C (2.076 A) bonds yet recorded.I2' Both decaphenylgermanocene and decaphenylstannocene have been shown to exhibit anti-tumour activity in mice cure rates being 40-80% and 40-90% for dose ranges of 280-700 and 160-460 mg kg-' respectively.In the tin case deaths due to the toxicity of the compound began to occur at doses greater than 440 mg kg-1.'29 The anti-mutagenic activity of pyrazoyl borate complexes of di- and triorganotins has also been in~estigated.'~' Addition of the stannylene [(Me,Si),CH12Sn to a cyclic alkyne gives the first stannacyclopropene (37) which can be crystallized and has Sn-C,,2 bond lengths of -2.135 8 and a C,,Z-Sn-C,,,~ angle of 36.6 (2)".',' Addition of {[( Me,Si),CHI2Sn} to Bu'CrP gives the first example of a phosphadistannacyc- lobutene (38) which has a planar Sn2CP ring and a Sn-Sn bond length of 2.878 (1) A.132 Regioselective hydrostannylation of terminal alkynes can be achieved using rhodium catalysts; for example PhC=CH and BuYSnH in the presence of RhCI( PPh3)3 give Ph( Bu3Sn)C=CH2 and PhHC=CHSnBu in the ratio 88 :12.13' '" J.B. Lambert and W. Schilf Organometallics 1988 7 1659. C. Breliere F. CarrC R. J. P. Corriu and G. Royo Organomefallics 1988 7 1006. H. Schmidbaur J. Rott G. Reber and G. Muller Z. Naturjorsch Ted B 1988 43 727. I 2x M. Weidenbruch F.-T. Grimm M. Herrndorf and A. Schafer J. Organomet. Chem. 1988 341 335. I29 P. Kopf-Maier C. Janiak and H. Schumann fnorg. Chim. Acra 1988 152 75. "'' S. A. A. Zaidi A. A. Hashmi and K. S. Siddigi J. Chem. Res. (S),1988 410. 131 L. R. Sita and R. D. Bickerstaff J. Am. Chem. Soc. 1988 110 5208. I32 A.H. Cowley S. W. Hall C. M. Nunn and J. M. Power Angew. Chem. Int. Ed. En& 1988 27 838. I73 K. Kikukawa H. Umekawa. F. Wada and T. Matsuda C'hem. Letr. 1988 881. 258 P. D. Lickiss A novel intramolecular tin-oxygen coordination [Sn-0 distance 2.781 (3) A] has been shown to be present in (2-methoxycarbonylcyclohexa-1 ,4-dien- 1-yl)trimethyltin by X-ray ~rystallography.'~~ An annual survey of the chemistry of lead for 1984 has been p~b1ished.l~~ 5 Group V Convenient high-yield synthesis of arsoles stiboles and bismoles e.g. (39) is achieved by using zirconium reagents in metallacycle transfer rea~ti0ns.l~~ The diene backbone can be varied readily and the zirconium reagent can be generated in situ from zirconocene dichloride which makes this an attractive route to these relatively rare compounds.This method can also be used to prepare Ga In Ge Sn and Se derivatives. The first 4-hydroxy- 1,3-azaarsole and 3-hydroxy- 1,2,4-diazaarsole have been prepared.13' Both compounds exist in the phenolic OH form with none of the keto tautomer being detected. (39) E = As Sb or Bi The first reported diarsenyl complex (q5-C5Me,)(CO),FeAs=AsAr (Ar = 2,4,6-BuiC,H2) is formed in the reaction between ArAsCI2 and (qS-C,Me,)-(CO)2FeAs(SiMe3)2. The complex could not be isolated pure but did form a chromium pentacarbonyl derivative ( q -C,Me,)(CO),FeAs[Cr( C0)5]=A~Ar.138 The arsaphosphene (40) coordinates to platinum according to Scheme 1 to give the first compound (41) containing a P-As-R ring.The crystal structure of (41) shows Fe Fe Reagent (Ph P)* RC H Scheme 1 134 B. Jousseaume P. Villeneuve M. Drager S. Roller and J. M. Chezeau J. Organornet Chem. 1988 349 c1. 135 J. Walters and D. de Vos J. Organomet. Chem. 1988 351 1. 136 P. J. Fagan and V. A. Nugent J. Am. Chem. SOC.,1988 110 2310. 137 G. Mark1 and S. Pflaum Tetrahedron Lett. 1988 29 3387. 138 L. Weber and D. Bunghardt J. Organomet. Chem. 1988 354 C1. Organometallic Chemistry -Part (ii) The Main-Group Elements 259 Pt-As and P-As bond lengths of 2.515 (1) and 2.289 (3) A respectively and a P-As-Pt angle of 58.7 (l)0.'39 The phosphidoiron complex (v5-C5Me5)( CO)FeP( SiMe3)2 reacts with ArAsCl (Ar = 2,4,6-Bu:C,H2) to give various products containing P=As or As=As bonds or ASP, As2P or As2P2 rings.The diphosphaarsane (42) can be isolated as a crystalline solid and has As-P bond lengths of 2.316(1) and 2.350(2)A and a P-As-P angle of 56.5 (l)0.'40 The Ga3As3 ring in [(Me3SiCH2),AsGaBr2I3 adopts a twist-boat conformation with Ga-As bond lengths [2.432 (2)-2.464 (1) A] shorter than those found in Ga2As2 rings of dimeric ar~inogallanes.'~' Treatment of SnCl with Bu:AsSiMe3 affords [Sn(p-AsBu;)Cl] in which the As is approximately tetrahedral the Sn-As bond lengths are -2.77 A and the Sn-As-Sn angle is -102°.'42 The first 1,3-azaarsinines (43) have been prepared'43 and their reactions with acetylenic compounds have been studied.'44 + R' R' = R2 = R3 = Ph R' = p-MeC,H4 R2 = R3 = Ph (42) (43) The 14-membered ring compound (44) forms with complete stereoselectivity according to Scheme 2.'45 The diimine can be reduced to the corresponding diamine with LiAlH4 and resolution of the racemates of both the diimine and diamine can be achieved via complexation to palladium.r 1 Me 80 "C -2 (CH,NHMe) Me (44) (R*,S*) Scheme 2 139 F. Edelmann C. Spang H. W. Roeskya and P. G. Jones Z. Naturforsch. Teil B 1988 43 517. 140 L. Weber D. Bunghardt U. Sonnenberg and R. Boese Angew. Chem. Int. Ed. EngL 1988 27 1537. 141 R. L. Wells A. P. Purdy A. T. McPhail and C. G. Pitt J. Organomet. Chem. 1988 354 287. 142 A. H. Cowley D. M. Girlando R. A. Jones C. M. Nunn J. M. Power and W.-W. du Mont Polyhedron 1988 7 1317. 143 G. Markl and S.Dietl Tetrahedron Lett. 1988 29 535. 144 G. Markl and S. Dietl Tetrahedron Lett. 1988 29 539. 145 J. W. L. Martin F. S. Stephens K. D. V. Weerasuria and S. B. Wild J. Am. Chem. SOC.,1988 110,4346. 260 P. D. Lickiss The structure of an arsinimine Ph,AsNCN has been determined by X-ray crystallography; this shows the arsenic to have an almost tetrahedral environment with an As-N distance of 1.739 (4)A which is greater than the sum of the covalent radii of As and N (1.71 A).146 The crystal structure of Me2AsAsMe2 has been determinedI4' and is shown to consist like the antimony and bismuth analogues of linear chains of molecules. There are no short intermolecular As-..As distances which is thought to be the reason for the lack of thermochromism in this compound.The syntheses of di-t-butylcyclopentadienyldichloro-arsineand -stibine are readily achieved by treatment of AsCI and SbCl with Bu&H,L~.'~* Both com- pounds are fluxional exhibiting a rapid 1,2-shift of the MCl2 group. An annual survey for 1986 of the chemistry of antimony has been publi~hed.'~~ The equilibria between symmetrical distibines R$b2 and R:Sb2 (R' = Me R2 = Et; R' = Me R2 = Ph etc.) to give unsymmetrical distibines RiSbSbR; have been investigated by n.m.r. spectros~opy.'~~ Redistribution reactions of stibines of the type R;SbER2 (e.g. R' = Me R2 = Ph E = S; R' = R2 = Me E = Se) to give products RlSb and R'Sb(ER2)2 have also been ~tudied.'~' Oxidation by H202 of several aryl stibines Ar3Sb (Ar = p-C1C6H4,0-MeOC,H, etc.) gives the correspond- ing oxides which are thought (from their i.r.spectra) to be dimers containing Sb,02 rings. Oxidation of mesity1,Sb affords me~ityl,Sb(OH)~ the structure of which shows the Sb to have a slightly distorted trigonal-bipyramidal environment the OH groups in apical positions and no hydrogen bonding between molecules to be present.'" A comparison of the physical and chemical properties of stibonium and bis- muthonium ylides for example (PhS02),C=MPh3 (M = Sb or Bi) with those of their arsonium analogues has been carried out. The close resemblance between stibonium and arsonium ylides is attributed to the interaction between substituent oxygen atoms and the antimony or arsenic atom. A similar effect also appears to be present in the bismuth corn pound^.'^^ An X-ray crystallographic study of (CI,GaSbBu\) shows the Ga,Sb3 ring to have a boat conformation with Ga-Sb distances of about 2.66 A.49 An annual survey for 1986 of the chemistry of bismuth has been publi~hed.'~~ A new class of organobismuth compounds -alkyl diarylbismuthinates Ar,Bi(O)OMe -can be prepared by treatment of Ar,Bi compounds with chloramine-T in methan01.l~~ These new compounds are mild and selective oxidizing reagents that react with activated glycols such as Ph,C(OH)C(OH)Ph to give benzophenone but do not react with unactivated species such as cyclohexane-l,2-diol.Stable crystalline bismuthonium ylides are isolated for the first time as products from the reaction between Ph3BiC03 and diones.Unlike arsonium and stibonium ylides the bismuth I46 K. Bailey I. Gosney R. 0. Could D. Lloyd and P. Taylor J. Chem. Res. 1988 (S) 386 (M) 2950. 147 K. Bailey I. Gosney R. 0. Could D. Lloyd and P. Taylor 2. Naturforsch. Teil B 1988 43 952. 148 S. T. Abu-Orabi and P. Jutzi J. Organomet. Chem. 1988 347 307. I49 L. D. Freedman and G. 0. Doak J. Organomet. Chem. 1988 351 25. 150 M. Ates H. J. Breunig and S. GiileG Polyhedron 1988 7 2601. 151 H. J. Breunig and S. GuleG Z. Naturforsch. Teil B 1988 43 998. I52 T. Westhoff F. Huber R. Ruther and H. Preut J. Organomet. Chem. 1988 352 107. I53 G. Ferguson C. Glidewell I. Gosney D. Lloyd S. Metcalfe and H. Lumbroso J. Chem. Soc. Perkin Trans. 2 1988 1829. I54 G. 0. Doak and L. D. Freedman J.Organornet. Chem. 1988 351 63. I55 T. Ogawa T. Murafuji and H. Suzuki Chern. Lett. 1988 2021. Organometallic Chemistry -Part (ii) The Main-Group Elements 261 analogues react readily with aldehydes to give cyclopropanes dihydrofurans or a,P-unsaturated carbonyl compounds depending on the nature of the aldehyde the ylide and the reaction conditi~ns.'~~~'~~ A series of stable pentacoordinate bismuth compounds of type (45) (Ar = p-tolyl or p-CF,C6H4) can be obtained according to Scheme 3.ls8 They react with S02C1 to give (46). Ar,BiCI SO,CI -____. Ar (45) Scheme 3 6 Group VI The reagent formed from Ph,Se and I, which is known and sold as phenylselenyl iodide has been shown by X-ray crystallography not to consist of simple PhSeI molecules but to be a charge transfer complex containing two Ph,Se and two I units linked together to form an eight-membered ring containing four seleniums and four iodine~."~ The first stable solid alkylselenyl iodide (Me,Si),CSeI has been prepared by treatment of [(Me,Si),CSe] with I and is isolated as blackish violet crystals in 79% yield.'60 This is also the first selenyl iodide to be stable in solution not being in equilibrium with the parent diselane and I,.Phenylselenophosphoric dichloride [PhP( Se)Cl,] has been foundI6' to be a useful reagent for the conversion of the C=O into the C=Se group thus enabling various selenoamides selenoaldehydes selenoketones etc. to be prepared in good yield using homogeneous conditions. Various selenocyanates e.g.PhSeCN Bu"SeCN and (PhS02)( Bu'Me,Si)- CHSeCN can be prepared in good yield by treatment of a cyanocuprate with (SeCN) at -78 "C. The fluoride desilylation of such a-silyl-substituted'62 selenocyanates provides a good route to various selenoaldehydes RC(Se)H (e.g. R = Me But Ph PhCH2).I6 Base-induced (e.g.with Et,N) elimination of cyanide from selenocyanates containing electron-withdrawing or conjugating substituents affords selenoketones RC(Se)R' (e.g. R = R' = Ph; R = CO,Et R' = Me) in good ~ie1ds.l~~ The cycloaddition chemistry of both selenoaldehydes and selenoketones I56 H. Suzuki T. Murafuji and T. Ogawa Chem. Lett. 1988 847. 157 T. Ogawa T. Murafuji and H. Suzuki Chem. Lett. 1988 849. I58 K. Akiba K. Ohdoi and Y. Yamamoto Tetrahedron Lett.1988 29 3817. 159 S. Kubiniok W.-W. du Mont S. Pohl and W. Saak Angew. Chem. Int. Ed. Engl. 1988 27 431. I60 W.-W. du Mont and I. Wagner Chem. Ber. 1988 121 2109. I61 J. P. Michael D. H. Reid B. G. Rose and R. A. Speirs J. Chern. SOC.,Chem. Comrnun. 1988 1494. I62 B. J. Meinke G. A. Krafft and A. Guram J. Org. Chem. 1988 53 3632. 163 B. J. Meinke and G. A. Krafft J. Am. Chem. SOC.,1988 110 8671. 164 B. J. Meinke and G. A. Krafft J. Am. Chem. SOC.,1988 110 8679. 262 i? D. Lickiss has also been further A convenient one-pot route to selenoalde- hydes RC(Se)H (e.g. R = Ph Pr" But) from aldehydes involves the treatment of the latter with (Me,Si),Se in the presence of a catalytic amount of Bu"Li.16' Another way to prepare RC(Se)H species involves the addition of selenium to a phos- phorane.166 For example addition of Se to Ph3P=CHPh at 90 "C leads to formation of PhC(Se)H which in the presence of a Diels-Alder trapping reagent such as 2,3-dimethylbutadiene is trapped as the selenacyclohexene.A new preparation of selenoketones gives reasonable yields and involves treatment of a dimagnesium salt derived from a hydrazone with Se,Cl and subsequent treatment with the base Bu3N. The reaction of selenoketones with RMgX or RLi differs from that of the analogous thioketone in that significant amounts of product result from addition of R to the ~e1enium.l~~ Treatment of a ketone with PhSeCl leads to formation of a ketone with an a-PhSeC1 substituent that can be readily removed by aqueous base to afford an enone.The PhSeC1 derivatives are crystalline and easy to purify and PhSeC13 thus appears to be a useful reagent for the introduction of tetravalent (rather than divalent) selenium into an organic molecule.'68 Several novel selenium coronands have been prepared'69p'70 and the structures of 1,3,7,9-tetraselenacyclododecane'69and 1,3,7,9,13,15-hexaselenacyclooctadecane'70 have been determined. The structure of the latter has an unusual ring geometry which is interpreted as the first evidence for the existence of a third-row anomeric effect. Conformational studies on compounds of type (47)also indicate that an anomeric effect exists in the S-C-Se fragment the largest effect being when R = NO2 and the smallest when R = NMe,.17' (47) R = NMe, NO, OMe H F or C1 The tetrathiafulvalene derivatives (48) have been prepared by a general route.(48; n = 3) undergoes reversible oxidation to a radical cation but not a di~ati0n.l~~ Tetraselenafulvalene can be lithiated with LDA at -80°C to give a tetralithio (48) n = 1 2 or 3 I65 M. Segi T. Nakajima and S. Suga J. Am. Chem. SOC.,1988 110 1976. L 66 G. Erker R. Hock and R. Nolte J. Am. Chem. Soc. 1988 110 624. 167 A. Ishii R. Okazaki and N. Inamoto Bull. Chem. Soc. Jpn. 1988 61 861. 168 L. Engman J. Org. Chem. 1988 53 4031. 169 B. M. Pinto B. D. Johnston R. J. Batchelor F. W. B. Einstein and I. D. Gay Can. J. Chem. 1988 66 2956. 170 B. M. Pinto R. J. Batchelor B. D. Johnston F. W. B. Einstein and I.D. Gay J. Am. Chem. SOC.,1988 110 2990. 171 B. M. Pinto B. D. Johnston J. Sandoval-Ramlrez and R. D. Sharma J. Org. Chem. 1988 53 3766. 172 P. J. Nigrey J. Org. Chem. 1988 53 201. Organometallic Chemistry -Part (ii) The Main-Group Elements 263 derivative which reacts with various electrophiles (e.g. Ph2Se2 or COJ to give moderate yields of tetrasubstituted products.'73 Oxidation of (49) with one equivalent of MCPBA gives a mixture of (50) and (51) as products in an approximate 3:2 ratio.'74 Compound (50) is the first selenoseleninate prepared to have an appreciable lifetime at room temperature whilst (51) is the first areneselenic anhydride isolated that is not stabilized by intramolecular coordination to an ortho substituent. New selenium-containing heterocycles such as (52) form charge transfer com- plexes with TCNQ which are electrically highly conductive e.g.conductivity of (52; E = S) is 1.8 S ~m-'.'~~ The novel heterocyclic system of substituted 1,2,3-selenaazaboroles [e.g. (53)] can be prepared in poor yield by treatment of dis- elenaboroles with sulphur diimide~.'~~ Et Se"'-R2 Etry'R1 (52) E = S or Se (53) R' = Me R2 = Bu' R' = Et R2 = SN(SiMe,) The sequential treatment with Me2N=CCI C1- and NaSeH in EtOH of various thiols phenols amines and some carbohydrate cis vicinal diols gives selenothiocarbamates selenodithiocarbonates selenoureas and novel cyclic seleno~arbonates.'~~ Treatment of 2-substituted 2-(chloromethyl)oxiranes with selenide ion affords good yields of 3-substituted 3-hydroxyselenetanes (e.g.3-phenyl and 3-eth~l).'~~ Several optically active selenium-functionalized binaphthyls have been prepared.'79 When used as reagents for the asymmetric ring-opening of cyclo- hexane oxide enantiomeric excesses between 16 and 50% are obtained.The ditellane (2,4,6-Bu3C6H2),Te2 is a red solid with C2 symmetry and in solution has a barrier to rotation about the Te-Te bond of 40.9 kJ mol-'. This is the first measurement of this barrier which is -20% less than that in the corresponding I73 S. Rajeswari Y. A. Jackson and M. P. Cava J. Chem. Soc. Chem. Commun. 1988 1089. 174 J. L. Kice Y.-H. Kang,and M. B. Manek J. Org. Chem. 1988 53 2435. 175 Y. Shiomi Y. Aso T. Otsubo and F. Ogura J. Chem. Soc. Chem.Cornmun. 1988 822. C. D. Habben Chem. Ber. 1988 121 1967. 177 C. M. Copeland J. Ghosh D. P. McAdam B. W. Skelton R. V. Stick and A. H. White Aust. J. Chem. 1988 41 549. 178 G. Polson and D. C. Dittmer J. Org. Chem. 1988 53 791. I79 S. Tomoda and M. Iwaoka J. Chem. Soc. Chew. Cornmun. 1988 1283. 264 P. D. Lickiss diselane.I8' In contrast to the reactions of dialkyl and diary1 tellurides with MeI which give simple telluronium salts the reaction of benzenecarbotellurates of type ArC(0)TeAr' with Me1 leads to cleavage of the Te-C(0) bond and the formation of telluronium salts of type [Ar'TeMe,]+ I-.18' Acetylenic tellurides e.g. PhCECTeEt have been prepared by treatment of PhCr CLi with tellurium followed by trapping of the intermediate lithium tellurolate with an alkyl halide.', Several Me3Te+ and Ph3Te+ salts [e.g.Me3Te+ I- Ph3Te+ NOS and (Ph3Te)2S04-5H20]have been prepared and their structures investigated by '25Te solid-state n.m.r. spectroscopy and X-ray crystallography. Evidence for weak covalent interactions in some of these compounds is seen in the coupling between the 125Te nucleus and halogen anion.'83 New thiocarbamate complexes PhTe(S2CNEt2)2[S2P(OEt)2],184 MeTeI(S,CNEt,) ,lS4 and C,H,Te( SzCNEt2)2185 have been prepared and their structures investigated by n.m.r. spectroscopy and X-ray crystallography. Synthetic routes to tellurium analogues of naturally occurring flavones and chromones have been developed'86 in order that their biological activity can be compared with that of their oxygen and selenium analogues.Tellurapyranones are reduced to the corresponding tellurapyrylium salts in good yield by diisobutyl- aluminium hydride. 187 The synthesis of RTeLi (R = Me or Ph) from RLi and tellurium at low temperature allows the convenient preparation of marry telluroethers. For example treatment of X(CH,),X (X = C1 or Br n = 1 3 6 or 10) with MeTeLi affords MeTe(CH,),TeMe and C(CH,Br) with PhTeLi gives C(CH2TePh)4.'8s Aromatic nitro compounds are reduced by PhTeNa to the corresponding azoxy compounds using NaBH in alkaline ethanol with a catalytic amount of Ph,Te present.'89 I80 W.-W. du Mont L. Lange H. H. Karsch K. Peters E.-M. Peters and H. G. von Schnering Chem. Ber. 1988 121 11. 181 H. B. Singh and N.Sudha Bull. Chem. Soc. Jpn. 1988 61 3735. 182 M. J. Dabdoub and J. V. Comasseto Organometallics 1988 7 84. M. J. Collins J. A. Ripmeester and J. F. Sawyer J. Am. Chem. SOC.,1988 110 8583. I84 D. Dakternieks R. Di Giacomo J. Am. Chem. Soc. 1988 110 6762. 185 D. Dakternieks R. Di Giacorno R. W. Gable and B. F. Hoskins J. Am. Chem. SOC.,1988 110 6753. 186 M. R.Detty Organometallics 1988 7 2188. 187 M. R. Detty Organometallics 1988 7 1122. 188 E. G. Hope T. Kemrnitt and W. Levason Organometallics 1988 7 78. 189 K. Ohe H. Takahashi S. Uemara and N. Sugita J. Chem. SOC., Chem. Commun. 1988 591.

ISSN:0069-3030    

DOI:10.1039/OC9888500241

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

10 Synthetic Methods By P. A. CHALONER School of Chemistry and Molecular Sciences University of Sussex Brighton BN 1 9QJ 1 Introduction The format of this report remains the same as in previous years with a division of the material into two sections. The first details reactions in which carbon-carbon bonds are formed or broken and new carbon skeleta constructed whilst the second deals with functional group transformations. As always such a review must be selective; if readers feel that their own interests have been underrepresented over the past three years they have at least the consola- tion that a new reviewer with a new set of interests and prejudices will be taking over for 1989. 2 C-C Connection and Disconnection Connection of Separate Fragments.-Enolates and their Equivalents.Reactions of enolates have again figured strongly in C-C bond forming methodology this year. Excellent reviews have been published on asymmetric aldol methodology using boron enolates' and proline-catalysed reactions.2 Selective C-alkylation of P-diketones was achieved using terraethylammonium pyrrolidonate in DMF as the base; yields and selectivities were generally between 70 and 93Y0.~ C-Alkylation was also promoted under very mild conditions when catalysed by Co( PPh3)2Cl .4 A number of highly stereoselective alkylation reactions have been noted. The lithium enolates of t-butyl hydroxypentanoates could be alkylated using reactive electrophiles with reasonable diastereoselectivity (Scheme 1),5 and 99% diastereoselectivity was achieved in the alkylation of vinylogous urethanes derived from tetronic acids (Scheme 2).6 Enantioselective allylation of P-diketones was catalysed by a palladium complex of (1) in up to 81% enantiomeric excess.' Two new alkylation routes to quaternary chiral centres have been developed.The sequential dialkylation of trityloxymethylbutyrolactone proceeded with excellent stereoselectivity and was applied to the synthesis of optically active butyrolactones ' I. Paterson Chem Znd. (London) 1988 390. * C. Agami Bull. Soc. Chim. Fr. 1988 499. T. Shono S. Kashimura M. Sawamura and T. Soejima J. Org. Chem. 1988 53 907. A. Gonzalez J. Marquet and M. Moreno-Manas Tetrahedron Lett. 1988 29 1469. Y. Ukaji and K. Narasaka Bull. Chem. Soc. Jpn. 1988 61 571.R. H. Schlessinger E. J. Iwanowicz and J. P. Springer Tetrahedron Lett. 1988 29 1489. ' T. Hayashi K. Kanehira T. Hagihara and M. Kumada J. Org. Chem. 1988 53 113. 265 P. A. Chaloner R' = alkyl R2X = Me,SO, PhCH21 or BuI Reagents i LiN3,THF HMPA -100°C; ii R2X Scheme 1 i ii - Reagents i BuLi THF -78 "C 30 min; ii PhCH,Br -78 "C 30 min Scheme 2 (Scheme 3). Force field calculations and n.m.r. spectroscopic studies showed that the stereochemical course of the reaction was controlled by a unique conformation of the starting material.$ Selectivities in the alkylation of silyl ketene acetals by dienyl iron complexes ranged from 6 1 to >100 1 (Scheme 4).9 Me Me Reagents i LiNPri MeI THF -78 "C; ii LiNPri EtI THF -78 "C; iii HCI MeOH; iv LiAiH, THF 25 "C; v NaIO, H20; vi CrO, AcOH 25 "C Scheme 3 K.Tomioka Y.-S. Cho F. Sato and K. Koga J. Org. Chem. 1988 53 4094. A. J. Pearson,and M. K.O'Brien Tetrahedron Lett. 1988 29 869. Synthetic Methods CO,Me Fe(C0h OSiMe Reagents moMe ,CH2CI, MeCN A 6-18 h Scheme 4 Bismuth(II1) chloride has been used as an efficient catalyst for the aldol reaction but diastereoselectivities were generally low." The use of indium metal (commercial material which had not been specially activated) for Reformatsky reactions has been advocated; the reaction proceeds at room temperature.' ' Clay montmorillonite has been used as an efficient heterogeneous catalyst for the reaction of silyl enol ethers with aldehydes or acetals and also for Michael reactions of silyl ketene acetals.I2 There has been continued interest in diastereoselective aldol reactions.The prod- ucts of chelation control were obtained with high selectivity in the aldol reaction of t-butyl thioacetate enol silane to alkoxyaldehydes (Scheme 5).13 Germanium OBu I OBu OBu SBu' + wsBu~ 0 SBu' OH OH Reagent SKI Scheme 5 enolates may be prepared in situ from lithium enolates and Me,GeX. Diastereoselec- tivity in their subsequent reactions is controlled by the presence or absence of lithium halides (Scheme 6).14 The aldol condensation of chiral ethyl ketones has been controlled by the use of chiral boron reagents; diastereoselectivity was impressive (Scheme 7).15 Diastereo-and enatioselective reactions have been accomplished for a-silyl ketones; the reac- tion was again very selective and desilylation was readily achieved (Scheme 8).The product was used in an asymmetric synthesis of the agression pheromone sitophilure.I6 10 H. Ohki M. Wada and K. Akiba Tetrahedron Lett. 1988 29 4719. S. Araki H. Ito and Y. Butsugan Synth. Commun. 1988 18 453. 12 M. Kawai M. Onaka and Y. Izumi Bull. Chem. SOC.Jpn. 1988 61 2157 1237. 13 C. Gennari and P. G. Cozzi Tetrahedron 1988,44 5965. 14 Y. Yamamto and J. Yamada J. Chem. SOC.,Chem. Commun. 1988 802. 15 I. Paterson and M. A. Lister Tetrahedron Lett. 1988 29 585. 16 D. Enders and B. Bhushan Lohray Angew. Chem. Int. Ed. Engl. 1988 27 581. P. A. Chalontr 9R2ql?h R' R1 i..R2ii % RZVPh R' Reagents i LiNPr; Et,O -78 "C; ii Me,GeX; iii PhCHO -78 to -40 "C; iv remove LiCl Scheme 6 0 &OBn + 0 OH 0 7% 64% e.e (Bn = CH,Ph) + OTf Scheme 7 4'JJR Bu'Me2Si Me 55-68% 92-98% d.e. >98% ex. Reagents i Bu2BOTf Pr;NEt CHzClz -10 "C 2 h; ii RCHO; -78 "C; iii oxidative work-up; iv flash chromatography; v HBF, H,O THF 20 "C 1-2 days Scheme 8 Enantioselective aldol reactions between non-chiral starting materials have been mediated by chiral bases such as (2).17The reactions of a-isocyanoacetamides with aldehydes were catalysed by a gold complex of (3). It was considered that the " M.Muraoka H. Kawasaki and K. Koga Tetrahedron Letr. 1988 29 337. -0..+ Synthetic Methods X = N-Me piperazinyl isocyano group was bound to the gold and the remote amine functionality was hydrogen bonded to the enolate.The related esters reacted similarly.18 A new development in the Mukaiyama reaction has led to a one-pot synthesis of P-chloro carboxylic acids and esters (Scheme 9).The initial product a bis-0-silylated . .. ph+o*H "\=(" e3 + PhCHO -OSiMe3 R = alkyl or phenyl K Reagents i Ti& CH2C12 -60 "C (1 h) 20 "C (2 h); ii H20 Scheme 9 p-hydroxy acid is chlorinated by the TiC14 .19 The trimethylsilyl triflate-catalysed aldol-type reactions of silyl enol ethers with acetals or related compounds (Scheme 10) occurs via an acyclic transition state and exhibits moderate to high erythro Reagents CF3S03SiMe3 CH,C12 -78 "C Scheme 10 selectivity independent of the geometry of the starting material.'" a-Alkylation and a-alkylideneation of carbonyl compounds has been effected by Lewis acid-catalysed reaction of silyl enol ethers with a-chloro thioethers (Scheme 11).The problems of regio- and stereochemical control were considered in detail.21 The use of a chiral leaving group in a Claisen-type acylation has led to the construction of a quaternary chiral centre with high enantioselectivity (Scheme 12).22 Interesting enantioselective Michael reactions have been noted this year.In an intramolecular reaction catalysed by (R) -(+)-1-phenylethylamine (4) was converted into (5) with up to 90% e.e. in the presence of 5 A molecular sieves (Scheme 13); '* Y. Ito M. Sawamura M. Kobayashi and T.Hayashi Tetrahedron Lelt. 1988 29 6321; Y. Ito M. Sawamura E. Shirakawa E. Hagashizaki and T. Hayashi hid. p. 235; Tetrahedron 1988 44 5253. 19 M. Bellassoved J.-E. Dubois and E. Bertounesque Tetrahedron Lett. 1988 29 1275. 20 S. Murata M.Suzuki and R. Noyori Tetrahedron 1988 44 4259. 21 I. Paterson Tetrahedron 1988 44 4207. 22 Y. Nagao Y. Hagiwara T. Tohjo Y. Hasegawa M. Ochiai and M. Shiro J. Org. Chem. 1988,53 5983. 270 P.A. Chaloner Reagents i TiCI,; ii NaIO, MeOH-H20 (9 l) 20 "C 16 h Scheme 11 0 Ph ,L i ii Ph )-C02Me -Me '%02Me Reagents i LiNCy(Pr') Pr 'NhS; ii HMPA 1 Scheme 12 "'I Ph7 0 H 0 Reagents (R)-(+)-! -phenylethylamine 5 8 molecular sieves Scheme 13 the product will prove a useful building block in alkaloid synthesis.23 Mukaiyama has reported a wide range of enantioselective additions of tin enolates and enethio- lates to enones in the presence of chiral diamines (Scheme 14); enantiomeric excesses were generally in the region of 70Y0.~~ / Ph __* i-iv msMe Reagents i Sn(OTf), MeCS2Me Et N s CH2C12 -78 "C; ii wNHNp; N Me iii Me3SiOTf; iv H+ Scheme 14 23 Y.Hirai T. Terada and T. Yamazaki J. Am. Chem. SOC.,1988 110 958. 24 T. Yura N. Iwasawa T. Mukaiyama and K. Narasaka Chem. Lett. 1988 1021 1025. Synthetic Methods 27 1 Carbon-carbon bond formation specifically at the y-position of dienolates was achieved via the germanium-masked dienolates such as (6) (Scheme 15).25 Reagents i LiNPr; THF; ii. Me3GeX; iii PhCH(OMe), TiCl Scheme 15 Alyl Alkynyl and Alkenyl Anions and their Equivalents.Uses of allylsilanes in synthesis have been reviewed.26 a-Branched allylsilanes have been prepared in a simple regio- and stereocontrolled manner using BuLi-KOBu' as the base and careful' y controlling reaction condition^.^' y- Alkenyl- y- butyrolactones were opened in a regio- and stereoselective manner in the presence of [Me,O]+ by allylsilanes to give methyl 4,fGalkadienoates (Scheme 16).28 Reagents [Me,O][BF,] Scheme 16 A number of enantioselective allylations using allylboranes have been noted. Homoallyl alcohols were prepared by reaction of chiral crotylboronates such as (7) with achiral aldehydes; enantioselectivities in the presence of 4 A molecular sieves were generally excellent.29 (2-y-Alkoxyallyl)diisopinocamphenylboraneswere added to aldehydes with complete diastereoselection for the syn-product and good enantioselection (Scheme 17).30 T-Allylpalladium complexes prepared by oxidative addition of palladium(0) to ally1 derivatives are generally rather electrophilic.However in the presence of SnCI, 0-allyltin( ~v) compounds are formed and show considerable selectivity for 25 Y. Yamamoto S. Hatsuya and J. Yamada J. Chem. SOC.,Chem. Commun. 1988 1639. 26 A. Hosomi Acc. Chem. Res. 1988 21 200. 21 A. Mordini G. Palio A. Ricci and M. Taddei Tetrahedron Lett. 1988 29 4991. 28 M. Kawashima and T. Fujisawa Buff. Chem. SOC.Jpn. 1988 61 4051. 29 W. R.Roush K. Ando D. B. Powers,. R.L. Hatterman and A.D. Palkowitz Tetrahedron Lett. 1988 29 5579. 30 H. C. Brown P. K. Jadhav and K. S. Bhat J. Am. Chem. Soc. 1988 110 1535. 272 P. A. Chaloner 95:5 MeCHO / 4:96 Reagents i ,THF -78°C; ii ,THF. -78°C Scheme 17 reaction with aldehydes over ketones.31 The radical reaction between 2-bromo-N- benzoylglycine methyl ester and allylstannanes has provided a useful new route to a-alkylated amino acids.32 The couplings of ally1 halides with carbonyl compounds to give homoallyl alcohols via formation of a wide range of organometallics continues to attract attention. A two-phase system using electrochemically regenerated bismuth metal showed good selectivity for aldehydes over ketones,33 whilst cadmium-metal-medi- ated reactions with enones resulted in exclusively 1,2-additi0n.~~ Reaction of acrolein dimethylacetal with chromium(11) chloride gave the equivalent of an a-methoxylated allylchromium reagent which added to aldehydes with reasonable diastereoselectivity (Scheme 18).35 ?* 88 12 Reagents CrCI, Me3Sil THF -3O"C 3 h Scheme 18 31 Y.Masuyama R. Hayashi K. Otake and Y. Kurusu J. Chem. SOC.,Chem. Commun. 1988 44; Y. Masuyama J. P. Takahara and Y. Kurusu J. Am. Chem. Soc. 1988,110,4473; Y. Masuyama K. Otake and Y. Kurusu Tetrahedron Lett. 1988 29 3563. 32 J. E. Baldwin R. M. Adlington C. Lowe I. A. O'Neil G. L. Sanders C. J. Schofield and J. B. Sweeney J. Chem. SOC.,Chem. Commun. 1988 1030. 33 M. Minato and J. Tsuji Chem. Lett. 1988 2049. 34 S. Araki H. Ito and Y.Butsugan J. Organomet. Chem. 1988 347 5. 35 K. Takai K. Nitta and K. Utimoto Tetrahedron Lett. 1988 29 5263. Synthetic Methods 273 The syntheses physical properties and uses of tin( IV) alkynyl compounds have been reviewed.36A one-pot synthesis of primary 2-alkynylamides was accomplished by the reaction of R-C_C-SiMe with ClSO,NCO followed by work-up with aqueous Alkynyltin reagents underwent regio-and chemoselective addition to acylpyridines activated by methyl chloroformate to give dihydropyridine deriva-tives (Scheme 19).,* 2-Substituted but-3-yn-1-01s were obtained by ring opening of unsymmetrical epoxides with alkynyltitanium compounds (Scheme 20).39 R R' R' -nMe3 -+ R' +RZ-=-S d 1 + R' N R * RZ ,G d N I R2 I C0,Me C0,Me R' = H Me or OMe; R2 = alkyl 95:5-80:20 Reagents ClC02Me CH2C12,0 "C Scheme 19 R' R' = alkyl Ar or SiMe,; R2 = Ar alkenyl alkynyl or SiMe,; R3 = H alkyl or Ar; R4 = H or R2,R4 = cycloalkyl Reagents i BuLi THF 6-25 "C; ii CITi(OPr'), THF -50 "C; iii R3&:4 THF -50 "C; iv 25 "C 1-3 days R2 Scheme 20 Enantioselective addition of divinylzinc to aldehydes in the presence of (8) has been reported; good enantiomeric excesses were obtained for both aryl and alkyl aldehyde^.^' Stille's group has reported the carbonylation-coupling of RSnBu with aryl triflates to give ArCOR (R = alkenyl alkynyl or alkyl) in the presence of Pd(dppf)Cl .41 Metallation and alkylation of 4H-1,3-dioxin gave a new P-acylalkenyl anion equivalent (Scheme 21).42(E)-4-Lithio-4-tosylbutenonedimethylacetal(9) was used 36 C.Cauletti C. Fiolani and A. Sebald Gazz. Chim. Ztal. 1988 118 1. 37 P. C. B. Page S. Rosenthal and R. V. Williams Synthesis 1988 621. 38 R. Yamaguchi E. Hata and K. Utimoto Tetrahedron Lett. 1988 29 1785. 39 N. Krause and D. Seebach Chem. Eer. 1988 121 1315. 40 W. Oppolzer and R. N. Radinov Tetrahedron Lett. 1988 29 5645. 41 A. M. Echavarren and J. K. Stille J. Am. Chem. SOC. 1988 110 1557. 42 R. L. Funk and G. L. Bolton J. Am. Chem. SOC.,1988 110 1290. I? A. Chaloner \/ Reagents i Bu"Li THF -78 "C; ii Rx; iii A Scheme 21 Ts -)qCOMe TsrnOMe% i-iv ..-Tsyy 0 Li ... . .OMe COR OMe COR Reagents i NaTs I1; ii Et,N; iii HC(OMe)3; iv MeLi LiBr THF -20 "C; v RCOX -20 "C; vi HzO; vii HCI H,O 2-24 h Scheme 22 as a similar synthon (Scheme 22)?3 P-Hydroxyalkylation and conjugate addition of cyclohexenone was accomplished via (10) (Scheme 23).44 &+ 0siM e Bu' d ___* i ii iii iv & PPh3 COEt (10) OH Reagents i Bu'Me,SiOTf PPh3 THF; ii BuLi THF; iii CH,=CHCOEt Me3SiOTf THF -78 "C; iv [Bu,N]F; v PhCHO Me,SiOTf THF -78 "C Scheme 23 43 C.Najera and M. Yus J. Org. Chem. 1988 53 4708. 44 S. Kim and P. H. Lee Tetrahedron Lett. 1988 29 5413. Synthetic Methods Two examples of a-acylalkenyl anion equivalents are also of note. Reaction of but-3-en-2-one with aldehydes in the presence of DABCO resulted in addition at the a-position to give (ll) which was cyclized on heating.Dehydration gave 6,8-dioxabicyclo[3.2. lloctanes in up to 85% isolated yield the products being used in pheromone synthesis (Scheme 24).45 Reaction of enones with aldehydes in the Reagents i DABCO; ii 140 "C 10 h sealed tube Scheme 24 presence of H2R~(PPh3)4 and with no solvent gave a-methylene P-hydroxy ketones (Scheme 25).46 Ready access to P-acyl- and P-arylpropanals has been achieved using a new silylated organotin homoenolate equivalent (Scheme 26) ?7 Other Anions and their Equivalents. Ortho subsitution of methoxypyridines and 4-halogenopyridines has been accomplished via regioselective lithiation and reaction with electr~philes.~~ Metallation of benzylamine derivatives was also selective for the ortho position (Scheme 27).49 Reactions or organometallic reagents with aldehydes and ketones continue to attract attention.1,3-Anti asymmetric addition of organotitanium compounds to 45 :55->99 :1 Reagents H,Ru( PPh,), 40 "C 40 h Scheme 25 45 N. Daude U. Eggert and H. M. R. Hoffman J. Chem. Soc. Chem. Commun. 1988 206. 46 I. Matsuda M. Shibata and S. Sato J. Organomet. Chem. 1988 340,C5. 47 J.-B. Verlhac J.-P. Quintard and M. Pereyre J. Chem. SOC. Chem. Commun. 1988 503. 48 F. Marsais F. Trkourt P. BrCant and G. QuCguinier J. Heterocycl. Chem. 1988 25 81; D. L. Comins and D. H. La Munyon Tetrahedron Lett. 1988 29 773. 49 Y. Simig and M. Schlosser Tetrahedron Lett. 1988 29 4277. P. A. Chaloner SiMe3 SiMeJ i ii Bu3SnvOMe Bu3SndOMe / %Me3 I ArvOMe \ Ar OMe -Reagents i Bu"Li THF -78 "C; ii Me,SiCI; iii R'COCI Pd(PPh3)2C12 THF 65 "C; iv [Bu,N]F THF 0 "C; v ArBr Pd(PPh3)4 C,H, 110 "C Scheme 26 Reagents i BuLi THF hexane -78 to 0°C; ii CO,; ii H2Oz Scheme 27 &substituted aldehydes bearing a dithioacetal group has been reported to proceed with excellent stereoselectivity (Scheme 28)." Titanium was also used as a regio- I R' OH RZ R;_/\xcHo ss-ss It II 96 :4 syn:anti Reagents MeTiCI, 0 "C 30 min Scheme 28 and stereoselective control element for condensation of a-methoxyallylphosphine oxides with aldehydes (Scheme 29); in many cases the diastereoselectivities were better than 10 1." Alkyltitanium complexes of chiral diols such as (12) were used for enantioselective addition to aldehyde^.^' 50 Y.Honda and G. Tuchihashi Chem. Lett. 1988 1937. 51 E. F. Birse A. McKenzie and A. W. Murray J. Chem. SOC.,Perkin Trans. I 1988 1039. 52 H. Takahashi A. Kawabata M. Niwa and K. Higashiyama Chem. Pharm. Bull. 1988 36 803. 277 Synthetic Methods 0 0 0 It Ph2pe i-iv ~ OMe 2.5 1 Iv YPh OMe Reagents i LiNPr; THF -78 "C 30 min; ii TiCI,(OPr'), THF -78 "C 2 h; iii Pr'CHO -78 "C 1 h; iv NH,CI KF H20; v KOBU' THF 30min Scheme 29 Ph Ph Ph Ph Functionalized ketones have been prepared directly by the coupling of organocuprates with acid chlorides; esters nitriles halides epoxides and to some extent ketones were tolerated by the reaction condition^.'^ A convenient preparation of /3-keto sulphones was realized by the reaction of phenylsulphonylmethyl- enedilithium with acid chlorides; the reaction of the monoanion was ineffi~ient.'~ The primary aminomethylation of organometallic compounds using N,N-bis(trimethylsilyl)methylthiomethylamine has been de~cribed.~' Asymmetric induc- tion has been observed for the first time in the addition of Grignard reagents to nitrones (Scheme 30).Diastereoisomer ratios were in the range of 80:20 and the course of the reaction could be predicted using Cram's rule.s6 0-OH Reagents i MeMgCI Et20; ii H, Pd/C MeOH Scheme 30 53 R. M. Wehmeyer and R. D. Rieke Tetrahedron Lett. 1988 29 4513. 54 M. W. Thomson B. M. Handwerker S. A. Katz and R. B. Belser J. Org.Chem. 1988 53 906. 55 L.Fiocca M. Fiorenza G. Reginata A. Ricci P. Dembech and G. Seconi J. Organomet. Chem. 1988 341 C23. 56 M. P. Cowling P. R. Jenkins and K. Cooper J. Chem. SOC.,Chem. Commun. 1988 1503. P. A. Chaloner Two papers have reported the enantioselective addition of dialkylzinc reagents to enones in the presence of dibutylnorephedrine and a nickel salt. Enantiomeric excesses up to 50% were a~hieved.~' Very high selectivity was noted in the conjugate addition of methyltitanium isopropoxide to an optically pure sulphoxide (Scheme 31); the product was used in the synthesis of P-~etivone.~' Conjugate addition to Ar = 4-MeOC6H Reagents i MeTi(OPr'), THF; ii Raney Ni EtOH Scheme 31 chiral 5-trimethylsilycyclohexenoneled to a synthesis of chiral alkylated cyclo- hexenones (Scheme 32).59 High-pressure asymmetric Michael additions of thiols and nitromethane to enones in the presence of (+)-quinidine gave optical yields of up to 60%.60 >96% e.e.Reagents i RMgX CuI; ii CuCI, DMF 60 "C 25-90 min Scheme 32 The Michael addition of a-alkoxy organocuprates to enals proceeded with a high degree of syn selectivity and the products could be readily converted into cis-disubstituted butyrolactones. Compound (13) was used similarly as the synthetic equivalent of a carbonyl ylide in a synthesis of tetrahydrofurans (Scheme 33):' The substitution of enol ethers by Grignard reagents has been reported to occur in the presence of nickel complexes. Trisubstituted alkenes could be prepared by the reactions of 6-alkyl-3,4-dihydro-2H-pyrans (Scheme 34).62 Allylsilanes were prepared in moderate to good yields in the reactions of dithioacetals with trimethyl- silylmethylmagnesium chloride (Scheme 35).63 57 K.Soai T. Hayasaka S. Ugajiu and S. Yokoyama Chem. Lett. 1988 157; K. Soai S. Yokoyama T. Hayasaka and K. Ebihara J. Org. Chem. 1988 53 4148. 58 G. H. Posner and T. G. Hamill J. Org. Chem. 1988 53 6031. 59 M. Asaoka K. Shima and H. Takai J. Chem. SOC.,Chem. Commun. 1988 430. 60 A. Sera K. Takagi H. Katayama and H. Yamada J. Org. Chem. 1988 53 1157. 61 R. J. Linderman and J. R. McKenzie Tetrahedron Lett. 1988,29,3911; R. J. Linderman and A. Godfrey J. Am. Chem. SOC.,1988 110 6249. 62 L. Jalander Synth. Commun.1988 18 343; P. Kocienski N. J. Dixon and S. Wadman Tetrahedron Lett. 1988 29 2353. 63 Z.-J. Ni and T.-Y. Luh J. Chem Soc. Chem. Commun. 1988 1011. 279 Synthetic Methods OSiMe3 __* i ii iii __+ O-\ R R (13) Me,SiCI; ii Et3N hexane; iii TiCI4 CH2C12 -78 "C Scheme 33 Reagents MeMgBr Ni(PPh3),C12 C6H6 A 36 h Scheme 34 n ,SiMe3 Reagents Me3SiCH2MgCI Ni( PPh3)2C12 Et,O C6Hs A Scheme 35 Two groups have given details of nucleophilic additions to iron tricarbonyl complexes of a,P-unsaturated ketones to give 1,Qdiketones (Scheme 36).@ Some Reagents i MeMgBr Et20 -78 "C 7 h; ii ButBr Scheme 36 new organomanganese compounds have been investigated; opening of epoxides and ethers and coupling with ally1 and vinyl derivatives have been described (Scheme 37).65 64 T.N. Danks D. Rakshit and S. E. Thomas J. Chem. Soc. Perkin Trans. 1 1988 2091; H. Kitahara Y. Tozawa S. Fujita A. Tajiri N. Morita and T. Asao Bull. Chem. Soc. Jpn. 1988 61,3362. 65 P. De Strong and D. R. Sidler J. Org. Chem. 1988 53 4892; K. Fugami J.-I. Hibino S. Nakatsukasa S.Matsubara K. Oshima K. Utimoto and H. Nozaki Tetrahedron 1988,44,4277. P. A. Chaloner R'VSR2 -% R'wSiR + R:Si Reagents i Me3SiMn(CO), CH2=CHC02Me Et,O 5 kbar 14-96 h; ii Me,SiMn(CO), hv MeCN CH2=CHC02Me 25 "C 1-12 h; iii H20 02,25 "C; iv (R:Si),MnMgMe Scheme 37 Cerium-mediated reactions of Grignard reagents have been used in the preparation of functionalized alkylsilanes (Scheme 38); the reactions of lactones were also improved.66 SiMe3 OMe -(Me0)2CHL./ Me& nMgCl + Me0 &C02Me i %Me3 OH iii (MeO),CH& %Me3 Reagents i CeCl,; ii Si02 Scheme 38 Methyleneation and Alkylideneation.A new synthesis for CH2(A1C1R),.2Et20 from aluminium metal and dichloromethane has been described the procedure being carefully monitored for safety. This is an excellent reagent for the methyleneation of ketones.67 The synthesis of vinylthiazoles and the related substituted benzothiazoles by Wittig reactions has been described. Subsequent cleavage of the heterocycle provides a sequence for a three-carbon homologation of aldehydes (Scheme 39).68The prepara- tion and reactions of diisopropoxypropyltriphenylphosphoniumbromide another three-carbon homologating agent have been described (Scheme 40).69Polyconju-gated aldehydes have been prepared using the new Horner- Wadsworth-Emmons reagent (14) with work up by flash ~hromatography.~' The allylideneation of 66 T.V. Lee J. R. Porter and F. S. Roden Tetrahedron Lett. 1988 29 5009. 67 A. M. Piotrowski D. B. Malpass M. P. Boteslawski and J. J. Eisch J. Org. Chem. 1988 53 2829. 68 A. Dondoni G. Fantini M. Fogagnolo A. Medici and P. Pedrini Tetrahedron 1988 44,2021. 69 J. Viala and M. Santelli Synthesis 1988 395. 'O T. Rein B. Akermark and P. Helquist Acta Chem. Scand. Ser. B 1988 42 569. Synthetic Methods 281 Me +/ 1-ivl Me Reagents i KOBU' C6H6 25 "C 48 h; ii Pr'CHO; iii Mel MeCN A 5-24 h; iv NaBH, MeOH -10 "C 20 min; v HgCI, H20 MeCN 15 min Scheme 39 ... + Br-bCHO JdL. Ph3P *CH( OPr i)2 iii CH(OPri)2 -RlL ivl R2 R 1bCHO Reagents i PPh, HBr Pr'OH CH,CI, lOT 10h; ii HC(OPr'), OT 30min; iii R'R'CO BuLi hexane; iv TsOH THF A 20 min Scheme 40 0 II (EtO) P (14) aldehydes was accomplished by successive formation of a palladium-ally1 complex from an allylic alcohol followed by transformation into an ylid and a Wittig reaction (Scheme 41).'l Vinylsilanes have been prepared stereoselectively from carbonyl compounds and Me,SiCH2Cl (Scheme 42).'* The corresponding silylated Grignard reagent was used in a nickel-catalysed reaction with dithioacetals (Scheme 43).73 Miscellaneous. Unsymmetrical pinacols have been prepared by the reactions of diary1 ketones with dialkyl ketones in the presence of ytterbium metal.Reactions with epoxides were also Reductive coupling of enones (Scheme 44) was N. Okuado 0. Uchikawa and Y. Nakamura Chem. Left. 1988 1449. 72 J. Barluenga J. L. Fernandez-Simon J. M. Concellon and M. Yus Synthesis 1988 234. 73 Z.-J. Ni and T.-Y. Luh J. Org. Chem. 1988 53 2129. 74 Z. Hou K. Takamine 0. Aoki H.* Shiraishi Y. Fujiwara and H. Taniguchi J. Chem. SOC. Chem. Commun. 1988 668. P. A. Chaloner PhvOH + C,H,,CHO -Ph-C7H15 4 1 E E E Z via PhvOCONHPh -PhA 5phu$R, I+ PdL2 PhNH- PhNH- 1 Ph"PR3 Reagents Bu,P Pd(PPh,), MeCN PhNCO A 5 h Scheme 41 Me3SiCH2Cl -+ Rj_/SiMe3 R2 >95'/0 E Reagents i Bu"Li TMEDA THF -78 to -60 "C 40 min; ii R1R2C0 -60 to -45 "C (R' R2 = H alkyl aryl); iii LiNp THF -78 to 20 "C 12 h; iv NH,CI H20 Scheme 42 Reagents Ni(PPh3)2C12 Et,O C6H6 or THF A 12 h Scheme 43 i ii 4 Reagents i Mg MgBr, Et20 Me,SiCl; ii H20 Scheme 44 promoted by Mg/MgBr2.75 Titanium tetrachloride was used for the coupling of imines to symmetric vicinal amines (Scheme 45); diastereoisomeric ratios were in the region of 90 10 for most substrate^.^^ A new synthesis of 1,2-glycol monoethers via samarium diiodide-mediated decar- bonylation of a-alkoxy acyl chlorides has been reported.Yields were not particularly high but a large number of examples were noted (Scheme 46).77Sm12 was also 75 J.-M. Pons and M. Santelli Tetrahedron Lett. 1988 29 3679. 76 P. Mangeney T.Tejero A. Alexakis F. Grosjean and J. Normant Synthesis 1988 255. 77 M. Sasaki J. Collin and H. B. Kagan Tetrahedron Lett. 1988 29 4847. Synthetic Methods R1 R' ,R1 kNR2 * H' R~NH 'NHR~ R~NH 'NHR~ R',R2 = alkyl or aryl Reagents i HgCI, Mg THF 25 "C 20 min; ii TiCI4 L25 "C 30 min 0 "C 12 h Scheme 45 + MeOCH2COCl -4 Reagents i SmI, THF 25 "C 1 min; ii HCI H20 Scheme 46 used for the reductive coupling of a,P-unsaturated esters with carbonyl compounds. The reaction proceeds uia radical intermediates after one-electron transfer and lactones were obtained in 40-82% yield.78 Aliphatic aldehydes were converted into the homologous methyl ketones using trimethylsilyldiazomethane followed by work-up with aqueous HCl.79 A new one- carbon homologation of alkyl and aryl halides was accomplished using a bis(trimethylstanny1)benzopinacolate-mediatedfree radical carbon-carbon bond forming reaction (Scheme 47) Ketones (ArCOR) were prepared from carboxylic RX + CH2=NOCH2Ph -* RCH2NHOCH2Ph Me3Sn0 OSnMe Reagent Ph#Ph Ph Ph Scheme 47 acids and aromatic hydrocarbons using 2-trifluoromethylsulphonyloxypyridine as the coupling agent.The reaction probably involves transacylation to give the acylated 2-hydroxypyridine followed by electrophilic attack on the arene.81 TiC1,-mediated additions of isocyanides R'NC to aldehydes R2CH0 gave a-hydroxycarboxamides R2CH(OH)CONHR' in very high yield in a Passerini-type reaction.82 Alcohols and ethers were functionalized in the a-position in very high yield in a photochemical reaction with (15) (Scheme 48).83 78 S.Fukuzawa A. Nakanishi T. Fujinami and S. Sakai J. Chem. SOC.,Perkin Trans. 1 1988 1669. 79 T. Aoyama and T. Shioiri Synthesis 1988 228. D. J. Hart and F. L. Seely J. Am. Chem. SOC.,1988 110 1631. 81 T. Keumi K. Yoshimura M. Shimada and H. Kitajima Bull. Chem. SOC.Jpn. 1988 61 455. 82 D. Seebach G. Adam T. Gees M. Schiess and W. Weigard Chem. Ber. 1988 121 507. 83 K. Ogura A. Yanagisawa T. Fujino and K. Takahashi Tetrahedron Lett. 1988 29 5387. I? A. Chaloner SMe SMe R’CH-( RICH=( -I-MeOH I_ [ S0,Tol SOzTol OH (15) 96‘10 SMe SMe RICH-( (15) + 2A0 SO2Tol -S02Tol -RICH R2 Reagents i hv PhCOPh 30 min; ii NaH R21; iii [H,O]+ Scheme 48 Cyc1ization.-Free radical cyclizations have continued to attract considerable atten- tion.Samarium diodide was used to initiate intramolecular pinacol couplings and for an intriguing double cyclization of 2-allyloxybenzoic acid chlorides to give cyclopropanols (Scheme 49).84 Approaches to the synthesis of carbacepham and Reagents Sml, 25 T 1 min Scheme 49 carbacephem systems by radical cyclization in the presence of Bu,SnH have been described (Scheme 50).85A tandem radical cyclization approach to the hexahy- drobenzofuran skeleton for avermectin synthesis has been described (Scheme 51).86 C02Me Reagents i CH2=CHCH2Br lithium hexamethyldisilazide THF -78 “C 20 min; ii Bu,SnH AIBN CsHa A 16 h Scheme 50 84 G. A. Molander and C. Kenny J.Org. Chem. 1988 53 2132; M. Sasaki J. Collin and H. B. Kagan Tetrahedron Lett. 1988 29 6105. 85 T. Kametani S.-D. Chu A. Itoh S. Maeola and T. Honda Heterocycles 1988 27 875; T. Kametani S.-D. Chu A. Itoh S. Maeda and T. Honda J. Org. Chem. 1988 52 2683. 86 P. J. Parsons P. A. Willis and S. C. Eyley J. Chem. SOC.,Chem. Commun. 1988 283. Synthetic Methods Reagents Bu,SnH AIBN C6H6 80 "C Scheme 51 A practical synthesis of bicyclopentanedicarboxylic acid has been described (Scheme 52); this is a useful starting material for the preparation of low molecular weight and polymeric bicy~lopentanes.~~ Reagents i :CBr2; ii MeLi pentane Et20 -78 "C; iii MeCOCOMe hv 8 h; iv NaOBr dioxan 0 "C (1 h) 25 "C (3 h) 50"C (1 h) Scheme 52 The intramolecular addition of allylsilanes to carbonyl electrophiles occurred in the presence of TiC14 to give predominantly the products of the chelation-controlled reaction (Scheme 53); five- six- and seven-membered ring compounds were pre- pared in this way." 00 R' = OEt NMe, NEt, or Me; R2 R3= alkyl or aryl Reagents TiCI, CH,C12 -78 "C Scheme 53 Two rhodium-catalysed reactions have proved useful.In (16) the rhodium-cata- lysed insertion of the diazoketone moiety occurred regioselectively with the ester group steering the insertion away from the P-methylene group (Scheme 54).89 Regiospecific cyclization of 1,6-enynes to give methylenecyclohex-2-enes was cata- lysed by Wilkinson's complex.90 87 P. Kaszynski and J. Michl J. Org. Chem. 1988 53 4593.88 G. A. Molander and S. W. Andrews Tetrahedron 1988 44 3869. a9 G. Stork and K. Nakatani Tetrahedron Lett. 1988 29 2283. 90 R. Grigg P. Stevenson and T. Worakun Tetrahedron 1988 44 4961. P. A. Chaloner COCHNz COZEt Reagents Rh,(OAc), CH2C12,25 "C Scheme 54 Cycloadditions and Annu1ations.-Reactions Forming Six-membered Rings. Both increased selectivity and an increased reaction rate in Diels- Alder reactions were achieved by the adsorption of the reactants on chromatography adsorbents." Quino- dimethanes were generated by proton-induced elimination of 2-hydroxyalkylben- zyltrimethylstannanes and various cycloaddition reactions were de~cribed.~' There has been considerable interest in enantioselective Diels- Alder reactions.The benzyl ester of (S)-proline was used as a chiral auxiliary in a Lewis acid- catalysed reaction (Scheme 55).93 Menthyloxyfuranone has found uses as a chiral I R:S = 97~3,endozexo = 9416 Reagent TiCI, -10°C Scheme 55 dienophile; selectivities were generally excellent.94 Many examples of diastereoselec-tive cycloadditions of chiral a$-unsaturated N-acyloxazolidinones have been described (Scheme 56).95 The asymmetric hetero-Diels- Alder reaction between the diene (17) and benzaldehyde was catalysed by a chiral Lewis acid (18) (Scheme 57).96 NAO P+ Q -hRi0 R' d CON RZ' (excess) ?-J Ri Reagents Et,AICI CH,CI, -100 "C 2-5 min Scheme 56 91 V. V. Veselovsky A. S. Gybin A. V. Lozanova A. M. Moiseenkov W. A. Smit and R. Caple Terrahedran Left.1988 29 175. 92 H.Sano H. Ohtsuka and T. Migita J. Am. Chem. Sac. 1988 110 2014. 93 H. Waldmann J. Org. Chem. 1988 53 6133; Angew. Chem. Znt. Ed. Engl. 1988 27 274. 94 B. L. Fennga and J. C. De Jong J. Org. Cfiem. 1988,53 1125. 95 D. A. Evans K. T. Chapman and J. Bisaha J. Am. Chem. SOC.,1988 110 1238. 96 N. Maruoka T. Itoh T. Shirasaka and H. Yamamoto J. Am. Chem. Sac. 1988 110 310. Synthetic Methods OMe 0 aPh 0' I 77% 95% e.e. Reagent (18) Ar = Ph or 3,5-Me,C,H3 Scheme 57 A tandem cycloaddition-radical cyclization procedure (Scheme 58) has been found to be a widely applicable strategy for the formation of polycyclic systems.97 Reagents. i benzyne generated from 2-diazobenzenecarboxylate; ii Bu,SnH AIBN C,H6 A Scheme 58 A new strategy for annulation of cyclohexenones involved successive conjugate addition coupling cyclopropanation and rearrangement (Scheme 59).98 Reactions Forming Fivemembered Rings.Nitrones have again this year been extremely popular dipoles and an interesting synthesis of p-amino ketones was accomplished via isoxazolines (Scheme 60).99 Isoxazolines prepared from aryl nitrones and alkynes were rearranged to enamine derivatives. loo A highly diastereoselective intramolecular nitrone cycloaddition to an a$-unsaturated ester was used to prepare a P-lactam precursor (Scheme 61)."' Ultrasound considerably accelerated the cycloaddition of unreactive conjugated nitrones with unactivated alkenes.''* 97 T. Ghosh and H.Hart J. Org. Chem. 1988,53 2396. 98 J. P. Marino and J. K. Long J. Am. Chem. SOC.,1988,110 7916. 99 V. Mancuso and C. Hootele Tetrahedron Lett. 1988,29 5917. 100 A. Liguori R. Ottana G. Romeo G. Sindoria and N. Uccella Tetrahedron 1988,44,1247,1255. 101 R. Annunziata M. Cinquini F. Cozzi and L. Raimondi Terrahedron Lerr. 1988,29 2881. 102 D. R.Borthakur and J. S. Sandhu J. Chem. Soc. Chem. Commun. 1988 1444. P. A. Chaloner OSiEt CN I 8+ ___* cL/s 5 equivalents H Reagents i -78 "C; ii Et,SiCI Et3N THF -78 to 0 "C; iii PhSOz-OTs Pd(PPh,),CI, CuI LiCI THF 67 "C; iv N2CHC02Et C,H, bis-( N-benzylsalicylaldiminato)Cu( II) 85 "C; v CsF MeCN 80 "C Scheme 59 Reagents i CHCI, A; ii H, Pd/C Scheme 60 i.' R3 \ N-0 SOIPh 0 /L..,/COCl Reagents i R2 ,CH,CI, Py,0-25 "C 30 min; ii 03,CH,CI2 -78 "C 30min; iii Me,S; iv R3NHOH; v DBU CCI, A Scheme 61 Synthetic Methods Cycloaddition of nitrile oxides with N-acryloyl sultams has been used in the preparation of optically active A2-isoxazolines (Scheme 62).'03 Functionalized cyclic ethers were prepared by a novel intramolecular cycloaddition of nitrile oxides to alkenes (Scheme 63).'04 Reagents i RCNO hexane ii L-Selectride THF 25 "C Scheme 62 i-iii zo BrMe2CCN=NOSiMe3 -0 H Reagents i F-; ii CH,=CHCH,OH; iii NaOCl Scheme 63 A convenient alternative approach has been described for the synthesis of 2-acetoxymethyl-3-trimethylsilylpropene,a useful annulating agent.lo5 The outcome of palladium-catalysed cyclopentannulation using (19) or (20) depends strongly on the nature of the leaving group (Scheme 64).The unusual regioselectivity of the reaction arises from and may be explained by a combination of steric and electronic factors.' O6 A new class of organobis(cuprate) reagents has been prepared and used in a wide range of spiroannulation reactions (Scheme 65).'07 Other Ring Sizes. Copper(11) supported on Nafion perfluorinated ion exchange polymer has proved to be an efficient cyclopropanation catalyst. Unlike rhodium catalysts which were leached at a significant rate the supported catalyst could be reused at least ten times."' Fischer carbene complexes have been used as 103 D. P. Curran B. H. Kim J.Daugherty and T. A. Heffner Tetrahedron Lett. 1988 29 3555. 104 A. Padwa U. Chiacchio D. C. Dean A. M. Schoffstall A. Hassner and K. S. K. Murthey Tetrahedron Letf.,1988 29 4169. 105 B. M. Trost M. Buch and M. L. Miller J. Org. Chem. 1988 53 4887. 106 B. M. Trost S. M. Migrani and T. N. Nanninaga J. Am. Chem. SOC.,1988 110 1602. 107 P. A. Wender and A. H. White J. Am. Chem. Soc. 1988 110 2218. 108 W. A. Nugent and F. J. Waller Synth. Commun. 1988 18 61. P. A. Chaloner I Z SiMe (19) I Z SiMe3 (20) Z = electron withdrawing group Reagents i Pd( PPh3)4 C6H6 Scheme 64 -0 CuSPhLiC>PhLi 0 ~ c ,+ CuSPhLi I ~ 96% U Reagents THF -15 "C 1 h Scheme 65 cyclopropanation agents in the preparation of donor-acceptor substituted cyclo-propanes and vinylcyclopropanes derived from 1,3-dienes (Scheme 66).'09 Intramolecular [2 + 21 cycloadditions of ketenes to alkenes has been used in the preparations of a bicycloheptanones (Scheme 67)."' The enantiospecific synthesis R R-,COzMe -.+ Ph+C02Me Me0 R = Me Ph or C0,Me Reagents (OC)5Cr- 80-1 10 "C solvent Ph Scheme 66 A.Wienand and H. U. Reissig Tetrahedron Lett. 1988 29 2315; M. Buchert and H. U. Reissig ibid. p. 2319. 1LO B. B. Snider and M. Niwa Tetrahedron Lett. 1988,29,3175; S. Y. Lee Y. S. Kulkami B. W. Burbaum M. I. Johnston and B. B. Snider J. Org. Chem. 1988 53 1848. Synthetic Methods 29 1 Reagents i LiNPr; THF HMPA -78 "C; ii CH2=CHCH2CH2CH2Br -78 "C 3 h; iii 25 "C; iv NaH c~cococ~, C6H6 A 30 min; v Et3N C,H,Me A Scheme 67 of substituted p-lactams could be achieved by the annulation of Schiff bases from D-glyceraldehyde acetonide with acyl halides and base (Scheme 68); the products can be used as intermediates for the preparation of alkaloids carbohydrates and amino acids."' Reagents i R1NH2 Et,O 0°C; ii R2CH2COCI Et3N CH,CI, -20°C Scheme 68 Rearrangements and Fragmentations.-A number of useful intramolecular ene reac- tions have been described this year including diastereoselective reactions using FeC1,-A1,O3 or ZnBr as the catalysts (Scheme 69).' l2 An enantioselective reaction Me02C / Me02C Me02C $&JyJ+/* C02Me C02Me C02Me 98.8% 1.2% Reagents FeCI,-AI,O, CH2C12 -78 "C 1 h Scheme 69 was catalysed by a chiral titanium alkoxide complex (Scheme 7O),ll3 and it is perhaps also noteworthy that enantioselective ene reactions of prochiral aldehydes with alkenes have been catalysed by a chiral aluminium complex.' l4 A novel Wittig rearrangement has been used as a new method for the diastereoselective preparation of 1,2-diols (Scheme 7 1).Steric interactions in the 111 D. R.Wagle C. Garai J. Chiang M. G. Monteleone B. E. Kurys T. W. Strohmeyer V. R. Hegde M. S. Manhas and A. K. Bose J. Org. Chem. 1988 53 4227. 112 L. F. Tietze and U. Beifuss Synthesis 1988 359; L. F. Tietze U. Beifuss M. Rulher A. Ruhlmann J. Antel and G. M. Sheldrick Angew. Chem. Inl. Ed. Engl. 1988 27 1186. 113 K. Narasaka Y. Hayashi and S. Shimada Chem. Lett. 1988 1609.'14 K. Manuoka Y. Hoshino T. Shirasaka and H. Yamamoto Tetrahedron Lett. 1988 29 3967. P. A. Chaloner 63'/o 16% Ph Ph >98% e.e. Reagents ph<lpH TiCI,(OPr'), CFCI,CFCI, 4 A molecular sieves ..xOH Ph 'Ph Scheme 70 \\ Reagents i Bu'Me,SiOTf Et3N CH2C12 5 "C 5-10 min; ii BuLi THF -78 fa -65 "C 5 h Scheme 71 transition state impose the strong anti syn preferen~e."~ In a diastereoselective reaction (Scheme 72) stereocontrol was exerted over three contiguous chiral centres.' l6 ButMe2Si0 OH Ill + (B) SiMe Bu'MezSiO OH (A) (B) (C) Z-isomer i_ 77% 94% d.e. 4% d.e. E-isomer -L 93'/o 10% d.e. 50% d.e. Reagents BuLi THF -78 "C 5 h Scheme 72 115 E. Nakai and T. Nakai Tetrahedron Left.,1988 29 5409.116 E. Nakai and T. Nakai Tetrahedron Lett. 1988 29 4587. Synthetic Methods The Beckmann fragmentation of cyclic ketoximes could be directed by the presence of a silyl group to give o-unsaturated nitriles with good selectivity (Scheme 73)."' AcO Reagents CF,S03SiMe, CH2CI2 0-25 "C Scheme 73 Azacyclic compounds were prepared by rearrangement and ring expansion of N-(arylsu1phonoxy)amines (Scheme 74).' l8 Reagents (4-N02-C,H,S0,0) EtOH -78 "C Scheme 74 A synthesis of ketoalkylcyclopropanols has been described; they could be readily converted into cyclopentanones (Scheme 79.' l9 1-Siloxy-1 -alkylcyclopropanes reacted with aryl triflates in the presence of palladium-ally1 complexes to give RCOCH2CH2Ar in moderate to good yields.'20 EtO OMgBr Reagents i PrSNMgBr ; ii NaOH H20 A Scheme 75 3 Functional Group Modifications Oxidation.-Additions to C=C.There have been numerous reports of new epoxida- tion reactions. Hydrogen peroxide was used to epoxidize water-insoluble non-activated alkenes in the presence of quaternary ammonium tetrakis(diperoxotungst0) 117 H. Nishiyama K. Sakuta N. Osaka H. Arai M. Matsumoto and K. Itoh Tetrahedron 1988,44 2413. 11* R. V. Hoffman and G. A. Buntain 1. Org. Chem. 1988 53 3316. 119 J. T.Carey and P. Helquist Tetrahedron Lett. 1988 29,1243. 120 S.Aoki T.Fujimura E. Nakamura and I. Kuwajima J. Am. Chem. Soc. 1988 110,3296. P. A. Chaloner phosphates(3-); the reaction was tolerant of esters and ketones.121 Stereospecific epoxidation of cis- and trans-stilbene was effected by oxygen transfer from the oxaziridinium salt (21) The enantioselective Sharpless epoxidation was used in syntheses of vinyl di01s'~~ and chiral ph~sphines,'~~ in each case by regio- and stereoselective opening of the initially formed epoxide (Scheme 76).Further details have been given of the asymmetric dihydroxylation of alkenes via ligand-accelerated osmium ~atalysis.'~~ I OH OH OH PPh2 OH R+ PPh2 + R,& PPh2 I A OH PPh2 Reagents i Bu'OOH Ti(OPr'), (+)-L-DIPT,CH2Clz,-20 "C,20 h; ii [Bu,N]F 0 "C,30 min; iii Bu'OOH Ti(OPr'), (+)-L-DET CH2CI2,-20 "C,3 h; iv TsCI Py,-1O"C 20 h; v LiPPh, THF Scheme 76 Other Oxidations. Again this year there have been reports of a range of selective oxidizing agents for secondary alcohols.Reagents included Bu'OC1 in the presence of pyridine'26 and H,O,-tricetylpyridinium 12-t~ngstophosphate.'~~ Both primary and secondary alcohols were oxidized by pyrazinium chlorochromate,128 and phenyl-dichlorophosphatewas used as an activating agent for DMSO in the Pfitzner- 121 C. Venturello and R. D'Aloisio J. Org. Chem. 1988 53 1553. 122 G. Hanquet X.Lusinchi and P. Milliot Tetrahedron Lett. 1988 29 3941. 123 T. Matsumoto Y. Kitano and F. Sato Tetrahedron Lett. 1988 29,5685. 124 H.Brunner and A. Sicheneder Angew. Chem. Int. Ed. Engl. 1988 27 718. 125 E. N. Jacobsen I. Marko W. S. Mungall G. Schroder and K. B. Sharpless J. Am. Chem. Soc. 1988 110 1968. 126 J. N. Milovanovic M.Vasojevic and S. Govkovic J. Chem..Soc. Perkin Trans. 2 1988 533. 127 K.Yamawaki H. Nishihara T. Yoshida T. Ura H. Yamada Y. Ishii and M. Ogawa Synth. Commun. 1988 18 869. 128 G. J. S. Doad J. Chem. Res. (S) 1988 270. Synthetic Methods 295 Moff at 0~idation.l~~ A convenient and efficient one-pot procedure for the direct conversion of aldehydes into esters using bromine as an oxidant has been devised (Br2 H20 MeOH NaHCO, 22 "C 3-5 h); secondary hydroxyl groups protected as MOM MEM Bn Bz Ph,Bu'Si or acetal derivatives all survived the reaction condition^.'^' a-Mesylation of ketones and a-dicarbonyl compounds was effected by PhI(0H)- (OMS) but few reactions were regio~elective.'~' Chiral a-hydroxy ketones were prepared by oxygenation of ketone enolates in the presence of P(OEt) and a chiral phase transfer catalyst such as a cinchonine salt.'32 The enantioselective synthesis of protected a-hydroxy aldehydes and ketones via the hydroxylation of metallated chiral hydrazones has been reported; enantiomeric excesses were generally better than 90% (Scheme 77).13 Oxidative ring cleavage of epoxides by CF3S03H-DMS0 provided an alternative preparation of a-ketols which was used in an approach to the taxane~.',~ n 0 Reagents i ;ii LiNPr; THF 0 "C;iii PhANSOzPh ,-85 "C; iv NaOH DMF; R3 NHz R3 v PhCH,CI; vi 03,CH2CI, -78 "C Scheme 77 The oxidation of nitroalkanes to ketones occurred in the presence of the cobalt Schiff base complex [Co(salpr)] under mild conditions and in excellent yields.'35 Ketoximes were prepared in a regiospecific manner from aryl-conjugated alkenes and ethyl nitrite in the presence of cobalt(~~).'~~ The enzyme isolated from Acinetobacter NC1B 9871 effected Baeyer-Villiger oxidation of meso-cyclo-hexanones such as (22) in better than 98% e.e.(Scheme 78).13' Asymmetric oxidation of selenides has been accomplished under Sharpless epoxi- dation condition^,'^^ whilst the asymmetric oxidation of sulphides by Bu'OOH was catalysed by the enzyme chlor~peroxidase.'~~ '29 H.-J. Liu and J. M. Nyangulu Tetrahedron Lett. 1988 29 3167. 130 D. R. Williams F. D. Klingler E. E. Allen and F. W. Lichtenthalen Tetrahedron Lett. 1988 29 5087. 131 J. S. Lodaya and G. F. Koser J. Org. Chem. 1988 53 210. 132 M.Masui A. Ando and T. Shioiri Tetrahedron Lett. 1988 29 2835. 133 D. Enders and V. Bhushan Tetrahedron Lett. 1988 29 2437. 134 B. M. Trost and M. J. Fray Tetrahedron Lett. 1988 29 2163. 135 A. Nishinaga S. Morikawa K. Yoshida and T. Matsuura Nippon Kagaku Kaishi 1988 487. 136 T. Okamoto K. Kobayashi S. Oka and S. Tanimoto J. Org. Chem. 1988 53 4897. 137 M. J. Taschner and D. J. Black J. Am. Chem. Soc. 1988 110 6892. 138 T. Shimizu M. Kobayashi and N. Kamagita Sulfur Lett. 1988 8 61. I39 S. Colonna N. Gagero A. Manfredi L. Casella and M. Gullotti J. Chem. SOC.,Chem. Commun. 1988 1451. l? A. Chaloner (22) 73% > 98% e.e. Reagents enzyme from Acinetobacter NClB 9871 glycine NaOH pH 8 NADPH (recycled) Scheme 78 Reduction.-Hydrogenation of Carbon -Carbon Multiple Bonds.The uses of ammonium formate in catalytic hydrogen transfer have been reviewed.',' Another asymmetric synthesis of carboxylic acids containing two adjacent chiral centres [such as (23)] has been achieved by hydrogenation in the presence of (24) with good selectively (92% e.e.).141 The fact that the two enantiomers of (25) are reduced at different rates in the presence of (BINAP)Ru(OAc) has been used in a practical kinetic resolution of the ally1 alcohol although recoveries were not particularly high.'42 A number of selective reductions of the carbon-carbon double bond in enones and unsaturated nitro compounds have been noted; use of the Hantzsch ester as reductant gave particularly successful re~u1ts.l~~ Enones were also reduced to ketones by conjugate addition using (Ph,PCUH)6 .la Alkylamines were obtained from nitroalkenes using LiEt,BH in the presence of borane; mechanistic studies suggested a reaction sequence involving 1,2-addition of Et,B to a nitroso intermediate.14' Hydrogenation of Carbonyl Compounds.A general method has been developed for the selective reduction of ketones in the presence of enones using NaBH in MeOH-CH,Cl (1:1) at -78 0C.146In selective carbonyl reduction methylaluminium bis(di-t-butylmethylphenoxide)may be used as a protective group for the more reactive carbonyl group in the molecule (Scheme 79).'47 The reduction of dicarbonyl compounds to hydroxycarbonyl derivatives and unsaturated carbonyl compounds to allylic alcohols was catalysed by zirconocene or hafnocene complexes using propan-2-01 as the red~ctant.'~' 140 S.Ram and R. E. Ehrenkaufer Synthesis 1988 91. 141 T. Hayashi N. Kawamura and Y. Ito Tetrahedron Lett. 1988 29 5969. 142 M. Kitamura I. Kasahara K. Manabe R. Noyori and H. Takaya J. Org. Chern. 1988 53 708. 143 Y. Inoue S. Imaizumi H. Itoh T. Shinya H. Hashimoto and S. Mujano Bull. Chem. SOC.Jpn. 1988 61 3020; M. Fujii ibid. p. 4029. 144 W. S. Mahoney D. M. Breslensky and J. M. Stryker J. Am. Chem. SOC.,1988 110 291. 145 G. W. Kabalka J.-Z. Gal N. M. Goudgaon R. S. Varma and E. E. Gooch Organometallics 1988,7,493. D. E. Ward C. K. Rhee and W. M. Zoghaib Tetrahedron Lett. 1988 29 517. K. Maruoka Y. Araki and H. Yamarnoto J.Am. Chem. Soc. 1988 110 2650. T. Nakano S. Umano Y. Kino Y. Ishii and M. Ogawa J. Org. Chem. 1988 53 3752. 146 147 148 Synthetic Methods 297 + ph~~cH2)4~0 HO [product ratio 7 1 :31 Reagents MeAl-(- 0 )* DIBAH -78 "C Scheme 79 The diastereoselective reduction of P-hydroxy ketones was effected using [Me,N]-[HB(OAc),] at -40 "C (Scheme 80). The reaction seems to involve complex forma- tion by exchange and intramolecular delivery of h~dride.'~~ Reagents [Me,N][HB(OAc),] -40 "C 5 h Scheme 80 Enantioselective reactions have again been widely reported. Baker's yeast is once more in vogue with asymmetric reductions of P-and y-nitro ketone^,'^' a-keto ester^,'^' and N-substituted acet~acetamides.'~~ A particularly intriguing example involved the first partial kinetic resolution of a planar chiral ketone-chromium tricarbonyl complex (Scheme 81).'53 Stereoselective reductions of prochiral ketones and of a prochiral imine were effected using an optically active methyldihydropyridine (26) and magnesium per- chlorate.Steric interactions were dominant and the hydroxy group of the reagent was used to anchor the ~ubstrate.'~~ Most of the chiral systems which have been used to reduce prochiral ketones have given selective results only with aryl alkyl I49 D. A. Evans K. T. Chapman and E. M. Carreira J. Am. Chem. Soc. 1988 110 3560. 150 K. Nakamura Y. Inoue J. Shibahara S. Oka and A. Ohno Tetrahedron Lett. 1988 29 4769. 151 K. Nakmura K. Inoue K. Ushio S.Oka and A. Ohno J. Org Chem. 1988 53 2589. 152 M. Kawai K. Tajima S. Mizuno K. Niimi H. Sugioka Y. Butsugan A. Kozawa T. Asano and Y. Imai Bull. Chem. Soc. Jpn. 1988 61 3014. 153 J. Gillois D. Buisson R. Azerad and J. Jaouen J. Chem. Soc. Chem. Commun. 1988 1224. 154 A. I. Meyers and J. D. Brown Tetrahedron Letr. 1988 29 5617. 298 P. A. Chaloner fyiqyl.+~+& 'OH ,' Cr(c0) C~(CO) C~(CO) C~(CO) 47% S-endo 5% S-exo ki 51% e.e. 71% e.e. ?H m cr(CO) 48% R-endo Reagents i baker's yeast glucose H,O EtOH; ii NaBH 25% e.e. Scheme 81 ketones and related substrates. A new reagent potassium diisopropylidene- glucofuranosylboratabicyclononane (27) however has been used with simple aliphatic ketones; thus (28) was reduced with 84% e.e.'55 Other Reductions.Acid chlorides have been reduced to aldehydes using the hyper- valent silicon reagent (29); yields were generally in excess of 95%.Is6 Highly activated uranium metal was prepared from UC14 and [(tmeda)Li],[Np]. With this reagent both benzoin and benzil were rapidly reduced to diphenylacetylene. A maximum of 30% could be isolated since further reduction to cis-stilbene was rapid.lS7 H.C. Brown B. T. Cho and W. S. Park J. Org. Chem. 1988 53 1231. lS6 R. J. P. Corriu G. F. Lanneau and M. Perrot Tetrahedron Lett. 1988 29 1271. 15' B. E. Cahn and R. D. Rieke J. Organomer. Chem. 1988 346 C45. Synthetic Methods 1,4-Bis(diphenylhydrosilyl)benzenegave better results in the deoxygenation of ace- tates than Ph,SiH."* A one-pot conversion of phenols into arenes has been described (Scheme 82); the intermediates in the reaction could also be coupled with alkenyl and alkynyl metal derivative^.'^^ OH Y = C1 OMe CHO or CH=CH Reagents i RS02F Et3N; ii HC02H Pd(PPh3)2C12 DMF 80°C 8-20 h Scheme 82 The first really successful asymmetric hydrogenation of imines has been reported using rhodium complexes of Cycphos as the catalysts.The presence of added iodide ion proved to be crucial to the reaction which in the best case gave up to 91% e.e. Only the imines of aryl aldehydes and ketones gave successful results.'60 Asymmetric reduction of oxime ethers was accomplished using borane in the presence of (30). The anti-ethers generally gave (S)-products and the syn-substrates (R)-amines in 79-92'/0 e.e.16' Nitropyridines could be reduced to aminopyridines using a titanium(0) slurry; conditions were mild and selectivities high.162 A range of aromatic nitro compounds were reduced to azoxy compounds by sodium benzenetellurolate prepared in situ from NaBH and catalytic PhTeTePh.I6 Non-redox Conversions.-Substitution at sp3- Hybridized Carbon.The regio- and chemoselective ring opening of epoxides with trimethylsilyl azides has been noted; attack of azide was at the less-substituted carbon atom.'64 Regioselective opening of 2,3-epoxy alcohols (31) with a titanium azide complex was also regioselective (Scheme 83); the 3-azido-1,2-diols were transformed into a-amino acids in two steps.'65 Opening of (32) with sodium benzenethiolate supported on zeolite CaY 158 H.Sano T. Takeda and T. Migita Chem. Lett. 1988 119. 159 Q. Chen and Y. He Synthesis 1988 896. 160 G. Kang W. R. Cullen M. D. Fryzuk B. R. James and J. P. Kutney J. Chern. Soc. Chem. Comrnun. 1988 1466. 161 Y. Sakito Y. Yoneyoshi and G. Suzukamo Tetrahedron Lett. 1988 29 223. 162 M. Malinowski Bull. SOC.Chim. Belg. 1988 97 51. 163 K. Ohe H. Takahashi S. Uemura and N. Sugita J. Chem. SOC.,Chem. Commun. 1988 591. 164 M. Emziane P. Lhosle and D. Sinou Synthesis 1988 541. 165 M. Caron P. R. Cartier and K. B. Sharpless J. Org. Chern. 1988 53 5185. P. A. Chaloner OH 0 -&OH + &OH (31) OH 31:l N3 Reagents Ti(N3)2(OPri)2,C6H6 70°C 5 min Scheme 83 was also regioselective.'66 Enantioselective cleavage of cyclohexene epoxide was effected by halogenodiisopinocampenylboranes (33); for X = I the reaction was close to completely enantio~elective.'~~ There continues to be considerable interest in the functionalization of enolates and related reactions.P-Dicarbonyl compounds were converted into azides using PhIO-Me,SiN (Scheme 84).16*Electrophilic sulphenylation of silyl ketene acetals N3 Reagents PhIO Me3SiN, CHCI, 25 "C (2 h) A (3 h) Scheme 84 derived from 3-hydroxy esters provided a useful diastereoselective synthesis of protected epoxyalcohols (Scheme 85).'69 Enantioselective fluorination of P-dicar-bony1 compounds was accomplished using (34),170 and a-selenylation with (35) both in about 60% e.e.l7' Me3Si0 OSiMe3 OSiMe3 ArSCl RdOEt -R&C02Et 4-I SAr SAr syn :anti = 20 :80-6 :94 Scheme 85 166 M.Onaka K. Sugita H. Takeuchi and Y. Izumi J. Chem. SOC.,Chem. Commun. 1988 1173. 167 N. N. Joshi M. Srebnik and H. C. Brown J. Am. Chem. SOC.,1988 110 6246. 168 R. M. Moriarty R. K. Vaid V. T. Ravikumar B. K. Vaid and T. E. Hopkins Tetrahedron 1988,44 1603. 169 G. Guanti L. Banfi E. Narisano and S. Thea Chem. Lett. 1988 1683. 170 E. Differding and R. W. Lang Tetrahedron Lett. 1988 29 6087. 171 C. Paulmier F. Outurquin and J.-C. Plaquevent Tetrahedron Lerr. 1988 29 5889. Synthetic Methods 301 Adamantanes have been brominated at the bridgehead position under mild condi-tions using Br,-H,O at 30°C.’72Silyl ethers may be directly converted into alkyl bromides using BBr .173 The selective formation of P-glycosidic linkages in oligosaccharide synthesis has been accomplished using an alkylsulphenyl triflate as activator.17* Desoxysugars have been prepared via a radical reaction of (36) (Scheme 86); migration of 0-benzyl (Cc AcO- 6 -Br AcO--0Ac )-Br )i.OAc AcO AcO (36) Reagents Bu3SnH AIBN C6H6 A 10 h Scheme 86 groups was also possible.175 Asymmetric cyclization of butylene dicarbamates was catalysed by chiral ferrocenylphosphine palladium complexes (Scheme 87).176 PhNHCOz-OzCNHPh -OH NHPh 80% 73% e.e.Reagents i . ii KOH MeOH A pph2 ‘CH(CH~OH)? * ’PPh2 \ ‘Pd-Cl c1I Scheme 87 Substitution at sp2-Hybridized Carbon.The lithiation of secondary allyl-and methal-lylamines was both regio-and stereoselective; reactions of the dilithio species with 1j2 C. A. Grob and P. Sawlewicz Helv. Chim. Acfa 1988 71 1508. S. Kim and J. H. Park J. Org. Chern 1988 53 3111. 174 F. Dasgupta and P. J. Garegg Carbohydr. Rex 1988 177 C13. 175 B. Giese S. Gilges K.-S. Groninger C. Lamberth and T. Witzel Liebigs Ann. Chem. 1988 615. 176 T. Hayashi A. Yamamoto and Y. Ito ‘Tetrahedron Left. 1988 29 99. 302 P. A. Chaloner a range of electrophiles was investigated (Scheme 88).'77 Vinylic chlorination of enones was achieved through Lewis acid-catalysed reaction with PhSeOC1.'78 Li I R~NH i ii R'N ........ Li ... . 1v R'NH R2 R2 R2 Reagents i BuLi; ii Bu'Li; iii MeSSMe; iv H,O Scheme 88 New procedures for the regeneration of carbonyl compounds from nitrogenous derivatives have been developed.Amberlyst 15 was a mild and selective acid catalyst,'79 and Dowex 50 proved to be selective for the derivatives of ketones over those of aldehydes.'80 Hydrazones were converted directly into geminal dibromides using two equivalents of bromine in Et,N-ether the reaction being particularly successful for sterically hindered substrates.18' Reactions that include amide hydrolysis and ester formation were found to be greatly accelerated by being performed in sealed Teflon vessels in a microwave oven.lB2 Aminolysis of prochiral dicarboxylic anhydrides was achieved using (37); diastereoisomeric excesses of up to 94% were reported.'83 More examples of the enantioselective formation and hydrolysis of acid derivatives catalysed by enzymes have been reported this year.Solvent effects were very impor- tant in the asymmetric acylation of amino alcohols by porcine pancreatic lipase (PPL) (Scheme 89).'84 Irreversible and highly enantioselective acylation of 2-halogeno-1-arylethanols in organic solvents was catalysed by a lipase from Pseudornonas Jluore~cens.'~~ A lipase from Pseudornonas species was used in the selective hydrolysis of (38); both products were obtained in better than 99% e.e.IB6 Enantioselective hydrolysis of open chain and cyclic nitropropane diol diacetates 3.7 HNKS 1 S Ar OAc 177 J. Barluenga F. J. Fafianis F. Foubelo and M. Yus J. Chem. Soc.Chem. Commun.,1988 1135. 17' N. Kamigata T. Satoh and M. Yoshida Bull. Chem. Soc. Jpn. 1988 61 449. 179 R. Ballini and M. Petrini J. Chem Soc. Perkin Trans. 1 1988 2563. 1an B. C. Ranu and D. C. Sarkar J. Org. Chem.. 1988 53 878. I81 F. S. Guziec and L. J. SanFilippo Synthesis 1988 547. 182 R. N. Gedye F. E. Smith and K. C. Westaway Can. J. Chem. 1988 66 17. 183 Y. Nagao Y. Hagiwara Y. Hasegawa M. Ochiai T. Inoue M. Shiro and E. Fujita Chem Lett. 1988 381. 184 V. Gotor R. Brieva and F. Rebolledo J. Chem. Soc. Chem. Commun. 1988,957. 185 J. Hiratake M. Inagaki T. Nishioka and J. Oda J. Org. Chem. 1988 53 6130. 186 K. Laumen and M. P. Schneider J. Chem. Soc. Chem. Commun. 1988 598. Synthetic Methods 3 03 TOH i_ -OH + TOAc NH2 NHAc NHCOMe (*) R > 95% e.e.S > 95% e.e. Reagents PPL EtOAc 25 "C 20 h Scheme 89 was effected by pig liver esterase (Scheme 90). Elimination of water or acetic acid from the products gave derivatives of nitroallyl alcohols which undergo diastereoselective Michael additions or SN2' substitution^.'^^ 8O-90% >95% e.e. Reagents pig liver esterase Scheme 90 Addition to Carbon- Carbon Multiple Bonds. The silylcupration of allene (Scheme 91) gave initially (39) a synthon for trimethylenemethane.'88 Substantial regio- and SiMe2Ph H,C=C=CH 4''-iii iv ,=cSiMezPh SiMe2Ph I X (39) Reagents i (PhMe,Si),CuLi THF -78 "C 1 h; ii I, THF 1 h; iii BuLi THF -7O"C 30min; iv X+ (DzO MeI HCHO Me,CO or MeCH=CHCHO) Scheme 91 stereochemical control was noted in the rhodium( I)-catalysed hydroboration of alkenes in both cyclic and acyclic systems (Scheme 92).lS9The rhodium-BINAP- catalysed hydroboration of norbornene proceeded in up to 64% e.e.19' The palladium-catalysed asymmetric disilylation of enones gave p-silyl enol ethers which could be hydrolysed and oxidized to give P-hydroxy ketones with good enantioselectivity (Scheme 93).I9l 187 M.Eberle M. Egli and D. Seebach Helv. Chim. Actu 1988 71 1. lX8 P. Cuadrado A. M. Gonzalez F. J. Pulido and I. Fleming Tetrahedron Lett. 1988 29 1825. 189 D. A. Evans G. C. Fu and A. H. Hoveyda J. Am. Chem. Soc. 1988 110 6917. 190 K. Burgess and M. H. Ohlmeyer J. Org. Chem. 1988 53 5178. 191 T. Hayashi Y. Matsumoto and Y.Ito J. Am. Chem. SOC.,1988 110 5579. P. A. Chaloner i + 50:50 i + ii + 90:lO Reagents i 9-BBN THF 25 "C; ii Rh(PPh,),CI Scheme 92 qPh OH 90°/o 87% e.e. Reagents i PhCl,SiSiMe, (BINAP)PdCI,; ii MeLi; iii [H,O]+; iv HBF,; v H20 Scheme 93 Miscellaneous. A number of interesting aldehyde addition reactions have been reported. The addition of hydrazoic acid in the presence of TiC14 and an alcohol gave a-azido ethers gas-phase thermolysis or photolysis of which gave mainly imino ethers.'92 Addition of trimethylsilyl cyanide to amino aldehydes in the presence of a Lewis acid may give either (40) the chelation control product or (41) from a non-chelation-controlled reaction. Using ZnBr2 (41) was the main product but in the presence of TiC14 (40) was formed with reasonable ~electivity.'~~ Using the Lewis acid prepared from Ti(OPri)2C12 and (42) asymmetric addition occurred in 61-93% e.e.194 Asymmetric hydrocyanation of aryl aldehydes was effected by KCN-HOAc in the presence of the enzyme oxynitrilase present in almond fl0~r.l~' 192 A.Hassner R.Fibiger and A. S. Amarasekara J. Org. Chem. 1988 53 22. 193 M. T. Reetz M. W. Drewes K. Harms and W. Reif Tetrahedron Lett. 1988 29. 3295. 194 H. Minamikawa S.Hayakawa T. Yamada N. Iwasawa and K. Narasaka Bull. Chem. SOC.Jpn. 1988 61 4379. 195 J. Brussee E. C. Roos and A. van der Gen Tetrahedron Lett. 1988 29 4485. Synthetic Methods An improved synthesis of vinyl iodides and phenylvinyl selenides from hydrazones has been described (Scheme 94).'96 dz- 90% Reagents i N-t-butyl-N',N',N",N"-tetramethylguanidine, 12 Et20 30 min; ii 90 "C no solvent 1 h; iii N-t-butyl-N',N',N,N"-tetramethylguanidine, PhSeBr THF Scheme 94 Again there have been a number of reports of new alcohol-protecting groups.THP ethers of allyl propargyl and benzylic alcohols were obtained in good to excellent yields and without dehydration when [Ph,PH]Br was used as the catalyst under mild condition^.'^' Primary alcohols reacted selectively with Ph,Si(OBu')Cl- Et3N; the alcohols protected a; ROSiPh,OBu' were stable to acid but could be readily deprotected with fluoride The diol(43) was monoprotected with good selectively (Scheme 95).'99 4,4'-Dinitrobenzhydryl ethers have found applications as protecting groups with good stability towards both acid and base.," (431 Reagents HC(OMe), D-camphorsulphonic acid CH2CI, 25 "C 24 h; ii DIBAH hexane CH,C12 -78 "C (30 min) 0 "C (10 min) Scheme 95 '5-6 D.H. R. Barton G. Bashiardes and J.-L. Fourrey Tetrahedron 1988 44 147. 197 V. Bolitt C. Mioskowski D.-S. Shin and J. R. Falck Tetrahedron Lett. 1988 29 4583. 198 J. W. Gillard R. Fortin H. E. Morton C. Yoakim C. A. Quesnelle S. Daignault and Y. Guindon J. Org. Chem. 1988 53 2602. 199 M. Takasu Y.Naruse and H. Yamamoto Tetrahedron Lett. 1988 29 1947. 200 G. Just Z. Y. Wang and L. Chan J. Org. Chem. 1988 53 1030.

ISSN:0069-3030    

DOI:10.1039/OC9888500265

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

11 Biological Chemistry Part (i) Enzyme Chemistry By N. J. TURNER Department of Chemistry University of Exeter Exeter EX4 400 1 Introduction This review covers the literature relevant to the use of enzymes for organic synthesis. The advantages and limitations of using enzymes and whole cells for synthesis have been described in a number of previous reviews.’-7 It is readily apparent from these reports that the oxidoreductases (e.g. baker’s yeast alcohol dehydrogenases) and hydrolytic enzymes (e.g. microbial lipases pig-liver esterase) have found the most widespread application owing to a combination of ease of use broad spectrum of substrates tolerated and predictable stereoselectivity of the biotransformation. In this review the objective has been to cover a wide range of enzyme-catalysed reactions that are either currently being applied to synthesis or have the potential to provide synthetic methodology in areas where chemical-based approaches are inefficient.2 Hydrolytic Enzymes Reactions in Aqueous Media.-Jones has found that the stereospecificities of the isozyme components of commercially available pig-liver esterase are essentially the same towards representative monocyclic and acyclic diester substrates.8 Thus pig- liver esterase can be exploited synthetically as a chiral catalyst with confidence that it will behave as if it were a single protein. Schneider has described the use of a highly selective lipase from a species of Pseudornon~s.~ Various enantiomerically pure secondary alcohols (e.g.PhCHMeOH PhCHCF,OH PhCH,CHMeOH) were prepared in high chemical and optical yields by lipase-catalysed hydrolysis of the ’ G. M. Whitesides and C.-H. Wong Angew. Chem. Int. Ed. Engl. 1985 24 617. J. B. Jones Tetrahedron 1986 42 3351. S. Butt and S. M. Roberts Nut. Prod. Rep. 1986 489. M. P. Schneider and E. H. Reimerdes Forum MikrobioL 1987 10 307. J. B. Jones Proc. 3rd FECS Int. Conf. Chem. Biotechnol. Biol. Act. Nat. Prod. 1985 (publ. 1987) Vol. 1 p. 18. P. E. Sonnet CHEMTECH 1988 18 94. ’H. G. Davies R. H. Green D. R. Kelly and S. M. Roberts ‘Biotransformations in Preparative Organic Chemistry The Use of Isolated Enzymes and Whole Cell Systems in Synthesis’ Academic Press London 1989. L. K. P. Lam C. M. Brown B. De Jeso L. Lym E. J. Toone and J.B. Jones J. Am. Chem. SOC.,1988 110 4409. K. Laumen and M. P. Schneider J. Chem. SOC.,Chem. Commun. 1988 598. 307 308 N. J. Turner corresponding racemic esters. The rate-determining step was postulated to be hydro- lysis of the acyl-enzyme intermediate since different acetates (e.g. OCOCH, OCOCF,) were hydrolysed at different rates. The stereoselectivity of Mucor miehei lipase with various substrates including phospholipids has been reviewed." A study has been made of the preferred orientation of ester groups in hydrolyses catalysed by pig-liver esterase using conformationally rigid substrates.' 'It was shown conclusively that cyclohexane rings with methoxycarbonyl groups in the equatorial (1) rather than axial (2) position are preferentially hydrolysed by pig-liver esterase by a factor of four to seven (Scheme 1).This result is in agreement with previous work by Tamm.'* Reagents i pig-liver esterase 5% MeOH Scheme 1 The esterase- (steapsin) catalysed hydrolysis of racemic isobutyl3,4-epoxybutyrate occurred with good stereoselectivity yielding the unreacted ester (3) having the R configuration (> 95% enantiomeric excess). This intermediate was subsequently hydrolysed non-selectively with alcalase to give (4)and converted into (R)-(-)-carnitine chloride (5).' (3) (4) A strategy for enhancing the enantiomeric specificity of lipase-catalysed hydrolysis of esters has been developed by Sih.I4 Thus in the hydrolysis of the substrates (6) little or no enantioselectivity was observed using lipase from a species of Pseudomonas.However the introduction of a non-hydrolysable ester-protecting group for the carboxylic acid (7) led to hydrolysis of the acetate group yielding the corresponding (R)-hydroxy t-butyl esters with >99% e.e. Porcine pancreatic lipase has been used to prepare the chiral intermediate (8) from the corresponding racemic acetate in enantiomerically pure form. This key lo P. E. Sonnet J. Am. Oil Chem. SOC. 1988 65 900. L. K. P. Lam and J. B. Jones J. Org. Chem. 1988 53 2673. l2 P. Mohr N. Waespe-SarEeviE C. Tamm K. Gawronska and J. G. Gawronski Helu. Chim. Acta 1983 66 2501. l3 D. Bianchi W. Cabri P. Cesti F. Francalanci and M. Ricci J. Org. Chem. 1988 53 104. A. Scilimati T. K. Ngooi and C. J. Sih Tetrahedron Lett.1988 29 4927. 309 Biological Chemistry-Part (i) Enzyme Chemistry 0 0 TBDMSO OAc C02Me Cl+ chiral building block was used for a convergent synthesis of the anti-tumour marine prostanoid punaglandin 4 (9) in overall yield of 1.5%.I5 y- 8- and E-lactones undergo ring opening with concomitant kinetic resolution in the presence of porcine pancreatic lipase horse-liver esterase or pig-liver esterase. Yields are in the region 60-90% with 35-92% e.e.I6 Crout has provided an interesting example of the tolerance of pig-liver esterase for unusual substrates by enzymically resolving the racemic organometallic ester 2-ethoxycarbonylbuta-1,3-dienetricarbonyliron (10). The enantiomeric excesses of both the product (11) and unreacted ester (10) were 85% and could be raised to 98% by one recry~tallization.’~ (c0)37e ,C02Et pig-liver esterase ____* 20% MeOH pH 7,40 h Reactions in Organic Solvents.-Several reviews have been published dealing with the use of enzymes particularly proteases esterases and lipases in organic sol-vent~.’*”~ Pancreatin in dry tetrahydrofuran-triethylamine (25 :1) catalyses the highly enantioselective esterification of the meso-diol (12) with 2,2,2-trichloroethyl acetate to yield the monoacetate (13) in 48% yield and 95% e.e.The diacetate (14) formed in 48% yield could be hydrolysed and reused. In the absence of triethyl-amine the transesterification was very slow.2o l5 K. Mori and T. Takeuchi Tetrahedron 1988 44 333. 16 L. Bianco E.Guibe-Jampel and G. Rousseau Tetrahedron Lett. 1988 29 1915. 17 N. W. Alcock D. H. G. Crout C. M. Henderson and S. E. Thomas J. Chem. Soc. Chem. Commun. 1988 746. la A. M. Klibanov CHEMTECH 1986 354. 19 A. Zaks and A. M. Klibanov Science 1984 224 1249. 20 F. Theil S. Ballschuh H. Schick M. Haupt B. Hafner and S. Schwarz Synthesis 1988 540. 310 N. J. Turner Two groups have prepared macrocyclic lactones by the use of lipases in organic solvents. The long-chain hydroxy esters (15) underwent lactonization in the presence of lipase to give the desired product (16) and the diolide (17). The ratio of (16) to (17) was found to be 2.7 1 when n = 15 falling to 1.5:1 when n = 12. The il 0 enantioselectivity of the reaction was demonstrated by the conversion of racemic methyl 10-hydroxyundecanoate into exclusively the (R)-isomer of the corresponding lactone.2’ An alternative approach relied on direct condensation of diacids with diols in non-aqueous media (e.g.iso-octane CC14 PhMe hexane and EtOH) in the presence of lipases from Cundidu cylundriceu Pseudomonus species and porcine pancreas. Best results were obtained with ring sizes of 24-28.22 Papain in a biphasic system consisting of McIlvaine buffer and ethyl acetate- triethylamine catalyses the condensation of [( p-methoxybenzyl)oxy]carbonyl-L-aspartic acid and L-phenylalanine methyl ester to give (18) -a precursor for the artificial sweetener aspartame -in 45% yield. This enzymic process offers the advantage over the chemical method that no protection of the side-chain carboxyl group of the aspartyl residue is required.23 By the use of organic solvents the amidase activities of certain serine and cysteine proteases (e.g.trypsin chymotrypsin papain and subtilisin) can be reduced whilst still retaining significant esterase activities. Under these conditions the enzymes can ’’ A. Makita T. Nihira and Y. Yarnada Terrahedron Leu. 1987 28 805. 22 Z. W. Wei and C. J. Sih J. Am. Chem. SOC.,1988 110 1999. 23 S. T. Chen and K. T. Wang J. Org. Chem. 1988 53 4589. 311 Biological Chemistry- Part (i) Enzyme Chemistry be used as peptide ligases in a kinetically controlled approach for the stepwise synthesis and fragment coupling of peptides. Importantly the products are free from the secondary hydrolysis that normally accompanies protease-catalysed peptide synthesis.This methodology was used to prepare peptides containing both D-and L-amino acids.24 When papain was modified with 2,4-bis-[ 0-methoxypoly(ethy1ene glycol)]-6- chloro-s- triazine [activated poly( ethylene glycol)] the resulting immobilized bio- catalyst was soluble in benzene and retained catalytic activity. To demonstrate its use N-benzoyl-L-alanine alkylamides were synthesized from N-benzoyl-L-alanine methyl ester and various alkylamine~.~~ The result of modifying thermolysin with poly(ethy1ene glycol) was to alter its specificity towards substrates. Thus in organic solvents hydrophilic as well as acidic amino acids were better carboxyl donors than hydrophobic residues contrary to what is observed in both the enzyme-catalysed synthesis and hydrolysis of peptide bonds in water.26 An interesting pointer to the future use of enzymes in environments other than water/organic solvents is provided by the studies on the interesterification reactions catalysed by lipases in supercritical carbon dioxide.Thus lipases from Rhizopus delemar R. japonicus and M. rniehei were found to catalyse interesterification of triolein and stearic acid in supercritical carbon dioxide at 50 "C and 29.4 MPa.27 3 Oxidoreductases Baker's yeast reduction of the N-protected keto proline (19) gave the (+)-cis-(2R 3S)-3-hydroxyproline (20) (80% e.e. 99% d.e.). Subsequent chemical trans- formations converted (20) into (-)-( 1S 5s)-2-oxa-6-azabicyclo[3.3.0]octan-3-one (Geissman- Waiss lactone) (21) and also provided for formal total syntheses of (-)-retronecine and related pyrrolizidine alkaloids.28 HO H (s-.'02Et baker'syeast ___ H c1- \ BOC BOC The keto alcohol (22) has been prepared on an 8 g scale by reduction of the corresponding prochiral diketone using Pichia terricola (>99% e.e.).(22) was then converted into the corresponding 3,5-dinitrobenzoate which was recrystallized to purity. This was then used as the enantiomerically pure starting material for the synthesis of the naturally occurring isomers of juvenile hormones I (23) and I1 (24). Overall yields were 2.7 and 1.2% re~pectively.~~ 24 C. F. Barbas 111 J. R. Matos J. B. West and C.-H. Wong J. Am.Chem. Soc. 1988 110 5162. 25 H. Lee K. Takahashi Y. Kodera K. Owada T. Tsuzuki A. Matsushima and Y. Inada Biotechnol. Lett. 1988 10 403. 26 A. Ferjancic A. Puigserver and H. Gaertner Biotechnol. Lett. 1988 10 101. 27 Y. M. Chi K. Nakamura and T. Yano Agric. Biol. Chem. 1988 52 1541. 28 J. Cooper P. T. Gallagher and D. W. Knight J. Chem. Soc. Chem. Cownun. 1988 509. 29 K. Mori and K. Fujiwhara Tetrahedron 1988 44 343. 312 N. J. Turner H (22) (23) R = Me (24) R = H Practical procedures have been developed for the enantioselective reduction of 2-acetylfuran and 2-trifluoroacetylfuran to the corresponding carbinols (S)-2-acetylfuran and (S)-2- trifluoroacetylfuran with 88-90% e.e. by using Ther-moanaerobium brockii alcohol dehydrogenase coupled with an NADPH regeneration system.30 Preparative scale horse-liver alcohol dehydrogenase-catalysed reductions of prochiral meso and racemic cis-and trans-decalindiones occur with concurrent regio- and stereospecificity to give good yields of enantiomerically pure keto alcohol products.In each case the reduction occurs to give the (S)-alcohol in a manner that is completely predicted by the cubic section active site model. The chiral synthon utility of such keto alcohols is illustrated by a direct and efficient synthesis of (+)-(4R)-twistanone (25) from (26) in 51% overall yield.31 Baker’s yeast is capable of catalysing transformations other than alcohol-ketone conversion. Thus an approach to the asymmetric synthesis of remote-functionalized sterols based on the enantioselective enzymic cyclization of the C 1 hydroxylated surrogate substrate (27) with Saccharomyces cerevisiae has been described.Incuba- tion of the functionalized squalene analogue (27) with baker’s yeast in phosphate buffer leads to stereospecific formation of the C28 hydroxylated sterol (+)-(28) in 30 D. G. Drueckhammer C. F. Barbas 111 K. Nozaki C.-H. Wong C. Y. Wood and M. A. Ciufolini J. Org. Chem. 1988 53 1607. 31 D. R. Dodds and J. B. Jones J. Am. Chem. SOC.,1988 110 577. Biological Chemistry- Part (i) Enzyme Chemistry 40.5% yield.32 Previous work by the same group used analogous cyclizations to prepare the cytotoxic agent ganoderic Z.33 Baker’s yeast has also been used to catalyse dehydrogenation of a thia analogue of stearic acid (29) to yield (30).Subsequent treatment with a second organism Lactobacillus plantarum stereospecifically converted (30) into the cyclopropyl com- pound (31).34 LS 1S. cerevisiae HH IL. piantarum 4 Carbon-Carbon Bond Formation Fructose 1,6-diphosphate aldolase from rabbit muscle has proved to be a useful catalyst for the synthesis of carbon-carbon bonds. In nature this enzyme mediates the condensation of D-glyceraldehyde 3-phosphate (32) and dihydroxyacetone phos- phate (33) to give fructose 1,6-diphosphate (34). The enzyme is highly specific for dihydroxyacetone phosphate as the nucleophilic component but accepts a number of achiral and chiral (both D and L) aldehydes as the electrophile. Recently it has been shown to catalyse aldol reactions of nitrogen-containing aldehydes providing several novel nitrogen-containing and C-alkyl sugars on 4-20 mmol scales.35 Two groups have used rabbit-muscle aldolase for efficient syntheses of the glycosidase inhibitors 1 -deoxymannojirimycin (35) and 1 -deoxynojirimycin (36).36,37 In both cases the aldolase was used in the key step to catalyse the condensation of dihy- droxyacetone phosphate and (KS)-3-azido-2-hydroxypropanal(37) to give the aldol product (38).Subsequent cleavage of the phosphate group using acid phos- phatase followed by hydrogenation yielded the desired compounds (35) and (36). Wong has investigated the substrate specificity of N-acetylneuraminic acid aldolase. By replacing the natural substrate N-acetylmannosamine with 6-0-acetyl- N-acetylmannosamine the aldolase-catalysed condensation with pyruvate gave the 32 J.C. Medina and K. S. Kyler J. Am. Chem. Soc. 1988 110,4818. 33 J. Bujons R. Guajardo and K. S. Kyler J. Am. Chem. Soc. 1988 110 604. 34 P. H. Buist and H. G. Dallmann Tetrahedron Lett. 1988 29 285. 3s J. R. Durrwachter and C.-H. Wong J. Org. Chem. 1988 53 4175. 36 T. Ziegler A. Straub and F. Effenberger Angew. Chem. Int. Ed. Engl. 1988 27 716. 37 R. L. Pederson M. J. Kim and C.-H. Wong Tetrahedron Lett. 1988 29 4645. 314 N. J. Turner R2 H (32) R' = OH R2 = CH,0P0,H2 (33) (34) R' = OH R2 = CH20P03H2 (37) R' = OH R2 = N (38) R' = OH R = N OH OH HO,. Ho+/*-oH N AC H20H ~ H 120H H compound (39) in 59% overall yield.6- O-Acetyl-N-acetylmannosamine was itself prepared enzymatically by regiospecific acylation of the 6-OH group of N-acetyl- mannosamine with isopropenyl acetate catalysed by protease N.38 AcOdoH ?H AcHN W C 0 2 H The mandelonitrilase from bitter almonds has previously been shown to be a useful catalyst for the synthesis of optically active cyanohydrii~s.~~ In a recent report benzaldehyde was converted into the (R)-cyanohydrin (40) in 94% yield and >98% e.e. The conditions involve the use of a potassium cyanide-acetic acid buffer (pH 5.4) with ethanol at 0 "C. Reactions could be performed on a 30-50 g scale.4o A novel catalytic activity of lipases has been discovered namely asymmetric Michael addition to provide optically active trifluoromethylated compound^.^'^^^ Lipases from species of Alcaligenes and Achromobacter catalysed the addition of various thiols and dialkylamines in organic solvents to (E)-ethyl 3-(trifluoromethy1)- and 2-(trifluoromethy1)-propenoate,yielding the corresponding Michael adducts.38 M. J. Kim W. J. Hennen H. M. Sweers and C.-H. Wong J. Am. Chem. SOC.,1988 110 6481. 39 F. Effenberger T. Ziegler and S. Forster Angew. Chem. Znt. Ed. Engl. 1987 26,458. 40 J. Brussee E. C. Roos and A. Van der Gen Tetrahedron Lett. 1988 29,4485. 4' T. Kitazurne T. Ikeya and K. Murata J. Chem. SOC.,Chem. Commun. 1986 1331. 42 T. Kitazume K. Murata Y. Kokusho and S. Iwasaki J. Fluorine Chem. 1988 39,75. Biological Chemistry- Part (i) Enzyme Chemistry 5 Enzymes Acting on Carbohydrates and Oligosaccharides Enzymes are being used to great effect to overcome the problem of selective protection in carbohydrate synthesis.Thus glucose can be regioselectively acylated at the 6-OH using 2,2,2-trichloroethyl butyrate in anhydrous DMF and subtilisin as the catalyst. Similar esterifications were carried out on the disaccharides maltose and cellobiose both giving >95% selectivity. Interestingly with sucrose subtilisin acylates the C1 hydroxy group to give (41) whereas in the chemical acylation the most reactive -OH is at the C6 position. The reactions could be carried out on gram scales with isolated yields of approximately 50% .43 0 CHzOk roH I OH OH (41) Related work has been carried out by Wong.44 Thus with the methyl furanosides of D-ribose D-arabinose D-xylose and 2-deoxy-~-ribose acetylation of the primary hydroxy functions was achieved with porcine pancreatic lipase in THF using 2,2,2- trifluoroethyl acetate as the acyl donor.In aqueous media (containing 10% DMF) selective deacylation of the corresponding peracetylated series was achieved using Candida cy Iandricea lipase. Cytidine 5’-monophospho-N-acetylneuraminic acid (CMP-NeuAc) (42) is an important intermediate in the biosynthesis of certain glycoproteins. It has been prepared by two groups each using a multi-enzyme approach (Scheme 2)?47 The key difference between the two systems is the method used to generate the expensive cytidine 5’-triphosphate (CTP) in situ from the relatively cheap cytidine 5’-monophosphate (CMP).white side^^^.^^ employs adenylate kinase pyruvate kinase and phosphoenol pyruvate (PEP) as the ultimate phosphate donor to convert CMP into CTP this reaction being carfied out on a gram scale. An alternative approach uses nucleoside monophosphokinase instead of adenylate kina~e.~’ Thereafter both methods use the enzyme CMP-NeuAc synthetase to couple CTP with N-acetyl- neuraminic acid (NeuAc) generating CMP-NeuAc. Sialyl transferases are a group of enzymes that catalyse the transfer of NeuAc from CMP-NeuAc to oligosaccharide chains of glycopeptides. Two representatives of this group have been used to construct a disialylated tetrasaccharide analogous to M and N blood group determinants of glycophorin A.48Thus chemically synthe- 43 S.Riva J. Chopineau A. P. G. Kieboom and A. M. Klibanov J. Am. Chem. SOC.,1988 110 584. 44 W. J. Hennen H. M. Sweers Y.-F. Wang and C.-H. Wong J. Org. Chem. 1988 53 4939. 45 E. S. Simon M. D. Bednarski and G. M. Whitesides Tetrahedron Lett. 1988 29 1123. 46 E. S. Simon M. D. Bednarski and G. M. Whitesides J. Am. Chem. Soc. 1988 110 7159. 47 C. Auge and C. Gautheron Tetrahedron Lett. 1988 29 789. 48 H. T. De Heij M. Kloosterman P. L. Koppen J. H. Van Boom and D. H. Van den Eijnden J. Carbohydr. Chem. 1988 7 209. 3 16 N. J. Turner AcHN MeCOC0,H OH -PEP -CTP CMP CDP i ix CTPi i g D p 0 I1y!--;:0 AcHN PYr PEP I I OH OH Reagents i NeuAc aldolase; ii adenylate kinase or nucleoside monophosphokinase; iii pyruvate kinase; iv CMP-NeuAc synthetase Scheme 2 sized phenyl 2-acetamido-2-deoxy-3- 0-p-D-galactopyranosyl-a-D-galactopyrano-side was treated sequentially with CMP-[’4C]-NeuAc in the presence of sialyl transferase from human placenta followed by CMP-[3H]-NeuAc and a sialyl trans- ferase from rat-liver microsomes to give the desired product in 10% yield.The use of glycosidases rather than glycosyl transferases offers a complementary method for constructing glycosidic bonds with high regioselectivity. Two approaches are possible (a) ‘transglycosidation’ using an activated sugar e.g. o-nitrophenyl sugars and (b) ‘reverse’ hydrolysis. An example of the first approach is given by the synthesis of monoacyl galactoglycerides (43) by P-galactosidase-catalysed trans-glycosidation of lactose or a-nitrophenyl galactopyranoside with 2,3-epoxypropanol and subsequent opening of the so formed 1-O-p-D-galaCtOpyranOSyl-2,3-epoxypropanol with a fatty acid.49 Yields for the initial glycoside formation were in the region 25-3070.Similarly fructose has been transferred by invertase-catalysed alcoholysis of sucrose in water-primary alcohol mixtures containing -do% organic solvent giving 540% alkyl P-D-fructofuranoside formation. No formation of fructosides was observed under anhydrous conditions. 6-Ketose formation due to surcrose itself acting as acceptor could be suppressed by increasing the concentration F. Bjoerkling and S. E. Godtfredsen Tefrahedron 1988 44 2957.317 Biological Chemistry- Part (i) Enzyme Chemistry OH HO / of aliphatic alcohol.50 By contrast a-D-glycosyl-D-fructoses were synthesized by use of a ‘reversed’ hydrolysis activity of a-glucosidase from Saccharomyces species. Using a simple batch method the major product was cy-D-glucosyl-(~+ 1)-D-fructose (44) with smaller amounts of a-(1+ 4)- a-(1 + 5)- and a-(1+ 6)-roH OH (44) linked products. With an immobilized a-glucosidase column and an activated carbon column (to remove product disaccharides thereby shifting the equilibrium in the synthesis direction) in series the same saccharides were formed (although in con- siderably lower yield) but the major product was a-D-glyCOSyl-(l + 4)-D-frUCt0Se.” 6 Miscellaneous Biotransformations The conversion of benzene (and analogues) by Pseudomonas putida into cyclo- hexadienediols [e.g.(45) and (46)] has provided organic chemists with a valuable synthon for natural product synthesis. Ley has used this transformation as the key step in the synthesis of the cellular secondary messenger myo-inositol 1,4,5-triphos- phate (47) starting from (45).52 Hudlicky has utilized the corresponding chiral compound (46) derived from enantioselective oxidation of toluene as a versatile starting material for the preparation of several prostaglandin and terpene ~ynthons.~~ Another potentially useful oxygenase that is beginning to be studied is cycloalk- anone oxygenase. Using an extract from Acinetobacter NCIB 9871 the ring 50 H. Fujimoto and K.Ajisaka Biotechnol. Lett. 1988 10 107. 51 A. J. J. Straathof J. P. Vrijenhoef E. P. A. T. Sprangers H. Van Bekkum and A. P. G. Kieboom J. Carbohydr. Chem. 1988 7 223. 52 S. V. Ley and F. Sternfeld Tetrahedron Lett. 1988 29 5305. 53 T. Hudlicky H. Luna G. Barbieri and L. D. Kwart J. Am. Chem. SOC.,1988 110 4735. 318 N. J. Turner H203p0v0H HO' OH (45) R = H OP03H2 (46) R = Me (47) expansion of a number of meso-ketones could be carried out to give the correspond- ing lac tone^.^^ Oxidation of the ketone (48) resulted in the five-membered ring lactone (49) from hydrolysis and relactonization of the initially formed seven-membered ring. ...Q,,* ?H cycloalkanone o+ oxygenase b OH 0 (48) (49) Microbial hydroxylation represents an area in which enzymes are likely to prove superior to traditional chemical methods.In most cases the enzymic reactions proceed with moderate to high regioselectivity but poor enantioselectivity. Furstoss and his group have recently claimed the first example of a highly enantioselective hydroxylation process. Thus the racemic lactam (50) underwent hydroxylation with Beauvaria sulfurescens to give a mixture of products the major component (30% yield) being (51)with an optical purity Of 90% .55 Similar enantioselectivity has been demonstrated using dopamine-P- hydroxylase which was used as the catalyst in the hydroxylation of 2-( l-cyclohexenyl)-2-aminoethanolat the pro-R position to give (R)-1-(cyclohexenyl)-2-aminoethanol(52).56 Beauvaria sulfurescens _____ eNH2 &H NYPh &NKPh 0 0 The hydrocarbon monooxygenase from Pseudomonas oleouqruns is a prototypical w-hydroxylase known to carry out hydroxylation at the terminal methyl group of alkanes as well as epoxidation of terminal olefins.It has now been shown that this enzyme system catalyses stereospecific sulphoxidation of methyl thioether substrates 54 M. J. Taschner and D. J. Black J. Am. Chem. Soc. 1988 110 6892. 55 A. Archelas J.-D. Fourneron R. Furstoss M. Cesario and C. Pascard J. Org. Chem. 1988 53 1797. 56 S. R.Sirimanne and S. W. May J. Am. Chem. SOC.,1988 110 7560. Biological Chemistry- Part (i) Enzyme Chemistry representing the first clear example of oxygenase-produced chiral aliphatic sul- phoxides yet reported.In addition this enzyme catalyses oxidative 0-demethylation of branched alkyl methyl and branched vinyl methyl ethers to secondary alcohols and ketones re~pectively.~’ Stereoselective alkene epoxidation has also been achieved using strains of species of Mycobacterium and Nor~ardia.~~ Among the various substrates and organisms tried the best results were achieved with but-3-en- 1 -01 and a Norcardia strain IPl yielding the corresponding (R)-epoxide in 13% yield and 84% e.e. A rabbit microsomal epoxide hydrolase is capable of enantioselectively opening a racemic ep~xide.~~ Thus treatment of 100 mg of the racemic epoxide (53) until 30% conversion resulted in a 60% e.e. for the (-)-(lR,2S,3R)-diol (54) and a 30% e.e.for the unreacted (-)-( 1 R,2R,3S)-epoxide. Br Br 7 Novel Biocatalysts Since the first demonstrations that antibodies could be successfully elicited and used to catalyse predefined reactions recent work has focused on increasing their efficiency and extending the range of reactions capable of being catalysed. Lerner has shown that phosphonate esters can be used to mimic a carboxyl esterolytic transition state.60 Among the twenty antibodies that were raised and screened for hydrolysis of the carboxylic ester five were found to be esterases. In addition the transition state analogue was a specific inhibitor of the esterase activity. One antibody accelerated the hydrolysis of a related substrate with a catalytic constant (k,,,) of 20 sC1 and a K of 1.5 mM at pH 8.0.This represents an acceleration of several million fold over the rate of spontaneous hydrolysis. Two groups have raised antibodies against a putative transition state (55)for the Claisen rearrangement of chorismate (56) to prephenate (57).6‘762The kinetic data co; OR OH OH (55) (56) (57) 57 A. G. Katapodis H. A. Smith and S. W. May J. Am. Chem. SOC.,1988 110 897. 50 A. Archelas S. Hartmans and J. Tramper Biocatalysis 1988 1 283. 59 G. Bellucci M. Ferretti A. Lippi and F. Marioni J. Chem. Soc. Perkin Trans. 1 1988 2715. 60 A. Tramontano A. A. Ammann and R. A. Lerner J. Am. Chem. SOC.,1988 110 2282. 61 D. Hilvert and K. D. Nared J. Am. Chem. SOC.,1988 110 5593. 62 D. Y. Jackson J. W. Jacobs R. Sugasawara S. H. Reich P.A. Bartlett and P. G. Schultz J. Am. Chem. Soc. 1988 110 4841. 320 N. J. Turner obtained62 showed that one of the antibodies against (55) could effectively catalyse the conversion of (56) into (579 (k,,,/k,,,, = 1 x lo4 compared with 3 x lo6 for chorismate mutase from Escherichia coli). Schultz has begun to extend the concept of antibody catalysis by an elegant e~periment.~~ He has raised an antibody to the cis-syn-thymine dimer (58) that catalyses the photocleavage of (59) as well as (58). The principle being exploited I R R (58) R = OH (59) R = NHCH,C02H here is that indoles are well known sensitizers of the photoreversal of pyrimidine dimers and it was expected that an antibody binding site specific for the polarized .rr-system of a thymine dimer might contain a complementary tryptophan residue.The wavelength dependence of the antibody-catalysed reaction as well as the quenching of antibody fluoresence upon substrate binding are indicative of a binding-site tryptophan. This study represents the extension of antibody catalysis to a new class of reactions namely C-C bond cleavage. The idea of preparing mbdified enzymes by chemical derivatization of existing enzymes is another potentially powerful strategy for designing new biocatalysts. A thermophilic semisynthetic flavoenzyme was prepared by alkylation of cysteine-149 at the active site of glyceraldehyde 3-phosphate dehydrogenase from Bacillus stearothermophilus with 7-(a-bromoacetyl)-l0-methylisoalloxazine. The initially for- med tetrameric flavoprotein irreversibly dissociated into dimers.These dimers were very stable and served as catalysts for the oxidation of 1,4-dihydronicotinamidesat temperatures as high as 55 "C. NADH was the best substrate examined under these condition^.^^ 63 A. G. Cochran R. Sugasawara and P. G. Schultz J. Am. Chem. Soc. 1988 110 7888. 64 D. Hilvert Y. Hatanaka and E. T. Kaiser J. Am. Chem. Soc. 1988 110 682.

ISSN:0069-3030    

DOI:10.1039/OC9888500307

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

11 Blological Chemistry Part (ii) Biosynthesis By T. J. SIMPSON Department of Chemistry University of Leicester University Road Leicester LEI 7RH 1 Introduction The previous Report' on biosynthetic studies of secondary metabolites and related work covered the period 1981-85. This Report will cover the period 1986-88. The area continues to be a tremendously active one and testing of biosynthetic mechan- isms and biogenetic ideas remains a great stimulus for synthetic organic chemistry and for the development and application of new methodologies. The application of genetic analysis and gene cloning methodologies have now come to occupy a dominant place in biosynthetic studies allowing such great advances in the study of the enzymology of the pathways of interest that the previous marked distinctions among primary and secondary metabolic and enzyme mechanistic studies are rapidly disappearing.Inevitably this Report must be highly selective with the main aim being to pick out some of the highlights and to convey an impression of how studies on the major biosynthetic pathways are developing. More comprehensive coverage of the areas to be discussed may be found in the regular specialized articles appearing in Natural Product Reports. 2 Fatty Acid and Polyketide Biosynthesis Fatty acid synthetase (FAS) is a multifunctional enzyme complex which shows various patterns of both structural and functional variation depending on its origin.2 In most prokaryotes and in chloroplasts ,the FAS comprises eight structurally independent and monofunctional enzymes.In vertebrates all these components are combined within a single octafunctional polypeptide chain. However in yeasts and lower fungi the FAS consists of two components. In Saccharomyces cerevisiae the two subunits are encoded by the FAS1 and FAS2 genes the former encoding acetyl- malonyl- and palmityl-transferases the dehydratase and the enoyl reductase active sites and the latter the P-ketoacyl synthetase P-ketoacyl reductase and acyl carrier protein domains. Both genes have been fully The fabB gene of T. J. Simpson Annu. Rep. Prog. Chem. Sect. B 1986 83,347. A. D. McCarthy and D. G. Hardie TIBS 1984,9 60. M. Schweizer L. M. Roberts H.-J. Holtke K. Takabayashi E. Hollerer B. Hoffmann G. Muller H. Kottig and E.Scheweizer Mol. Ges Genet. 1986 203 479. E. Schweizer G. Muller L. M. Roberts M. Schweizer J. Rosch P. Wiesner J. Beck D. Stratmann and I. Zanner Fat Sci. Technol. 1987 89 570. 32 I 322 T. J. Simpson Escherichiu coli encoding P-ketoacyi synthetase I has also been sequenced and the active site identified by tagging with [3H] cerulenin and sequencing of radiolabelled peptide fragments following proteoly~is.~ The E. coli and S. cerevisiae condensing enzymes have a common sequence of five amino acids (Ala-Cys-Ala-Thr-Ser) which are believed to contain the active-site cysteine. The stereochemical course of the hydration-dehydration reaction catalysed by the E. coli P-hydroxydecanoyl thioester dehydratase has been shown to be a syn process with protonation occurring on the si face at C2 of the dec-2-enoyl thioester (Scheme 1).6 The enzyme has been sequenced and the active site identified.7 'H C7H15 'H,O H COSR ' H $1:!3R c7H'5xxH H Scheme 1 There is growing evidence that acyl carrier proteins (ACPs) may play a crucial role in the overall control of both fatty acid and polyketide chain assembly.A three-dimensional structure for the E. coli ACP has been determined by n.m.r. methods.8 This structure shows the presence of a hydrophobic cleft which has been identified as a likely site of acyl chain binding. A heat-stable factor required for the synthesis of fatty acids in the erythromycin-producing organism Saccharopoly-spora erythruea has been purified and identified as a discrete ACP suggesting that the FAS of S.erythruea is a dissociable complex like that of E. coli.' The observation that antibiotic biosynthetic genes are not scattered but occur in closely linked clusters in Streptomycetes has led to great advances in understanding the genetics of polyketide biosynthesis in these organisms. Developments in gene cloning methodology have made it feasible to clone biosynthetic genes from one organism and to transfer the entire region or parts of it into other suitable hosts. This has enabled biosynthetic genes to be characterized and new 'hybrid' antibiotics to be created." The complete gene clusters for the biosynthesis of erythromycin in S. erythraea" and actinorhodin ( 1) an isochromanequinone antibiotic produced by Streptomyces coelicolor,'2 have been cloned as contiguous stretches of DNA.Co-synthetic studies in blocked mutants have identified at least six biosynthetic genes for actinorhodin 5 S. Kauppinen M. Siggaard-Andersen and P. von Wettstein-Knowles Carlsberg Res. Commun 1988 53 357. 6 J. M. Schwab J. B. Klassen and A. Habib J. Chem. SOC.,Chem. Commun. 1986 357. 7 J. E. Cronan W.-B. Li R. Coleman M. Narasimhan D. DeMendoza and J. M. Schwab J. Biol. Chem. 1988 263 4641. 8 T. A. Holak S. K. Kearsley Y. Kim and J. H. Prestegard Biochemistry 1988 27 6135. 9 R. S. Hale K. N. Jordan and P. F. Leadlay FEBS Left. 1987 224 133. 10 D. H. Sherman F. Malpardita M. J. Bibb H. M. Kieser S. E. Hallam J. A. Robinson S. Bergh M. Uhlen T. J. Simpson and D.A. Hopwood in 'Proceedings of the VlII International Congress of Biotechnology Paris' eds. G. Durand L. Bobichon and J. Florent SocietC Francais de Microbiologie 1988 p. 123. I1 P. Matsushima R. Stanzak R. N. Rao and R. H. Baltz Biotechnology 1986 4 229. 12 F. Malpardita and D. A. Hopwood Mol. Gen. Genet. 1986 205 60. Biological Chemistry- Part (ii) Biosynthesis (1) (actI ~c~III-VII).'~ Recent evidence indicates that the actI actIII and actVII genes code for the necessary condensation reduction and dehydration activities associated with the polyketide ~ynthase.'~ The act111 gene has been sequenced and does indeed show homology with other oxido-red~ctases.'~ The act1 and act111 genes have been used to probe restriction digests of genomic DNA from a large number of other Streptomycetes.16 Many of these showed the presence of DNA homologous to both act1 and act111.Interestingly the tetracenomycin (2) producer Streptomyces glaucescens contains DNA homologous to act I but not act111 con- sistent with the fact that tetracenomycin biosynthesis does not require a reduction step during polyketide chain assembly. These and many other aspects of genetic studies on polyketide assembly have been re~iewed.'~~'' Results over a number of years mainly from stable-isotope labelling studies," have indicated that necessary reductions and loss of oxygen from polyketide inter- mediates generally (but see below) occur concomitant with chain elongation as in fatty acid biosynthesis. Further support has come from the successful incorporation of partially elaborated chain elongation intermediates into tylosin (3) as indicated in Scheme 2.19 Success was achieved by feeding the intermediates as their N-acetyl cysteamine thioesters.When fed as their ethyl oxyesters incorporation of label occurred only after prior degradation. Similar results have been reported for eryth- romycin,20 nargenicin,21 and nonactin.22 Until recently there had been no reports l3 H. G. Floss S. P. Cole X.-G. He B. A. M. Rudd J. Duncan I. Fujii C. J. Chang and P. J. Keller in 'Regulation of Secondary Metabolite Formation' ed. H. Kleinkauf H. von Dohrern H. Dornauer and G. Nesemann VCH Meinheim 1986 pp. 283-304. 14 S. P. Cole B. A. M. Rudd D. A. Hopwood C. J. Chang and H. G.Floss J. Antibiot. 1987 40 340. 15 S. E. Hallam F. Malpardita and D. A. Hopwood Gene 1988 74 305. 16 F. Malpardita S. G. Hallam H. M. Kieser H. Motarnedi C. R. Hutchinson M. J. Butler D. A. Sugden M. Warren C. McKillop C. R. Bailey G. 0.Humphreys and D. A. Hopwood Nature (London) 1987 325 818. C. Chen in 'Antimicrobial Chemotherapy-Prospects for the Future' ed. S. Harnmon Wiley Chichester 1988. " T. J. Simpson Chem. SOC.Rev. 1987 16 123. 19 S. Yue J. S. Duncan Y. Yamamoto and C. R. Hutchinson J. Am. Chem. SOC., 1987 109 1253. 20 D. E. Cane and C. C. Yang J. Am. Chem. SOC.,1987 109 1255 *' D. E. Cane and W. R. Ott J. Am. Chem. SOC.,1988 110 4840. 22 J. A. Robinson and Z. Spavold J. Chem. SOC.,Chem. Commun. 1988 4. 324 T.J. Simpson 00 I Me / ;I Me Scheme 2 of the isolation of partially assembled polyketide intermediates from cultures of producing organisms. However compounds (4)-(6) which are clearly derived from the chain assembly process leading to the mycinamycins e.g. (7) have been isolated from mutants of Micromonospora gri~eorubida.~~ Me Me e H02C OH L MOH O D 0o 0H OH Ho2ve ke Me Me Me Me The biotin-mediated carboxylation of acetyl-CoA to malonyl-CoA is a key step in both fatty acid and polyketide biosynthesis. In contrast to previous proposals it has been shown by making use of the double isotope fractionation test that this is not a concerted process for the conversion of pyruvate into o~aloacetate.~~ The conversion of linoleic acid into the divinyl ether colneleic acid (8) and the a-and y-ketols (9) and (lo) and the analogous conversions of linolenic acid into 12-oxophytodienoic acid (1 1) by lipoxygenases from potato and flax seed have been studied with "0-and 2H-labelled s~bstrates.~~ The intermediacy of the correspond- ing 9-and 13-hydroperoxides and the allene epoxide (12) have been demonstrated.Two groups have reported the synthesis of chiral (R)-and (S)-[l-13C,2-2Hl]malonates.26927 The absolute configurations were confirmed by using them as 23 K. Kinoshita S. Takenaka and M. Hayashi J. Chem. Soc. Chem. Commun. 1988 943. 24 S. J. O'Keefe and J. R. Knowles J. Am. Chem. Soc. 1986 108 329; Biochemistry 1986 25 6077. 25 L. Crombie D. 0. Morgan and E. H. Smith J.Chem. Soc. Chem. Commun. 1987 502; L. Crombie and D. 0. Morgan ibid. 1987 503; 1988 556 558. 26 P. M. Jordan J. B. Spencer and D. L. Corina J. Chem. Soc. Chem. Commun.,1986 911. '' S. Huang J. M. Beale P. H. Keller and H. G. Floss J. Am. Chem. Soc. 1986 108 1100. Biological Chemistry- Part ( ii) Biosynthesis 325 0 Me CO2H OH (9) Me CO2H substrates for yeast FAS and by mass spectral analysis of the derived palmitic acid,26 and by n.m.r. analysis.27 The aflatoxin pathway continues to be of major interest and has been the subject of a number of studies. In contrast to previous results28 which indicated that hexanoyl-CoA acted as a chain primer for polyketide elongation incorporation of 13C-labelled malonate into averufin (13) provided evidence for an acetate starter eff e~t.~~ In order to obtain more information the stereochemistry of incorporation of acetate-derived hydrogen into averufin and the fatty acids of Aspergillus para- sitic~~~' and into cladosporin (14) and oleic acid in Cladosporium ~ladosporoides~~ &yyJ4 aI3 \ Me / HO Me HO 0 HH (13) (14) have been compared by incorporation of [2-13C,2-'H3]acetate and stereochemical analysis by 'H-decoupled 'H,13C heteronuclear shift correlation In clados-porin two acetate-derived 2H labels are incorporated at C13 but only one is retained at C11 and with opposite stereochemistry to that observed in the fatty acids of C.cladosporoides. In A. parasiticus however the single 2H labels retained at C2' and 28 For a review of this and related work see C.A. Townsend fire Appl. Chem. 1986 58 227. 29 I. M. Chandler and T. J. Simpson J. Chem. Soc. Chem. Comrnun. 1987 17. 30 C. A. Townsend S. W. Brobst S.E. Ramer and J. C. Vederas J. Am. Chem. Soc. 1988 110 318. 31 P. B. Reese B. J. Rawlings S. E. Ramer and J. C. Vederas J. Am. Chem. Soc. 1988 110 316. 32 P. B. Reese L. A. Trimble and J. C. Vederas Can. J. Chem. 1986 64,1427. 326 T. J. Simpson C4’ of averufin show the same absolute stereochemistry of incorporation as the fatty acids. This is taken to be consistent with the proposal of a hexanoyl-CoA primer derived from fatty acid metabolism. The next intermediate in the conversion of averufin into aflatoxin has been shown to be 1’-hydroxyversicolorone (15).This has been isolated from a new mutant strain of A. p~rasiticus~~ and its incorporation in labelled form into aflatoxin B1demon-~trated.~~ A later step in aflatoxin biosynthesis is the conversion of the anthraquinone versicolorin A into the xanthone sterigmatocystin. This necessitates the post-aromatic loss of a phenolic oxygen from versicolorin A. Precedent for this has now been established by the dem~nstration~~ that a cell-free system from Pyrenochaeta terrestris catalyses the NADPH-dependent reductive removal of oxygen from the 6-position of emodin (16) to give chrysosphanol (17). (16) R = OH (17) R = H A facile synthesis of isotopically labelled anthraquinones has been reported36 and used to prepare [methyl-2H3]chrysophanol whose specific incorporation into tajixanthone (18) in Aspergillus uariecolor was demonstrated by 2H n.m.r.In contrast it has been shown37 that the xanthone skeleton of mangostin (19) is derived from rn-hydroxybenzoate and three malonates via the benzophenone (20). An interesting proposal38 that alternariol (21) may be biosynthesized via ring cleavage and Me v MeYMe Me Me \o / Lo Me Me 33 C. A. Townsend K. A. Plavcan K. Pal S. W. Brobst M. S. Irish E. W. Ely and J. W. Bennett J. Org.. Chem. 1988 53 2472. 34 C. A. Townsend P. R. 0. Whittamore and S. W. Brobst J. Chem. SOC.,Chem. Commun. 1988 736. 35 J. A. Anderson B.-K. Lin H. J. Williams and A. I. Scott J. Am. Chem. SOC.,1988 110 5899. 36 S. A. Ahmed E. Bardshiri and T.J. Simpson J. Chem. SOC.,Chem. Commun. 1987 883. 37 G. J. Bennett and H.-H. Lee J. Chem. Soc. Chem. Commun. 1988 619. 38 E. E. Stinson W. B. Wise R. A. Moreau A. J. Jurewicz and P. E. Pfeffer Can.J. Chem. 1986,64 1590. Biological Chemistry- Part ( ii) Biosynthesis 327 OH rearrangement of lichexanthone has been shown39 not to be tenable by incorporation studies with [ l-'3C,'s02]acetate. In other work making use of oxygen labelling it has been shown by "0 n.m.r. that hydroxymellein (22) arises from direct benzylic hydroxylation of mellein follow- ing incorporation of "0-labelled acetate and oxygen and from direct conversion of 2H-labelled mellein.40 ''0 labelling studies have established the mechanism of formation of multicolosic acid (23) via cleavage of an aromatic prec~rsor.~' The HOzCFc07H OH 0 origins of the oxygen atoms in the phytotoxin betaenone B were e~tablished~~ by feeding [ l-'3C,'802]acetate and by treatment of cultures of Phoma betae with the cytochrome P-450 inhibitor ancymidol.As a result the intermediate (24) accumu-lated which suggests a biosynthetic pathway involving an intramolecular Diels- Alder cyclization at a late stage (Scheme 3). ' Me Me MeCazNa -+ H H OH Me Me Scheme 3 39 J. Dasenbrock and T. J. Simpson J. Chem. SOC.,Chem. Cornmun. 1087 1235. 40 C. Abell A. C. Sutkowski and J. Staunton J. Chem. SOC.,Chem. Cornmun. 1987 586. 41 J. S. E. Holker M. Kaneda S. E. Ramer and J. C. Vederas J. Chem. SOC.,Chem. Cornmun.,1987 1099. 42 H.Ockawa A. Ichichara and S. Sakamura J. Chem. SOC. Chem. Cornmun.,1988 600. 328 T. J. Simpson The origins of the oxygen atoms in the polyether antibiotics nara~in,~~ maduramy-cin,& and len~remycin~~ have been established. The most important of the polyethers is monesin whose biosynthesis is believed to proceed uia an epoxide-mediated cyclization cascade from a putative polyene precursor. A fully asymmetric synthesis of this has been described.46 The chemical feasibility of these cascades has been demonstrated by two group^^',^' who synthesized isomeric epoxides [e.g. (25)] and Me Me 0 Me 0 (25) demonstrated their rapid stereospecific cyclization to polyether structures upon saponification followed by acidification. The stereospecific synthesis of the diepoxide (26)has also been described.49 On treatment with pig-liver esterase this was converted in >70% yield into the cyclized product.However monitoring by n.m.r. showed that this was a stepwise process. A monocyclic lactone was formed within 1 h but further conversion into (27) occurred over a 24 h period (Scheme 4). This contrasts with the rapid cascade observed in aqueous solutions at low pH and has implications for the enzyme-catalysed process. -MeO2C OH 1 oQ-Q--coH Me OH Me Scheme 4 There has been much speculation concerning the biogenetic basis of the extensive structural and stereochemical homologies observed within the polyether and macrolide classes of antibiotics. These ideas have recently been extended to show that these homologies can transcend both classes.50 43 Z.Spavold J. A. Robinson and D. L. Turner Tetrahedron Lett. 1986 27 3299. 44 H. R. Tson S. Rajan T. T. Chang R. R. Fiala G. W. Stickton and M. W. Bullock J. Antibiot. 1987 40 94. 45 D. E. Cane and B. R. Hubbard J. Am. Chem. SOC.,1987 109 6533. 46 D. A. Evans and M. DiMare J. Am. Chem. Soc. 1986 108 2476. 47 W. C. Still and A. G. Romero J. Am. Chem. SOC.,1986 108 2105. 48 S. L. Schrieber T. Sammakia B. Huh and G. Schulte J. Am. Chem. SOC.,1986 108 2106. 49 S. J. Russell J. A. Robinson and D. J. Williams J. Chem. SOC.,Chem. Commun. 1987 351. SO D. O'Hagan Tetrahedron 1988 44 1691. Biological Chemistry- Part ( ii) Biosynthesis 329 Careful 13C labelling studies” have shown that the kinamycin antibiotics [e.g.(28)] must be derived via the benz[a]anthraquinone (29). One of the two carbons from the acetate-derived unit removed in this process is retained as the cyanamide carbon.52 &Me @ HO / \ Me \ -; ,;; __c /I I \ N bAc I \. OH 0 OH OH CN (29) (28) The origins of the carbon skeleton of the aurantinins (30) novel carbocyclic metabolites of Bacillus aurantinus have been determined by feeding 13C-labelled prec~rsors.’~ They contain five C-methyl groups derived from methionine two from the methyl of cleaved acetate units and a carboxyl derived from a cleaved acetate unit as indicated. The carbon skeleton of the indolizidine alkaloid cyclizidine (3 1) is derived entirely from acetate and propionate units with the cyclopropyl ring being derived from a single propionate unit.s4 Biosynthetic studies on marine polyketide-derived metabolites are rare.However [1-‘4C]propionate has been suc- cessfully incorporated into the dendiculatins (32) produced by the marine pulmonate Siphonaria dendic~lata.~~ Me Me w he -C0,Na I OH MeCH,CO,Na (32) methionine A P. J. Seaton and S. J. Could J. Am. Chem. SOC.,1987 109 5282. ’*P. J. Seaton and S. J. Could J. Am. Chem. SOC.,1988 110 5912. 53 A. Nakagawa Y. Konda A. Hatano Y. Hirigaya M. Onda and S. Omura J. Org. Chem. 1988,53,2660. 54 F. J. Leeper P. Padmanbhan G. W. Kirby and G. N. Sheldrake J. Chem. SOC.,Chem. Commun. 1987 505. 55 D. C. Manker M. J.Garson and D. J. Faulkner J. Chem. SOC.,Chem. Commun. 1988 1061. 330 T. J. Simpson 13 C-labelled acetates and methionine have also been incorporated into brevitoxin B,56,57and the complex results obtained were interpreted in terms of incorpora- tion of label via succinate 2-oxoglutarate propionate and 3-hydroxy-3-methyl- g~utarate.~’ 3 Terpenoids The role of leucine in mevalonate biosynthesis has been studied58 by incorporation of l3C-labe1led leucines into the sesquiterpenoid paniculide A in tissue cultures of Andrographis paniculata. The observed labelling pattern could be rationalized by the breakdown of leucine via HMG-CoA to acetyl-CoA and acetoacetate which are then incorporated into mevalonate via the anabolic HMG-CoA pathway. A number of papers have been published which provide further details on the molecular biology of HMG-CoA syntha~e~~ and HMG-CoA reductase.60 The purification of mevalonate Sdiphosphate decarboxylase and its inhibition by fluoromevalonate analogues have been described.61,62 Isopentenyl diphosphate (IPP) isomerase has been purified to homogeneity from fruits of Capsicum ann~um.~~ The preparation of phosphonylphosphinyl analogues of IPP and dimethylallyl diphosphate (DMAPP)64 and farnesyl diphosphate (FPP)65 and their interactions with prenyl- transferases and monoterpene cyclases has been described.66 The biosynthesis of cyclic monoterpenes has been the subject of an important review.67 The cyclization of geranyl diphosphate to the enantiomeric bornyl diphos- phates (33) has been studied68 using purified enzyme preparations from Salvia oficinalis and Tunacetum vulgare.Whereas the cyclase from T. vulgare accepts only (+)-(3S)-linalyl diphosphate to give only (-)-(33) the cyclase from S. oficinalis can cyclize both enantiomers of linalyl diphosphate. Further mechanistic on the pinene cyclases I and I1 isolated from S. oficinalis have also been published. 56 M. S. Lee D. J. Repeta K. Nakanishi and M. G. Zagorski J. Am. Chem. Soc. 1986 108 7855. 57 H.-N. Chou and Y. Shimizu J. Am. Chem. Soc. 1987 109 2184. 58 P. Anastasis I. Freer K. H. Overton D. Pickin D. S. Rycroft and S. B. Singh J. Chem. Soc. Perkin Trans. I 1987 2427. 59 G. Gil J. R. Smith J. L. Goldstein and M. S. Brown Proc. Natl. Acad.Sci. USA 1987 84 1863. 60 T. F. Osborne G. Gil M. S. Brown R. C. Kowal and J. L. Goldstein Roc. Natl. Acad. Sci. USA 1987 84 3614. 61 k.E. Chiew W. J. O’Sullivan and C. S. Lee Biochim. Biophys. Acta 1987 916 271. 62 J. E. Reardon and R. H. Abeles Biochemistry 1987 26 4717. 63 0. Dogbo and B. Camara Biochim. Biophys. Acta 1987 920 140. 64 R. W. McClard T. S. Jujita K. E. Stremler and C. D. Poulter J. Am. Chem. Soc. 1987 109 5542. 65 K. E. Stremler and C. D. Poulter J. Am. Chem. Soc. 1987 109 5542. 66 T. Gotoh T. Koyama and K. Ogura Chem. Lett. 1987 1627. 67 R. Croteau Chem. Rev. 1987 87 929. 68 R. Croteau D. M. Satterwhite D. E. Cane and C. C. Chang J. Biol. Chem. 1986 261 1348. 69 R. B. Croteau C. J. Wheeler D. E. Cane R. Ebert and H.-J.Ha Biochemistry 1987 26 5383. Biological Chemistry- Part (ii) Biosynthesis 33 1 Variations in natural abundance 2H levels have been used as a probe for biosyn- thetic mechanisms in monoterpene biosynthesis. 2H n.m.r. analysis of a-and p-pinenes suggested that isotopically sensitive partitioning within the pinene cyclase enzyme and a correlation between optical purity and site-specific deuterium-protium ratios has been observed for a-~inene.~' Natural (+)-limonene shows relative 2H depletion of 25% for the isopropenyl methyl hydrogens relative to the 7-methyl. This is attributed72 to the IPP-DMAPP isomerization. The isopropenyl methylene hydrogens are enhanced to a relative value of 2.61 (cJ the statistical value of 2 in the absence of any kinetic isotope effect).All of these data are consistent with a loss of a proton from C9 of the a-terpinyl cation during limonene biosynthesis (Scheme 5). I Me (3.0) Me *Me I I I + :-'Me Me. 'Me ( ) relative *H levels Scheme 5 The first step in iridoid biosynthesis is hydroxylation of geraniol to 8-hydroxy- geraniol(34). A detailed study of the regioselectivity and 2Hisotope effects observed in the hydroxylation of geraniol by a cytochrome P-450 mono-oxygenase from Catharanthus roseus has been reported.73 The further conversion of (34) into loganin has been studied74 in a cell-free-system from suspension cultures of Rauwo&a serpentina. Both monoaldehydes (35) and (36) have been isolated and both are converted into iridiodial.This is then cyclized to loganin via (37) rather than via iridiotrial. The cyclization of farnesyl idphosphate (FPP) to trichodiene (38) has been studied using an enzyme preparation from Trichotheciurn roseurn. It has been shown75 that (3R)-nerolidyl diphosphate is a true intermediate between FPP and trichodiene and that it cyclizes via an anti-boat conformation. The enzyme trichodiene cyclase has been purified to >95 YO homogeneity from Fusarium ~pororrichoides.~~ The same 70 R. A. Pascal M. W. Baum C. K. Wagner L. R. Rogers and D. Huang J. Am. Chem. Soc. 1986 108 7074. 71 G. J. Martin P. Janvier S. Akoka F. Mabon and J. Jurezak Tetrahedron Lett. 1986 27 2855. 72 M. F. Leopold W. W. Epstein and D. M. Grant J. Am. Chem. Soc. 1988 110 616.73 H. Fretz and W.-D. Woggon Helu. Chirn. Acta 1986 69 1959. 74 S. Uesato H. Ikeda T. Fujita H. Inouye and M. H. Zenk Tetrahedron Left. 1987 28 4431. 75 D. E. Cane and H.-J. Ha J. Am. Chem. Soc. 1986 108 3097; 1988 110 6865. 76 T. H. Hohn and F. van Middlesworth Arch. Biochem. Biophys. 1986 251 756. 332 T J. Simpson (34) R' = R2 = CH20H (35) R' = CHO R2 = CH,OH (36) R' = CH,OH R2 = CHO workers have shown77 that labels the oxygens indicated (a)in the conversion of trichodiene into T2-toxin (39). Treatment of cultures of Gibberella pulicaris with ancymidol suppressed biosynthesis of diacetoxyscirpenol (40) with concomitant accumulation of major quantities of trichodiene." Other significant work in the trichothecin area includes the preparation of u.v.-induced mutants of F.sporotrichoides which are blocked in T2-toxin production and accumulate diacetoxy- scirpen01,~~ and the incorporation of 2H- and 13C-labelled mevalonates into 3-acetyldeoxynivalenol (41) in Fusarium culmorum.80 A novel application of kinetic pulse labelling led to the identification of transient intermediates to (41) and sambucinol and to a new dead-end shunt metabolite.81 (39) R = OCOCH2Pri (40) R = H A number of papers dealing with the enzymatic cyclization of FPP to pentalene (42) have been published. Previous studies have shown that the first step in the cyclization of FPP to pentalene via humulene appears to be the intramolecular analogue of the prenyltransferase reaction.Incorporation of (R)-and (S)-[1-2H]FPP and 2H n.m.r. analysis show that inversion occurs at C1 of FPP during this cycliz- ation.'* (9R)- and (9S)-[9-3H,4,8-14C]FPP were prepared enzymatically from (1R)-and (1s)-[ 1 -3H]DMAPP and [4-14C]IPP. These were incubated83 with both crude and purified pentalene ~ynthetase,~~ and analysis of the resultant pentalene showed that during cyclization H9re of FPP becomes H8 of pentalene while H9 si undergoes 77 A. E. Desjardins R. D. Plattner and F. van Middlesworth Appl. Enoiron. Microbiol. 1986 51 493. " F. van Middlesworth A. E. Desjardins S. L. Taylor and R. D. Plattner J. Chem. SOC.,Chem. Commun. 1986 1156. '9 M. N. Beremand Appl. Environ. Microbiol. 1987 53 1855. 80 L. 0. Zamir K. A. Devor Y.Nadeau and F. Sauriol J. Biol. Chem. 1987 262 15 354. 81 L. 0. Zamir and K. A. Devor J. Biol. Chem. 1987 262 15 348. P. H. Harrison J. S. Oliver and D. E. Cane J. Am. Chem. SOC. 1988 110 5922. 83 D. E. Cane C. Abell R. Lattman C. T. Kane B. R. Hubbard and P. H. Harrison J. Am. Chern. Soc. 1988 110 4081. 84 D. E. Cane and C. Pargellis Arch. Biochem. Biophys. 1987 254 421. Biological Chemistry- Part ( ii) Biosynthesis 333 a net intramolecular transfer to Hla as indicated in Scheme 6. Since cyclization has already been shown to involve electrophilic attack on the si face of the C 10-C 11 double bond of FPP the formal SEr reaction takes place with net anti stereochemistry. CB-Enz cB-Enz I r= / I Scheme 6 ''C-labelled allicide (43) is incorporated into both alliacolide (44) and 12-hydroxyalliacolide (45) in cultures of Marasmius allia~eus.~~ Thus the 4-hydroxy group is introduced by direct hydroxylation rather than ria a 4,Sepoxide.A number of other papers of note describe the incorporation of I3C-labelled acetates into the fungal sesquiterpenoids quadrone (46),86 fomajorins (47),87 and 7,12-dihydroxyster- purene (48) .88 OH 0 R' (47) R = Me or CO,H RZ R1' 0& '0 Me 0 (43) R' = R2 = H (44) R' = OH R2 = H (45) R' = R2 = OH I 85 A. G. Avent J. R. Hanson and B. L. Yeoh .I.Chem. Res. (S) 1986 422. 86 D. E. Cane Y. G. Whittle and T. C. Liang Bioorg. Chem. 1986 14 417. 87 D. M. X. Donnelly J. O'Reilly J.Polonsky and M. H. Sheridan J. Chem. SOC.,Perkin Trans. 1 1987 1869. 88 C. Abell and A. P. Leech Tetrahedron Len. 1987 28 4887. 334 T. J. Simpson The stereochemistry of the formation of the exocyclic methylene function in ent- kaurene (49) has been examinedg9 using mevalonate containing a chirally label- led methyl group. Incorporation into (49) using a cell-free preparation from Marah macrocarpus indicated that the methyl to methylene elimination had occurred with the endo orientation indicated in Scheme 7. The mechanism usually proposed for the formation of the cation (51) via the pimarenyl cation (50) is in contravention of Baldwin’s rules. An alternative route via the cyclobutyl cation (52) has been examined.” However no incorporation of the appropriate cyclobutyl intermediates was observed.Model studies” have provided some support for the formally dis- allowed 5-endo-trig cyclization of (50) to (51). Enz-B 7 Scheme 7 A number of monoclonal antibodies which recognize specific features of the gibberellin molecule have been prepared9’ from antigenic gibberellin-protein com- plexes that are linked through C3 or C17. The same chemistry has been used to prepare gibberellins attached to photoaffinity labels and other probes for studying gibberellin biosynthesis and mode of action.93 The purification of a number of the enzymes on the gibberellin pathway have been described; these include a GA1-2P-hydroxyla~e~~ and Gb-~xidase.~’ 89 R. M. Coates S. C. Koch and S. Hedge J. Am. Chem.Sac. 1986 108 2762. 90 R. M. Coates and H.-Y. Yang J. Org. Chem. 1987 52 2065. 91 R. M. Coates and H.-Y. Yang 1. Chem. SOC.,Chem. Commun. 1987 232. 92 J. P. Knox M. H. Beale G. W. Butcher and J. MacMilIan PZunta 1987 167 9. 93 M. H. Beale R. Holley and J. MacMiIlan in ‘Plant Growth Substances 1985’ ed. M. Bopp Springer- Verlag Heidelberg 1986 p. 65. 94 V. A. Smith and J. MacMiIlan plant^ 1986 167 9. 95 S. J. Gilmour A. B. Bleecher and J. A. D. Zevaart Plant Physiol 1987 85 87. Biological Chemistry- Part ( ii) Biosynthesis 335 A novel antheridiogen has been isolated from Anemia rnexi~ana.~~ The structure (53) which was proposed on biogenetic grounds has been confirmed by total synthesis.97 The ;hj?-hydroxy group in aphidicolin (54) originates in water whereas the 17-hydroxy group is introduced from the atm~sphere.~~ -OH Incorporations of [5-'3C,5-2H2]mevalonate and [2-'3C,2H3]acetate into ursolic acid (55) and oleanolic acid (56) in tissue cultures of Rabdosia japonica confirm that the C12-Cl3 double bond of (55) is introduced by elimination of the 12-pro-R- hydrogen in a cis fashion and also confirm the occurrence of predicted 1,2-hydride shifts in the biosynthesis of (55) and (56).99 Me & Me Me 0,H Ho Me ,Me A number of papers on meroterpenoid biosynthesis have been published.Incor- porations of '3C,2H-labelled mevalonates into viridicatumtoxin (57)indicate that a 1,3-hydride shift from C15 to C19 occurs during the formation of the spirobicyclic ring system.'oo The biosynthesis of the austalides has been studied"' using I3C- and *H-labelled acetates and mevalonates and the synthesis and incorporation of 96 M.Furber L. N. Mander J. E. Nester N. Takahashi and H. Yamane Phytochemistry 1989 28 63. 97 M. Furber and L. N. Mander J. Am. Chem. SOC.,1988 110 4084. 98 M. J. Ackland J. F. Gordon J. R. Hanson B. L. Yeoh and A. H. Ratcliffe J. Chem. SOC.,Chem. Commun. 1987 1492. 99 S. Seo Y. Yoshimura A. Uomari K. Takeda H. Seto Y. Ebijuka and U. Sankawa J. Am. Chem. SOC. 1988 110 1740. 100 R. M. Horak V. J. Maharaj S. F. Marais F. R. van Heerden and R. Vleggaar J. Chem. Soc. Chem. Commun. 1988 1562. 101 A. E. de Jesus R. M. Horak P. S. Steyn and R. Vleggaar 1.Chem. SOC. Perkin Trans. 1 1987 2253.nMe 7'.J. Simpson OH CONH2 nu '3C,'80-labelled 3,5-dimethylorsellinate into austinlo2 and andilesin A'03 has been reported. 4 Shikimate and Related Metabolites The shikimate pathway continues to be of considerable interest not least because it offers an attractive target for selective antimicrobial and herbicidal agents. Progress has been greatly facilitated by the increased availability of the enzymes on the pathway by gene cloning to construct overproducing strains of E. coli. In this way the complete amino acid sequence of 3-dehydroquinate synthetase has been eluci- dated,Io4 and shikimate kinase which catalyses the conversion of shikimate into shikimate 3-phosphate has been cloned and purified.lo5 In E. coli the enzymes of the pathway are all monofunctional.However in S. cerevisiae one pentafunctional enzyme is found which is encoded by the arom gene. The nucleotide sequence of the arom gene has been determined and functional regions within the derived polypeptide have been compared with the corresponding enzymes from E. coIi.'06 This demonstrated that the arom polypeptide contains monofunctional domains and supports the theory that the S. cerevisiae evolved by gene fusion from monofunc- tional bacterial genes. 3-Dehydroquinate synthetase catalyses an apparently complex sequence of reac- tions which converts DAHP (58) into 3-dehydroquinate (59). Synthetic analogues of DAHP containing fluorine at C3 were converted by the enzyme into 6-fluoro derivatives of (59) and subsequently 3-dehydroshikimate and shikimate.lo7 The 2-deoxy analogue of (58) has been converted into the enol ether (60).The stereochemistry of the p-elimination of phosphate has been established'08 by stereo- specific labelling of (58) with 2H at C7. '% ' W H -02c&" -0zc OH o@ -02c OH 0 (58) (59) (60) F. E. Scott T. J. Simpson L. A. Trimble and J. C. Vederas J. Chem. Soc. Chem. Commun. 1986 214. 103 C. R. McIntyre F. E. Scott T. J. Simpson L. A. Trimble and J. C. Vederas J. Chem. Soc. Chem. Commun. 1986 501. I04 G. Miller and J. R. Coggins FEBS Lett. 1986 200 11. G. Miller A. Lewendon M. G. Hunter and J. R. Coggins Biochem. J. 1986 237 427. 106 K. Duncan R. M. Edwards and J. R. Coggins Biochem. J. 1987 246 375. 107 P. Le Marechal C.Froussios and R. Azerad Biochemie 1986 68 1211. 108 T. S. Widlanski S. L. Bender and J. R. Knowles J. Am. Chem. Soc. 1987 109 1873. Biological Chemistry- Part ( ii) Biosynthesis 337 The conversion of shikimate 3-phosphate (61) into EPSP (62) catalysed by EPSP synthase (the target for the herbicide glyphosphate) is thought to proceed via an addition-elimination mechanism involving nucleophilic attack of the 5-hydroxy group of (61) on C2 of PEP. The presence of an acid-labile intermediate was demon~trated'~~ and this has now been isolated by denaturing the enzyme under mild basic conditions followed by ion-exchange h.p.1.c. The intermediate has been shown by detailed n.m.r. analysis to correspond to the key tetrahedral intermediate (63).'lo @o"fiOH OH -~o..~o~co~-@o..~o~~o~ : OH o@ OH (61) (63) (62) 'H n.m.r.studies have shown that aqueous solutions of chorismic acid contain 10-20°/0 of the diaxial conformer (64) whereas only the diequatorial conformer (65) is observed in methanol."' The thermal Claisen rearrangement of chorismate to prephenate (66) is considerably slower in methanol than in aqueous solution. -02c< 0 0 c 'd H OH -0zc OH (64) (65) (66) The enzyme-catalysed process has been studied using secondary 3H isotope effects with chorismate labelled at C4. These allow mechanisms involving the 4-hydroxy group to be eliminated and an alternative to be proposed"* in which an enzyme- bound nucleophile stabilizes developing charge at C5.The thermal Claisen rear- rangement has also been studied using synthetic analogues of chorismate and by observing solvent and isotope effects. These indicate a transition state involving substantial C-0 bond cleavage but little formation of the C-C bond.'13 So-called C7N units which are believed to be derived from the shikimate pathway but not via shikimate have been implicated in the biosynthesis of many antibiotics. 4-Amino- and 3-hydroxyanthranilate have been shown .to be intermediates in the biosynthesis of ~treptonigrin"~ and LL-C10037a.''5 In contrast the C,N unit found I09 K. S. Anderson J. A. Sikorski and K. A. Johnson Biochemistry 1988 27 1604 7395. 110 K. S. Anderson J. A. Sikorski A. J. Benesi and K. A. Johson J. Am. Chem. SOC.,1988 110 6577.111 S. D. Copley and J. R. Knowles J. Am. Chem. Soc. 1987 109 5008. 112 W. J. Guilford S. D. Copley and J. R. Knowles J. Am. Chem. Soc. 1987 109 5013. 113 J. J. Gajewski J. Jurayi D. R. Kimbrough M. E. Gande B. Ganem and B. K. Carpenter J. Am. Chem. SOC.,1987 109 1170. 114 W. R. Erickson and S. J. Gould J. Am. Chem. SOC.,1987 109 620. 115 Y. G.Whittle and S. J. Gould J. Am. Chem. Soc. 1987 109 5043. 338 T. J. Simpson in asukamycin and manumycin appears to be derived via intermediates from the TCA cycle and triose phosphate p001."~ [l-13C]shikimate has been incorporated into the cyclohexanecarboxylic acid moiety but not the C7N unit of the ansatrienin antibiotics; no label from [6-2H]shikimate was retained however.' l7 Feeding experiments in young shoots of Acer nikoense have shown that phenyl- alanine and cinnamic acid are incorporated into the diarylheptanoid acerogenin A (67).The central carbon (0) is derived from C2 of acetate."' The synthase which catalyses the biosynthesis of the stilbene resveratrol (68) in Arachis hypogeae 'has been cloned and sequenced."' It shows a remarkable degree of homology with the consensus sequence of chalcone synthases from various sources. The synthesis of 6'-deoxychalcones has been shown to require the combined presence of chalcone synthase and an NADH-dependent reductase in cell-free extracts of Glycyrrhiza echinatat2' and Glycine max.121 The reductase from the latter has been purified to homogeneity. 6'-Deoxychalcones are precursors to both iso- flavanoids and rotenoids.The pattern of incorporation of 13C2-acetate into amor- phigenin (69) by seedlings of Amorpha fmticosa confirms'22 that deoxygenation must occur before cyclization of the polyketide-derived ring. An isoflavone synthase was recently isolated from G. max and a mechanism for the rearrangement proposed. However an alternative mechanism involving epoxidation of the aryl ring rather than the heterocyclic ring as originally proposed has been suggested.12* Both mechanisms involve spirodienone intermediates. I16 J. M. Beale R. E. Herrold H. G. Floss H. Nakagawa S. Omura R. Thiericke and A. Zeeck J. Am. Chem. SOC.,1988 110 4435. 117 R. Casati J. M. Beale and H. G. Floss J. Am. Chem. SOC.,1987 109 8102. 118 T.Inouye N. Kenmochi N. Furukawa and M. Fujita Phytochemistry 1987 26 1409. 119 G. Schroder J. W. S. Brown and J. Schroder Eur. J. Biochem. 1988 172 161. 120 S.-I. Ayake A. Udugawa and T. Furuya Arch. Biochem. Biophys. 1988 261 458. 121 R. Welle and H. Grisebach FEBS Lett. 1988 236 221. 122 L. Crombie 1. Holden N. van Bruggen and D. A. Whiting J. Chem. SOC.,Chem. Commun. 1986 1063. Biological Chemistry- Part (ii) Biosynthesis The formation of the chromene rings found in many rotenoids and other phenolics was thought to involve epoxidation of prenyl substituents and subsequent ring closure and dehydration. However although rot-2’-enoic acid (70) was well incorpor- ated into deguelin (71) by seedlings of Tephrosia vogelii the hydroxychroman (72) was not.123 Similar results were obtained with crude and purified enzyme prep- arations.These results make the intermediacy of epoxides unlikely. An alternative mechanism involves cyclization of the o-quinone methide (73). Incorporation of (70) labelled with 13C at C4’ produced deguelin labelled at both methyls but with a strong preference (73%) for C8’,indicating that the electrocyclization is stereoselec- tive but not stereo~pecific.’~~ The major route to amorphigenin (69) is also from rot-2’-enoic acid via stereospecific cyclization to rotenone in which the (E)-methyl of (70) becomes the methylene in rotenone. This is followed by a non-specific hydroxylation which results in a randomization of label between C7’ and C8’ in amorphigenin.However a secondary route appears to involve a positionally non- specific hydroxylation of the prenyl methyls in rot-2’-enoic acid followed by a chemospecific cyclization to (69).125 OH (72) Me” *Me -8‘ H -Mh OMe (71) OMe (69) 123 L. Crornbie J. Rossiter and D. A. Whiting J. Chem. SOC.,Chern. Cornrnun. 1986 352. 124 M. J. Begley L. Crornbie J. Rossiter M. Sanders and D. A. Whiting J. Chern. SOC.,Chem. Cornmun. 1986 353. lZ5 P. Bhandari L. Crornbie and D. A. Whiting J. Chern. SOC.,Chern. Comrnun. 1988 1085. 340 T. J. Simpson 5 Alkaloids and other Amino-acid-derived Metabolites The (S)-tropic acid moiety found in tropane alkaloids is formed from phenylalanine via an intramolecular 1,2-carboxyl migration. It has now been shown that during the concomitant 1,2-hydrogen shift it is the 3-pro-S-hydrogen of phenylalanine which migrates.'26 The generally accepted classical hypothesis for the biosynthesis of the tropane moiety of cocaine (74) needs to be modified as a result of experiments which showed that [2-I4C]-1 -methyl-A'-pyrrolinium chloride did not label C 1 of cocaine when fed to Erythoxylurn coca ~1ants.I~' However [l-'3C,'SN]-4-(methyl-amino)butanal did label the C5-N bond.The pathway shown in Scheme 8 was proposed.'28 Evidence for the intermediacy of (75) was obtained by a trapping experiment using 1-methylpyrrolidine-2-acetic acid. * -4: OEt ,COzMe COSCoA (74) (75) Scheme 8 The iminium ion (76) has been shown'29 to be an intermediate to the pyrrolizidine bases rosmarinecine (77) and retronecine (78).Both are known to be formed from two molecules of putrescine via hom~spermidine.'~~ The two pathways must diverge (76) 126 E. Leete Can. J. Chem. 1987 65 266. 127 E. Leete S. H. Kim and J. Rana Phytochemistry 1988 27 401. 128 E. Leete and S. H. Kim,J. Am. Chem. Soc. 1988 110 2976. 129 H. A. Kelly and D. J. Robins J. Chem. SOC.,Chem. Commun. 1988 329. 130 H. A. Kelly and D. J. Robins J. Chem. SOC.,Perkin Trans. l. 1987 177. Biological Chemistry- Part ( ii) Biosynthesis 341 after (76) because l~-hydroxymethyl-8a-pyrrolizidine is incorporated into ros- whereas the 1a-isomer is a better precursor of retr0ne~ine.l~~ rnarine~ine'~' Late stages in the biosynthesis of the indolizidine alkaloids salframine (79) and swain- sonine (80) have been studied'33 with the aid of specifically deuterated chiral precursors (81) and (82).The results indicate a pathway in which 1-oxoindolizidine acts as a branch point. (81) is converted into salframine via the corresponding 1,6-dihydroxy and 6-0x0 compounds. The route to swainsonine is via the 1,2-diol and the iminium ion (83). The biosynthesis of cyclizidine has been discussed above. Incorporations of variously deuterated cadaverines into various quinolizidine alkaloids have been reported,'34 providing useful information on the biochemical events occurring during the biosynthesis and interconversions of these alkaloids. .OH (82) (83) (80) The biosynthetic origins of all the carbons of ephedrine (84) and related alkaloids have been established finally.'35 Both labels from [2,3-'3C,]pyruvate were incorpor- ated as a unit into C2 and C3 of (85) in Ephedra gerardinia plants.Detailed '3C-labelling studies have shown'36 that the first benzylisoquinoline alkaloid from which the whole family are formed is (S)-norcoclaurine (85) rather than (S)-norlaudanosoline (86). Studies with S-adenosylmethionine containing chiral methyl groups showed that the 6-0-methylation of (87) to give reticuline (88) occurs with inversion of configuration at the meth~1.I~' During the further conversion of reticuline into jatrorhizine (89) the methoxy group at C2 of (89) has the same configuration as that at C6 of (88). The methyl group transfer occurs via the corresponding methylenedioxy bridge in berberine.Late intermediates in the biosynthesis of the ergot alkaloids chanoclavine and elymoclavine (90) have been established. While no incorporation of the previously proposed diol (91) could be observed,'38 the incorporation of *H label from (92) into (90) was detected by mass spectral analysis.'39 In addition an isotope trap 131 E. K. Kunec and D. J. Robins J. Chem. Soc. Chem. Commun. 1986 250. 132 E. Leete and J. Rana J. Nut. Prod. 1986 49 838. 133 C. M. Harris M. J. Schneider F. S. Ungemach J. E. Hill and T.M. Hams J. Am. Chem. SOC.,1988 110 940. 134 D. J. Robins and G. N. Sheldrake J. Chem Res. (S) 1987 159; 1988 230; T. Hemscheidt and I. D. Spenser Can. J. Chem. 1987 65 170.135 G. Grue-Sorensen and I. D. Spenser J. Am. Chem. SOC. 1988 110 3714. 136 S. Loeffler R. Stadler N. Nagakura and M. H. Zenk J. Chem. Soc. Chem. Commun. 1987 1160. 137 M. Kobayashi T. Frenzel J. P. Lee M. H. Zenk and H. G. Floss J. Am. Chem. SOC.,1987 109 6185. 138 A. P. Kozikowski M. Okita M. Kobayashi and H. G. Floss J. Org. Chem. 1988 53 863. 139 A. P. Kozikowski J.-P. Wu M. Shibuya and H. G. Floss J. Am. Chem. Soc.. 1988. 110 1970. 342 T.J. Simpson OH (85) R' = R2= R3 = R4 = H (86) R' = R3= R4 = H,R2= OH (87) R' = Me,R2= OH,R3= R4 = H (88) R' = R3= R4= Me,R2 = OH experiment with (92) anowed the presence of (93) in cultures of Claviceps to be detected. On the basis of these results a pathway was proposed for ring closure via the vinyloxirane (94).The isonitrile group in hapalindole A (95) a metabolite of 'ezH R%H \ H H (91)R = OH (931 (92) R = H 1 OH &$H H the marine cyanophyte Hapalosiphon fontinalis has been shown to be derived from glycine by incorporation of [2-'3C,'5N]glycine.'40 The intermediacy of the 5-formimino group in tetrahydrofolate was suggested which would be consistent with V.Bornemann G. M. L.Patterson and R. E. Moore J. Am. Chern. SOC.,1988 110 2339. Biological Chernistry- Part ( ii) Biosynthesis NC the observed incorporation of one methylene from glycine in the biosynthesis of the formamide moiety in tuberin.141 The isontrile carbon in the marine sponge metabolite diisocyanodociane (96) is labelled by ''C-cyanide.'42 L-[Methyl-13C]methionine labels the isonitrile group of the hazimycins in the bacterium Micrornonosporu ecbinosp~ra,'~~ but the carbon source of the isonitrile group in xanthocillin a metabolite of Penicilliurn notaturn remains obscure despite extensive labelling studies.'44 Biosynthetic work on the naturally occurring isocyanides is discussed in a recent comprehensive review of this varied group of rnetab01ites.l~~ Considerable progress continues to be made in understanding the biosynthesis of the p-lactam antibiotics and much of the important work on penicillins and cephalosporins has been discussed in a recent authoritative review.146 The key sequence in penicillin biosynthesis involves the double cyclization of the LLD-ACV tripeptide to give isopenicillin N catalysed by isopenicillin N synthase (IPNS).On the basis of present knowledge the catalytic cycle is proposed to proceed as shown in Scheme 9 the key feature being the intermediacy of highly reactive ferryl(~v) species such as Enz=Fe=O formed from an initial Fe -O2 complex at the active The mechanistic details of this sequence has been. probed by exhaustive studies14' using cloned IPNS and a huge variety of substrate analogues many of 141 K. M. Cable R. B. Herbert and J. Mann J. Chem. SOC.,Perkin Trans. 1 1987 1593. M. J. Carson J. Chem SOC.,Chem. Commun. 1988 35. 143 M. S. Puar H. Munayyer B. Hedge B. K. Lee and A. J. Wartz J. Antibiot. 1985 38 530. 144 K. M. Cable R. B. Herbert and J.Mann Tetrahedron Lett. 1987 28 3159. 145 M. S. Edenborough and R. B. Herbert Nut. Prod. Rep. 1988 5 229. 146 J. E. Baldwin and E. P. Abraham Nut. Prod. Rep. 1988 5 129. 147 For latest examples see J. E. Baldwin R. M. Adlington L. G. King M. F. Parisi,'W. G. Sobey J. D. Sutherland and H.-H. Ting J. Chem. SOC.,Chem. Commun. 1988 1635; J. E. Baldwin W. J. Norris R. T. Freeman M. Bradley R. M. Adlington S. Long-Fox and C. J. Schofield ibid. p. 1128; J. E. Baldwin R.M. Adlington M. Bradley W. J. Noms N. J. Turner and A. Yoshida ibid. p. 1125; J. E. Baldwin R. M. Adlington B. P. Domayne-Hayman G. Knight and H.-H. Ting ibid. 1987 1661. 344 T. J. Simpson ACV AA HOzC AA'\H / HOzC HOIC' Scheme 9 which have been converted into novel P-lactam structures.The IPNSs from multi- farious eukaryotic and prokaryotic sources have been cloned to provide a large body of comparative sequence data.14* They all appear to contain two highly conserved cysteine residues the importance of which have been tested by site- directed mutagenesis studies using Cephalosporium acremonium IPNS in which the cysteines are replaced by ~erines.'~~ The conversion of isopenicillin N into cephalo- sporins requires its isomerization to penicillin N followed by ring expansion and hydroxylation. These last two steps are catalysed by the single bifunctional enzyme deacetoxycephalosporin-C synthetase and hydr~xylase.'~' This has been cloned and shown to have significant sequence homology with IPNS.'" Studies with specifically 148 L.G. Carr P. L. Skatrud M. E. Scheetz S. W. Queener and T. D. Ingolia Gene 1986 48 257; B. K. Leskiw Y. Aharonowitz M. Mevarech S. Wolfe L. C. Vining D. W. S. Westlake and S. E. Jensen ibid. 1988 62 187; R. Ramon L. Carramoline C. Patino F. Sanchez and M. A. Penalva ibid. 1987 57 171. 149 S. M. Samson J. L. Chapman R. Belagaje S. W. Queener and R. D. Ingolia Roc. Nat. Acad. Sci. USA 1987 84 5705. 150 J. E. Baldwin E. P. Abraham R. M. Adlington J. D. Coates M. J. C. Crabbe N. P. Crouch J. W. Keeping G. C. Knight C. J. Schofield M. Thornally H.-H. Ting C. A. Vallejo and T. Wallis Biochem. J. 1987 245 831. 151 S. M. Samson J. E. Dotzlaf M. L. Slisz G. W. Becker R. M. van Frank L. E. Veal N.-K. Yeah J. R. Miller S. W.Queener and T. D. Ingolia Biotechnology 1985 5 1207. Biological Chemistry- Part (ii) Biosynthesis 345 deuterated samples of penicillin N suggest that the ring expansion occurs in two steps and that the required removal of a 2-methyl hydrogen precedes the loss of C3 h~dr0gen.l~~ The proposed mechanism is summarized in Scheme 10. OH Step 1 RHN EyFe=Enz I Enz=Fe=O + pencillin N 0 COZH OH RHN RHN r COzH C02H I Step 2 RHNx$ + Fe=Enz + H20 0 CO2H Scheme 10 Incorporations of chirally labelled samples of glycerol and of ornithine into clavulanic acid (97) have been reported."53 Both the ring and primary alcohol oxygens are enriched'54 by 1802. Two ornithine-containing metabolites clavaminic acid (98) and proclavaminic acid (99) have been isolated155 from a cell-free enzyme preparation from Streptomyces clavuligerus supplemented with a-ketoglutarate and Fe2+.Surprisingly (98) has the opposite stereochemistry at C3 and C5 relative to clavulanic The absolute configuration of proclavaminic acid has been estab- lished by a synthesis from a resolved sample of P-hydroxyornithine and its incorpor- ation into clavaminic acid by a partially purified synthase has been re~0rted.l~~ Both (98) and (99) have been incorporated into clavulanic acid by a broken-cell preparation from S. clavuligerus. N-Acetylglycylclavaminic acid (100) has been isolated from a clavulanic acid negative mutant of S. ~lavuligerus.'~~ [4-2H2,5-13 Clornithine is incorporated into (100) with retention of one 2H at C8 but no 2H I52 J.E. Baldwin R. M. Adlington R. T. Alpin N. P. Crouch C. J. Schofield and H.-H. Ting J. Chem. SOC.,Chem. Commun. 1987 1654. 153 C. A. Townsend and S.3. Mao J. Chem. SOC.,Chem. Commun. 1987 86; C. A. Townsend M.F. Ho and S.S. Mao ibid. 1986 638. I54 C. A. Townsend and W. J. Krol J. Chem. Soc. Chem. Commun. 1988 1235. 155 S. W. Elson K. H. Baggaley J. Gillett S. Holland N. H. Nicholson J. T. Sime and S. R. Woroniecki J. Chem. SOC.,Chem. Commun. 1987 1736. 15' K. H. Baggaley K. H. Nicholson and J. T. Sime J. Chem. Soc. Chem. Commun. 1988 567. 157 S. W. Elson K. H. Baggaley J. Gillett S. Holland N. H. Nicholson J. T. Sime and S. R. Woroniecki J. Chem. SOC., Chem. Commun. 1987 1739. 158 B. W. Bycroft A. Penrose J.Gillett and S. W. Elson J. Chem. SOC.,Chem. Commun. 1988 980. 346 T. J. Simpson incorporation into clavulanic acid is found. These results suggest that a P-keto intermediate (101) may be involved in the conversion of clavaminic acid into clavulanic acid. A similar type of intermediate has been invoked to explain the base-catalysed racemization of clavulanates. (99) (98) R = H (100) R = COCH,NHCOMe 1 H All the hydrogens in the hydroxyethyl side chain of thienamycin are derived from methionine and the stereochemical fate of the methyl group of methionine on incorporation into thienamycin (102) has been studied with chiral methyl-labelled rnethi~nine.'~~ OH [2-'3C,'5N]nocardicin G (103) has been shown to be incorporated intact into nocardicin A (104) whereas the 2'-epimer was degraded to (p-hydroxypheny1)gly- cine prior to incorporation.16' A partially purified cell-free system has been prepared from Nocardia uniformis which produces nocardicin A (104) from nocardicin E (105) and S-adenosylmethionine.'61Whole-cell experiments'62 have shown that the transfer of the 3-amino-3-carboxypropyl moiety from methionine to nocardicin A proceeds with inversion of configuration at C4.159 D. R. Houk K. Kobayashi J. M. Williamson and H. G. Floss 1. Am. Chem. SOC.,1986 108 5365. 160 C. A. Townsend and B. A. Wilson 1. Am. Chem. SOC.,1988 110 3320. 161 B. A. Wilson S. Bantia G. M. Salituro A. McE. Reeve and C. A. Townsend J. Am. Chem. SOC.,1988 110 8238. 162 C. A. Townsend A.McE. Reeve and G. M. Salituro J. Chem. SOC.,Chem. Cornmun. 1988 1579. Biological Chemistry- Part ( ii) Biosynthesis I CO2H (103) R = H X = H &NH2 (104) R = CH2CH2CH(NH2)C0,H X = NOH (105) R = H X = NOH Incorporation of 13C- and "N-labelled precursors demonstrate that the unusual amino acid 5-hydroxy-4-oxonorvaline(HON) is biosynthesized in Streptomyces akiyoshiensis uia condensation of an activated form of aspartate with acetyl- or malonyl-CoA to form a c6 intermediate that is converted into HON by loss of the acetate-derived carboxyl.163 A similar condensation between acetyl-CoA and glutamic semialdehyde has been proposed as the first step in the biosynthesis of carbapenam~.'~~ L-Nitrosuccinate has been identified as an intermediate in the biosynthesis of 3-nitropropanoic acid in Penicillium atro~eneturn.'~~ Both oxygens of the nitro group are derived from the atmosphere.'66 The results suggest the biosynthetic pathway shown in Scheme 11.Scheme 11 The modified uracil moiety in sparsomycin (106) has been sho~n'~' to be derived by extensive modification of tryptophan. The remaining carbons are derived from methionine cysteine and S-methylcysteine. HO \ 163 R. L. White A. C. DeMarco and I. C. C. Smith J. Am. Chem. Soc. 1988 110 8222. 164 B. W. Bycroft C. Maslen S. J. Box A. G. Brown and J. W. Tyler J. Chem. SOC.,Chem. Commun. 1987 1623. 165 R. L. Baxter A. B. Hanley and H. W.-S. Chan J. Chem. Soc. Chem. Commun. 1988 757. 166 R. L. Baxter and S.L. Greenwood J. Chem. Soc. Chem. Commun.,1986 175. 167 R. J. Parry and M. E. Eudy J. Am. Chem. Soc. 1988 110 2316. 348 T. J. Simpson 6 Porphyrins Porphobilinogen (PBG) chirally labelled at C11 has been incorporated into hydroxy- methylbilane by PBG deaminase in order to investigate whether hydroxymethyl- bilane is the true enzymatic intermediate or whether it is formed by trapping of an azafulvene by water. Degradation of the product to glycolic acid showed that the reaction proceeded with retention of configuration a result taken to be inconsistent with the release of a planar intermediate.168 There has been considerable progress in understanding the structure and mode of action of deaminase. F.p.1.c. has been used to purify deaminase from E.~oli'~~ and human erythrocyte^."^ Both genes have been cloned and sequenced and show a considerable degree of homology between the two enzymes.171 This has led to the overexpression of the E. coli enzyme by several groups of workers resulting in 100 to 200 fold overproduction.'72-174 Studies with overproduced enzyme have given the unexpected result that the enzyme group to which the first PBG molecule (to be incorporated into hydroxymethylbilane by deaminase) becomes bound is not an amino acid residue as previously thought but is in fact a novel covalently bound cofactor. 172,173,175 Even more surprising is the demonstration that this cofactor is in fact a dipyrromethane derived from two molecules of PBG! Confirmation of its derivation from PBG has been provided by incorporation of label from [5-14C]ALA,173 [5-13C]ALA,'75 and [1 1-I3C]ALA (ALA = 8-aminolaevulinic The 13C n.m.r.spectrum of the [5-13C]ALA-enriched deaminase shows a methylene carbon with a chemical shift in the range expected for an a-methylpyrrole suggesting that the cofactor is attached to one of the four cysteine residues in the enzyme. Previous result^"^ from 3H n.m.r. studies with 3H-labelled PBG which had suggested that the initial site of attachment of the initial PBG to be incorporated into hydroxy- methylbilane was a cysteine residue have been reinterpreted as being due to an initial attachment of the enzyme's substrate at a second cysteine residue. The gene for cosynthetase has been found to be adjacent to that for deaminase in E.coli and they appear to be translationally A favoured mechanism for the conversion of hydroxymethylbilane into uro'gen I11 involves the intermediacy of the spiro-pyrrolenine (107). Strong evidence for this has come from the synthesis of the analogous spiro-lactam (108) which appears to exist as two non-interconvert- ible conformers one of which is a powerful inhibitor of co~ynthetase.'~~ Studies with model pyrrolenines suggest that the further conversion of (107) into uro'gen 16' J.-R. Schauder S. Jendrezejewski C. Abell G. J. Hart and A. R. Battersby J. Chem. SOC.,Chem. Commun. 1987 436. 169 G. H. Hart C. Abell and A. R. Battersby Biochem. J. 1986 240 273. 170 R. W. M. De Rooij C. M. Hamer and J. H. P. Wilson Clin. Chim. Acta 1987 162 61.17' N.Raich P.H. Romeo A. Dubert D. Beaupain N. Cohen-Solal and M. Goosens Nucieic Acids Res. 1986 14 5955; S. D. Thomas and P. M. Jordan ibid. p. 6215. 172 G. H. Hart A. D. Miller F. J. Leeper and A. R. Battersby J. Chem. SOC. Chem. Commun 1987 1762. 173 P. M. Jordan and M. J. Warren FEBS Lett. 1987 225 879. 174 A. I. Scott T. 0. Baldwin M. Treat C. A. Roessner S. K. Grant N. J. Stolowich and H. J. Williams Roc. Nut. Acad. Sci. USA in press. 175 A. I. Scott N. J. Stolowich H. J. Williams M. D. Gonzales C. A. Roessner S. I. K. Grant and C. Pichon J. Am. Chem. SOC.,1988 110 5898. 1 76 J. N. S. Evans G. Burton P. E. Fagerness N. E. MacKenzie and A. I. Scott Biochemistry 1986,25,892. 177 A. Saserman A. Nepveau Y. Echelard J. Dymetryszyn M. Drolet and C.Goyer J. Bacteriol 1987 169 4257; P. M. Jordan B. I. A. Mgbeje S. D. Thomas and A. F. Alwan Biochem. J. 1988 249,613. 178 W. M. Stark G. J. Hart and A. R. Battersby J. Chem. SOC. Chem. Commun. 1986 465. Biological Chemistry- Part ( ii) Biosynthesis HO2C HO2C H02C C02H C02H (107)X-Y = -CH=N-0 II (108) X-Y = -C-NH-111 proceeds via a fragmentation-recombination mechanism rather than a series of [1,5]-sigmatropic rearrangements.’ 79 Full details have been published of earlier work which established the sequence of methylations in the biosynthesis of vitamin B12. This paper proposes a new nomenclature system of BI2biosynthetic In this system the reduced forms of Factors I 11 and I11 become ‘precorrins’ 1 2 and 3 in which the number indicates the total number of methyl groups introduced from S-admosylmethionine.Details of the system are best left to the cognoscenti. Further information on the sequence of events after precorrin-3 (109) has been obtained. Incorporations of precorrin-3 and the corresponding 12-methyl analogue (1 10) were compared under HOzC CO2H \ COzH (109) R = CHZCOZH (110) R = Me 179 A. R. Battersby M. G. Baker H. A. Broadbent C. J. R. Fookes and F. J. Leeper J. Chem. SOC.,Perkin Trans. 1 1987 2027; C. J. Hawker W. M. Stark and A. R. Battersby J. Chqm. SOC.,Chem. Commun. 1987 1313. 180 H. C. Uzar A. R. Battersby T. A. Carpenter and F. J. Leeper J. Chem. SOC.,Perkin Trans. 1 1987 1689. 350 T. J. Simpson strictly controlled conditions.lS1 Whereas (1 10) showed high incorporation (109) did not suggesting that precorrin-3 does not undergo decarboxylation.Previous results have shown that the fourth methylation occurs at C17 and if decarboxylation occurs before the fifth methylation at C12 as appears mechanistically reasonable then the intermediates (111) and (112) are likely to exist. COzH H02C (1 11) R = ,CH,COlH (112) R = Me Previous studies on the biomimetic methylation of pyrrocorphins have been extended to models with nitrile side chains analogous to the normal acetate and propionate side chains.'82 A review of the origins of the molecular structures of vitamin B, concludes that the corrin ring structure could readily have formed under prebiotic condition^.'^^ 7 Miscellaneous Metabolites Several papers have been published describing studies on the biosynthesis of the structurally varied cofactors found in methanogenic bacteria including methanop- terin,ls4 methanof~ran,'~' and pyrroloquinoline quinone.'86 Further evidence has appeared for stepwise enzymatic cyclopropane ring cleavage in the biosynthesis of ethylene."' The 2-amino-3-hydroxycyclopent-2-enone moiety found in reductio- mycin (113) and many other antibiotics has been shown to be derived uia an intramolecular cyclization of 5-aminolaevulinic acid.The remainder of the reduc- 181 F. Blanche S. Handa D. Thibaut C. L. Gibson F. J. Leeper and A. R. Battersby J. Chem. SOC.,Chem. Commun. 1988 1117. 182 C. Leumann T. Fruh M. Gobel and A.Eschenmoser Angew. Chem. Int. Ed. Engl. 1987 26 261. 183 A. Eschenmoser Angew. Chem. Int. Ed. Engl. 1988 27 5. 184 P. J. Keller H. G. Floss Q. Le Van B. Schwarzkopf and A. Bacher J. Chem. Am. Soc. 1986,108,344. W. Eisenreich B. Schwarzkopf Q. Le Van P. J. Keller and A. Bacher J. Chem. SOC.,Chem. Commun. 1988 1294. 186 D. R.Houck J. L. Hanners and C. J. Unkefer J. Am. Chem. SOC.,1988 110 6920. J. E. Baldwin R. M. Adlington G. A. Lajore C. Lowe P. D. Baird and K. Prout J. Chem. SOC.,Chem. Commun. 1988 775. Biological Chemistry- Part (ii) Biosynthesis tiomycin molecule is derived from 4-hydroxyben~oate.'~~ The elusive four-carbon precursor of the dimethylbenzenoid moiety of riboflavin has been shown to be 3,4-dihydroxy-butan-2-one 4-phosphate (1 14).Its formation from pentose phosphate by a highly purified enzyme from Candida guilliermondii has been observed directly by MF:H 08 J. M. Beale J. P. Lee A. Nakagawa S. Omura and H. G. Floss J. Am. Chem. SOC.,1986 108 331. R. Volk and A. Bacher J. Am. Chem. SOC.,1988 110 3651.

ISSN:0069-3030    

DOI:10.1039/OC9888500321

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

12 Host-Guest Chemistry By J. F. STODDART Department of Chemistry The University She field S3 7HF 1 Preamble Since this area was first and last reviewed’ in Annual Reports in 1983 by far the most significant event has been the award of the 1987 Nobel Prize in Chemistry to Donald J. Cram Jean-Marie Lehn and Charles J. Pedersen ‘for their development and use of molecules with structure-specijic interactions of high selectivity’.2Much has been”said and written3v4 about the merit and significance of this long overdue recognition from Stockholm of these three pioneering chemists -so different in their professional backgrounds yet totally unified in spirit by the fundamental scientific goals they identified and reached. No commentators have expressed their feelings more warmly spontaneously and forthrightly than Bernard Dietrich and Jean-Pierre Sauvage,’ who by their own humble admissions were ‘two inexperienced Ph.D.students’ working alongside Lehn in his young laboratory in Strasbourg in 1968. They observe in their eulogy that the ‘award pays homage to the scientists that have introduced a completely novel view of chemistry starting a real revolution in the way chemists look at molecular interactions’. After discussing the seminal contribu- tions made by the joint laureates Dietrich and Sauvage offer’ the following personal reflections ‘The compounds synthesized required the incorporation of more and more demanding features molecular recognition transport through a membrane acti- vation and chemical transformation (catalysis) etc.. . Such expressions as ‘recep- tor-substrate’ or ‘host-guest’ molecular systems entered the current language of chemists and analogy with biology was rapidly reached. For the first time the chemist was not frightened to build in a completely artificial way systems whose functions mimic biological processes. In a few years the field exploded an important reason being that all is a priori permitted. Imagination can manifest freely provided the synthetic and analytical tools level with the ambitions of the project. The various works revealed recently on the occasion of several inter- national meetings or in numberless publications demonstrate how fast the field ’ J. F. Stoddart Annu. Rep. Prog. Chern. Sect. B 1983 80 353. ’ Nobel Prize Citation Nobel Festival 10 December 1987; see J.Incl. Phenom. 1988 6 103. See for example M. R. Truter Chern. Brit. 1987 23 1149; L. Milgrom New Scientist 22 October 1987 No 1538 p. 31; J. F. Stoddart Nature 1988,334 10; H. E. Schroeder (and C. J. Pedersen) Pure Appl. Chern. 1988 60 445. For typical articles see Chern. fnd. 1987 731; Chern. Eng. News 19 October 1987 p. 4 and 30; Chern. Brit. 1988 24 754. B. Dietrich and J.-P. Sauvage New J. Chern. 1988 12 725. 3 53 354 J. F. Stoddart initiated by the 1987 Nobel prize winners in chemistry has evolved and with such a fruitful anarchy. The effective and potential applications covered by the present research efforts span from polymers to chemical catalysis through immunobiology solution chemistry of ions (analysis separation .. . .) non-linear optics molecular electronics artificial photosynthesis.. . It must be added that the aesthetical dimension of the molecular systems designed elaborated and studied is of great value to the vast majority of the scientists involved in the research field. If the state of knowledge at the end of the sixties was such that the start of a new era in chemistry was possible the involvement of men of exceptional value was obviously essential. For the researchers who paqicpated in the fields rewarded in 1987 there was no other possible choice than Pedersen Lehn and Cram. In spite of their large differences the research works of these scientists are strongly interconnected. At the same time the Nobel committee recognized a huge dis- covery made by an individual researcher of the industrial sector and the imposing works of two prestigious scientists.’ Along with the Nobel Lectures ‘The Discovery of Crown Ethers’ by Pedersen,6 ‘Supramolecular Chemistry -Scope and Perspectives Molecules Supermolecules and Molecular Devices’ by Lehn,7 and ‘The Design of Molecular Host Guest and Their Complexes’ by Cram,* two authoritative by the French and American cognoscenti are compulsory reading for all those curious about host -guest chemistry.2 Clathrates Classically host-guest interactions have been observed in solid state structures of (usually stoicheiometric) mixtures of compounds i.e. clathrates.” Possibly inspired by the stepwise construction of the trianthranilides,’* a new synthesis has been de~cribed’~ of one of the old chestnuts amongst such hosts namely tri-o-thymotide (1) -TOT for short -and some TOT analogues.The synthetic methodology which is based upon sequential coupling of appropriately substituted and protected salicylic acid monomers followed by cyclization of the deprotected open-chain trimers represents an important breakthrough in the preparation of trisalicylides since it provides a means of preparing a wide range of constitutionally asymmetric as well as symmetric trisalicylides. These new compounds should greatly advance our understanding of the clathration behaviour of TOT host types and perhaps also reveal better and more versatile host structures. ti C. J. Pedersen Angew. Chern.Int. Ed. Engl. 1988 27 1021; J. Incl. Phenorn. 1988 6 337. J.-M. Lehn Angew. Chern. Ini. Ed. Engl. 1988 27 89; J. Incl. Phenom. 1988 6 351. * D. J. Cram Science 1988,240,760; Angew. Chern. Int. Ed. Engl. 1988,27 1009; J. Incl. Phenom. 1988 6 397. J.-M. Lehn Science 1985 227 849. 10 D. J. Cram Angew. Chem. Inr. Ed. Engl. 1986 25 1039. I’ ‘Molecular Inclusion and Molecular Recognition -Clathrates I and 11’ in ‘Topics in Current Chemistry 140 and 149’ ed. E. Weber Springer-Verlag Berlin 1987 and 1988. 12 W. D. Ollis and J. F. Stoddart in ‘Inclusion Compounds’ ed. J. L. Atwood J. E. D. Davies and D. D. MacNicol Academic Press New York 1984 Vol. 2 p. 168. l3 T. D. Harris S. R. Oruganti L. M. Davis P. M. Keehn and B. S. Green Tetrahedron 1987 43 1519.Host- Guest Chemistry 0& CHMe2 Amongst a range of new clathrate with roof-shaped molecular backbones and different functional groups on the ridges the trans-dicarboxylic acid (2) is by far the most prolific host in forming inclusion compounds -with indeed no less than 27 different guests including n-BuOH and DMF for which X-ray crystal structures are available. Dimer clustering of the host (2) as a result of hydrogen bonding between one of the carboxyl groups on host pairs leaves the other carboxyl group free for guest binding and probably accounts for the predominant 1 1 stoicheiometries exhibited by these inherently bifunctional hosts. This type of coordination-assisted lattice inclusion to afford host-guest aggregates has been termed coordinatoclarhration by Weber.l4 In crystalline inclusion complexes of alcohol^'^ and phenols,16 the hydroxyl groups not unexpectedly are involved in hydrogen bonding.Crystallographic evidence is at hand to support the view that the selective clathrate inclusion of primary ( RNH2) and secondary (R2NH) amines can be attributed" to a cyclic pattern of hydrogen bonding involving the RNH2 and R2NH amino groups and the hydroxyl groups in the hosts (RR)-(3)and (*)-(3). Remarkably the meso analogue (RS)-(3)is ineffective in forming amine clathrates under similar conditions. Compounds such as (RR)-(3)have considerable potential as resolving agents since they can be obtained directly from tartaric acid. Indeed Toda and Tanaka" have resolved a number of bicyclic enones employing (RR)-(3).(R)-(4) X = C02H (RR)-(3),(+)-(3)€i (RS)-(3) (R)-(5) X = OH 14 E. Weber I. Csoregh J. Ahrendt S. Finge and M. Czugler J. Org. Chem. 1988 53 5831. l5 J. M. Shin F. Toda and M. S. Jhon J. Incl. Pbenom. 1987 5 567. 16 I. Goldherp. Z. Stein K. Tanaka and F. Toda J. Incl. Phenom. 1988 6 15. 17 E. Weber N. Dorpinghaus and I. Goldberg 1. Chem. SOC.,Chem. Commun. 1988 1566. F. Toda and K. Tanaka Tetrahedron Lett. 1988 29 551. 356 J. F. Stoddart In a more general sense chiral clathrate inclusion has been attracting increasing attention as a means of resolving neutral racemic organic compounds on a prepara- tive scale. For example axially-chiral 1,l ’-binaphthyl-2,2’-dicarboxylic acid (R)-(4) has been employed” successfully in the resolution of (RS)-phenylalkan- 1-01s with a variety of alkyl groups (Me Et Prn Pr‘ Bun Bu’) giving optical purities ranging from 18-90% in favour of either (R)or (S) alcohols depending on the nature of the alkyl group.Selective crystalline complexation with (R)-binaphthol (R)-(5) resolves2’ completely (i.e.enantiorneric excesses of 100%) a wide range of racemic amine N-oxides and phosphine oxides. In both cases continuous intermolecular hydrogen bonding interactions involving the oxides as proton acceptors and the hydroxyl groups in the axially-chiral host as donors are observed in the crystals. -H H THF Scheme 1 Molecular aggregation based on selective hydrogen bonding in the solid state provides a model for controlling the molecular recognition of one molecule by another.The challenge is to encourage co-crystallization betweeen the diflerent molecules. This has been achieved2’ ingeniously with 1,3-bis( m-nitropheny1)urea (6) a rare example of a dual function organic molecule which behaves only as an intermolecular proton donor and not as an intermolecular proton acceptor. It co-crystallizes (Scheme 1) with a wide range of proton accepting solvents such as THF; meta electron-withdrawing groups (e.g. NOz) are a prerequisite for the co-crystallization to take place. X-Ray crystallography of (6)vTHF shows that the urea framework is essentially coplanar thus placing the ortho C-H protons along- side the carbonyl group and possibly reducing the proton accepting strength of the oxygen atom to the extent that it will not form intermolecular hydrogen bonds at all.This leaves the N-H protons free to bind guests and they do. 3 Cyclodextrins The rapidly expanding commercial interest in the naturally-occurring cyclodextrins (CDs) has been reflected in the launching of ‘Cyclodextrin News’ in 1986 by James Pagington and J6zsef Szejtli.22 The Proceedings of the Third and Fourth International 19 S. Kanoh Y. Hongoh S. Katoh M. Motoj and H. Suda J. Chem. Soc. Chem. Commun. 1988 405. 20 F. Toda K. Mori Z. Stein and I. Goldberg Tefrahedron Lett. 1989 30 1841; J. Org. Chem. 1988 53 308; for a discussion of reaction control by host-guest complexation in the solid state see F. Toda J. Incl. Phenom. 1989 7 247. *’ M. C. Etter and T.W. Panunto J. Am. Chem. SOC.,1988 110 8596 and references therein. 22 ‘Cyclodextrin News’ ed. J. Szejtli and J. S. Pagington Vols. 1-3 19861989. This independent and privately-funded newsletter is published monthly by FDS Publications P.O. Box 41 Trowbridge Wiltshire BA14 8UE. UK. Host- Guest Chemistry 3 57 Symposia held in Lancaster (1986) and Munich (1988) have appeared23 along with a general review24 and a comprehensive monograph,25 both stressing the growing technological importance of CDs and their derivatives. A recent Thematic Issue of Carbohydrate Research has been devoted26 to CDs (cyclomalto-oligosaccharides) with the present author as guest editor. It contains over 40 papers covering an immensely broad spectrum of contemporary topics in CD research.(9)R = R' = H R' = OH (aCD) AgOTl 1 Pd/C/HC02H/THF/MeOHIH,0 SnCI, (7)R = Bn -(8) R = Bn R' = H R' = OBn Et,O OR PhSeOTl (11) R=Bn,R'=OBn.R2=H -(10)R=Bn (7) R = Bn ClCHpCHpCl 1 Pd/C/H2/MeOH (12) R = R' = H R' =OH Scheme 2 The find steps in the total synthesis ofaCD (9) and its manno isomer (12) One of the most exciting developments in the CD field during these last two years has been the total synthesis by Ogawa and his collaborator^^^-^^ of a-CD y-CD and isomers of aCD wherein (i) one of the six (~-1,4-linkages is replaced by an a-1,6-linkage and (ii) all the a-D-glucopyranoses are replaced by a-D-mannopyranoses. The first total synthesis of a-CD was achieved2' in 0.3% overall yield after 21 steps starting from maltose.The key step (Scheme 2) was the penulti- mate SnC1,-AgOTf-promoted cycloglycosylation of the p-D-rnaltohexaosyl fluoride (7) to afford in 21% yield the octadecabenzyl ether (8) which was subsequently deprotected to give aCD (9). The efficiency of the cyclization clearly depends on the CD ring size. In the case of yCD cycloglycosylation of the corresponding ~-D-tnaltOOCtaOSyl fluoride under the same conditions could only be achieved28 in 8.4% yield. In the synthesis of the manno isomer (12) of aCD a PhSeOTf-promoted 23 'Proceedings of the Third International Symposium on Cyclodextrins Lancaster 1986 J. Incl. Phenom. 1987 5 1-287 and 397-549; 'Proceedings of the Fourth International Symposium on Cyclodextrins Munich 1988 ed. J.Szejtli and 0.Huber Kluwer Academic Publications Dordrecht Holland 1988. 24 J. S. Pagington Chem. Brit.,1987 23 455. 25 J. Szejtli 'Cyclodextrin Technology' Kluwer Academic Publishers Dordrecht Holland 1988. 26 'Thematic Issue on Cyclodextrins (Cyclomalto-oligosaccharides)' Carbohydr. Res. 1989. 27 T. Ogawa and Y. Takahashi Carbohydr. Res. 1985 138 C5; Y. Takashashi and T. Ogawa Carbohydr. Rex 1987 164 277. 28 Y. Takahashi and T. Ogawa Carbohvdr. Res. 1987 169 127. 358 J. F. Stoddart cycloglycosylation (Scheme 2) of the a-D-methylthioglycoside (10) afforded (64% ) the octadeca-0-benzylcyclomannohexaose(1l),which gave (12) on catalytic hydro- gen~lysis.~~ Although the total synthesis of aCD and yCD are of purely academic interest given their ready availability from microbial sources the ability to synthesize CD analogues promises to provide a fascinating collection of new water-soluble molecular receptors.With the art of oligosaccharide synthesis becoming so highly developed in many laboratories around the world the prospects are very encouraging to say the least. Many new chemically-modified CDs have been introduced an to the scene in recent years but it must be said that the area is still plagued by many compounds that are undoubtedly grossly impure. A more professional approach is needed if the area is to gain high respectability. Even the much used 2,6-per-O-methyl-P- cyclodextrin (DMP CD) whether prepared by literature procedures or obtained commercially is usually less than 70% pure.A procedure involving (i) benzoylation (ii) chromatography to remove principally a hexabenzoate [(DM + l)PCD-B,] containing an extra methoxyl group and (iii) de-0-benzoylation of the eluted heptabenzoate (DMPCD-B,) has been recommended3' as one way to acquire pure DMPCD. The method can also be applied3' to the purification of DMaCD. Advantage was taken of the availability of the pure unsymmetrical hexabenzoate [(DM + l)PCD-B,] to 'map-out' its structure by high resolution 'H and 13C n.m.r. spectroscopies. Using modern pulse techniques 41 out of the 49 heterotopic ring protons and (ii) 29 out of the 42 heterotopic ring carbons were assigned unam- biguously. The recent ~bservation~~ that the aCD PCD and yCD can be deuterated at their C-2 C-3 and C-6 positions by Raney nickel-catalysed H-D exchange in D20 should also do much to aid the structure determination of CD derivatives.Thus the technology and know-how already exists to purify and characterize chemically-modified cyclodextrins and their complexes. Only two more will be illustrated here -namely X-ray crystallography and fast atom bombardment mass spectrometry (f.a.b.m.s.). A solid state structure determination of the crystalline inclusion complex of 2,3,6-per-O-methyl-P-cyclodextrin with m-iodophenol reveals33 that the host has a markedly distorted conformation wherein one of the seven trimethylated D-glUCOpyranOSe units adopts an unusual (OS,) twist-boat con- formation rather than the usual ("C,)chair conformation. This observation antici- pates chemical modifications that are a direct consequence of conformational changes that can obviously be induced to occur within the CD molecules.Although f.a.b.m.s. does not give information of a structural nature the ease with which it can be applied to detect the formation of supramolecular adducts between methy- lated CDs and (i) organometallic cations and (ii) neutral metallo-organic complexes renders3" it a facile technique for studying the second sphere coordination of 29 M. Mori Y. Ito and T. Ogawa Tetrahedron Letf. 1989,30 1273. 30 C. M. Spencer J. F. Stoddart and R. Zarzycki J. Chem. Soc. Perkin Trans. 2 1987 1323; see also J. R. Johnson N. Shankland and I. H. Sadler Tetrahedron 1985 41 3147; I. Tabushi T. Nabeshirna K. Yarnamura and H.Fujita Bull. Chem. SOC.Jpn. 1987 60,3705. 31 D. R. Alston T. H. Lilley J. F. Stoddart and R. Zarzycki Carbohydr. Rex 1989 OOO,000 and references therein. 32 Y. Kuroda M. Yamada and I. Tabushi Tetrahedron Lett. 1988 29 4467. 33 K. Harata J. Chem. Soc. Chem. Commun. 1988 928. 34 P. R. Ashton J. F. Stoddart and R. Zarzycki Tetrahedron Lerr. 1988 29 2103. Host -Guest Chemistry 359 transition metal complexes by chemically-modified CDs. The ability of CDs and their derivatives to act as second-sphere ligands towards a wide range of transition metal complexes including the anti-tumour drug Carb~platin,~’ has greatly extended the already voracious appetite these naturally-occurring hosts have for multifarious guests. The topic has been the subject of a very recent comprehensive review35 and clearly led to the discovery36 that all three CDs form inclusion complexes with o-carborane the first main group inorganic compound to find refuge in a CD.Since the industrial uses of CDs were reviewed37 in 1987 it need only be stressed here that they are forever finding new applications in pharmaceuticals agrochemicals foods cosmetics and toiletries as their cost continues to fall. Separ- ation science has also benefitted from this welcome trend whereas just over 50 separations of compounds were reported up to the early 80s in the five-year period from 1984 to 1988 the number rose dramatically to more than 500. Two techniques have been in the vanguard of this explosive growth. One is capillary g.c.with chemically-modified CDs such as tripentyl-a-cycl~dextrin~~ and analogues as the relatively low melting liquid phases and the other is h.p.1.c. with CD-bonded stationary phases (Cy~lobond~~) on silica gel.40 There is a bonus of course in the chromatography since the phases are chiral many racemic modifications can be resolved with relative ease. The use of CDs both natural and chemically-modified as enzyme models and analogues4‘ continues to attract a lot of attention. In the control of electrophilic aromatic substitutions K~miyama~~ has added the para-selective hydroxymethyla- tion of phenol to the formidable list of previous successes which include regioselec- tive formylations and carboxylations. The most selective synthesis (para :ortho = 15.7) of 4-hydroxymethylphenol from phenol and formaldehyde was achieved42 with PCD carrying 2-hydroxypropyl substituents.More recently remarkably high regioselective P-O(2‘) cleavages (98 94 76 and 67% respectively to be precise) of 2’,3’-cyclic monophosphates of cytidine uridine adenosine and guanosine to the corresponding 3’-monophosphates have been achieved43 at pH 11.08 and 20 “C using aCD as catalyst. The explanation for the (3 x lo5)-fold difference between the p-nitrophenyl and ethyl acrylate esters in the acceleration by PCD of the acyl 35 J. F. Stoddart and R. Zarzycki Rec. Trau. Chim. Pays-Bas 1988 107 515; for an up-to-date publication from the Japanese school see A. Harada K. Saeki and S. Takahashi Organometallics 1989 8 730.36 A. Harada and S. Takahashi J. Chem. SOC.,Chem. Commun. 1988 1352. 37 ‘Cyclodextrins and their Industrial Uses’ ed. D. Duchine Editions de Santt Paris 1987. 31) W. A. Konig S. Lutz and G. Wenz Angew. Chem. Int. Ed. Engl. 1988 27 979; W. A. Konig S. Lutz P. Mischnick-Lubbecke B. Brassat and G. Wenz J. Chromatogr. 1988 447 193; W. A. Konig P. Mischnick-Lubbecke B. Brassat S. Lutz and G. Wenz Carbohydr. Rex 1988 183 11; W. A. Konig S. Lutz G. Wenz and E. von der Bey J. High Resolut. Chromatogr. Chromatogr. Commun.,1988 11 506; W. A. Konig S. Lutz C. Colberg N. Schmidt G. Wenz E. von der Bey A. Mosandl C. Giinther and A. Klustermann J. High Resolur. Chromatogr. Chromatogr. Commun.,1988 11 621. 39 Cyclobond is commercially available from Advanced Separation Techniques Inc.37 Leslie Court P.O. Box 297 Whippany New Jersey 07981 USA. 40 D. W. Armstrong Science 1986,232 1132; Anal. Chem. 1987,59 84A; T. J. Ward and D. W. Armstrong ‘Chromatographic Chiral Separations’ ed. L. J. Crane and M. Zief Marcel Dekker New York 1987 p. 131. 41 M. L. Bender in ‘Enzyme Mechanisms’ ed. M. I. Page and A. Williams The Royal Society of Chemistry London 1987 p. 56. 42 M. Komiyama J. Chem. SOC.,Chem. Commun. 1988 651; for a summary of the earlier work see H. Hirai J. Incl. Phenom. 1984 2 455. 43 M. Komiyama Chem. Lett. 1988 689; J. Am. Chem. SOC.,1989 111 3046. 360 J. F. Stoddart transfer reactions to give the acyl-CD has now been examinedu in considerable detail by molecular mechanics.There seems to be general agreement between Menger and Breslow that the relative rate enhancement observed for the p-nitrophenol ester is a consequence of the particularly good leaving group qualities of the p-nitropheno- late anion and a combination -in a reaction with a late transition state -of a stereoelectronically-distorted ester group twisting of the conjugated acrylate system and rotation of the ferrocenylacrylate unit within the CD cavity. Thus the formation of a distorted ester in the derived acyl-CD affects adversely partioning of a tetrahe-dral intermediate unless the substrate is endowed with a particularly good leaving group. An enzyme-catalysed ester or amide cleavage need not necessarily suffer from this limitation. Although yCD catalyses the benzoin condensation the yCD thiazolium salt haloenzyme mimic (13) even with its relatively flexible link to the yCD primary hydroxyl group is a very much improved catalyst.45 Breslow and Kool believe that the catalytic effect can be enhanced even further with insertion of a more rigid link to orient the thiazolium ring ‘correctly’ with respect to the reactants bound within the cavity of the CD without presumably itself displacing them.Presently there is much interest (see the following Section) in analogues of the thiamine pyrophosphate (TPP) dependent enzymes. Whilst some C-C bond-forming reactions like the benzoin condensation can be accelerated by models such Me I OH 44 F. M. Menger and M. J. Sherrod J. Am. Chem. SOC.,1988 110 8606; H.-J.Thiem M. Brandl and R. Breslow J. Am. Chem. SOC.,1988 110 8612. 45 R. Breslow and E. Kool Tetrahedron Let?. 1988 29 1635. Host- Guest Chemistry 36 1 as (13) other TPP-dependent reactions for example that catalysed by pyruvate decarboxylase has proved more difficult to model. However when the thiazolium ring of thiamine is linked with the macrocyclic quaternary ammonium receptor (14) enhanced substrate selectivity and catalytic activity in decarboxylations of a-keto acids is observed.46 4 Cyclophanes For its sheer novelty and daring scope the research of Diederich and his collaborators into the complexation of neutral molecules in aqueous solutions by cationic cyclo- phane hosts is worthy of special mention. His 1988 review in Angewandte Chemie4’ puts his ambitious conceptual targets and practical contributions into both a scholarly context and a highly professional light.Since he says all that needs to be said so well this reviewer can do no better than to refer readers to the original47 for information and enlightenment. My remarks will be restricted to a brief description of a very recently published communication4* on a catalytic cyclophane (15) that contains a thiazolium ring. It exhibits saturation kinetics and is a highly selective and efficient catalyst for the oxidation of aromatic aldehydes (e.g.2-naphthaldehyde) to carboxylic acids in the presence of potassium ferricyanide as oxidizing agent. No naphthoin formation was observed. However back in December 1986,the UCLA group had already described49 a macrobicyclic thiazolium host which catalyses the benzoin condensation giving high yields (up to 93%) of product.At the time the comment was made that ‘it is the most efficient catalyst for the benzoin condensation known today.’ In pursuit of chiral water soluble receptors that contain lipophilic cavities Wilcox and his associate^^^^^' have appealed imaginatively to macrocyclic dibenzodiazocines + + Etzru3/”Me -Me vQ \lEt2 46 N. Bergmann and F. F. Schmidtchen Tetrahedron Lett. 1988 29 6235. 41 F. Diederich Angew. Chem. Int. Ed. Engl. 1988,27,362 and references therein. Subsequent publications include R. Dharanipragada S. B. Ferguson and F. Diederich J. Am. Chem. SOC.,1988 110 1679; F. Diederich G. Schiirmann and I.Chao J. Org. Chem. 1988 53 2744; R. J. Loncharich E. Seward S. B. Ferguson F. K. Brown F. Diederich and K. N. Houk J. Org. Chem. 1988 53 2474; F. Diederich M. R. Hester and M. A. Uyeki. Angew. Chem. Inr. Ed. EngL 1988 27 1705. 4H L. Jimenez and F. Diederich Tetrahedron Lert. 1989 30,2759. 4Y H. D. Lutter and F. Diederich Angew. Chem. In(. Ed. Engl. 1986 25 1125. 50 C. S. Wilcox Tetrahedron Lett. 1985,26 5749; C. S. Wilcox and M. D. Cowart Tetrahedron Lert. 1986 27 5563; C. S. Wilcox L. M. Greer and V. Lynch J. Am. Chem. Soc. 1987 109 1865; M. D. Cowart I. Sucholeiki R. R. Bukownik and C. S. Wilcox J. Am. Chem. SOC. 1988 110 6204. 5’ C. S. Wicox and M. D. Cowart Carbohydr. Rex 1987 171 141; R. R. Bukownik and C. S. Wilcox J. Org. Chem. 1988 53 463 362 J.F. Stoddurt P-? (Troger’s base analogues) and to cyclophanes called ‘glycophanes’ based on C-glycosyl carbohydrate precursors. Cyclophanes of the type (16) and (17) are not only water-soluble and chiral but they should also bind aromatic substrates in aqueous media. Macrocycle (16) is the first reported macrocyclic cyclophane to be soluble in D20 in neutralform. Another approach to the design and construction of rigid chiral cyclophanes has been described by Dougherty and his collaborator^.^^ It relies upon 2’6-disubstituted- 9,lO-ethenoanthracene residues two of which have been incorporated into cyclo- phane hosts such as (18) and (19) using different linker units namely phenylene and cyclohexano groups. As in the cationic receptor (15) the charged groups -this time anionic centres -are positioned and directed well away from the lipophilic cavities.Host (18) with phenylene linkers bindss3 much more strongly in aqueous solutions to methyl quinolinium (iodide) for example than does host (19) with its cyclohexano linkers. This observation suggests that (i) donor-acceptor v-stacking interactions and (ii) ion-dipole attractions can contribute ~ignificantly~~-~~ to aqueous binding on top of hydrophobic and electrostatic effects as the two major R 52 M. A. Petti T. J. Shepodd and D. A. Dougherty Tetrahedron Lett. 1986 26 807; T. J. Shepodd M. A. Petti and D. A. Dougherty J. Am. Chem. SOC.,1986 108 6085; M. A. Petti T. J. Shepodd R. E. Barrans Jr. and D. A. Dougherty J. Am.Chem. SOC.,1988 110 6825; see also W. Heinz H.-J. Rader and K. Miillen Tetrahedron Lett. 1989 30,159. 53 T. J. Shepodd M. A. Petti and D. A. Dougherty J. Am. Chem. SOC., 1988 110 1983. 54 D. A. Stauffer and D. A. Dougherty Tetruhedron Lett. 1988 29 6039. 55 H. J. Schneider and T. Blatter Angew. Chem. Int. Ed. EngZ. 1988 27 1163; H. J. Schnieder T. Blatter S. Simova and I. Theis J. Chem. SOC.,Chem. Commun. 1989 580. 363 Host-Guest Chemistry binding forces. A neutral analogue (20) of (18) has been to have substantial binding affinities for quaternary ammonium and imminium compounds in chloroform that cannot be attributed to hydrophobic effects most likely they arise54 from ion-dipole attractions similar to those that stabilize the secondary structures of proteins i.e. the strong tendency56 for positively-charged amino acid sidechains (e.g. in Lys Arg Asn and Glu) to position their positive charges directly over the face of the aromatic rings in the amino acids Phe Tyr and Trp. Another intramolecular interaction observed5’ in proteins is the attractive edge-to-face interaction between two aromatic rings in say Phe Tyr and Trp. This type of stabilizing interaction involving neutral (and charged) aromatic rings is also now comm~nplace~~-~~ amongst synthetic molecular receptors and their complexes and adducts. Donor- acceptor .rr-stacking interactions between neutral cyclophane-like crown ethers such as bisparaphenylene-34-crown-10(21) and bipyridinium dications (e.g.Diquat and Paraquat) have been well and used59 to advantage in the design of a tetracationic cyclobis(paraquat-p-phenylene)(22) capable of binding hydroquin- one and catechol dimethyl ethers using both types [(i) and (ii)] of stabilizing interactions.A recent exciting developrnenf2 is the discovery of a high yielding synthesis of a [2]catenane the X-ray structure of which is shown in Figure 1. It reveals that the noncovalent bonding interactions that template its formation ‘live on’ in the highly ordered product. Rotaxanes can also now be made to order! 56 S. K. Burley and G. A. Petsko FEBS Lett. 1986,203,139; M. Meot-Ner (Mautner) and C. A. Deakyne J. Am. Chem. SOC.,1985 107 469,474. 57 R. 0.Could A. M. Gray P. Taylor and M. D. Walkinshaw J. Am. Chem. SOC.,1985 107 5921; S.K. Burley and G. A. Petsko Science 1985 229 23; J. Am. Chem. SOC.,1986 108 7995. 58 A. M. Z. Slawin N. Spencer J. F. Stoddart and D. J. Williams J. Chem. Soc. Chem. Commun. 1987 1070; D. R. Alston A. M. Z. Slawin J. F. Stoddart D. J. Williams and R. Zarzycki Angew. Chem. Int. Ed. Engl. 1987 26 692; G. J. Moody R. K. Owusu A. M. Z. Slawin N. Spencer J. F. Stoddart J. D. R. Thomas and D. J. Williams Angew. Chem. Int. Ed. EngL 1987 26 890. 59 B. Odell M. V. Reddington A. M. Z. Slawin N. Spencer J. F. Stoddart and D. J. Williams Angew. Chem. Int. Ed. Engl. 1988 27 1547; P. R. Ashton B. Odell M. V. Reddington A. M. Z. Slawin J. F. Stoddart and D. J. Williams Angew. Chem. Int. Ed. EngL 1988 27 1550; see also M. Buhner W. Geuder W. K. Cries S.Hiinig M. Koch and T. Poll Angew Chem. Znt. Ed. Engl. 1988 27 1553. 60 J. F. Stoddart Pure Appl. Chem. 1988 60 467 and references therein. 61 P. R. Ashton E. J. T. Chrystal J. P. Mathias K. P. Parry A. M. Z. Slawin N. Spencer J. F. Stoddart and D. J. Williams Tetrahedron Lett. 1987 28 6367; P. L. Anelli N. Spencer and J. F. Stoddart Tetrahedron Lett. 1988 29 1569; P. L. Anelli A. M. Z. Slawin J. F. Stoddart and D. J. Williams Tetrahedron Lett. 1988 29 1573. 62 P. R. Ashton T. T. Goodnow A. E. Kaifer M. V. Reddington A. M. Z. Slawin N. Spencer J. F. Stoddart C. Vicent and D. J. Williams Angew. Chem. In[. Ed. EngL 1989 28 in press. 364 J. F. Stoddart Figure 1 The X-ray crystal structure ofa [2]catenanemade up of (21) and (22) The interest63 of the Strasbourg group in the DNA-binding properties of acyclic bisintercalands containing two 2,7-diazapyrenium moieties has led64 to the realiz- ation of cyclointercalands e.g.(23) incorporating two phenazine rings and bicyc- lobisintercalands e.g. (24) based on acridine units. The binding and photochemical properties of these compounds prepared by efficient procedures involving intramolecular acetylenic coupling reactions developed in the cyclophane host field by Whitlock et have been assessed and probed with characteristic elegance. Another area where T-T donor-acceptor interactions are important is in the synthesis and conformational properties of macrocyclic porphyrin dimers.66 Confor- mational switching is observed in these large and highly flexible molecules on 63 A.J. Blacker J. Jazwinski and J.-M. Lehn Helu. Chim. Acta 1987 70 1; J. Jazwinski A. J. Blacker J.-M. Lehn M. Cesario J. Guilheim and C. Pascard Tetrahedron Lett. 1987 28 6057. 64 J.-M. Lehn F. Schmidt and J.-P. Vigneron Tetrahedron Lett. 1988 29 5255; S. Claude J.-M. Lehn and J.-P. Vigneron Tetrahedron Lett. 1989 30 941. 65 R. E. Sheridan and H. W. Whitlock Jr. J. Am. Chem. SOC.,1988 110 4071; M. E. Haeg B.J. Whitlock and H. W. Whitlock Jr. J. Am. Chem. Soc. 1989 111 692; A. B. Brown and H. W. Whitlock Jr. J. Am. Chem. SOC. 1989 111 3640 and references therein. 66 C. A. Hunter M. N. Meah and J. K. M. Sanders J. Chem. SOC. Chem. Commun. 1988 692 694. Host-Guest Chemistry protonation or on binding 1,4-diazabicyclo[2.2.2]octane ligands (one and then a second) to the bis-zinc derivative.Double decker porphyrins bridged by four azobenzene units which can be isomerized (E/Z)photochemically have also been rep~rted.~’ 5 Calixarenes The names Gutsche and calixarenes are synonomous. His monograph6’ on these compounds which have clearly captured his imagination as well as commanded his attention during the past 15 years provides informative instruction and gripping reading. There is little anyone can add in 1989 to this classic work except to draw attention to some of the very latest advances. OH 2 + I TiCI Dioxan A Br OH Scheme 3 A one-step synthesis of a tetra-linked calixarene In the synthetic field several methods have been described69 for the selective diametrical functionalization of calix[4]arenes at their upper rims by transfer of functionality (by appealing to the Claisen rearrangement) to the para positions and by selective reactions (obtained by removal of certain t-butyl substituents and by selective electrophilic substitutions) at the para positions of the phenol rings.A fascinating announcement’’ concerns the synthesis of mono- di- and tetra-linked calixarenes e.g. (25),the latter two ‘in very low yield’ using a simple but ingenious approach (Scheme 3). By contrast the water-soluble cyclic tetramer (26) was isolated7’ in quantitative yield after a week from an aqueous solution containing the disodium salt of chromotropic acid and an excess of formaldehyde. The authors7’ 67 K.H. Neumann and F. Vogtle J. Chem. SOC.,Chem. Commun. 1988 520; see also H.-W. Losensky H. Spelthann A. Ehlen F. Vogtle and J. Bargon Angew. Chem. Inr. Ed. Engl 1988 27 1189. 68 C. D. Gutsche ‘Calixarenes’ in ‘Monographs in Supramolecular Chemistry’ ed. J. F. Stoddart The Royal Society of Chemistry Cambridge 1989; for a review by the same author see ‘Progress in Macrocyclic Chemistry’ ed. R. M. Izatt and J. J. Christensen Wiley New York 1987 Vol. 3 Chapter 3; see also C. D. Gutsche Pure Appl. Chem. 1988 60,483 and C. D. Gutsche I. Alain M. Iqbal T. Mangiafico K. C. Nam J. Rogers and K. A. See J. Incf. Phenom. 1989 7 61. 69 J.-D. van Loon A. Arduini W. Verboom R. Ungaro G. J. van Hummel S. Harkema and D. N. Reinhoudt Tetrahedron Lett. 1989,30 2681; see also E.M. Collins M. A. McKervey and S. J. Harris J. Chem. Soc. Perkin Trans. 1 1989 372. 70 V. Bohmer H. Goldmann W. Vogt J. Vicens and Z. Asfari Tetrahedron Lett. 1989,30 1391; see also H. Goldmann W. Vogt E. Paulus and V. Bohmer J. Am. Chem. Soc. 1988 110 6811. 71 B. Poh C. S. Lim and K. S. Khoo Tetrahedron Lett. 1989 30 1005. 366 J. F. Stoddart have proposed the trivial name cyclotetrachromotropylene for (26) which is confor- mationally flexible on the ‘H n.m.r. time scale at room temperature. Chiral dimetalla- 4-t-butylcalix[ 8larenes that incorporate two titanium alkoxides into their molecular cavities have been prepared72 by reacting 4-t-butylcalix[ 8larene with one equivalent of a base (RNH2) then two equivalents of titanium( IV) isopropoxide.When a chiral amine e.g. (R)-(+)-1-( 1 -naphthyl)ethylamine is employed diastereoisomeric salts are formed. The reactions of the complexes and their potential as protecting groups resolving agents and chiral auxiliaries in organic synthesis are being explored.72 Na Na03gOHHo OH Hog’”. OH Ho 0 R X (27) Bun S03Na (28) CH2C02Et But The novel investigations by Shinkai73 on water-soluble calixarenes continue to advance with demonstrations (i) that p-sulphonatocalix[ nlarenes (27) can recogn- ize74 the sizes of guest molecules and (ii) that the ‘cone’ conformation for p-sulphonatocalix[4]arene is ~tablilzed~~ by organic cationic guests. At the air-water interface calix[ nlarene esters (28) monolayer behaviour characteristic of their ring size binding Na+ ions when n = 4 and K+ ions when n = 6.The solid state structure77 of [NH4][calix[4]arenesu1phonate][ MeOSO,][ H,O] is that of an inclusion complex in which NH4+ and MeOS0,- ions and water molecules are intercalated into the organic host structure with the SO3-head groups pointing into the polar regions occupied by the intercalated species. The association of calixarenes with transition metal complexes has received attention. The interaction of the p-bromobenzenesulphonate of p-(2-aminoethyl)calix[4]arene with Ni2+ Cu2+ Pd2+ Co2+,and Fe2+ has been investi- gated,78 and the stylized representation (29) for the hexacoordinated octahedral complexes has been proposed tentatively. Mercurated calixarenes (30; R = CzHS 72 G.E. Hofmeister F. E. Hahn and S. F. Pedersen J. Am. Chem. SOC.,1989 111 2318. 73 S. Shinkai Pure Appl. Chem. 1986 58 1523; 1987 59 425; J. Incl. Phenom. 1989 7 193; S. Shinkai S. Mori H. Koreishi T. Tsubaki and 0. Manabe J. Am. Chem. SOC.,1986 108 2409; S. Shinkai K. Araki and 0. Manabe J. Am. Chem. SOC.,1988 110 7214. 74 S. Shinkai K. Araki and 0. Manabe J. Chem. SOC.,Chem. Cornmun. 1988 187. 75 T. Arimura M. Kubota K. Araki S. Shinkai and T. Matsuda Tetrahedron Lett. 1989 30 2563. 76 Y. Ishikawa T. Kunitake T. Matsuda T.Otsuka and S. Shinkai J. Chem. SOC.,Chem. Commun. 1989 736. 77 S. G. Bott A. W. Coleman and J. L. Atwood J. Am. Chem. SOC.,1988 110,610; see also A. W. Coleman S. G. Bott S. D. Morley C. M. Means K. D. Robinson and J. L. Atwood Angew.Chem. Inr. Ed. Engl. 1988 27 1361; J. L. Atwood A. W. Coleman H. Zhang and S. G. Bott J. Incl. Phenom. 1989 7 203. 78 C. D. Gutsche and K. C. Nam 1.Am. Chem. Soc. 1988 110 6153. Host- Guest Chemistry 367 n-C4H, n-C8HI7 n-C,,H,,) have been employed7 successfully in the preparation of so-called perforated monolayers of an air-water interface prior to transfer to glass microscope slides. The two-dimensional networks of molecular pores may be regarded as first generation prototypes for the fabrication of thin film composite membranes consisting of uniform oriented and adjustable micropores of molecular dimensions. I I (29) OR RO 'Bu Me 'Bu 'Bu 'Bu In ingenious manner the Reinhoudt group8' have married a half spherand with a calix[4]arene and produced a calixspherand (3l) which forms kinetically-stable complexes with Na+ K+ Rb+ and Cs' ions.This new host represents an important extension of the spherand principle to the complexation of the larger K+ and Rb+ ions. 6 Spherands This class8." of host has also received considerable attention from the Twente In the synthesis of hemispherands they have addressed successfully two different synthetic problems. One was to synthesize a relatively flexible macrocyclic compound containing two aromatic rings and then to introduce the third (central) 79 M. A. Markowitz R. Bielski and S. L. Regen J. Am. Chem. SOC.,1988 110 7545. no D. N. Reinhoudt P. J. Dijkstra P. J. A. in't Veld K. E. Bugge S. Harkema R. Ungaro and E.Ghidini J. Am. Chem. SOC.,1987 109 4761; D. N. Reinhoudt and P. J. Dijkstra Pure Appl. Chem. 1988,60,477. 8' P. J. Dijkstra M. Skowronska-Ptasinska D. N. Reinhoudt H. J. den Hertog Jr. J. van Eerden S. Harkema and D. de Zeeuw J. Org. Chem. 1987 52 4913. a2 P. J. Dijkstra H. J. den Hertog Jr. J. van Eerden S. Harkema and D. N. Reinhoudt J. Org. Chem. 1988 53 374. 83 P. D. J. Grootenhuis J. van Eerden P. J. Dijkstra 5. Harkema and D. N. Reinhoudt J. Am. Chem. SOC.,1987 109 8044. 368 J. F. Stoddart aromatic ring so avoiding the high 'ground state' energies that result from the repulsions between the electron-rich binding sites in the more rigid products.81 The other was the synthesis of hemispherands such as the 4-H-pyran derivative (32) which can be converted viu its pyrylium salt (33) into derivatives such as (34) that contain other heterocyclic rings e.g.pyridinium in place of the pyrylium ring.82 These new functionalized hemispherands with preorganized binding sites have been evaluateds3 for their abilities to complex with neutral guests viz. malononitrile. Me "6 o; Me (32) (33) X=O (34)X-NMe NO2 (35) The UCLA group" have recenty recently identifieds4 (35) as a highly preorganized chromogenic ion-selective indicating system that is highly selective for Li+ and Na+ ions. Whereas (35) is yellow (35-.Li+) and (35-.Na') spheraphexes are deep blue or violet in 80% dioxane-20% water. The method has been developeds4 using a range of modified spherands for the spectrophotometric assay of Na' and K+ ions in serum and plasma.D. J. Cram R. A. Carmack and R. C. Helgeson J. Am. Chem. SOC. 1988 110 571; A. Kumar E. Chapoteau B. P. Czech C. R. Gebauer M. Z. Chimenti and 0. Raimondo Clin. Chem. 1988 34/9. Host-Guest Chemistry The first examples of two new general classes of compounds with molecular cavities have been described." They are based on a m-terphenyl framework in which the outer aromatic rings are orthogonal to the central one. They have suggestive shapes (Figure 2) and have been referred to as cuppedophanes (a) and cap- pedophanes (b) ! Figure 2 Diagrammatic representations of (a) cuppedophanes and (b) cappedophanes 7 Cyclotriveratrylene Hosts The chemistry of cyclotriveratrylene hosts has been superbly well summarizedg6 in 1987 by its champion AndrC Collet.More recently he and Canceill have describedg7 an appealing two-step synthesis (Scheme 4) from the diols (36) of the D3 (37) and C, (38) cryptophanes previously obtained by a template route. Whereas the latter gives preferentially the C3hisomers (38) the 'new' synthetic approach favours the D isomers (37). :mCH20H 0 HCHO (CH,)" +(! n 2-3 h 155°C OWOMe Scheme 4 A two-step synthesis of D (37) and C, (38) cryptophanes from the diols (36) The hexaol cyclotricatechylene obtained on demethylation of cyclotriveratrylene has been used88 as the construction pad for a new family of cavitands e.g. (39) and (40).Although in these molecules the [l.l.l]orthocyclophane units and six associ-ated oxygen atoms are rigid the remainders of the molecules (the methylene groups x5 T.K. Vinod and H. Hart J. Am. Chem. Soc. 1988 110 6574. 86 A. Collet Tetrahedron 1987 43 5725. 87 J. Canceill and A. Collet J. Chem. SOC.,Chem. Commun. 1988 582. 88 D. J. Cram J. Weiss R. C. Helgeson C. B. Knobler A. E. Dorigo and K. N. Houk J. Chem. SOC. Chem. Commun. 1988 407. 370 J. F. Stoddart and the 1,3-bridging aromatic rings) are very mobile conformationally. In the case of the host (40) which forms a 1:1 complex with CH,Cl, the crystal solution and calculated (molecular mechanics) structures are almost identical. (39) X = CH (40) X = N 8 Cavitands There have been a number of different incentives that have promoted the rapid development by Cram and his of cavitands as preorganized host molecules for a wide range of guest species.Cavitands with the general structure (41; R = H Me Br I) have been preparedg9 and found to form crystalline solvates with a range of guest molecules including MeCN PhMe CH2C12 and CHC13 where complementarity is high. Even when it is low e.g. with benzene and cyclohexane solvates have been isolated. The portals at the base of the bowls are only able to allow very small ions or molecules to pass through (see the following Section). The realization" of cavitands such as (42) which bind simultaneously in the solid state two guest molecules Me2C0 above in the bowl and CH2C12 below in the box in separate but interlinked cavities with the potential of exhibiting binding cooperativity and anticooperativity is an exciting one.The possibility of constructing tunable (on/off) molecular cavities which communicate with each other makes this class of cavitand an attractive source of modular receptor sites for bound species under- going chemical change -a highly desirable feature in the design of enzyme analogues and other biological mimics. a9 D. J. Cram S. Karback H.-E. Kim C. B. Knobler E.F. Maverick J. L. Ericson and R. E. Helgeson J. Am. Chem. SOC.,1988 110 2229. J. A. Tucker C. B. Knobler K. N. Trueblood and D. J. Cram J. Am. Chem. SOC.,1989 111 3688; see also E. Dalcanale P. Soncini G. Bacchilega and F. Ugozzoli J. Chem. SOC.,Chem. Commun. 1989,500. 9' L. M. Tunstad J. A. Tucker E. Dalcanale J. Weiser J.A. Bryant J. C. Sherman R. C. Helgeson C. B. Knobler and D. J. Cram J. Org. Chem. 1989 54 1305. Host -Guest Chemistry 371 Numerous cavitand precursors containing commonly eight phenolic hydroxyl groups have been from resorcinol and a wide range of aldehydes. They have been studied as lipophilic polar hosts92 for their abilities to solubilize hydrophilic guests e.g. D-glucose in organic solvents and as redox-active hosts93 when ferrocene units are incorporated during their synthesis. 9 Carcerands Alongside growing e~idence’~ that carbon can exist as closed-surface hollow spheres such as the c60 compound known as buckminsterfullerene or footballene which is believed to be composed of 12 pentagonal and 20 hexagonal rings in the shape of a pentagonal dodecahedron with potentially enough room inside them to house small molecules and (lanthanum) ions,95 Cram and his colleagues have reported the first closed molecular container compounds -the so-called car~erands.~~,~’ Carcerand (43)was ~ynthesized’~ from two cavitand precursors the tetrathiol and a tetrachloride.The critical shell-closing step involves the formation of four carbon- sulphur bonds under an atomosphere of argon in a tetrahydrofuran-dimethylfor-mamide mixture containing caesium carbonate. The insoluble carcaplex -the car- cerand (43) with gas solvent molecules and ions trapped inside -had to be purified (43) (44) 92 Y. Aoyama Y. Tanaka H. Toi and H. Ogoshi J. Am. Chem. SOC.,1988 110 634; Y. Aoyama Y. Tanaka and S.Sugahara J. Am. Chem. SOC.,1989 111 5397. 93 P. D. Beer and E. L. Tite Tetrahedron Lett. 1988 29 2349; P. D. Beer M. G. B. Drew A. Ibbotson and E. L. Tite J. Chem. Soc. Chem. Commun. 1988 1498. 94 H. W. Kroto Science 1988 242 1139. 95 J. R. Heath S. C. O’Brien Q. Zhang Y. Liu R. F. Curl H. W. Kroto F. K. Tittle and R. E. Smalley J. Am. Chem. SOC.,1985 107 7779; D. M. Cox D. J. Trevor K. C. Reichmann and A. Kaldor J. Am. Chem. SOC.,1986 108 2457. 96 D. J. Cram S. Karbach Y. H. Kim L. Baczynskj and G. W. Kalleymeyn J. Am. Chem. SOC.,1985 107 2575; D. J. Cram S. Karbach Y. H. Kim L. Baczynkskyj K. Marti R. M. Sampson and G. W. Kalleymeyn J. Am. Chem. SOC.,1988 110 2554. 97 J. C. Sherman and D. J. Cram J. Am. Chem. Soc. 1989 111 4527; see also M.W. Browne The New York Times 21 March 1989. 372 J. F. Stoddart by solvent extraction procedures. In recent times solubility has been achieved97 by arranging to have the portals which allow the passage of water molecules in and out surrounded by P-phenylethyl groups. Incarcerated solvent molecules e.g. Me,NCHO Me2NCOMe and Me,SO in the carceplexes based on carcerand (44) exhibit quite remarkable ‘Hn.m.r. spectropic behaviour. In the words of the authors,97 ‘carcerand interiors provide a new phase of matter’. Many potential applications to problems in materials and medical sciences can be envisaged. Why is it possible to construct such elaborate molecular structures as the cavitands and the carcerands -when you know how that is -with such apparent ease? Blum and believe it is because their atoms are assembled on a minimal surface the so-called P-surface.PhMe A I CH2CI2 7 A 10 Kbars CH2C12/A 10 Kbars 1 Ti& LiAIH4 __t THF RT Scheme 5 The two-step synthesis of kohnkene (49) and its conversion into dideoxykohnkene (50) Z. Blum and S. Lidin Acta Chem. Scand. 1988 B42 332. Host-Guest Chemistry 10 Molecular Belts The pumpkin-shaped molecule cucurbituril which was featured last time round,' is another example of a molecular structure readily assembled by acid-catalysed condensations between urea glyoxal and formaldehyde. Both the thermodynamics and kinetics of the molecular recognition of alkylammonium ions by cucurbituril have now been analy~ed~~ in considerable detail.By relying'OO,'O' on the extremely high treble diastereoselectivities recorded every- time a Diels-Alder reaction takes place between dienophilic units in (45)and diene units in (46),the [12lcyclacene derivative (49),christened kohnkene,'" has been isolated and fully characterized along with the intermediate 1 :1 (47)and 2 1 (48) adducts. The dideoxy derivative (50),obtained"' on deoxygenation of (49),crystal-izes with a disordered water molecule entrapped in its hydrophobic cavity. Both kohnkene (49)and dideoxykohnkene (50)have been empl~yed"~ as sensor coatings on quartz piezoelectric crystals for detecting aromatic vapours. Nitrobenzene is particularly well sensed by the kohnkene coating. 11 Cryptophanes If the bisdieneophile (45)is replaced by an (all-syn) trisdienophile then a stepwise synthetic procedure analogous to that outlined for the synthesis of kohnkene (49) 99 M.L. Mock and N.-Y. Shih J. Am. Chem. SOC.,1988 110 4706; 1989 111 2697. 100 F. H. Kohnke A. M. Z. Slawin J. F. Stoddart and D. J. Williams Angew. Chem. Znt. Ed. Engl. 1987 26 892. 101 L. Milgrom New Scientist No. 1641 3 Dec. 1988 p. 61; J. F. Stoddart Chem. Brit. 1988 24 1203; J. Zncl. Phenom. 1989 7 247; P. Ellwood J. P. Mathias J. F. Stoddart and F. H. Kohnke Bull. SOC. Chirn. Belg. 1988 97 669; F. H. Kohnke and J. F. Stoddart Pure Appl. Chem. 1989 61 1581; F. H. Kohnke J. P. Mathias and J. F. Stoddart Angew. Chem. Int. Ed. Engl. Adu. Mater. to be published. 102 P. R. Ashton N.S. Isaacs F. H. Kohnke A. M. Z. Slawin C. M. Spencer J. F. Stoddart and D. J. Williams Angew. Chem. Int. Ed. Engl. 1988 27 966. 103 M. A. F. Elmosalamy G. J. Moody J. D. R. Thomas F. H. Kohnke and J. F. Stoddart Anal. Proc. 1989 26 12. 374 J. F. Stoddart in Scheme 5 leadslo4 to the construction of trinacrene (51) a molecular cage compound. Cage-like hosts such as the expanded tris( bipyridine) compound (52) high selective molecular recognition towards isomeric trihydroxybenzenes as their guests. 12 Cryptands With two decades of development behind them cryptands are now Everywhere to be found. The selection of what to highlight must be personal to say the least. The principle of intracomplex macrocyclization has been invoked'06 to explain the high yields (>90°/0) obtained in the synthesis of dihydroxycryptands isolated as mixtures of meso-and (*)-isomers from reactions of N,N'-bis(oxiranylmethy1)diazacrown ethers with amines which form complexes with the macrocycle and then react irreversibly with the two epoxide rings.The Miami group"' have demonstrated that 2-n-tetradecy1[2.2.2]cryptand aggregates in aqueous solution forming micelles in the absence of cations (Li+/ Na+/K+/Ag+/Ba2+) and vesicles in their presence. Leaving oxygen out altogether it has been found"' that macrobicyclic diammonium salts will mediate the selective symport of bromide ions and protons as a result of the formation of anion cryptates. Three-dimensional cryptates consisting of four pyridyl units interspersed between four bridgehead nitrogen atoms were synthesized in one step from 2,6-bi~(aminomethy1)pyridine~~~ and 2,6-bis(bromomethyl)pyridine under two-phase (CH,Cl,/aqueous KOH) conditions.The synthesis and molecular recognition behaviour of macrobicyclic and macropolycyclic hosts incorporating a wide range of subunits -naphthyl biphenyl bithiazole bisimidazole bipyrimidine metallopor- phyrins to mention but a few -have been the subject of detailed investigation and In similar vein a tetraazacyclophane has been linked diagonally to 1,10-diaza-4,7,13,16-tetraoxacyclodecaneto yield113 a molecular receptor contain- ing two different recognition sites. Anion binding particularly of threefold sym- metrical NO3-ions has been a~hieved"~ with some novel aza macrotricycles of the cyclophane type.104 P. R. Ashton N. S. Isaacs F. H. Kohnke G. Stagno d'Alcontres and J. F. Stoddart Anp 'w. Chem. Inf. Ed. EngL 1989 28 000. F. Ebmeyer and F. Vogtle Angew. Chem. Znr. Ed. Engl. 1989 28 79; see also P. Belser L. de Cola and A. von Zelewsky J. Chem. Soc. Chem. Commun. 1988 1057 and F. Barigelletti L. de Cola V. Balzani P. Belser A. von Zelewsky F. Vogtle F. Ebmeyer and S. Grammencdi J. Am. Chem. Soc. 1989 111 4662 for a discussion of the photochemical photophysical and electrochemical properties of caged ruthenium( 11)-polypyridine complexes. 106 N. G. Lukyanenko and A. S. Reder J. Chem. SOC.,Chem. Commun. 1988 1225. 107 L. E. Echegoyen L. Portugal S. R. Miller J. C. Hernandez L. Echegoyen and G.W. Gokel Tetrahedron Lett. 1988 29 4065. I08 B. Dietrich T. M. Fyles M. W. Hosseini J.-M. Lehn and K. C. Kaye J. Chern. SOC.,Chem. Commun. 1988 691. '09 H. Takemura T. Shimyozu and T. Inazu Tetrahedron Letr. 1988 29 1789. 'Io 1. 0. Sutherland Chem. Soc. Rev. 1986 15 63; J. Incl. Phenom. 1989 7 213; Pure Appl. Chem. 1989 61,1547. 'IL J.-M. Lehn and J. B. Regnouf de Vains Tetrahedron Lert. 1989 30,.2209. 112 M. Gubelmann A. Harriman J.-M. Lehn and J. L. Sessler J. Chem. SOC.,Chem. Commwn. 1988 77. I13 A. D. Hamilton and P. Kazanjian Tetrahedron Letr. 1985 26 5735. 114 T. Fujita and J.-M. Lehn Terrahedron Lett. 1988 1709; for the complexation of organic anions by a water-soluble teracationic cubic azacyclophane see Y. Murakarni J. Kikuchi T.Ohno and T. Hirayama Chem. Leu. 1989. 88. Host- Guest Chemistry CI I 0 L N' u Cl (53) (54) With the exception of macrobicyclic receptors with carbon bridgeheads such as (53) synthesized' l5 at Columbia cryptands with bridgeheads other than nitrogen are Still rare commodities! A remarkable influence of solvent size on the stability of the complex formed between (53) and imidazole has been noted in this investiga- tion. For example the chlorinated hydrocarbon solvents methylene chloride chloroform 1,1,l-trichloroethane and 1,1,2,2-tetrachloroethanegive binding con- stants for (53) with imidazole of 240 490 8161 and 128 000 M-' respectively corresponding to a span >3.5 kcal mol-' in binding energies. It is suggested that the binding cavity in (53) is sensitive to the size and shape of solvent molecules and that large solvents do not penetrate and solvate it as well as smaller ones.Thus complex formation is favoured in solvents whose molecular dimensions are large relative to those of the binding site. A fascinating farnily'l6 of new cryptands are the macrobicyclic hosts (54)which liind C1-ions preferentially when n = 8 10 or 12 and F-ions exclusively when n = 6. In its highly selective binding of fluoride (54) resembles the small cavity Li+ and Na+ ion-selective spherands (see Section 6). Macropolycyclic crown ethers can also serve as second sphere ligands for transition metal complexes. In a recent example two host molecules were found' '' to encapsu- late tetraammineplathum( II) at least in the solid state.13 Crown Ethers and other Macrocyclic Hosts If cryptands posed a nearly impossible challenge to the reviewer then this Section can only reveal fleetingly in 'telephone directory' fashion the tip of an iceberg. A number of specialized reviews' '8-'25 come only partially to the rescue; much of the 115 K. T. Chapman and W. C. Still J. Am. Chem. Soc. 1989 111 3075; see also J. D. Kilburn A. R. MacKenzie and W. C. Still J. Am. Chem. Soc. 1988 110 1307. 116 M. Newcomb and M. T. Blanda Tetrahedron Lett. 1988,29,4261; see also M. Newcomb T. H. Horner and M. T. Blanda J. Am. Chem. Soc. 1987 109 7878. 1 I7 D. R. Alston A. M. Z. Slawin J. F. Stoddart D. J. Williams and R. Zarzycki Angew. Chem. Int. Ed. Engl. 1987,26,692; for an example of macrobicyclic polyethers as second sphere ligands for tetraammine platinum(iI) see the following communication on p.693. I I8 E. Weber 'Crown Compounds-Properties and Practice' Merck-Schuchardt 1987 p. 33. S. Quici and P. L. Anelli Chimica Oggi in press. 120 'Progress in Macrocyclic Chemistry' ed. R. M. Izatt and J. J. Christensen Wiley New York 1987 Vol. 3. 121 J. F. Stoddart Top. Stereochern. 1987 17 207; Biochern. Soc. Trans. 1987 15 1188. 376 J. E Stoddart very recent original literature describing the results of some highly inventive and innovative research is not yet long enough off the press to have become assimilated into the science as a whole. Briefly the highlights include the fundamental investigations by Kollman'26 and his in San Francisco using a range of computational methods that include molecular mechanics and the so-called free energy perturbation method into the conformational properties of 18-crown-6 (18C6) in particular and its interactions with alkyl ammonium ions and neutral molecules in general.developments in synthetic methodology like the phase-transfer catalysed syn- thesis'28 of oligoethylene glycols and their derivatives the c~ntribution'~~ of the templating action of the K' ion on these and related cyclooligomerizations the use13o of high pressure (1100 MPa) in the synthesis of N,N'-dimethyldiazacorands the preparati~n'~' of a three-dimensional analogue (55) of 18C6 the de~elopment'~~ of the organotin-mediated synthesis of macrocyclic tetraesters originally introduced by Shanzer,12' the synthesis of corands based on 2-methoxyresorcin01,'~~ crown ether Grignard reagent^,'^^ e.g.2-(bromomagnesio-l,3-xylyl-l5C4,and perfluoro crown ether analogues'35 of 18C6 15C5 and 12C4. (55) (56) H. M. Colquhoun J. F. Stoddart and D. J. Williams Angew. Chem. In!. Ed. Engl 1986 25 487; New Scientist No. 1506 1 May 1986 p. 44. 123 J. F. Stoddart in 'Enzyme Mechanisms' ed. M. I. Page and A. Williams The Royal Society of Chemistry London 1987 p. 35. 124 M. W. Hosseini La Recherche No. 206 January 1989 Vol. 20 p. 24. 125 K. E. Krakowiak J. S. Bradshaw and D. J. Zamecka-Krakowiak Chem. Rev. 1989,89 929. 126 P. A. Kollman Acc. Chem. Res. 1985 18 105. 127 M. Billeter A.E. Howard I. D. Kuntz and P. A. Kollman J. Am. Chem. SOC. 1988 110 8385; P. D. J. Grootenhuis and P. A. Kollman J. Am. Chem. SOC. 1989 111 2152 4046; D. Gehin P. A. Kollman and G. Wipff J. Am. Chem. SOC. 1989 111 3011. 128 R. A. Bartsch C. V. Cason and B. P. Czech J. Org. Chem. 1989 54 857. 129 C. A. Vitali and B. Masci Terahedron 1989 45 2201 2213. J. Jurczak R. Ostaszcwski and P. Salanski J. Chem. SOC. Chem. Commwn. 1989 184. 131 D. M. Walba R.M. Richards M. Hermsmeier and R. C. Haltwanger J. Am. Chem. SOC. 1987,109,7081. 132 A Mordini and S. Roelens J. Org. Chem. 1989 54 2643. 133 E. Chapoteau B. P. Czech A. Kumar A. Pose R. A. Bartsch R.A. Holwerda N. K. Dalley B. E. Wilson and J. Weining J. Org. Chem. 1989 54 861. 134 P. R. Markies 0,s.Akkerman F. Bickelhaupt W. J. J. Smeets and A. L. Spek J. Am. Chem. SOC. 1988 110 4284. 135 W.-H. Lin W. I. Bailey Jr. and R.J. Lagow J. Chem. SOC. Chem. Commun. 1985 1350; Pure Appl. Chem. 1988 60,473. Host- Guest Chemistry 377 the complexation by crown ethers of neutral guest molecules'36 in particular in this regard the evolution'37 by the Reinhoudt of a host for urea provides a case history in the practice of supramolecular chemistry that has attained the highest possible levels of scientific and technical accomplishment. One of the most appealing receptors is the uranyl complex (56) in which an electrophilic metal cation is 'immobilized' with a Schiff base portion of a macrocyclic ligand thus activating the host towards complexing with urea.The ultimate objective of the research -with perhaps more efficient kidney dialysis machines in mind -is to design host molecules for urea that are able to assist in the selective transport of urea through liquid immobilized membranes. This objective has been realized'39 for imidazolium cations. There have been numerous spin-offs from the urea project a of macrocyclic polyethers that complex intramolecularly with themselves the com- ple~ation'~' of new hetero di- and tri- of water molecules and the reali~ation'~~ nuclear complexes. From other laboratories the organometallic r0ta~anes.I~~ Et2Mg( 18C6) Et,Zn( 18C6) and Ph,Mg( 1,3-xylyl-l8C5) are fascinating compounds. the complexation of metal cations particularly by the so-called lariat ethers developed by the Miami They have extended their earlier triumphs' to N,N'-disubstituted-4,13-diaza-l8C6derivatives,14 the so-called bibracchial lariat ethers (BiBLE for short!) with donor'^^ and ~r-acceptor'~~ groups and peptide ~ide-arms.'~~ The electrochemical behaviour of some of these new systems has been in some detail.Recent exciting developments include (i) the I36 For a theoretical evaluation of C-H...O hydrogen bonding and its implications for molecular recognition by crown ethers see R. A. Kumpf and J. R. Damewood Jr. J. Chem. Soc. Chem. Commun. 1988 621 and also R. D. Rogers J. Incl. Phenom. 1988 6 629. 137 D. N. Reinhoudt J. Coord. Chem. 1988 18 21; D. N. Reinhoudt and H. J. den Herthog Bull. Soc. Chim. Belg.1988 97 645. 138 V. M. L. Aarts C. J. van Staveren P. D. J. Grootenhuis J. van Eerden L. Kruise S. Harkema and D. N. Reinhoudt J. Am. Chem. Soc. 1986 108 5035; C. J. van Staveren D. E. Fenton D. N. Reinhoudt J. van Eerden and S. Harkema J. Am. Chem. Soc. 1987 109 3456; C. J. van Staveren J. van Eerden F. C. J. M. van Veggel S. Harkema and D. N. Reinhoudt J. Am. Chem. Soc. 1988 110 4994; C. J. van Staveren V. M.L. J. Aarts P. D. J. Grootenuis W. J. H. Droppers J. van Eerden S. Harkema and D. N. Reinhoudt J. Am. Chem. Soc. 1988 100 8134; see also V.M.L.J. Aarts P. D. J. Grootenhuis and D. N. Reinhoudt Rec. Trau. Chim. Pays-Bas 1988 107 94. I39 T. B. Stolwijk E. J. R. Sudholter D. N. Reinhoudt J. van Eerden and S. Harkema J. Org. Chem. 1989 54,1000. 140 P.D. J. Grootenuis J. van Eerden E. J. R. Sudholter D. N. Reinhoudt A. Roos S. Harkema and D. Feil J. Am. Chem. Soc. 1987 109 4792. 141 J. van Eerden M. Skowronska-Ptasinska P. D. J. Grootenhuis S. Harkema and D. N. Reinhoudt J. Am. Chem. Soc. 1989 111 700. 142 F. C. J. M. van Veggel S. Harkema M. Bos W. Verboom G. K. Woolthuis and D. N. Reinhoudt J. Org. Chem. 1989 54,2351; F. C. J. M. van Veggel M. Bos S. Harkema W. Verboom and D. N. Reinhoudt Angew. Chem. Int. Ed. Engl. 1989 28 746. 143 A. D. Pajerski G. L. BergStresser M. Parvez and H. G. Richey Jr. J. Am. Chem. Soc. 1988 110,4844; P. R. Markies T. Nomoto 0. S. Akkerman and F. Bickelhaupt J. Am. Chem. Soc. 1988 110 4845. I44 D. A. Gustowski V. J. Gatto J. Mallen L. Echegoyen and G. W.Gokel J. Org. Chem. 1987 52 5172. I45 K. A. Arnold A. M. Viscariello M. Kim R. D. Gandour F. R. Fronczek and G. W. Gokel Tetrahedron Lett. 1988 29 3025. 146 S. R. Miller D. A. Gustowski Z. Chen G. W. Gokel L. Echegoyen and A. E. Kaifer Anal. Chern. 1988,60,2021; L. E. Echegoyen H. K. Yoo V. J. Gatto G. W. Gokel and L. Echegoyen J. Am. Chem. Soc. 1989 111 2440. 147 B. D. White J. Mallen K. A. Arnold F. R. Fronczek R. D. Gandour L. M. B. Gehrig and G. W. Gokel J. Org. Chern. 1989 54 937. 148 H. K. Yoo H. Zhang J. L. Atwood and G. W. Gokel Tetrahedron Lett. 1989 30 2489. 378 J. E Stoddart advent of steroidal lariat ethers'49 as the first examples of niosomes (nonionic liposomes) based on amphiphiles having an uncomplexed crown ether residue as the head group and (ii) self-assembling hydrogen-bonded systems'50 based on BiBLEs carrying adenine and thymine-terminated propyl side arms.Ring/side-arm c~operativity'~' have been two themes addressed with and Li+ ion ~electivity"~ N-pivot lariat ethers based on monoaza- 12C4 and 14C4 systems respectively. Also with Li+ ion complexation in mind both solution-state and solid-phase I3C n.m.r. spectroscopy using the cross-polarization magic angle spinning technique have been employed'53 along with X-ray crystallography to investigate the conformational behaviour of the cis-syn-cis and cis-anti-cis isomers of dicyclohexano-14C4. the preparation and complexation properties of some new chiral crown ethers and macrocyclic polyethers incorporating (i) carbohydrate ~esidues,'~~ (ii) the trichothecene nucleus 155 and (iii) subunits from the enzyme-catalysed hydrolysis 156 of 2,6-diacetoxybicyclo[3.3.l]nonane and 2,6-diacetoxy-3,3,7,7-tetramethyl-bicyclo[3.3.llnonane. An ingenious investigation describe^'^' the use of chiral azoph-enolic acerands such as (RRRR)-(57) and its enantiomer as colour indicators to ascertain the absolute configurations of a wide range of chiral amines. The enan- tiomeric amine-selective coloration is based on the empirical observation that the indicator-species combinations for which better host-guest complementarity exists are those combinations which exhibit a blue-shift. (RRRRj-(57) I49 L. E. Echegoyen J. C. Hernandez A. E. Kaifer G. W. Gokel and L. Echegoyen J.Chem. Soc. Chem. Commun. 1988 836; H. Fasoli L. E. Echegoyen J. C. Hernandez G. W. Gokel and L. Echegoyen J. Chem. SOC.,Chem. Commun. 1989 578. 150 G. W. Gokel L. Echegoyen M. Kim J. C. Hernandez and M. de Jesus J. Incl. Phenom. 1989 7 73. 151 K. A. Arnold J. Mallen J. E. Trafton B. D. White F. R. Fronczek L. M. Gehrig R. D. Gandour and G. W. Gokel J. Org. Chem. 1988 53 5652. 152 Y. Nakatsuji R. Wakita Y.Harada and M. Okahara J. Org. Chem. 1989 54 2988. 153 G. W. Buchanan and R. A. Kirby Tetrahedron Lett. 1987,28,1507; G. W. Buchanan R. A. Kirby and J. P. Charland J. Am. Chem. SOC.,1988 110 2477; see also M. E. Fraser S. Fortier M. K. Markiewicz A. Rodrigue and J. W. Bovenkamp Can. J. Chem. 1987,65 2558; G. W. Buchanan M. Z. Kan J. A. Ripmeester J.W. Bovenkamp and A. Rodrigue Can. J. Chem. 1987 65 2564. 154 C. Vicent M. Martin-Lomas and S. Penades Tetrahedron 1989 45 3605; M. M. Basson M. W. Bredenkamp and C. W. Holzapfel Tetrahedron Lett. 1989 30 591. 155 D. W. Anderson R. M. Black D. A. Leigh and J. F. Stoddart Tetrahedron Lerr. 1987 28 2653 2657; D. W. Anderson P. R. Ashton R. M. Black D. A. Leigh A. M. Z. Slawin J. F. Stoddart and D. J. Williams J. Chem. SOC.,Chem. Commun. 1988 904. 156 K. Naemura T. Matsumura M. Komatsu Y. Hirose,and H. Chikamatsu J. Chem. SOC.,Chem. Commun. 1988 239. 157 T. Kaneda K. Hirose and S. Misumi J. Am. Chem. Soc. 1989 111 742; for an efficient procedure for the synthesis of (2R 3R IlR 12R)-and (2S 3S llS 12S)-tetraphenyl-18 C6 see J. Crosby M. E. Fakley C.Gemmell K. Martin A. Quick A. M. Z. Slawin H. Shahriari-Zavereh J. F. Stoddart and D. J. Williams Tetrahedron Lett. 1989 30 3849. Host-Guest Chemistry 379 the application of crown ether derivatives to bring about a chemical or physical effect e.g. achiral azophenolic acerands giving'58 amine-selective coloration a 2,2'-bipyridylbis-15C5 ligand that displays'59 negative binding cooperativity towards the diquat dication on chelating a transition metal crowned phthalocyanines that undergo'60 aggregation with alkali metal cations such that their electrical conduc- tivity is increased compared to the non-aggregated phthalocyanines the so-called chundte ( channel + bundte) approach'61 to the design of transmembrane molecular channels silica1 gel bound (chiral) macrocycles'62 for the separation selective removal and concentration of metal and (racemic) alkylammonium cations the crown ether enhan~ement'~~ of the rates of enzyme-catalysed reactions in organic solvents multifunctionalized crown ethers as enzyme models'64 for the synthesis of peptides and the use of tetra-aza macrocycles for potential tumour targetti~~g'~~ with copper-radiolabelled,'66indium-111 labelled,'67 and kinetically-stable yttrium- .sbelled'68 macrocycle-antibody conjugates.9) the de~elopment'~~ of macrocyclic polyammonium receptors for the complexa- ti or^'^^ and sensing'70 of ATP for the activation of formate"' in the presence of ATP giving a formylated macrocycle for ATP ~ynthesis''~ from ADP and acetylphos- phate (f.intermediate is a macrocyclic phosphoramidate) for catalytic ATP hydro- l~sis'~' when the receptor molecule carries an intercalator group in addition to the anionic binding site. the incorporation of macrocyclic polyethers into catenanes' by using transition metals as covalent tern plate^,'^^ culminating very recently in the synthesis of a IS8 T. Kaneda S. Umeda Y. Ishizaki H. Kuo S. Misumi Y. Kai N. Kanehisa and N. Kasai J. Am. Chem. SOC.,1989 111 1881. P. D. Beer and A. S. Rothin J. Chem. SOC.,Chem. Commun. 19d8 52. 160 0.E. Sielcken J. Schram R. J. M. Nolte J. Schoonman and W. Drenth J. Chem. SOC.,Chem. Commun. 1988 108; 0. E. Sielcken L. A. van de Kuil W. Drenth and R. J. M. Nolte J. Chem. SOC.,Chem. Commun. 1988 1232.161 L. Jullien and J.-M. Lehn Tetrahedron Lefr. 1988 29 3803. I62 J. S. Bradshaw R. L. Bruening K. E. Krakowiak B. J. Tarbet M. L. Bruening R. M. Izatt and J. J. Christensen J. Chem. Soc. Chem. Commun. 1988 812; J. S. Bradshaw R. M. Izatt J. J. Christensen K. E. Krakowiak B. J. Tarbet R. Bruening and S. Lifson J. Incl. Phenom. 1989,7 127; J. S. Bradshaw K. E. Krakowiak B. J. Tarbet R. L. Bruening J. F. Biernat M. Bochenska R. M. Izatt and J. J. Christensen Pure .4ppl. Chem. 1989 61 1619 I63 D. N. Reinhoudt A. M. Eendebak W. F. Nijenhuis W. Verboom M. Kloosterman and H. E. Schoemaker J. Chem. SOC.,Chem. Commun. 1989 399. 164 K. Koga and S. Sasaki Pure Appl. Chem. 1988,60 539; S. Sasaki and K. Koga J. Incl. Phenom. 1989 7 267. 165 D. Parker J.R. Morphy K. Jankowski and J. Cox fire Appl Chem. 1989 61 1637. 166 J. R. Morphy D. Parker R. Kataky A. Harrison M. A. W. Eaton A. Millican A. Phipps and C. Walker J. Chem. SOC.,Chem. Commun. 1989 792. I67 A. S. Craig I. M. Helps K. J. Jankowski D. Parker N. R. A. Beeley B. A. Boyce M. A. W. Eaton A. T. Millican K. Millar A. Phipps S. K. Rhind A. Harrison and C. Walker J. Chem. SOC.,Chem. Commun. 1989 794. 168 J. P. L. Cox K. J. Jankowski R. Kataky D. Parker N. R. A. Beeley B. A. Boyce M. A. W. Eaton K. Millar A. T. Millican A. Harrison and C. Walker J. Chem. SOC.,Chem. Commun. 1989 797. 169 J. F. Marecek P. A. Fischer and C. J. Burrows Terrahedron Left. 1988 29 6231. I70 Y. Umezawa M. Kataoka W. Takami E. Kimura T. Koike and H. Nada Anal.Chem. 1988,60,2392. 171 H. Jahansouz Z. Jiang R. H. Himes M. P. Mertes and K. B. Mertes J. Am. Chem. SOC.,1989,111,1409. 172 M. W. Hosseini and J.-M. Lehn J. Chem. SOC.,Chem. Commun. 1988 397. I73 M. W. Hosseini A. J. Blacker and J.-M. Lehn J. Chem. SOC.,Chem. Commun. 1988 596. 174 C. 0. Dietrich-Buchecker and J.-P. Sauvage Chem. Rev. 1987 87 795; see also D. K. Mitchell and J.-P. Sauvage Angew. Chem. Int. Ed. Engl. 1988 27 930 and J. Guilhem C. Pascard J.-P. Sauvage and J. Weiss Angew. Chern. Int. Ed. Engl. 1988 110 8711. 380 J. E Stoddart molecular trefoil knot -a real tour de force by the Dietrich-Buchecker/Sauvage Just occasionally a refreshingly simple and novel idea emerges from within an apparently well-developed research area.The macrocyclic hosts designed and synthesized by Hamilton and his fall into this category. Inspired by the X-ray crystal structure of the active site of ribonuclease T ,which binds its nucleotide substrate via both hydrogen bonding and hydrophobic stacking interactions involv- ing the aromatic nucleotide base and a tryrosine residue the challenge of nucleotide base recognition has been addressed successfully judging from the rapid appearance in the literature of synthetic receptors for thymine,'77 guanine,'78 and adenine'79 derivatives. Ditopic binding of tripentanoylguanosine and 1 -butylthymine for example is observed by macrocyclic receptors e.g. (58) and (59) containing 7r-electron rich 2,7-dialkoxynaphthalene units and a 7-amino- 1,s-naphthyridine residue (which complements guanine) or a 1,2-bis(2-amin0-6-pyridyl)ethanelinkage (which complements adenine).The proposed receptor interactions have been substantiated structurally in the solid state (X-ray crystallography) and thermodynamically in (CDC1 usually) solution (stability constant measurements). They have led'" to the synthesis of an artificial receptor for barbiturates such as barbital where six hydrogen bonds are present in the complex (60). Me R = 2',3',5'-Tri-O-pentanoyIribose R = PBtAyl (58) (59) 14 Molecular Clefts One of the major advances in host-guest chemistry since the 1983 report' has been initiated by Julius Rebek. Although not the first"' to contemplate making synthetic molecular receptors with cavities of a cleft-like rather than of a circular or spherical 175 C.0.Dietrich-Buchecker and J.-P. Sauvage Angew. Chem. Int. Ed. Engl. 1989 28 189. 176 A. D. Hamilton N. Pant and A Muehldorf Pure Appl. Chem. 1988 60,533; for further discussion of carboxylic acid complexation by a synthetic analogue of vancomycin see N. Pant and A. D. Hamilton J. Am. Chem. Soc. 1988 110 2002. 177 A. D. Hamilton and D. Van Engen J. Am. Chem. Soc. 1987,109,5035; A. V. Muehldorf D. Van Engen J. C. Warner and A. D. Hamilton J. Am. Chem. Soc. 1988 110,6561. 178 A. D. Hamilton and N. Pant J. Chem. SOC.,Chem. Commun. 1988 765. I79 S. Goswami and A. D. Hamilton J. Am. Chem. Soc. 1989 111 3425. 180 S. Chang and A. D. Hamilton J. Am. Chem. SOC.,1988 110 1318. 181 J. W. Cornforth Roc.R. SOC.London Ser. B 1978 203 101. Host-Guest Chemistry nature (Figure 3) to act as enzyme mimics hels2 has been singularly successful in meeting the challenge -and a Rebek molecular cleft is now an immediately recogniz- able structural feature on the chemical landscape. A few simple examples that illustrate the binding principle towards a range of substrates are shown in Figure 4. Since the first cornrn~nication'~~ appeared in 1985 seven full and numerous additional communications'91-203 have been published. 182 J. Rebek Jr. Science 1987 235 1478; J. Mol. Recog. 1988 1 1; J. Incl. Phenom. 1989 7 7; Pure Appl. Chem. 1989 61 1517. 183 J. Rebek Jr. 9. Askew N. Islam M. Killoran D. Nemeth and R. Wolak J. Am. Chem. Soc. 1985 107 6736.184 J. Rebek Jr. L. Marshall R. Wolak K. Parris M. Killoran B. Askew D. Nemeth and N. Islam J. Am. Chem. Soc. 1985 107 7476. 185 J. Rebek Jr. L. Marshall J. McManis and R. Wolak J. Org. Chem. 1986 51 1649. 186 J. Rebek Jr. 9. Askew M. Killoran D. Nemeth and F.-T. Lin J. Am. Chem. SOC.,1987 109 2426. 187 J. Rebek Jr. B. Askew D. Nemeth and K. Parris J. Am. Chem. SOC.,1987 109 2432. 188 J. Rebek Jr. 9. Askew P. Ballester and A. Costero J. Am. Chem. SOC.,1988 110 923. 189 B. Askew P. Ballester C. Buhr K. S. Jeong S. Jones K. Parris K. Williams and J. Bebek Jr. J. Am. Chem. SOC.,1989 111 1082. I90 K. Williams 9. Askew P. Ballester C. Buhr K. S. Jeong S. Jones and J. Rebek Jr. J. Am. Chem. SOC.,1989 111 1090. 191 J. Rebek Jr.B. Askew P. Ballester and M. Doa J. Am. Chem. SOC.,1987 109 4119. I92 J. Rebek Jr. 9. Askew P. Ballester C. Buhr S. Jones D. Nemeth and K. Williams J. Am. Chem. Soc. 1987 109 5033. I93 J. Rebek Jr. 9. Askew P. Ballester C. Buhr A. Costero S. Jones and K. Williams J. Am. Chem. SOC. 1987 109 6866. 194 J. Rebek Jr. K. Williams K. Parris P. Ballester and K.4. Jeong Angew. Chem. Int. Ed. Engl. 1987 26 1244. I95 J. Wolfe D. Nemeth A. Costero and J. Rebek Jr. J. Am. Chem. Soc, 1988 110 983. I96 K. S. Jeong and J. Rebek Jr. J. Am. Chem. SOC.,1988 110 3327. 197 L. Marshall K. Parris J. Rebek Jr. S. V. Luis and M. I. Burguette J. Am. Chem. SOC. 1988 110 5192. 198 J. B. Huff B. Askew R. J. Duff and J. Rebek Jr. J. Am. Chem. SOC.,1988 110 5908.199 J. S. Lindsey P. C. Kearney R. J. Duff P. T. Tjivikua and J. Rebek Jr. J. Am. Chem. SOC.,1988 110 6575. 200 W. L. Jorgensen S. Boudon and T. 9. Nguyen J. Am. Chem. SOC.,1989 111 755. 201 T. Benzing P. T. Tjivikua J. Wolfe and J. Rebek Jr. Science 1988 242 266. 202 B. M. Tadayoni K. Parris and J. Rebek Jr. J. Am. Chem. SOC.,1989 111 4503. 203 Y. Li and K. N. Houk J. Am. Chem. SOC.,1989 111 4505. 382 J. F. Stoddart Functional groups diverge away Functional groups converge from the cavity and from to create an active site substrates held inside Figure 3 The binding of a substrate (a) by a macrocycle and (6) within a molecular cleft Figure 4 Examples of molecular cleft-like compounds that (a) bind Ca2+ ions (compare with a classical chelate such as EDTA) (b) bind alcohols and diammines and (c) bind oxalic acid and imidazolium cations A lot of fundamental issues have already been addressed.They include The binding of divalent metal (e.g. Caz+) ions'97 using the more basic syn lone pairszo3 on the carboxylate groups; the binding of P-arylethylamines'88 and substrate^'^^.'^^ such as those shown in Figure 4(a) and (b); the binding of bipyridine and melamine within synthetic receptors'99 that have multipoint contacts; Host- Guest Chemistry 383 0 the binding of nucleic acid bases189~190~192-194,'96 through hydrogen bonding and r-stacking interactions; 0 the transport (see Figure 5) of amino and adenine derivatives2" across liquid membranes; creating asymmetric microenvironments which exhibit chiral differentiation towards racemic and amines;'" the development of a new class of per acid^"^ to investigate reaction selectivities in olefin epoxidations; catalysing the hemiacetal cleavage'95 of the glycolaldehyde dimer; the intramolecular catalysis of enolization;202 commenting on the active site of the serine pro tease^;'^^ speculating on modelling the active site of ly~ozyrne.'~~ R = Et R = Ribosyl R = Deoxyribosyl Hydrogen Bonding & Stacking Figure 5 Diagrammatic representation of the transportation across a liquid membrane of adenine derivatives using a molecular cleft-like compound Molecular clefts of different varieties are now beginning to emerge from numerous other laboratories20L206 and their use in binding urea205 and uric acid206 has been explored with mixed fortunes in the latter case.This has drawn the comment206 'that in the design of relatively rigid receptors imprecision exacts a heavy toll'. The bisubstrate reaction template (Scheme 6) devised by Kellj et d207 is a clever and daring demonstration of the kinds of problems that now need to be tackled increas- ingly in host-guest chemistry. The fact that the rate enhancement for reaction of the substrates (62) and (63) in the presence of the reaction template (61) to give the product (64) is only 6 is beside the point. 204 S. C. Zimmerman and C. M. J. VanZyl J. Am. Chem. SOC. 1987 109 7894; S. C. Zimmerman C. M. J. VanZyl and G. S. Hamilton J.Am. Chem. SOC.,1989 111 1373. 205 T. W. Bell and J. Lin J. Am. Chem. SOC.,1988 110 3673. 206 T. R. Kelly and M. P. Maguire J. Am. Chem. SOC., 1987 109 6549; Tetrahedron Lett. 1989 30 2485. 207 T. R. Kelly C. Zhao and G. J. Bridger J. Am. Chem. SOC.,1989 111 3744. 384 J. F. Stoddart .Me Me Me Scheme 6 The template-directed synthesis of the secondary amine (64) from the primary amine (62) and the bromide (63) in the presence of (61) The preparation of molecular clefts incorporating analogues of Troger's base as chiral structural elements has been reported2'* and very recently chiral recognition of aromatic carboxylate anions has been achieved209 by an optically-active abiotic receptor containing a rigid guanidinium binding unit.Chiral host molecules derived by chemically modifying monensins have revealed*l' enantiomeric complex forma- tion towards several racemic amine salts in a liquid-membrane type electrode system. In this connection the preparation2" of a new class of nonmacrocyclic yet preorgan- ized hosts e.g. (65) for cations is a promising development. 208 C. S. Wilcox L. M. Greer and V. Lynch J. Am. Chem. SOC.,1987 109 1865. 209 A. Echavarren A. Galan J.-M. Lehn and J. de Mendoza J. Am. Chem. SOC.,1989 111 4994. 210 K. Maruyama H. Sohmiya and H. Tsukube J. Chern. Sac. Chern. Comrnun. 1989 864. *" T. Iimori W. C. Still A. L. Rheingold and D. L. Staley J. Am. Chern. SOC.,1989 111 3439. Host- Guest Chemistry 15 Double Helicates Host-guest chemistry has set the scene and is paving the way for what will be one of the most far-reaching developments in synthesis -the spontaneous self-assembly of large structured and ordered molecular arrays from reasonably simple starting materials.The principle which made it possible to template covalently the synthesis of ~atenanes,”~ has now been employed by Lehn and co-workers212 to form a homologous series of metallo-organic double helices (Figure 6) reminiscent of the tertiary structure of DNA. When CuI ions are added to chloroform solutions of oligobipyridine ligands double-stranded heli~ates~’~-*~~ with ligand molecules wrap- f CU’I U Figure 6 Diagrammatic representation of double-stranded helicates comprising ligands containing (a) two (b) three (c)four and (d) five 2,2‘-bipyridine subunits 212 J.-M.Lehn A. Rigault J. Siegel J. Harrowfield B. Chevier and D. Moras Proc. Nat. Acad. Sci. USA 1987,84 2565; J.-M. Lehn and A. Rigault Angew. Cfiern.,Int. Ed. Engl 1988 27 1095. 213 For examples of molecular helicity in inorganic complexes see E. C. Constable M. G. B. Drew and M. D. Ward J. Chern. Soc. Cfiern.Comrnun. 1987 1600. 214 For a discussion of the spontaneous formation of superhelical strands see H. Yanagawa Y. Ogawa H. Furuta and K. Tsuno J. Am. Cfiern.SOC.,1989 111 4567. J. E Stoddart ped around tetrahedrally-coordinated CuI ions are produced. The self-assembly process exhibits positive cooperativity (complexation of one metal ion facilitates binding of the next and so on) and self-self recognition (preferential pairing to the same ligands in the presence of a mixture).This elegant piece of research has considerable implications for biological medical and materials sciences. 16 And Looking to the Future Host-guest chemistry is still in its infancy. Increasingly it is capturing the imagina- tion of young and adventuresome chemists. Collected works have appeared which summarize the growth of the field in Italy’” and in Japan.*16 Together with Vogtle’s and Lindoy’s monograph^^^',^^' these are forerunners of many more to come. Now it will be the fundamental role that host-guest chemistry will play in translating the multifarious functions of biological systems into new molecular mechanical and electronic devices that will promote its dramatic expansion as an enabling branch of chemical science in the run up to the 21st Century.The intellectual challenges posed by this prospect are limitless. The opportunities are endless. 215 ‘Macrocyclic and Supramolecular Chemistry in Italy’ Proceedings of the Meeting-Parma 6 May 1988 University of Parma 1988. 216 ‘Current Topics in Macrocyclic Chemistry in Japan’ ed. E. Kimura Hiroshima University School of Medicine 1987. 217 F. Vogtle ‘Supramoleculare Chemie’ Teubner Stuttgart 1989. 218 L. F. Lindoy ‘The Chemistry of Macrocyclic Ligand Complexes’ Cambridge University Press 1989.

ISSN:0069-3030    

DOI:10.1039/OC9888500353

出版商:RSC    

年代:1988

数据来源: RSC

摘要:

Author Index Aarts V.M.L. 377 Abboud J.-L.M. 64 70 Abd-El-Aziz AS. 173 Abderrahman M.B. 134 Abel T. 124 Abeles R.H. 330 Abell C. 327 332 333 348 Abelman M.M. 144 160 Abelt C.J. 192 Abraham E.P. 343 344 Abraham M.H. 56 Abraham R.J. 20 29 Abramovitch R.A. 177 Abu-Orabi S.T. 260 Achiwa K. 44 Acker M. 96 Ackermann P. 173 Ackland M.J. 335 Adam G. 134 283 Adam R. 203 Adam S. 150 227 Adam W. 193 212 Adams Nye S. 100 Adlington R.M. 87 134 272 343 344 345 350 Agami C. 124 265 Agarwal K.K. 24 Agrafiotis D.K. 28 Aguilar E. 133 Aharonowitz Y. 344 Ahmad S.A. 71 Ahmad-Junan S.A. 175 211 Ahmed S.A. 167 326 Ahrendt J. 355 Aidhen J.S. 71 Aihara M. 111 Aitken D.J.143 Ajisaka K. 317 Akamatsu H. 188 Akasaka T. 45 Akermark B. 115 133 280 Akiba K. 261 267 Akkerman O.S. 244 376,377 Akoka S. 331 Akutagawa S. 238 Akutsu Y. 253 Alagona G. 19 Alain I. 365 Alam I. 188 Alberts I.L. 27 Albery W. 64 Albinati A. 105 Alcock N.W. 309 Aldridge T.E. 55 Alexakis A. 106 133 134 282 Algrim D.J. 64 Ali S.M. 93 Al-Jalal N. 180 Allavena C. 241 Allaveno C. 112 Allen A.D. 66 Allen D.S. 24 Allen E.E. 127 295 Allen F.H. 25 Allinger N.L. 19 20 29 Allouche A. 82 Allwohn J. 242 Alpin R.T. 345 Alpoim M.C.M.de C. 142 Alston D.R. 358 363 375 Alston P.V. 43 44 Altona C. 30 Alwan A.F. 348 Amarasekara AS. 135 304 Amato J.S.200 Amatore C. 175 Ambler P.W. 144 231 Amin M. 58 Amin S. 184 Ammann A.A. 319 Amoroux R. 113 Amos R.D. 27 Amyes T.L. 61 Anand N. 201 Anastasis P. 330 Anderson C.B. 153 Anderson D.W. 378 Anderson J.A. 182 326 Anderson K.R. 251 Anderson K.S. 337 Ando A. 295 Ando K. 271 Ando W. 45 98 195 211 251 256 Andreini B.P. 94 Andres J. 37 Andrews L.E. 222 Andrews M.A. 237 Andrews R.C. 181 Andrews S.W. 285 Andrianarison M. 256 Anelli P.L. 363 375 Ang K.-P. 164 Angeletti E. 120 Angell E.C. 43 214 Angermund K. 195 Anklekar T.V. 205 Annunziata R. 43 287 Antel J. 291 Antelo J.M. 68 Antinolo A. 11 Anunziata J.D. 173 Anvia F. 64 70 Aoe K. 140 Aoki O.281 Aoki S. 234 293 Aono A. 44 Aoyama T. 114 283 Aoyama Y. 371 Apeloig Y. 54 55 Appel R. 136 Appelman E.H. 222 Appelt A. 243 Arad D. 54 Arai H. 135 293 Araki K. 366 Araki S. 267 272 Araki Y. 119 296 Arce F. 68 Archelas A. 318 319 Arcoria A. 56 Arduini A. 365 Arenas J.F. 36 Arenz S. 249 Ariel S. 42 Arif A.M. 136 Arimura T. 366 Ariyama T. 171 Armacost L.M. 147 Armstrong A. 106 Armstrong D.R. 242 Armstrong D.W. 359 Armstrong-Chong R.J. 178 Amett E.M. 30 63 Amold K.A. 377 378 Arnold Z. 117 387 Author Index Arnoldi A. 212 Arques A. 216 Arteca G.A. 32 Asano T. 297 Asao T. 279 Asaoka M. 153 278 Asensio G. 96 150 Asfari Z.365 Ashby E.C. 53 57 112 Ashe A.J. 111 243 Ashton P.R. 186 358 363 373 374 378 Ashwell M. 109 Asirvatham E. 220 Askew B. 381 Aso Y. 91 263 Asokan C.V. 148 Ates M. 260 Atkinson R.S. 90 Atsubo T. 263 Attina M. 61 Atwood J.L. 366 377 Audia J.E. 159 Auge C. 315 Aumann R. 195 Avent A.G. 333 Avila D.V. 82 Avila L.Z. 80 Ayake S. 338 Azerad R. 297 336 Baba N. 128 Bacaloglu R. 62 173 Bacchilega G. 370 Bachand C. 196 Bacher A. 350 351 Baciocchi E. 198 Back T.G. 101 Baczynskyj L. 371 Bader R.F.W. 29 Backvall J.-E. 92 93 96 137 Baertschi S.W. 192 Baggaley K.H. 345 Baghdanov V.M. 212 Bagheri V. 254 Bagno A. 65 Bahadori S. 51 Bailey C.R.323 Bailey K. 260 Bailey W.F. 241 Bailey W.I. jun. 376 Baine N.H. 214 Baird P.D. 350 Baker A.D. 43 Baker B.E. 160 178 234 Baker J. 28 Baker M.G. 222 349 Baker S.R. 197 233 Bakshi R.K. 86 108 113 Balaban A.T. 188 Balaji V. 32 Balanikas G. 184 Balasubramanian K.K. 71 72 Balavoine G. 85 Baldridge K.K. 28 Baldwin J.E. 45 46 50 78 87 134 272 343 344 345 350 Baldwin J.J. 200 Baldwin R.L. 9 Baldwin T.O. 348 Baldy A. 82 Balicki R. 214 Balke W.H. 167 Ballester P. 381 Ballesteros M. 39 Ballini R. 128 135 302 Ballistreri F.P. 56 102 Ballschuh S. 150 309 Baltz R.H. 322 Balzani V. 374 Ban Y. 140 Banciu M. 188 Banfi L. 300 Bantia S. 60 346 Baraldi P.G.92 Barbas C.F. 111 311 312 Barbieri G. 180 Barco A. 92 Barczynskyj L. 188 Bardshiri E. 167 326 Bares J.E. 64 Bargon J. 365 Barigelletti F. 374 Barinelli L.S. 198 230 Barlow G.E. 12 Barluenga J. 96 101 107 133 135 150 221 281 302 Barna J.C.J. 4 Barner B.A. 181 Barois-Gacheriau C. 116 Barr D. 242 Barr D.A. 201 Barrans R.E. jun. 362 Barrett A.G.M. 195 225 239 Barrio J.R. 171 Barron A.R. 136 193 246 Barry D.C. 18 Barry J. 128 Bartlett P.A. 78 Bartlett R.J. 27 37 Bartoli D. 28 112 Barton D.H.R. 78 85 134 177 214 305 Bartsch R.A. 376 Barzaghi M. 32 Bash P.A. 22 Bashiardes G. 226 305 Basset J.M. 178 Basson M.M. 378 Batal D.J. 97 Batcheller S.A.256 Batchelor R.J. 262 Bates P.A. 98 Battersby A.R. 222 348 349 350 Battle P.D. 15 Battye P.J. 49 Bauer C. 4 Bauer W. 101 242 243 Baum M.W. 331 Baumgartner M.T. 175 Baumstock A.L. 107 Bautista M.T. 10 Bax A. 7 Baxter R.L. 347 Baxter S.G. 194 Baxter S.M. 177 Bay E. 174 Bayly C.I. 35 Bayod M. 101 Bazhenov D.V. 101 Beachley O.T. jun. 247 Beale J.M. 324 338 351 Beale M.H. 334 Bean J.M. 154 Beaupain D. 348 Becher J. 216 Beck J. 321 Becker G.W. 344 Becker R.S. 185 Beckett R.P. 226 Beckwith A.L.J. 79 81 82 Bediou F. 113 Bednarski M.D. 315 Beeley N.R.A. 379 Beer P.D. 371 379 Begley M.J. 339 Behr A. 225 Beifuss U. 291 Belagaje R.344 Belfield K.D. 45 Bell S.H. 178 Bell T.W. 383 Bellard S.H. 25 Bellassoued M. 129 269 Bellucci G. 59 319 Bellus D. 144 Belser P. 374 Belser R.B. 277 Belyasmine A. 99 117 Benac B.L. 246 Benati L. 101 Ben-David Y. 183 Bender M.L. 359 Bender S.L. 336 Benesi A.J. 337 Benetti S. 92 Benhaddou R. 109 Benigni D.A. 197 233 Benken R. 182 Benn R. 13 Benneche T. 215 Bennett G.J. 326 Bennett J.W. 326 Bennett M.A. 178 Benoit R.L. 64 Ben-Rayana E. 37 Benseler F. 22 Bentley T.W. 54 Benzing T. 381 Berchtold G.A. 49 Author Index Beremand M.N. 332 Berendsen H.J.C. 21 22 Bergan J.J. 128 Bergh S. 322 Bergman J. 205 Bergman R.G. 177 Bergmann N.361 BergStresser G.L. 377 Berkovich E.G. 179 Berman H.M. 18 Bernardi F. 33 35 36 37 41 44 Bernasconi C.F. 61 62 64 Berndt A. 242 Bernstein F.C. 25 Berson J.A. 36 45 47 50 Berthelot M. 70 Bertounesque E. 269 Bertrin J. 29 Bertrand M. 94 Beugelmans R. 175 Beveridge D.L. 22 Beyer W. 171 Bhandal H. 78 Bhandari P. 339 Bhanumati S. 171 Bhat K.S. 122 271 Bhupathy M. 141 Bhushan V. 295 Bhushan Lohray B. 267 Biali S.E. 53 Bianchi D. 308 Bianchini R. 59 Bianco L. 309 Bianconi P.A. 253 Bibb M.J. 322 Bickelhaupt F. 241 244 376 377 Bickerstaff R.D. 257 Biehl E.R. 176 Bielski R. 367 Biernat J.F.,379 Bilger C. 110 Billet G. 255 Billeter M.38 376 Billups W.E. 163 Binkley J.S. 22 Binns M.R. 125 Birchall T. 243 Bird C.W. 214 Birney D.M. 36 50 Birse E.F. 276 Bisaha J. 153 286 Bitterwolf T.E. 248 Bjaneye-Boundjou G. 171 Bjoerkling F. 316 Black D.J. 218 295 318 Black R.M. 378 Blacker A.J. 364 379 Blanc A. 113 Blanchard M. 171 Blanche F. 350 Blanco L. 76 132 Blanda M.T. 375 Blaney J.M. 18 Blank N.E. 186 Blaser D. 163 Blatter T. 188 362 Blechert S. 158 Bleecher A.B. 334 Bliznyuk A.A. 29 Bloch R. 119 Blom R. 248 Blotny G. 60 Blum Z. 372 Bochenska M. 379 Bodenhausen G. 6 Boduszek B. 62 Bodwell G.J. 187 Bohmer V. 365 Boehshar M. 99 Boelens R. 6 21 Boersma J. 243 Boese R.163 259 Bofill J.M. 37 163 Boger D.L. 43 76 202 Bois-Choussy M. 175 Boivie R.H. 24 Boivin J. 85 Boleslawski M.P. 88 Bolitt V. 215 305 Bolton G.L. 11 5 273 Bonaccorsi R. 37 BonaEiC-Kouteckg V. 37 Bonini B.F. 253 Bonneau P.R.,135 Bonnett R. 222 Boother J. 24 Borden W.T. 35 47 Bordwell F.G. 64 Bornemann V. 342 Borror A.L. 204 Borthakur D.R. 43 287 Bortolin R. 252 Bos M. 377 Bose A.K. 291 Bosum A. 158 Boteslawski M.P. 280 Bothner-By A.A. 10 Bott S.G. 366 Bottoni A. 36 37 41 44 Boucher R.J. 154 Bouchoule C. 171 Bouding A. 254 Boudjouk P. 251 Boudon S. 381 Bovenkamp J.W. 378 Bowen J.P. 29 Bowman W.R. 73 Box S.J. 347 Boyce B.A. 379 Boyd D.B.19 28 Boyle P.H. 217 Bozell J.J. 178 234 Brabec L. 68 Brackenridge I. 106 Bradley D.C. 247 Bradley M. 343 Bradshaw J.S. 221 376 379 Brady J.W. 21 Braish T.F. 156 Bram G. 128 Branca J.C. 64 Branchaud B.P. 78 79 Brand M. 171 Brand S. 43 Brandl M. 360 Brandsma L. 99 242 243 Branz S.E. 183 Braslau R. 136 Brassat B. 359 Bratz M. 43 Brauman J.I. 251 Braun A.M. 85 Braun M. 120 Braun-Keller E. 24 Bravo P. 105 114 Brean L. 132 BrCant P. 275 Bredas J.L. 163 Bredenkamp M.W. 378 Brelikre C. 257 Brernner J.B. 221 Brennan J. 88 Breslensky D.M. 296 Breslow R. 43 360 Breukmann R. 41 Breunig H.J. 260 Brevard C. 12 13 Brewersdorf M. 11 1 Brewster A.212 Brice M.D. 25 Brickmann J. 23 Bridger G.J. 383 Brieva R. 302 Briggs R.W. 248 Brighty K. 156 Broadbent H.A. 349 Brobst S.W. 325 326 Brondum K. 216 Brook A.G. 250 Brooks B.R. 19 Brown A.B. 364 Brown A.G. 347 Brown C.M. 307 Brown D. 215 Brown F. 22 Brown F.K. 21 361 Brown H.C. 86 91 109 110 113 118 122 271 298 300 Brown J.D. 297 Brown J.W.S. 338 Brown L.E. jun. 184 Brown M.S. 330 Brown S.S.D. 252 Browne E.J. 221 Browne M.E. 178 Browne M.W. 371 Bruccoleri R. 20 Bmccoleri R.E. 19 Bmckner R. 110 Briigge H. 250 W m h) N v W 0 W w Author Index 39 1 Chinoporos E. 204 Cho B.T. 298 Confalone P.N. 208 Conlon D.A.45 Crooks W.J. 111 108 Crosby J. 378 Cho I.-S. 171 Conn R.S. 200 Croteau R. 330 Cho Y.-S. 266 Connell R.D. 133 Crouch N.P. 344 345 Choi Y.L. 78 79 Conrads M. 94 Crout D.H.G. 131 309 Chopineau J. 315 Constable E.C. 242 385 Csoeregh I. 355 Chou H.-N. 330 Cook D.B. 29 Cuadrado P. 98 303 Chou K.-C. 22 Chou S.-S.P. 92 153 Chou T.-S. 92 Cooney M.J. 165 Cooper D.L. 29 30 Cooper J. 311 Cuevas J.C. 222 Cullen W.R. 239 299 Cummins C.C. 177 Chow Y.L. 62 Cooper J.A. 154 Curci R. 191 Christen M. 131 Christensen J.J. 379 Cooper K. 234 277 Cooper N.J. 172 Curl R.F. 371 Curran D. 57 112 Chrusciel J. 251 Cooper S.R. 222 Curran D.P. 40 74 77 83 Chrystal E.J.T. 363 Coote S.J. 232 289 Chu S. 196 Copeland C.M. 263 Czarnik A.W. 243 Chu S.-D. 284 Copley S.D. 337 Czech B.P.368 376 Chuang C.-P. 179 Copperucci A.C. 254 Czernecki S. 109 Chuchani G. 58 Coppi L. 217 Chudzynska H. 247 Corbeil J. 196 Dabdoub M.J. 264 Chuit C. 254 Corbera J. 39 Daggett V. 22 Chung S.Y. 70 Corey E.J. 24 108 161 200 Dai W.-M. 205 Chung W.-S. 40 Corina D.L. 324 Daignault S. 305 Chung Y.-S. 243 Corley D.G. 220 Dai-Ho G. 172 Ciattini P.G. 88 121 Cornforth J.W. 380 Dakternieks D. 264 Cieplak P. 38 Cornwall P. 154 Dalcanale E. 370 Cinquini M. 287 Correia C.R.D. 157 Dalley N.K. 221 376 Ciorbe V. 188 Corriu R.J.P. 254 257 298 Dallmann H.G. 313 Ciufolini M.A. 178 312 Cortez C. 185 D’Aloisio R. 90 294 Claramunt R.M. 64 Costero A, 381 Dalton D.R. 24 Clark T. 22 Cotton F.A. 11 Damewood J.R. jun. 377 Claude S. 364 Coughlin E.B. 176 Dammel R.256 Claxton E.E. 254 Couret C. 256 Damrauer R. 254 Clegg W. 242 Covitz F. 66 Danaher E.B. 25 Clennan E.L. 23 Cowart M.D. 361 Danehay C.T. jun. 135 Clore G.M. 6 21 22 Cowley A.H. 136 193 246 d’Angelo J. 43 154 Closs F. 208 248 256 257 259 D’Angelo L.L. 85 Coates J.D. 344 Cowling M.P. 277 Danheiser R.L. 99 141 145 Coates R.M.. 334 Cox B.G. 67 166 254 Cochran A.G. 320 Cox D.M. 371 Daniel C. 89 Coggins J.R. 336 Cox J.P.L. 379 Danikiewicz W. 173 Cohen N.C. 18 Cozzi F. 287 Danishefsky S.J. 159 162 Cohen T. 141 142 145 Cozzi P.G. 267 169 Cohen Y. 182 Crabbe M.J.C. 344 Danks T.N. 231 279 Cohen-Solal N. 348 Crabtree R.H. 11 Dannenberg J.J. 29 Colberg C. 359 Craig A.S. 379 Dany F. 178 Cole S.P. 323 Craig D. 154 Darba P. 7 Coleman A.W. 366 Cram D.J.188 354 368 369 Daris J.-P. 196 Coleman R. 322 370 371 Darlington W.H. 154 Colin S. 106 Cramer R.D. 111 19 Dasenbrock J. 327 Collet A. 369 Crandall J.K. 97 Dasgupta F. 301 Collin J. 76 11 1 282 284 Crawford L.P. 174 Da Silva Jardine P. 161 Collins E.M. 365 Creary X. 55 Dauben W.G.. 46 Collins M.A. 28 Creighton S. 33 Dauber P. 19 Collins M.J. 264 Cremer D. 27 28 31 164 Daude N. 275 Colloc’h N. 23 Cremonesi P. 186 Daugherty J. 289 Colonna S. 43 295 Crenshaw L. 176 Daute P. 36 Colovray V. 93 Crews P. 220 David S. 223 Colquhoun H.M. 376 Crich D. 76 80 Davidson I.M.T. 249 Comasseto J.V. 264 Crippen G.M. 18 Davies A.G. 82 Combellas C. 175 Cristau H.J. 116 Davies B.J. 174 Comins D.L. 275 Crombie L. 112 324 338 339 Davies H.G. 307 Commenges G.11 Cronan J.E. 322 Davies H.M.L. 156 Concellbn J.M. 107 281 Crookes M.J. 68 Davies S. 9 10 Author Index Davies S.G. 144 226 231 232 238 Davies S.J. 4 Davis A. 20 Davis F.A. 193 Davis L.M. 354 Davison I.G.E. 82 Deakyne C.A. 363 Dean D.C. 289 Dearing A. 18 Deb B. 148 DeBie D.A. 67 Declercq J.-P. 194 256 DeClercq P.J. 154 de Cola L. 374 DeFrees D.J. 22 Degl’Innocenti A, 220 254 Degorre F. 65 De Heij H.T. 315 De Jeso B. 307 de Jesus A.E. 335 de Jesus M. 378 De Jong J.C. 286 Dejroongruang K. 165 De Kimpe N. 133 141 194 de Koning L.J. 58 Delair T. 197 Delduc P. 76 Dell C.P. 154 Delsuc M.A. 4 De Luca M.R. 208 DeLue N.R. 91 110 De Mahieu A.F.141 DeMarco A.C. 347 DeMaria P. 67 Dembech P. 254 277 DeMendoza D. 322 de Mendoza J. 222 384 Demerseman P. 179 De Mesmaeker A. 144 de Miguel L.M.V. 205 217 DeMunari S. 105 Denerseman P. 110 den Hertog H.J. jun. 222 367 377 Denmark S.E. 123 125 Dereppe J.M. 4 De Rooij R.W.M. 348 Desai M.C. 161 Desjardins A.E. 332 Deslongchamps P. 43 158 Destro R. 209 De Strong P. 279 Detty M.R. 264 Devant R.M. 120 de Vlieg J. 22 Devor K.A. 332 de Vos D. 258 Dewar M.J.S. 36 46 de Zeeuw D. 367 Dharanipragada R. 361 Diederich F. 361 Dieter R.K. 167 212 Dietl S. 210 259 Dietrich A. 247 Dietrich B. 353 374 Dietrich H. 243 Dietrich-Buchecker C.O. 379 380 DiFabio R.108 Differding E. 300 Di Giacomo R. 264 DiGiovanni J. 185 Dijkstra P.J. 222 367 DiMare M. 328 Dinnocenzo J.P. 45 Dinur U. 19 Di Raddo P. 183 Dirnens V. 249 Disch R.L. 165 Ditrich K. 11 1 Dittami J.P. 72 203 Dittmer D.C. 194 263 Dixneuf P.H. 101 Dixon N.J. 87 234 278 Doa M. 381 Doad G.J.S. 98 294 Doak G.O. 260 Dodds D.R. 312 Dodoni A, 280 Doering W.von E. 41 Dorpinghaus N. 355 Dogbo O.,330 Doh C.H. 219 Dolbier W.R. jun. 141 Dolphin D. 223 Domayne-Hayman B.P. 343 Dondoni A. 88 121 Donnelly D.M.X. 333 Dordor-Hedgecock I.M. 226 Dorigo A.E. 369 Dorta R.L. 79 Dotterer S.K. 173 Dotz K.H. 182 Dotzlaf J.E. 344 Doubleday C. 37 Doubleway A.25 Dougherty D.A. 96 362 Doutheau A. 197 Doweyko A.M. 19 Doyle M.J. 242 Doyle M.P. 236 254 Drager M. 256 258 Drage J.S. 178 Drake C.A. 86 Drenth J. 18 Drenth W. 379 Dresely S. 106 Drew B. 371 Drew M.G.B. 385 Drewes M.W. 304 Drewes S.E. 124 Drews R. 45 Drolet M. 348 Droppers W.J.H. 377 Druechhammer D.G. 312 Dubert A. 348 Dubois J.-E. 269 Dubourg A, 256 Duddeck H. 156 Duebelly B. 243 Duerr B.F. 243 Dufaud V. 178 Duff R.J. 381 Duggan P.J. 81 Duisenberg A.J.M. 242 Dumont W. 141 144 du Mont W.-W. 261 264 Dunams T. 43 Duncan J. 323 Duncan K. 336 Duncan S.M. 154 Dunlop N.K. 71 Dunn P.J. 219 Dupree R. 15 Durand D.J. 15 Durrwachter J.R.313 Dvoiik D. 117 Dybowska A. 141 Dymetryszyn J. 348 Earl K.A. 10 Eaton M.A.W. 379 Eaton P.E. 178 Eberbach W. 199 Eberle M. 135 303 Ebert R. 330 Ebihara K. 278 Ebijuka Y. 335 Ebmeyer F. 374 Echavarren A.M. 237 273 3 84 Echegoyen L. 374 377 378 Echegoyen L.E. 314 377 378 Echelard Y. 348 Edelmann F. 259 Edenborough M.S. 343 Edwards R.M. 336 Eendebak A.M. 379 Effenberger F. 124 313 314 Effland R.C. 216 Eggert U. 275 Egli M. 135 303 Eguchi H. 205 Eguchi S. 78 Ehlen A. 365 Ehlers J. 89 Ehrenkaufer R.E. 133 296 Eichorn T.A. 217 Eilbracht P. 96 Einhorn C. 112 241 Einhorn J. 179 Einstein F.W.B. 262 Eisch J.J. 88 280 Eisenberg R. 251 Eisenhart E.K.40 Eisenreich W. 350 Eitel M. 204 Ekerdt J.G. 246 Elber R. 20 Eldin S. 66 164 Elguero J. 64 Author Index 393 Elliott T.L. 77 Ellis K.L. 154 Ellwood P. 373 Elmosalamy M.A.F. 373 Elove G.A. 9 Farooq O. 124 172 Fasoli H. 378 Faulkner D.J. 329 Fedorynski M. 141 Fehlner J.R. 85 Fortt S.M. 76 Foubelo F. 135 302 Fourneron J.-D. 318 Fourrey J.-L. 305 Fox M.A. 24 El-Reedy A.M. 191 Elson S.W. 345 Ely E.W. 326 Emerson K. 118 232 Emsley J. 57 Emziane M. 109 299 Enders D. 123 267 295 Feigel M. 101 242 Feil D. 377 Fekih A. 214 Feldman D. 172 Feldman K.S. 75 Fengl R.W. 145 Fenton D.E. 377 Francalanci F. 308 Francisco C.G. 79 Franck B. 189 Franck R.W. 40 Franco J. 68 FranGois J.-P. 129 Franse V. 130 Endo T. 164 Engbersen J.F.J. 67 Engberts J.B.F.N.69 Engelhardt L.M. 221 246 England W.P. 43 Englander S.W. 9 Engman L. 262 Epstein W.W. 11 331 Ericson J.L. 370 Ferguson G. 260 Ferguson S.B. 361 Feringa B.L. 286 Ferjancic A. 3 11 Fernandez J.M. 118 232 Fernindez-Simon J.L. 107 Ferretti M. 319 Ferringa B.L. 133 28 1 Fraser M.E. 378 Fraser-Reid B. 79 Frauenrath H. 144 Fray M.J. 295 Frichette M. 64 Freedman L.D. 260 Freedman M.B. 200 Freeman R. 4 9 10 Freeman R.T. 343 Erikson W.R. 337 Ferris J.P. 100 Freer I. 330 Eriksson M. 185 Fesik S.W. 7 Freire R. 79 Erker G. 262 Ernst B. 144 Fessner W.-D. 41 Fevig T.L. 77 Frenzel T. 341 Fretz H. 331 Ernst R.R. 6 Fiala R.R. 328 Freyer A.J. 159 Eschenmoser A. 350 Fibiger R. 135 304 Friedrich J. 9 10 Eschler B.M. 150 Field M.J. 20 22 36 44 Frierson M.R. 29 Escudie J.256 Fife T.H. 67 Frigo D.M. 247 Estel L. 213 Figge L. 41 Fringuelli F. 43 Etter M.C. 356 Filler R. 64 Frisch M.J. 22 Eudy M.E. 347 Evans D.A. 91 105 153 286 Filosa M.P. 204 Finet J.-P. 177 Frische K. 108 Fritz H. 199 297 303 328 Finge S. 355 Fronczek F.R. 377 378 Evans J.N.S. 348 Fiocca L. 277 Frost J.W. 80 Evans S.A. jun. 108 Evans S.V. 42 Fiolani C. 273 Fiorentino M. 191 Froussios C. 336 Fruh T. 350 Evans W.J. 247 Fiorenza M. 277 Fryzuk M.D. 239 299 Evilia R.F. 12 Firnberg D. 85 Fu G.C. 91 303 Exner O. 30 63 Fischer A. 61 Fu X.Y. 89 Fischer D.A. 154 Fuchs P.L. 156 Facchine K.L. 10 Fischer M.J. 39 Fulling G. 132 Fadel A. 126 Fischer P.A. 379 Fuentes L.M. 195 Fadhil G.F. 33 70 Fishbein J.C. 58 Furstner A. 244 Fagan P.J. 258 Fagerness P.E.348 Faggi C. 254 Fishpaugh J.R. 167 212 Fishwick G.W.C. 44 Fitzgerald G. 37 Fugami K. 74 75 279 Fujii I. 323 Fujii M. 296 Failla S. 102 Fleet G.W.J. 146 Fujii N. 153 Fainzilberg A.A. 91 Fairchild D.E. 62 Fleming I. 98 138 249 303 Fleming J.A. 143 Fujimoto E.K. 57 Fujimoto H. 317 Fajardo M. 11 Fakley M.E. 378 Faktor M.M. 247 Flinther B. 250 Floriano M.A. 54 Floss H.G. 323 324 338 341 Fujimura T. 234 293 Fujinami T. 132 283 Fujino T. 283 Falarni M. 118 Falck J.R. 215 305 346 350 351 Fogagnolo M. 88 121 280 Fujio M. 70 Fujisaki S. 171 Fallis A.G. 40 77 Foland L.D. 145 146 Fujisawa T. 86 150 271 Falorni M. 134 Font J. 39 Fujita E. 205 302 Fan C. 93 Fontecilla-Camps J.C. 18 Fujita M. 251 338 Faiianis F.J. 135 302 Fookes C.J.R. 349 Fujita S. 279 Fantin G. 88 121 280 Formosinho S.J.32 Fujita T. 331 374 Farina V. 197 233 Forster S. 314 Fujita T.S. 330 Farley B. 32 Forte M. 209 Fujiwara K. 120 311 Farnia S.M.F. 172 Fortier S. 378 Fujiwara S.-i. 172 Faron K.L. 146 Fortin R. 305 Fujiwara T. 157 Author Index Fujiwara Y. 281 Fukudo K. 117 Fukuzawa S. 132 283 Fullon B. 192 Funaki I. 143 Funamizu M. 95 Funhoff D.J.H. 46 Funk R.L. 115 144 160 273 Furber M. 335 Furin G.G. 249 Furlani D. 15 Furlano D.C. 179 Furstoss R. 318 Furukawa N. 338 Furuta H. 385 Furuta K. 130 Furuya T. 338 Fustero S. 133 Fyfe C.A. 12 Gable R.W. 264 Gadwood R.C. 156 Gaertner H. 311 Gagero N. 295 Gaines D.F. 244 Gajewski J.J. 337 Gakh A.A. 91 Gal J.-F.70 Gal J.-Z. 296 GalPn A. 384 Galbo J.P. 156 Galera S. 29 Gallagher M.J. 245 Gallagher P.T. 31 1 Galledou B.S. 94 Galli C. 174 175 Gallucci J.C. 179 Ganazzoli F. 105 Gande M.E. 337 Gandhi R.P. 43 Gandolfi R. 40 Gandour R.D. 377 378 Ganem B. 337 Gao J. 38 Gao Y. 192 Gaoni Y. 146 Garai C. 291 Garcia-Garibay M. 42 Gardette M. 106 Garegg P.J. 301 Gareil M. 175 Gariboldi P. 209 Garrett B.C. 28 Carson M.J. 329 343 Gaspar P.P. 255 Gassman P.G. 45 154 Gasteiger J. 24 29 Gatti C. 32 Gatto V.J. 377 Gaudemar M. 129 Gaudin J.-M. 150 Gauss J. 27 28 Gautheron C. 315 Gavai A.V. 161 Gawley R.E. 205 Gawronska K. 308 Gawronski J.G. 308 Gay I.D.262 Geacintov N.E. 185 Gebauer C.R. 368 Gedye R.N. 302 Gees T. 134 283 Gehin D. 376 Gehrig L.M. 377 378 Geib S.J. 215 Gelernter H.L. 24 Gemmell C. 378 Genest M. 21 Genet J.P. 229 Gennari C. 267 Gepalsamy A, 72 Gerhart F. 129 Gerratt J. 29 Gervay J. 43 Gesmer H. 4 Geuder W. 363 Ghera E. 183 Ghidini E. 367 Ghio C. 19 Chose A.K. 18 Ghosez A. 79 Ghosez L. 153 Ghosh A.K. 161 Ghosh C.K. 177 Ghosh J. 263 Ghosh T. 71 287 Giacomelli G. 118 134 Giammona A. 20 Giberson C.B. 188 Gibson C.L. 350 Giese B. 79 81 301 Giguere R.J. 154 Gil G. 330 Gilabert D.M. 133 Gilbert A. 180 Gilbert L. 119 Gilbreath S.G. 184 Gilges S. 301 Gill G.B.21 1 Gill P.M.W. 28 Gillard J.W. 305 Gillespie R.J. 29 Gillett J. 345 Gillette G.R. 250 Gillois J. 297 Gilmour S.J. 334 Gingrass M. 123 Ginsberg D.M. 15 Girard C. 119 Girlando D.M. 259 Gladysz J.A. 118 232 Glauser W.A. 163 Gleiter R. 41 100 221 Glidewell C. 69 260 Glukhovtsev M.N. 31 164 Gobel M. 350 Goddard R. 195 Godfrey A. 278 Godfrey M. 33 70 Godtfredsen S.E. 316 Gobel T. 79 Gokel G.W. 374 377 378 Gold V. 57 Goldberg I. 355 356 Goldberg Yu.,249 Goldmann H. 365 Goldstein J.L. 330 Gollnick K. 193 Gomez J. 37 Gompper R. 208 Gong L. 244 Gong W.H. 160 178 Gonzales M.D. 348 Gonzalez A. 265 Gonzalez A.M. 98 303 Gonzalez J.M. 96 150 Gonzalez M.68 Gooch E.E. 296 Goodford P.J. 18 19 Goodman M. 21 Goodnow T.T. 363 Goosens M. 348 Gopalsamy A. 199 Gordon J.F. 335 Gordon M.S. 28 Cork J. 93 197 Gorgues A, 99 Goridis C. 18 Gorques A. 117 Gosney I. 260 Gostevsky B.A. 249 Goswami S. 380 Gothe S.A. 40 Goto M. 98 252 254 Gotoh T. 330 Gotor Y.,302 Goudgaon N.M. 296 Could R.O. 260 363 Could S.J. 329 337 Govkovic S. 294 Coyer C. 348 Grabowski E.J.J. 128 Grady G.L. 135 Graham W.A.G. 177 Grammenudi S. 374 Grant D.M. 11 331 Grant G.H. 29 Grant S.K. 348 Gras J.L. 94 Graslund A. 185 Gravatt G.L. 226 238 Gray A.M. 363 Green B.S. 354 Green R.H. 307 Greene M.I. 18 Greenwood S.L.347 Greer L.M. 361 384 Gref A. 85 Grein F. 35 Grellier P.L. 56 Gribble G.W. 183 206 Griebeck A.G. 43 Author Index Gries W.K. 363 Griesbaum K. 96 Griesbeck A.G. 193 Griesinger C. 6 21 22 Griffin R.G. 14 Griffiths D.R. 186 Griffiths K.D. 178 Grigg R. 44 103 201 203 236 285 Griller D. 75 79 112 254 Grimm F.-T. 257 Grionlonfoun N. 97 Grisebach H. 338 Grishin Y.K. 101 Grisoni S. 229 Grissom J.W. 208 Grob C.A. 301 Groninger K.S. 81 301 Grohmann K. 48 Grondey H. 13 Gronenborn A.M. 6 21 22 Gronowitz S. 167 Grootenhuis P.D.J. 367 376 Grosjean F. 133 134 282 Gross M.L. 186 Gross R.S. 71 Grubbs R.H. 96 Grue-Sorensen G. 341 Grunewald G.L.166 Guajardo R. 313 Guanti G. 300 Gubelmann M. 374 Guce B.-Z. 53 GuleG S. 260 Giiner O.F. 44 Giinther C. 359 Giinther H. 182 188 Guertsen G. 67 Guerzoni,' L. 67 Guest M.F. 36 44 Gugelchuk M. 41 GuibC-Jampel E. 132 309 Guignant A. 43 154 Guiheneuf G. 64 Guilard R. 222 Guilford W.J. 337 Guilheim J. 364 Guilhem J. 379 Guindon Y. 305 Gulevich Yu.V. 225 Gullotti M. 295 Gunaratne H.Q.N. 201 Gunawardana I.W.K. 221 Gund P. 18 Gung W.Y. 157 Guo B. 67 GUO,B.-Z. 105 GUO,Q.-X., 47 Guo T. 43 Gupta A.C. 113 Gupta R.R. 217 Guram A. 261 Gurjar M.L. 81 Gustowski D.A. 377 Gutsche C.D. 188 365 366 Guy H.R. 18 Guyon R. 55 Guziec F.S. jun. 138 302 Ha H.-J.330 331 Ha S.N. 20 Ha T.K. 129 Haase D. 250 Habben C.D. 263 Habecker C.N. 200 Habermas K.L. 125 Habib A. 322 Hackett M. 177 Haddon R.C. 31 165 Hadrich I. 96 Hadii D. 37 Haeglock M.E. jun. 364 Haenel M.W. 186 Hafner B. 150 309 Hafner K. 188 Hagaman E.W. 14 Hagashizaki E. 269 Hager R. 255 Hagihara T. 229 265 Hagiwara Y. 269 302 Hagler A.T. 19 20 21 Hahn F.E. 366 Hajdaz D. 251 Hake H. 40 Hale R.S. 322 Haley M.M. 163 Hall S.W. 136 193 256 257 Hallam S.E. 322 323 Hallberg A. 167 Halpern J. 80 Haltiwanger R.C. 376 Hamanaka K. 170 Hamasaki T. 207 Hamatani T. 11 1 Hamdouchi C. 106 Hamedi-Sangsari F. 113 Hamer C.M. 348 Hamer R.R.L.216 Hamill T.G. 278 Hamilton A.D. 374 380 Hamilton D.G. 11 Hamilton G.S. 383 Hamilton H.D. 188 Hammarstrom L.-G. 29 Hammond R.B. 33 Han A.-L. 178 Han J. 89 Hanafusa T. 88 101 Hancock R.A. 44 Handa S. 350 Handke I. 192 Handwerker B.M. 277 Handy N.C. 27 28 Hanessian S. 25 Hanley A.B. 347 Hanners J.L. 350 Hanquet G. 294 Hansen E.W. 68 Hansen F.B. 4 Hanson J.R. 333 335 Hanusa T.P. 246 Happ C.S. 22 Happ E. 22 Harada A. 359 Harada N. 220 Harada S. 186 Harada T. 186 Harada Y. 378 Harata K. 358 Harayama T. 374 Harcourt M.P. 67 Hardee J.R. 170 Harder S. 242 243 Hardie D.G. 321 Harkema S. 222 365 367 377 Harkness B.R. 42 Harling J.D.75 Harman W.D. 179 Harmata M. 162 Harms K. 304 Harpp D.N. 123 Harrelson J.A. 30 63 Harriman A. 374 Harrington R.E. 150 Harris C.M. 184 341 Harris H.A. 244 Harris J.M. 55 56 Harris R.K. 15 Harris R.L. 173 Harris S.J. 365 Harris T.D. 354 Harris T.M. 7 184 192 341 Harrison A. 379 Harrison P.H. 332 Harrowfield J. 385 Hart D.J. 78 179 283 Hart G.H. 348 Hart G.J. 348 Hart H. 71 176 187 287 369 Harter W.G. 201 Hartmann U. 247 Hartmann W. 134 Hartmans S. 319 Harusawa S. 161 Harvey R.G. 183 185 Harvey S. 245 Harwood L.M. 154 Hasebe M. 110 Hasegawa H. 170 Hasegawa T. 95 Hasegawa Y. 269 302 Hashimoto H. 296 Hashimoto S. 161 Hashmi A.A. 257 Hassall C.H.18 Hassan M. 21 Hasselmann D. 45 Hassenrueck K. 217 Hassner A. 43 55 135 289 304 Author Index Hata E. 273 Hatakeyama S. 193 Hatanaka Y. 320 Hatano A. 329 Hatsuya S. 129 233 271 Hatta T. 205 Hatterman R.L. 271 Haupt M. 150 309 Hauser F.M. 93 183 212 Havlas Z. 34 Hawker C.J. 349 Hawkinson D.C. 55 Haworth IS. 20 Hay B.P. 79 Hayakawa H. 98 Hayakawa S. 304 Hayasaka T. 278 Hayashi H. 171 255 Hayashi M. 324 Hayashi R. 229 272 Hayashi T. 115 127 143 177 229 232 239 254 265 269 296 301 303 Hayashi Y. 226 291 Hayashizaki K. 177 232 Hayes T.K. 130 Haynes R.K. 125 150 Hazlett R.N. 98 He X.-G. 323 He Y. 299 Headley A.D. 70 Healy E.F.46 Healy J. 242 Healy M.D. 246 Heaney H. 73 Heasley G.E. 59 Heasley V.L. 59 Heath J.R. 371 Heath P. 180 Heaton D.E. 246 Hebeisen P. 159 Hecht S.S. 184 Heck R.F. 215 Hedge B.,343 Hedge S. 334 Hedge V.R. 291 Heeg M.J. 255 Hees U. 194 Heffner T.A. 289 Hegedus L.S. 203 225 Hehre W.J. 39 48 Heilmann S.M. 209 Heinekey D.M. 11 Heinisch G. 216 Heinmaa I. 15 Heintz M. 175 Heinz W. 362 Hejnaes K.R. 4 Helgaker T. 28 Helgeson R.C. 368 369 370 Heller S.R. 25 Helps I.M. 379 Helquist P. 115 133 148 280. 293 Heltmann U.,250 Hemperly S.B. 150 Hemscheidt T. 341 Henderson C.M. 309 Henderson W.G. 70 Hendrickson J.B. 24 Hennen W.J. 314 315 Henretta J.P.156 Herb R. 220 Herber R.H. 255 Herbert R.B. 343 Herchen S.R. 204 Hermsmeier M. 376 Hernandez J.C. 374 378 Herndon J.W. 102 Herndon W.C. 29 Herrndorf M. 257 Herrold R.E. 338 Hertler W.R. 253 Herzyk P. 18 Hess R.A. 50 Hessler D.P. 85 Hester M.R. 361 Heumann A. 97 Heus-Kloos Y.A. 99 Hewawasam P. 183 Hewawawam P. 93 Heyn R.H. 250 Hibbert F. 57 67 Hiberty P.C. 30 Hibino J.-I. 279 Hickey D.M.B. 174 Higaki M. 136 Higashimura H. 216 Higashiyama K. 276 Higgs H. 25 Higuchi K. 252 Hill C.L. 85 Hill J.E. 341 Hill R.K. 188 Hillier I.H. 36 44 Hilvert D. 49 319 320 Himes R.H. 379 Hinton J.F. 248 Hirai H. 359 Hirai Y. 270 Hiramatsu H.120 Hirao K. 35 Hiratake J. 128 302 Hirayama S. 173 Hirigaya Y. 329 Hirose K. 378 Hirose Y. 378 Hirshberg M. 21 Hite G.E. 186 Hite R.G. 125 Ho M.F. 345 Hochstrasser R. 59 Hock R. 262 Hodgson S.M. 242 HodoSEek M. 37 Hoeger C.A. 46 Hoekstra W. 43 Hoffman R.V. 293 Hoffman R.W. 106 Hoffmann B. 321 Hoffmann H.M.R. 130 275 Hoffmann M.R. 28 Hoffmann R.W. 111 124 Hofmeister G.E. 366 Hohn T.H. 331 Hojo M. 216 Hol W.G.J. 18 Holak T.A. 322 Holden I. 338 Holker J.S.E. 327 Holland H.L. 138 Holland S. 345 Hollerer E. 321 Holley R. 334 Holloway M.K. 200 Holtke H.-J. 321 Holton R.A. 161 Holwerda R.A. 376 Holzapfel C.W. 378 Hommeltoft S.I.251 Honda K. 255 Honda T. 196 284 Honda Y. 121 252 276 Hongoh Y. 356 Hootele C. 287 Hope E.G. 264 Hope H. 246 Hopf H. 94 Hopfinger A.J. 18 Hopkins R.B. 92 Hopkins T.E. 300 Hopwood D.A. 322 323 Horak R.M. 335 Hore P.J. 4 Hori M. 212 Horie T. 62 Horiuchi C.A. 114 Horiuchi N. 101 Horjales E. 23 Horner T.H. 375 Hortmann A.G. 209 Hoshino M. 200 211 Hoshino Y. 178 252 291 Hoskins B.F. 264 Hosomi A. 138 249 271 Hosseini M.W. 374 376 379 Hossner F. 231 Hou W. 90 Hou Z. 281 Houk D.R. 346 350 Houk K.N. 30 35 37 46 47 49,63 361 369 381 Houpis I.N. 161 Hovanes B.A. 55 Hoveyda A.H. 91 303 HOW,G.-F. 164 Howard A.E. 18 35 38 376 Howes A.J. 251 Hoye T.R.141 Hoyer D. 181 Hrovat D. 35 47 Hu C.-J. 134 Author Index Hu J. 90 Hu N. 244 Hu N.X. 91 Huang D. 331 Huang H.-W. 134 Huang S. 66 324 Huang Y.-Z. 141 Hubbard B.R. 328 332 Huber B. 248 Huber F. 260 Huch V. 243 Hudlicky T. 180 317 Hubsch T. 43 Hunig S. 363 Huff J.B. 381 Huffman J.C. 162 169 246 Hughes D.L. 128 Huie E.M. 208 Huh B. 328 Humber D.C. 197 Hummelink T. 25 Hummelink-Peters B.G. 25 Humphreys G.O. 323 Hunold R. 242 Hunter C.A. 223 364 Hunter M.G. 336 Hursthouse M.B. 98 247 251 Hussain B. 247 Hussain N. 184 Hussain S.M. 191 Husson H.-P. 143 Hutchinson C.R. 323 Hwang C.-K. 219 Ibbotson A. 371 Ibers J.A.177 Ibrahim P.N. 61 Ichichara A. 327 Ichikawa Y. 87 255 Ichinose Y. 79 98 148 255 Idle J. 44 Iglesias E. 60 Ihle N.C. 157 Iimori T. 384 Iitaka Y. 255 Ikeda H. 331 Ikegami S. 161 Ikenaga K. 178 Ikeya T. 86 314 Ila H. 148 Ilijev D. 73 Imada Y. 237 Imai E. 212 Imai Y.,297 Imaizumi S. 296 Iman M.R. 29 Inada Y. 31 1 Inagaki M. 302 Inagaki S. 34 35 41 58 89 Inamoto N. 115 137 262 Inazu T. 374 Ingolia T.D. 344 Inoue K. 297 Inoue S. 238 Inoue T. 157 302 Inoue Y. 170 296 297 Inouye H. 331 Inouye T. 338 in’t Veld P.J.A. 367 Iqbal M. 365 Infune S. 91 Irish M.S. 326 Imgartinger H. 100 Irrgang B. 54 Isaacs N.S. 66 186 373 374 Isaka M.140 Ischtwan J. 28 Ishar M.P.S. 43 Ishida T. 137 Ishihara M. 219 Ishii A. 115 262 Ishii Y. 91 119 168 238 294 296 Ishikawa M. 99 Ishikawa Y. 100 366 Ishimori M. 108 Ishizaki K. 78 Ishizaki Y. 379 Ishizuka H. 21 1 Islam N. 381 Ito H. 267 272 Ito M.M. 164 Ito S. 171 Ito Y. 99 103 115 127 143 150 177 229 232 237 239 269 296 301 303 358 Itoh A. 196 284 Itoh H. 256 296 Itoh I. 172 Itoh K. 43 135 293 Itoh M. 157 Itoh T. 286 Iwahara T. 252 Iwanaga K. 130 Iwanowicz E.J. 265 Iwaoka M. 263 Iwasaki S. 314 Iwasawa N. 125 270 304 Iwata N. 212 Iyengar N.R. 62 Iyengar R. 48 Izatt R.M. 379 Izumi T. 95 Jackson R.F.W. 106 109 Jackson Y.A. 263 Jacobi P.A.147 167 Jacobs S.J. 255 Jacobsen E.N. 90 294 Jacobson EM. 51 Jacobson R.A. 153 Jadhav P.K. 122 271 Jahansouz H. 379 Jahn R. 100 Jakus N. 4 Jalander L. 278 Jalon F. 11 James B.R. 223 239 299 Jamison W.C.L. 152 Janiak C. 248 255 257 Jankowski K. 379 Janoschek R. 32 Jansen J.F.G.A. 133 Janvier P. 331 Jaouen J. 297 Jarglis P. 127 Jazwinski J. 364 Jedlinski Z. 132 Jeffery T. 99 Jefford C.W. 49 Jeffrey D. 162 Jencks W.P. 58 65 69 Jendrezejewski S. 348 Jenkins P.R. 277 Jenny C.-J. 178 Jensen H.J.A. 28 Jensen S.E. 344 Jenson F. 47 Jeong K.S. 381 Jernstrom B. 185 Jew S. 220 Jhon M.S. 355 Jiang Z. 379 Jie C. 36 Jiminez L. 361 Jin Z.244 Jinbu Y. 188 Jinguji M. 219 Jochum C. 24 Johansson C.I. 62 Johns A. 75 Johnson A.P. 24 Johnson C.D. 70 Johnson J.R. 358 Johnson K.A. 337 Johnston B.D. 262 Johnston M.I. 290 Johnstone R.A.W. 178 Jolly R.S. 73 206 Jonas J. 12 Jonczyk A, 141 Jones A.D. 44 Jones D.W. 46 49 Jones G. 154 Jones G.B. 192 Jones J.B. 307 308 312 Jones P.G. 259 Jones R.A. 246 248 259 Jones S. 381 Joon E. 15 Jordan B.M. 73 Jordan K.N. 322 Jordan P.M. 324 348 Jergensen P. 28 Jorgensen W.L. 20 24 38 191 381 Joshi B.V. 98 Joshi N.N. 109 300 Joule J.A. 213 Jousseaume B. 258 Jullien L. 379 Jung M.E. 43 154 178 Jung S.-H. 142 Jung Y.H. 178 Junjappa H.148 Junk P.C. 246 Juntunen S.K. 137 Juo R.R. 161 Jurayi J. 337 Jurczak J. 331 376 Jurewicz A.J. 326 JurSiC B. 110 134 Just G. 305 Kabalka G.W. 101 296 Kabbaj O.K. 33 Kabe Y. 252 Kaczmarek L. 214 Kadish K.M. 222 Kafafi S.A. 181 Kagan H.B. 76 111 282 284 Kahn L.R. 22 Kahn S.A. 171 Kahn S.D. 39 48 Kahne D. 80 Kai Y. 186 247 379 Kaifer A.E. 363 377 378 Kaiser E.T. 320 Kaji A. 143 166 Kajigaeshi S. 171 Kajii Y. 255 Kajitani M. 171 Kakihana M. 88 Kakimoto N. 255 Kakou Y. 220 Kalcher J. 32 34 Kaldor A. 371 Kalleymeyn G.W. 188 371 Kamagita N. 295 Kamal A, 217 Kamasaki T.; 72 Kambe N. 172 Kametani T. 196 284 Kamigata N. 170 302 Kamimura A.166 Kaminura A. 107 Kanabus-Kaminska J.M. 75 Kanatomo S. 234 Kanda N. 140 Kane C.T. 332 Kaneda M. 327 Kaneda T. 378 379 Kanehira K. 229 265 Kanehisa N. 379 Kaneko K. 215 Kaneko T. 124 Kanematsu K. 220 Kaneto C. 43 Kang G. 299 Kang G.-J. 239 Kang M.-C. 161 Kang Y.-H. 263 Kanne D. 251 Kanner B. 254 Kanoh S. 356 Kanters J.A. 242 243 Kantor E.A. 249 Kaplan J. 57 Kaptein R. 6 21 22 Karaman R.M. 55 Karbach S. 188 370 371 Karcher M. 100 Karkour B. 145 Karni M. 55 Karplus M. 19 20 21 22 Karsch H.H. 243 264 Kasahara A. 95 Kasahara I. 89 296 Kasai N. 186 247 379 Kashimura S. 120 265 Kaszynski P. 285 Katagiri N. 43 Katajima H. 283 Kataky R.379 Kataoka H. 157 162 Kataoka T. 212 Katapodis A.G. 319 Katayama H. 215 278 Katayama S. 117 Kato J.-i. 164 Kato K. 171 Kato N. 157 Katoh M. 171 Katoh S. 356 Katoh T. 140 Katopodis A.G. 138 Katritzky A.R. 56 173 205 209 217 Katsifis A.G. 125 Katz S.A. 277 Kauffmann T. 124 Kaufmann E. 241 Kauppinen S. 322 Kawa H. 241 Kawabata A. 276 Kawai K. 119 Kawai M. 123 125 267 297 Kawamura N. 127 212 239 296 Kawano H. 119 238 Kawasaki H. 268 Kawase T. 252 Kawashima M. 271 Kay L.E. 21 Kaye K.C. 374 Kaymeyama M. 170 Kayser M.M. 132 Kazanjian P. 374 Kearney P.C. 381 Kearsley S.K. 322 Keavy D.J. 183 Keeffe J.R. 66 67 164 Keehn P.M. 354 Keeping J.W.344 Keissling L.L. 162 Keller P.H. 324 Keller P.J. 323 350 Kelly B.J. 90 Kelly D.R. 307 Kelly H.A. 340 Author Index Kelly M.F. 217 Kelly M.J. 40 Kelly T.R. 178 383 Kelly W.J. 183 Kemal O. 154 Kemmitt T. 264 Kemp J. 201 Kende A.S. 96 100 159 162 Kenmochi N. 338 Kennard O. 25 25 Kennedy G.J. 12 Kennedy M. 156 Kenny C. 284 Kesselmayer M.A. 44 Kesselring U.W. 37 Kessler H. 21 22 Ketcham R. 192 Keumi T. 170 283 Kevill D.N. 55 57 Khalil M. 29 Khan M.A. 248 Khan M.Z. 378 Khanapure S.P. 176 Kharrat A. 80 Khetani V.D. 230 Khoo K.S. 365 Kibayashi T. 91 Kice J.L. 263 Kidd K.B. 246 248 Kieber-Emmons T. 18 Kieboom A.P.G. 315 317 Kieser H.M.322 323 Kiffer D. 65 Kiji S. 114 Kikkawa H. 255 Kikm H.-E. 370 Kikuchi J. 374 Kikuchi O. 72 203 Kikukawa K. 178 257 Kilburn J.D. 375 Kilian W. 254 Killian R.B. 61 Killoran M. 381 Kim B.H. 289 Kim C.-B. 57 Kim D. 74 Kim H.B. 161 Kim H.K. 253 Kim H.Y. 70 Kim J.C. 185 Kim K.S. 185 Kim M. 71 377 378 Kim M.J. 313 314 Kim S. 67 139 274 301 Kim S.-W. 167 Kim S.H. 340 Kim S.J. 98 147 Kim T.J. 219 Kim Y. 322 Kim Y.H. 185 188 371 Kimbrough D.R. 337 Kimura E. 379 Kimura M. 219 King G. 33 Author Index King L.G. 343 King P.M. 38 Kino Y. 296 Kinoshita K. 324 Kira M. 95 Kirby A.J. 61 181 Kirby G.W. 329 Kirby R.A.378 Kirk J.N. 106 Kirk K.L. 179 Kishi Y. 157 Kitahara H. 279 Kitahara Y. 95 Kitajima H. 170 Kitarnura M. 89 119 238 296 Kitamura T. 66 99 Kitano Y. 294 Kitazume T. 86 314 Kitson D.H. 21 Kiyoi T. 177 202 239 Kiyomine A. 207 Klaeren S.A. 237 Klarner F.-G.,45 Klassen J.B. 322 Klavetter F.L. 96 Klein D.J. 186 Klein J. 182 Klein J.T. 216 Klein L.L. 197 Klein M. 187 Klibanov A.M. 309 315 Kliern U. 212 Klingler F.D. 127 295 Klinowski J. 14 Klohr S.E. 219 Kloosterman M. 315 379 Klumpp G.W. 241 Klusenor P.A.A. 242 Klustermann A. 359 Kneale C.J. 87 Kneisley A. 132 Knight D.W. 154 3 11 Knight G. 343 344 Knobler C.B. 369 370 Knochel P. 105 116 135 Knoll K.95 Knowles J.R. 324 336 337 Knowles P. 167 Knox J.P. 334 Knubel G. 189 Kobayashi K. 103 150 157 237 295 346 Kobayashi M. 232 269 295 341 Kobayashi S. 152 Kobayashi T. 254 Kobayashi Y. 75 Koch M. 363 Koch S.C. 334 Kochi J.K. 54 170 180 181 Kocienski P. 87 234 278 Kocjan D. 37 Kodera Y. 311 Koehler J.E.H. 21 Konig W.A. 359 Kopf-Maier P. 257 Koetzle T.F. 25 Koga K. 266 268 379 Koga N. 89 Kohnke F.H. 186 373 374 Koike H. 252 Koike T. 379 Kojima H. 252 Kojima M. 42 Kok R.A. 29 Kokotailo G.T. 12 Kokusho Y. 314 Kolb M. 129 Kollman P.A. 18 19 20 21 22 35 38 376 Komatsu K. 188 Komatsu M. 378 Komiyama M. 359 Kornornicki A.41 Konda Y. 329 Kondo T. 112 Kondo Y. 191 Kong Y.K. 250 Konieczny S. 255 Konig W.A. 89 Konno A. 47 Kool E. 360 Koppel I. 70 Koppen P.L. 315 Koreeda M. 44 Koreishi K. 366 Korkowski P.F. 141 Kornblum N. 173 Korth H.G. 81 Korvola J. 68 Koser G.F. 295 Kotelko B. 221 Kottig H. 321 Kowal R.C. 330 Kowalczlk M. 132 Kowalczyk B.A. 46 Kowalski C.J. 145 Koyama K. 173 Koyama T. 330 Kozawa A, 297 Kozikowski A.P. 341 Koz’min A.S. 91 Kozyrev A.N. 222 KraiTt G.A. 261 Krafft M.E. 108 147 Krakowiak K.E. 221 376 379 Kr61 V. 11 7 Kratz D. 100 Kraulis P.J. 6 Kraus G.A. 153 158 Krause N. 109 273 Kravitz J.I. 147 167 Kremmydas S. 150 Krepski L.R.209 Kresge A.J. 56 59 64 66 67 164 Krief A, 141 144 Krishna M.V. 101 Krohn A. 18 Krol M.C. 30 Krol W.J. 345 Krolski M.E. 204 233 Kroto H.W. 371 Krouse S.A. 95 Krow G.R. 43 Kriiger C. 186 195 Kriiger M. 111 Kruise L. 377 Kryshtal G.V. 117 Kubas G.J. 10 Kubiniok S. 261 Kubo T. 43 Kubota M. 366 Kuckert E. 195 Kudo M. 95 Kudo T. 32 Kudou N. 95 Kuehnling W.R. 208 Kiinzer H. 44 173 Kulkarni Y.S. 290 Kullnig R.K. 144 Kumada M. 229 265 Kumagi T. 207 Kumar A. 368 376 Kumazawa T. 162 169 Kumobayashi H. 238 Kumonaka T. 215 Kumpf R.A. 377 Kunec E.K. 341 Kunitake T. 366 Kuntz I.D. 376 Kunwar A.C. 81 Kunz T. 132 Kunzer H. 232 Kuo H. 379 Kupczyk-Subotkowska L.47 63 Kurasawa Y. 216 Kurata T. 171 Kuriyan J. 20 Kuroda M. 252 Kuroda Y. 358 Kurono M. 212 Kurtz H.A. 32 Kurusu Y. 229 272 Kurys B.E. 291 Kutney J.P. 239 299 Kutzen-Mies K. 193 Kuwajima I. 140 234 293 Kuzma P.C. 184 Kwart L.D. 180 Kwok F.B. 105 Kwok F.C. 53 Kwon H.B. 164 Kyler K.S. 313 Laatikainen R. 10 Labeots L.A. 165 Laber N. 199 Laborde E. 138 Laboureur J.L. 141 Lachkar A. 64 Lagow R.J. 241 376 Lahti P.M. 182 Lai G.S. 145 Lai Y.-H. 187 Laidig K.E. 30 63 Lajore G.A. 350 Laknifli A. 82 Lal S. 193 Laloi M. 65 Lam L.K.P. 307 308 Lamb D.M. 12 Lambert J.B. 251 257 Lamberth C. 301 Lameignerc E.40 Lamothe S.,43 La Munyon D.H. 275 Lamy-Schelkens H. 153 Landen H. 40 Lane C.F. 91 110 Lang R.W. 300 Lange L. 264 Lanneau G.F. 298 Lansbury P.T. 156 Lanz J.W. 106 124 Larchevique M. 131 Lardicci L. 118 134 Larock R.C. 160 178 234 Larsen D.L. 24 Larsen R.D. 118 232 Larson G.L. 94 253 Larson S. 101 Larson S.D. 146 Laswell W.L. 195 Lathbury D.C. 74 Lattman R. 332 Lau T.-C. 85 Laucher D. 181 Laue E.D. 4 Lauer W. 130 Laumen K. 302 307 Laurent E. 134 Laurenzo K.S. 173 Lautz J. 21 22 Lavallee J.-F. 158 Laws A.P. 188 Lawson K.R. 212 Laynez J. 64 Lazraq M. 256 Leadlay P.F. 322 Leasge M. 254 LeBlanc B.F. 51 Lebreton J. 157 Lecolier S.101 Le Coopanec P. 85 LeCoq A. 99 117 Led J.J. 4 Ledermann M. 194 Lee B.K. 343 Lee C.C. 173 Lee C.S. 330 Lee D.C. 148 160 Lee H. 183 311 Lee H.-H. 326 Lee H.K. 185 219 Lee H.W. 70 Lee I. 70 Lee J.P. 341 351 Lee J.Y. 246 Lee J.Y.-C. 184 Lee K. 172 Lee K.R. 209 Lee M.S. 330 Lee P.H. 274 Lee S.-J. 92 Lee S.-M. 187 Lee S.Y. 67 290 Lee T.J. 27 28 Lee T.V. 154 280 Lee W.-O. 85 Lee Y.B. 43 Leech A.P. 333 Leeper F.J. 222 329 348 349 350 Leeson P.D. 174 Leete E. 340 341 Lefebvre D. 64 Legars P. 112 Lehn J.-M. 354 364 374 379 384 385 Leigh D.A. 378 Leis J.R. 59 62 Leisung M. 81 Leitner W. 89 127 Le Marechal P. 336 LeMaster D.M.7 21 Lenenko S. 179 Lennartz H.-W. 41 Lenoble C. 185 le Noble W.J. 40 Lenoir D. 54 Leone-Bay A. 174 Leong V.S. 172 Leong W. 99 Leopold M.F. 11 331 Lerner R.A. 319 Lesage M. 79 112 Leskiw B.K. 344 Lesuisse D. 49 Leumann C. 350 Le Van Q. 350 Levason W. 264 Levin D. 129 Levine B.H. 161 180 Levitt M.H. 14 Levy G.C. 4 Lewendon A. 336 Lewis F.D. 42 Lewis N.J. 174 Lewis R.T. 142 162 169 Ley S.V. 180 3 17 Lhosle P. 299 Lhoste P. 109 Li C.S. 78 Li H. 40 Li W.B. 322 Li Y. 381 Author Index Liang T.C. 333 Lichtenthalen F.W. 295 Lichtenthaler F.W. 127 Lidin S. 372 Liebeskind L.S. 145 Liebkind L.S. 196 Liebrnan J.F. 181 Liepns E. 255 Lifson S.,19 379 Liguori A.287 Lii J.H. 19 Liljefors T. 23 29 Lilley T.H. 358 Lim C.S. 365 Lim J.J. 80 Lin B.-K. 182 326 Lin F.-T. 381 Lin J. 383 Lin W.H. 376 Lin Y. 117 239 Linden A. 210 Linderman R.J. 99 278 Lindhardt T. 101 Lindholm E. 29 Lindoy L.F. 386 Lindsay Smith J.R. 170 Lindsey J.S. 10 381 Liotta D. 43 152 Lipkowitz K.B. 19 Lippi A. 319 Lippmaa E. 14 15 Lisicki M.A. 10 Lister M.A. 267 Liu H.-J. 136 295 Liu H.T. 74 Liu K.-T. 134 Liu Y. 371 Livinghouse T. 73 206 Lloyd D. 260 Lluch J.M. 29 Lodaya J.S. 295 Loeffler S. 341 Lotsch G. 216 Lohray B.B. 123 Loncharich R.J. 35 46 361 Long A.K. 24 Long J.K. 159 287 Long-Fox S. 343 Lopez J.C.40 Lopez L. 94 Lopez M.C.G. 68 Lorenz K. 127 Losensky H.-W. 365 Louie T.J. 59 Love C. 234 Lowe C. 134 272 350 Lowenthal R.E. 161 Lozanova A.V. 44 286 Lu X. 91 117 239 Lu Y. 117 Lubell W.D. 126 Lucas C. 178 Lucchi M. 40 Luche J.-L. 112 179 241 Author Index 401 Luck R.L. 11 McLean W.N. 178 Marcantoni E. 128 135 Luengo J.I. 44 148 240 Luthi P. 134 MacLeod J.K. 226 McManis J. 381 Marecek J.F. 379 Margraf B. 40 Luh T.-Y. 278 281 McManus S.P. 55 56 Mariano P.S. 171 172 Luis S.V. 381 McMeekin P. 44,201 Marinier A. 43 Luisi P.L. 134 MacMillan J. 334 Marino J.P. 138 159 287 Lukacs G. 40 McMurray J.E. 225 Marion D. 21 Lukevics E. 249 255 McMurry J.E. 88 142 Marioni F. 59 319 Lukyanenko N.G.374 Lumbroso H. 260 McPhail A.T. 259 Madesclaire M. 136 Markies P.R. 244 376 377 Markiewicz M.K. 378 Luna H. 180 Madi Z.L. 6 Markley J.L. 7 Lund H. 57 Maeda S. 196 284 Marko I. 90 294 Lund T. 57 Maeno H. 150 Markowitz M.A. 367 LUO,F.-T. 175 Maerkl G. 210 249 258 259 Markwalder J.A. 157 Lusinchi X. 214 294 Lutomski K.A. 181 Magnus P. 162 169 Maguire M.P. 383 Marquet B. 134 Marquet J. 265 Lutter H.D. 361 Luttrull D.K. 59 Mahalingam S. 184 Maharaj V.J. 335 Marsais F. 213 Marshall G.R. 18 Lutz S. 89 359 MaHay J. 94 Marshall J.A. 157 Luxen A. 171 Mahdi W. 243 Marshall L. 381 Lycksell P.-O. 185 Lym L. 307 Mahler U. 120 Mahmoud S. 243 Marsham P.R. 212 Marsmann H. 250 Lynch J.E. 195 Mahoney W.S. 296 Martel A. 196 Lynch V. 361 384 Maier B.U. 6 Martens J.250 Ma D. 239 Maigret B. 23 Maigrot N. 210 Marth C.F. 88 Marti K. 371 Ma S. 90 91 Maitlis P.M. 12 Martin G.J. 331 Maas M. 191 Makano T. 254 Martin H.-D. 40 217 Maas W.E.J.R. 14 Makino K. 216 Martin I. 58 Mabon F. 331 Makita A. 310 Martin J.C. 164 McAdam D.P. 263 Makosza M. 173 Martin J.W.L. 259 McAfee M.J. 156 Mal D. 183 Martin K. 378 Macaulay J.B. 40 Malinowski M. 214 299 Martin R.M. 178 Maccagnani G. 253 Mallen J. 377 378 Martin V.S. 100 McCammon J.A. 20 Mallet M. 213 Martin Y.C. 25 Maccarone E. 56 Malpardita F. 322 323 Martinelli M.J. 147 McCarthy A.D. 321 Malpass D.B. 88 280 Martinetti G. 120 McClard R.W. 330 Malrieu J.-P. 33 Martin-Lomas M. 378 Maccoll A. 82 Man P.P. 14 Martreux A. 113 McConnell J.A. 251 Manabe K. 89 296 Maruoka K.119 296 McCormick W.C.L. 152 Manabe O. 366 Maruoka N. 286 McCullough D.W. 142 145 Mancuso V. 287 Maruyama K. 384 McDonald B.P. 212 Mander L.N. 335 Maruyama M. 200 McDouall J.J.W. 28 33 Manders W.F. 255 Maryanoff C.A. 152 MacDougall P.J. 29 Mandolini L. 70 Marzabadi M.R. 209 McGarvey G.J. 94 Manek M.B. 263 Masamane S. 252 McGhee W.D. 177 Machiguchi T. 95 Manesis N. 21 Manfredi A. 43 295 Masarrat Ali S. 176 Masci B. 376 Macielag M. 179 Manfredini S. 92 Mash E.A. 150 McIntyre C.R. 336 Mangeney P. 133 134 282 Maslen C. 347 McIver J.W. 28 37 Mangiafico T. 365 Masnovi J. 102 McKee M.L. 41 Manhas M.S. 291 Massa W. 242 McKeer L.C. 170 Manker D.C. 329 Massouri A. 76 McKenna E.G. 88 McKenzie A. 216 Manley B.C. 241 Mann B.E. 12 Masui M. 295 Masuyama Y.229 272 MacKenzie A.R. 375 Mann J. 343 Mataka S. 205 McKenzie J.R. 278 MacKenzie N.E. 348 Manthey J.W. 173 Mantlo N.B. 162 169 Mataoka M. 379 Mathew L. 82 MacKerell A.D. jun. 21 Manuoka K. 291 Mathey F. 210 McKervey M.A. 156 365 Mao S.-S. 345 Mathias J.P. 363 373 McKillop C. 323 Maple J.R. 19 Mathvink R.J. 76 McKinnon D.M. 209 Mar A. 247 Matos J.R. 311 McLaren K.L. 78 Marais F. 275 Matsubara S. 11 1 279 McLaughlin L.W. 22 Marais S.F. 335 Matsuda H. 111 402 Author Index Matsuda I. 275 Matsuda K. 148 Matsuda T. 178 257 366 Matsuda Y. 124 Matsumiya K. 117 Matsumoto H. 252 Matsumoto J. 216 Matsumoto M. 81 135 293 Matsumoto S. 178 Matsumoto T. 294 Matsumoto Y. 115 303 Matsumura T. 378 Matsuo N.96 171 Matsuoka K. 117 Matsushima A. 31 1 Matsushima P. 322 Matsuura T. 295 Matsuyama H. 170 Matsuzawa S. 140 Mattioda G. 113 Matyjaszewski K. 253 Maverick E.F. 370 Mawson S.D. 59 May C.S. 25 May S.W. 138 318 319 Mayer B. 40 Mayer D. 18 Mayr H. 54 Mazur Y. 46 Mazzanti F. 253 Mbiya K. 153 Meah M.H. 223 Meah M.N. 364 Means C.M. 366 Medici A. 88 121 280 Medina J.C. 313 Meghani P. 213 Mehrotra M.M. 200 Meier H. 130 Meier M.S. 78 Meijide F. 68 Meinke B.J. 261 Mello R. 191 Melnick M.J. 159 Menachem Y. 171 Menard M. 196 Menchetti S. 90 Menendez M. 64 Menger F.M. 85 360 Menicagli R. 135 Meot-Ner M. 181 363 Merkel A. 34 Merkushev E.B.171 Merlic C.A. 137 Mertes K.B. 379 Mertes M.P, 379 Messeguer A. 88 Metcalfe S. 260 Meth-Cohn O. 221 Metternich R. 124 Metz K.R. 248 Mevarech M. 344 Meyer E.F. jun. 25 Meyer M. 249 Meyers A.I. 143 176 181 297 Meyers H.V. 220 Meyers J.N. 18 Mezey P.G. 32 Mgbeje B.I.A. 348 Michael J.P. 261 Michels G. 194 249 Michl J. 32 37 251 285 Middleton D.S. 199 Midland M.M. 23 Migita T. 81 86 286 299 Migrani S.M. 289 Mikata Y. 43 Milgrom L. 353 373 Millar K. 379 Millar M.D. 59 Miller A.D. 348 Miller G. 336 Miller J.A. 99 Miller J.E. 246 Miller J.R. 344 Miller K.J. 46 Miller M.A. 165 Miller M.L. 289 Miller R. 80 Miller R.D. 49 Miller R.F. 75 Miller S.A.156 Miller S.R. 374 377 Millican A. 379 Milliot P. 294 Mills J.E. 152 Mills O.S. 212 Milovanovic J.N. 294 Minami K. 143 Minami T. 167 226 Minamide N. 170 Minamikawa H. 304 Minato A. 99 Minato M. 272 Minato T. 34 35 41 58 89 Mink C. 188 Minkin V.I. 31 164 Minter D.E. 215 Mioskowski C. 215 305 Mischnick-Liibbecke P. 359 Mishima M. 70 Mishra P.K. 10 Misiolek A. 132 Misiti D. 108 Misumi S. 378 379 Mitani M. 173 Mitchell D.K. 379 Mitchell M.B. 44 174 Mitchell R.H. 187 Miura T. 74 75 Miyai T. 129 Miyake M. 180 Miyamoto T. 216 Miyane T. 239 Miyanoti H. 252 Miyashi T. 47 Miyaura N. 178 Miza Y. 130 Mizuno S. 297 Mo D. 117 Moberg C.97 Mochida K. 167 255 Mock M.L. 373 Moeller P.D.R. 43 197 Moerlein S.M. 171 Mohr P. 308 Mohtachemi R. 248 Moise F. 247 Moiseenkov A.M. 44,286 Molander G.A. 284 285 Molina P. 216 Mprller B.S. 215 Monn J.A. 166 Monteleone M.G. 291 Montevecchi P.C. 101 Montez B. 15 Moody C.J. 167 179 192 Moody D.J. 373 Moody G.J. 363 Moore H.B. 59 Moore H.W. 145 146 Moore R.E. 220 342 Moras D. 385 Mordini A. 271 376 Moreau R.A. 326 Moreno-Manas M. 229 265 More O’Ferrall R.A. 67 Morera E. 88 121 Morgan D.O. 324 Mori K. 150 309 311 356 Mori M. 140 358 Mori N. 187 Mori S. 366 Moriarty R.M. 300 Morikawa S. 167 212 239 295 Morikswa T. 75 Morita E. 121 Morita N.279 Moriwaki M. 171 Moriyama K. 200 Morize I. 23 Morley S.D. 366 Mornon J.P. 23 Morokuma K. 35 47 89 Morosawa S. 219 Morphy J.R. 379 Moms A.D. 142 Morris G.A. 4 Morris J.L. 219 Morris R.E. 98 Morris R.H. 10 11 Morton H.E. 305 Mosandl A. 359 Mosandl T. 212 Mosquera M. 68 Motallebi S. 59 Motamedi H. 323 Motherwell W.B. 75 142 Motherwell W.D.S. 25 Motoc I. 18 Author Index Motoi M. 356 Moursounidis J. 183 Mozumi M. 200 Mruzek M.H. 82 Muchmore C.R. 102 Mudryk B. 173 Muehldorf A.V. 188 380 Mullen K. 362 Muller A. 21 21 250 Muller G. 101 242 243 248 257 321 Muller P. 133 Mujane T. 202 Mujano S. 296 Mukai C. 162 Mukai T.207 Mukaiyama T. 125 270 Mukhopadhyay C. 18 Mullay J. 29 Mulvey R.E. 242 Munawar M.A. 171 Munayyer H. 343 Mungall W.S. 90 294 Munro S. 23 Murafuji T. 260 261 Murahashi S.I. 237 Murai F. 211 Murai S. 113 Murakami Y.,374 Muraoka M. 268 Murata I. 219 Murata K. 314 Murata S. 269 Murcko M.A. 30 Murdoch J.R. 33 Murphy J.A. 75 Murphy P.J. 88 Murphy P.M. 208 Murray A.W. 276 Murray C.K. 141 Murthey K.S.K. 289 Murthy K.S. 43 Musavirov R.S. 249 Musser M.T. 173 Mutin R. 178 Muzart J. 102 Myers M. 141 Nabeshima T. 358 Nada H. 379 Nadeau Y. 332 Naemura K. 378 Nagai Y. 252 253 254 Nagakura N. 341 Nagao Y.,205 269 302 Nagareda K. 88 Nagase S.32 33 Nagel D.L. 186 Nagem T.S. 66 Nagumo S. 158 Naidoo K. 214 Najafi M.R. 103 Najera C. 93 274 Nakadaira Y. 95 255 Nakagawa A. 329 351 Nakagawa H. 338 Nakai E. 292 Nakai T. 292 Nakajima T. 113 262 Nakamura A. 236 247 Nakamura E. 140 234 293 Nakamura H. 220 Nakamura J. 171 Nakamura K. 129 297 311 Nakamura T. 81 Nakamura Y. 172 281 Nakanishi A. 132 283 Nakanishi K. 330 Nakano K. 117 Nakano M. 32 Nakano T. 168 296 Nakashima H. 167 Nakashiro E. 164 Nakata T. 129 Nakatani K. 285 Nakatsuji Y. 378 Nakatsukasa S. 279 Nakayama J. 200 21 1 Nakazaki M. 186 Nakazawa T. 219 Nakoo T. 186 Nam K.C. 365 366 Nambu M. 163 Namiki T. 164 Nam-Tran H.37 Nanninaga T.N. 289 Naoi Y. 252 Naora H. 236 Narasaka K. 265 270 291 304 Narasimhan M. 322 Narasimhan N.S. 71 Nared K.D. 49 319 Narisano E. 300 Naruse Y. 108 305 Nasehzadeh A. 56 Natarajan L.V. 185 Naujoks E. 94 Nay B. 170 Naylor C.B. 18 Ndibwami A. 43 Nedogrey E.P. 249 Needham D.E. 85 Neeson S.J. 103 168 Negichi E.-i. 178 Negishi E. 149 225 236 231 Neidle S. 18 Nemeth D. 381 Nemoto H. 117 Nepveau A. 348 Nester J.E. 335 Neumann K.H. 365 Neumann W.L. 148 Neumann W.P. 255 Newbold R.C. 159 Newcomb M. 57 83 112 375 Ngooi T.K. 132 308 Nguyen D.T. 19 Nguyen T.B. 381 Ni Z.-J. 278 281 Nibbering N.M.M. 53 58,65 Nicholas K.M. 198 230 Nicholson N.H.345 Nicolaou K.C. 162 169 219 Nicoletti T.M. 184 Niecke E. 193 Nieger M. 136 Nielsen R.B. 178 Niemann B. 136 Nigrey P.J. 262 Nihira T. 310 Niimi K. 297 Nijenhuis W.F. 379 Nikitidis G. 167 Nikkokavouras J. 88 Nilges M. 21 22 Nilsson L. 19 21 Nishi T. 238 Nishida A. 99 145 166 254 Nishida S. 180 Nishihara H. 294 Nishimura K. 237 Nishinaga A. 295 Nishioka T. 302 Nishiyama H. 135 293 Nitta K. 272 Niwa M. 276 290 Noth H. 208 Noga J. 37 Nogales D.F. 59 Nolte R.J.M. 262 379 Nomoto T. 244 377 Nomura K. 85 Nordahl J.G. 156 Norden B. 185 Norman B.H. 44 202 Normant J.F. 133 134 282 Noro T. 150 Norris J.R. 5 Norris W.J. 343 Novak P.M.144 Novelli R. 174 Novic M. 6 Nowak R. 248 Nowick J.S. 141 Noyori R. 89 119 238 269 296 Nozaki H. 109 279 Nozaki K. 79 86 312 Nozoe T. 95 Nuber B. 210 Nubo Y. 109 Nugent V.A. 258 Nugent W.A. 77 148 289 Nugiel D.A. 219 Numata H. 193 Nunn C.M. 193 246 248 256 257 259 Nunn D.S. 147 Oas T.G. 14 Obi K. 255 404 Author Index O’Brien J.H. 12 O’Brien M.K. 266 O’Brien S.C. 371 Ochi N. 193 Ochiai M. 205 269 302 Ockawa H. 327 O’Connor B. 178 236 Oda D. 88 Oda J. 128 302 Odell B. 363 O’Farrell C. 174 Ogasawara K. 131 Ogawa A. 113 172 Ogawa M. 91 168 294 296 Ogawa T. 11 1 260 261 357 Ogawa Y. 162 169 385 Ogoshi H. 371 Oguni N. 124 Ogura F.91 263 Ogura K. 283 330 Oh B.H. 7 Oh D.Y. 172 O’Hagan D. 328 Ohara M. 43 Ohashi N. 178 Ohbuchi S. 157 Ohdoi K. 261 Ohe K. 108 264 299 Ohgo Y. 119 Ohki H. 267 Ohkuma T. 238 Ohlmeyer M. 91 303 Ohno A. 129 136 297 Ohno M. 78 95 152 Ohno N. 171 Ohno T. 374 Ohnuki T. 236 Ohsaka T. 157 Ohshita J. 99 Ohta A. 253 Ohta T. 238 Ohtsuka H. 286 Oishi T. 129 Ojima I. 164 225 Oka S. 129 136 295 297 Okada H. 171 Okada S. 119 Okahara M. 378 Okamoto K. 188 Okamoto T. 93 171 295 Okamoto Y. 90 186 Okamura W.H. 46 Okazaki R. 115 133 137 262 O’Keefe S.J. 324 Okino S. 171 Okita M. 341 Okor D.I. 98 Okukado N. 281 Olafson B.D. 19 Olah G.A.124 172 Olah J.A. 172 Olano B. 133 Oldenburg C.E.M. 156 Oldfield E. 15 Oliva A. 29 Olivella S. 37 163 Oliver J.S. 332 Olivucci M. 33 35 37 41 Ollis W.D. 354 Ollmann R.R.,46 Olmstead T.A. 160 Omkaram N. 42 Omura S. 329 338 351 Onaka M. 123 125 267 300 Onan K.D. 40 Onda M. 329 O’Neil LA. 134 272 Ono M. 172 Ono N. 107 166 Onozuka M. 253 Oohara T. 191 Oon S.-M. 236 Oota O. 120 Oppolzer W. 150 273 O’Reilly J. 333 Orsini F. 209 Ortar G. 88 121 Ortega F. 62 173 Ortiz E. 253 Ortuno R.M. 39 43 154 Oruganti S.R. 354 Osaka N. 135 293 Osborne T.F. 330 Oschkinat H. 6 22 O’Shea D.M. 142 Oshima K. 74 75 79 86 98 148 255 279 Oshiro K. 121 Ostaszwski R.376 Oster T.A. 184 O’Sullivan W.J. 330 Otake K. 229 272 Otera J. 109 Otero A. 11 Otsubo T. 91 Otsuka T. 366 Ott W.R. 323 Ottana R. 287 Ottenbrite R.M. 44 Otter B.A. 71 Outurquin F. 300 Ovenall D.W. 253 Overman L.E. 39 160 Overton K.H. 330 Owada K. 31 1 Owens K.A.,47 Owusu R.K. 363 Ozaki Y. 167 Padmanbhan P. 329 Padwa A. 43 44 202 289 Page M. 28 37 Page P.C.B. 105 273 Pagelot A. 13 Pagington J.S. 357 Pagni R.M. 101 Paguaga E. 80 Pain A.E. 31 Paine J.B. 223 Pajerski A.D. 245 377 Pal K. 326 Palazon J.M. 100 Paley M.S. 55 Paley R.S. 138 Palio G. 271 Palkowitz A.D. 271 Palm J. 23 Pals M.A. 183 Pancholi K.D. 174 Pansegrau P.D.176 Pant N. 380 Panuto T.W. 356 Paquette LA. 41 44 Parbhoo B. 252 Pargellis C. 332 Parisi M.F. 343 Park J. 67 Park J.H. 139 301 Park W.S. 298 Parker D. 89 379 Parker K.A. 78 199 Parris K. 381 Parry K.P. 363 Parry R.J. 347 Parsons P.J. 74 284 Parvez M. 160,.245 377 Pasau P. 144 Pascal R.A. 331 Pascard C. 318 364 379 Past J. 15 Pastor S.D. 57 Patel M. 202 Paterson I. 265 267 269 Pathre S.V. 209 Patino C. 344 Patricia J.J. 241 Pattenden G. 78 197 211 Patterson C.W. 75 Patterson D.E. 19 Patterson D.G. 29 Patterson G.M.L. 342 Pattou D. 23 Paukstelis J.V. 24 Paul V.J. 220 Paulmier C. 300 Paulus E. 365 Pautard A.M. 108 Pawlak J.M.165 Payne N.G. 11 Pazil J.C. 247 Pearl L.H. 18 Pearson A.J. 230 266 Pearson W.H. 201 Peasley K. 28 Pecunioso A. 135 Pedersen C.J. 353 354 Pedersen S.F. 366 Pederson R.L. 313 Pedrini P. 88 121 280 Pegram J.J. 153 Pelcman B.. 205 Author Index Pelizzoni F. 209 Peiia M.E. 59 62 Penades S. 378 Penalva M.A. 344 Peng M.-L. 92 Pennington C.H. 15 Pennington W.T. 247 Penotti F. 29 Penrose A. 345 Pentaleri M. 43 Pepermans H. 21 Percy J.M. 181 Peres Y. 112 Pereyre M. 113 275 Perichon J. 175 Perri S.T. 145 146 Perrot M. 298 Pesce G. 94 Pessina A. 134 Pestana J.A.X. 85 Peters E.-M. 212 264 Peters K. 212 264 Petersen C.P. 204 Petit A.128 Petit F. 113 Petit J.P. 55 Petit Y. 131 Petrini M. 128 135 302 Petsko G.A. 363 Petti M.A. 362 Pevarello P. 40 Pfandler P. 6 Pfeffer P.E. 326 Pflaum S. 258 Pham T.N. 57 Phipps A. 379 Pho H.Q. 236 Pichon C. 348 Pickard J. 154 Pickardt J. 247 Pickin D. 330 Pierini A.B. 175 Piettre S.R. 43 197 Pigou P.E. 69 144 Pikulin S. 45 Pilz M. 242 Pina R. 48 Pindur U. 203 204 Pines A. 15 Pinhas A.R. 195 237 Pinnick H.W. 173 Pinson J. 175 Pinto B.M. 262 Pinto I. 74 Piorko A. 173 Piotrowski A.M. 88 280 Piovosi E. 114 Pirrung M.C. 147 Pitt C.G. 259 Piva O. 102 Pizzo F. 43 Plaquevent J.-C. 300 Plattner R.D. 332 Plavcan K.A. 326 Pleier J.M.192 Plessner T. 154 Plummer M. 144 Podlogar B.L. 163 Poggi G. 35 Poh B. 365 Pohl S. 250 252 261 Poll T. 363 Pollack R.M. 60 66 164 Pollart D.J. 145 Pollini G.P. 92 Polonsky J. 333 Polson G. 194 263 Poly W. 130 Pons J.-M. 225 282 Ponticello G.S. 200 Poon C.-K. 85 Popall M. 182 Pople J.A. 22 Porter J.R. 280 Portugal L. 374 Pose A. 376 Posner G.H. 220 278 Potts K.T. 100 208 Poulter C.D. 330 Power J.M. 256 257 259 Power P.P. 246 Powers D.B. 271 Prados P. 222 Prakash G.K.S. 124 Prasad J.S. 196 Prasad J.V.N.V. 113 Prat M. 229 Prenosil J. 134 Prestegard J.H. 21 322 Preut H. 260 Price R.C. 58 Priepke H. 110 Prieto A. 253 Prieto M.F.R.68 Prinzbach H. 41 Pritzkow H. 210 Profeta S. 19 Prout K. 350 Przystas T.J. 67 Ptak M. 21 Puar M.S. 343 Puigserver A. 31 1 Pujari M.P. 67 Pulido F.J. 98 303 Purdy A.P. 259 Qi H.-B. 178 Qian J.H. 70 Qiang L.G. 214 Qin X.-Z. 47 Queener S.W. 344 QuCguinier G. 213 275 Quesnelle C.A. 305 Quian J.H. 64 Quici S. 375 Quick A. 378 Quiiioa E. 220 Quintard J.-P. 113 275 Rabczenko A. 18 Raber D.J. 163 Rabinowitz M. 172 182 Rabjohn N. 86 Raddatz P. 132 Radhakrishnan T.P. 29 Radinov R.N. 273 Radner F. 170 Radurnz H.-E. 132 Rader H.-J. 362 Raff L.M. 34 Raghavachari K. 22 241 Raghavachari R. 43 Raich N. 348 Raimondi L. 287 Rairnondi M. 29 Raimondo O.368 Rainbow L.J. 112 Raithby P.R. 222 242 Rajagopalan S. 103 Rajamannar T. 71 Rajan S. 328 RajanBabu T.V. 77 148 253 Rajeswari S. 263 Rakhmankulov D.L. 249 Rakshit D. 279 Ram S. 133 296 Ramachandran P.V. 118 Ramanathan H. 72 203 Ramer S.E. 325 327 Ramesh M. 134 Ramig K. 141 Ramirez F.J. 36 Ramon R. 344 Rana J. 340 341 Ranaivonjatovo H. 256 Raney K.D. 192 Ranu B.C. 154 302 Rao A.V.R. 81 Rao R.N. 322 Rao S. 22 Rao V.S.R. 18 Rapoport H. 126 Rappoport Z. 53 Rasmussen K. 20 Rastelli A. 40 Raston C.L. 184 245 246 Ratananukul P. 236 Ratcliffe A.H. 335 Rathke M.W. 91 110 Raudino A. 29 Rausch M.D. 248 Ravenscroft M.D. 68 174 Ravikumar V.T.300 Rawlings B.J. 325 Rayner C.M. 105 Re M.A. 215 Reamer R.A. 128 Reardon J.E. 330 Rebek J. jun. 381 Reber G. 257 Rebolledo F. 302 Reddington M.V. 363 Reddy A.V.N. 217 Author Index Reddy G.S. 253 Reddy K.A. 81 Reddy R.T. 176 Reddy S.P. 215 Reddy T. 193 Reddy V.P. 46 50 Reddy V.V. 29 Reder AS. 374 Redmon M.J. 28 Reed A.E. 241 Reed D. 242 Reed M.W. 145 Rees C.W. 219 Reese P.B. 325 Reetz M.T. 119 304 Reeve A.McE. 346 Rege S. 156 Regen S.L. 367 Reginata G. 277 Regitz M. 194 249 Regnouf de Vains J.B. 374 Reich H.J. 40 Reichelt J. 23 Reichmann K.C. 371 Reid D.H. 261 Reif W. 304 Reimerdes E.H. 307 Rein T. 115 133 280 Reinhoudt D.N.222 365 367 377 379 Reischl W. 46 Reissig H.-U. 132 290 Remington R.B. 27 Renaldo A.F. 204 233 Renneke R.F. 85 Repeta D.J. 330 Resnati G. 105 114 Rettig S.J. 247 Rewcastle G.W. 205 217 Reye C. 254 Reynolds C.A. 37 38 Reynolds M.E. 76 Rhee C.K. 117 296 Rheingold A.L. 215 384 Rhind S.K. 379 Rho Y.S. 93 Rhodes P. 25 Ribas J. 229 Ricard L. 210 Ricca D.J. 44 Ricci A. 217 254 271 277 Ricci M. 308 Rice J.E. 27 28 Rice J.P. 15 Richards F.M. 7 Richards R.M. 376 Richards W.G. 38 163 Richardson K.A. 154 Richey H.G. jun. 245 377 Richter H. 249 Rickborn B. 183 Ridd J.H. 62 63 Ridley D.D. 150 Ried W. 217 Riede J. 243 Rieke R.D. 140 277 298 Rieker W.F.176 Rigault A. 385 Rigby J.H. 156 Rigler R. 21 Rihter B. 102 Rimbault C.G. 49 Ripka W. 18 Ripmeester J.A. 264 378 Ritchie T.J. 80 Rittinger S. 100 221 Riva S. 315 Rivera M. 153 Rivier J. 21 Rivikre H. 85 Robage K.D. 43 Robb M.A. 28 33 35 36 37 41 44 Robert J.M. 12 Roberts D.A. 234 Roberts K.A. 66 Roberts L.M. 321 Roberts N.K. 178 Roberts S.M. 179 197 307 Roberts V.A. 21 Robertson G.B. 178 Robey F. 18 Robins D.J. 340 341 Robinson E.D. 157 Robinson G.H. 247 Robinson J.A. 322 323 328 Robinson K.D. 366 Rockell C.J.M. 154 Roden F.S. 280 Roder H. 9 Rodgers D.P.S. 177 Rodgers J.D. 152 Rodin W.A. 163 Rodrigo R. 183 198 Rodrigue A.378 Rodriguez J. 130 Rodriguez W.R. 163 Roelens S. 376 Roelofs N.H. 182 Roeskya H.W. 259 Rosslein L. 106 Roessner C.A. 348 Rogan E.G. 186 Rogers D.W. 165 Rogers J. 365 Rogers J.A. 25 Rogers J.R. 25 Rogers L.R. 331 Rogers R.D. 377 Rogic M.M. 91 110 Rohloff J.C. 161 Roller S. 258 Romanelli L. 75 Romaniko S.V. 91 Romberger M.L. 142 Romeo G. 287 Romeo P.H. 348 Romero A.G. 328 Romine J.L. 143 Romines K.R. 156 Ronco G. 55 Rondan N.G. 47 Rone R. 21 Roos A. 377 Roos E.C. 304 314 Roos G.H. 124 Rosch J. 321 Rose B.G. 261 Rosenthal S. 99 273 Rosini G. 128 Ross A.M. 66 164 Ross D.S. 170 Rossi R. 94 Rossi R.A. 175 Rossini G. 135 Rossiter J.339 Roth G.P. 181 Roth W.R. 41 Rothin AS. 379 Rott J. 257 Roush W.R. 271 Rousseau G. 132 309 Rowley M. 157 Roy P. 60 Royan B.W. 210 Royer J. 143 Royer R. 110 Royo G. 257 Rozen S. 171 Ruasse M.F. 59 Rubin D.H. 18 Ruckle R.E. 75 Rudd B.A.M. 323 Ruderman W. 85 Rudisill D.E. 204 233 Ruelle P. 37 Ruther R. 260 Ruggeri R. 88 Ruhlmann A. 291 Ru-Huai Y. 21 Ruiz J.M. 46 Rulher M. 291 Ruloff C. 243 Runsink J. 94 Ruolf P. 68 Ruppin C. 101 Russell S.J. 328 Ruzziconi R. 198 Ryan C.A. 21 Rycroft D.S. 330 Rydberg D.B. 141 Ryu I. 113 172 Saak W. 252 261 Sabol M.R. 125 Saboureau C. 175 Saburi M. 119 238 Saddler J.C. 156 Sadek M.23 Sadler I.H. 358 Saegusa K. 88 Saegusa T. 167 202 212 239 Author Index Saeki K. 359 Saenger W. 21 Sagl D.J. 164 Sainte F. 153 Saito H. 164 Saito Y. 85 Saitoh H. 219 Sakaguchi Y. 171 255 Sakai K. 139 140 158 Sakai S. 132 283 Sakakura T. 85 177 Sakamoto K. 95 Sakamoto T. 191 Sakamura S. 327 Sakata G. 216 Sakata S. 161 Sakito Y. 299 Sakizadeh K. 209 Sakurai H. 95 Sakurai K. 193 Sakuta K. 135 293 Salanski P. 376 Salaun J. 126 145 Salituro G.M. 346 Sall D.J. 166 Salter E.A. 27 Saltur P.B. 217 Saluja P.S.P. 54 Samaraseera U. 251 Samat A. 82 Sammakia T. 328 Samoson A. 14 15 Sampson R.M. 188 371 Samson S.M. 344 Sanchez F.344 Sanchez F.-J. 88 Sanchez M. 68 Sanchez-Ferrando F. 39 Sandall J.P.B. 63 Sanders A.F. 24 Sanders G.L. 134 272 Sanders J.K.M. 223 364 Sanders M. 339 Sandhu J.S. 43 287 Sandosham J. 215 Sandoval-Ramirez J. 262 San-Filippo L.J. 138 302 Sangokoya S.A. 247 Sankawa U. 335 Sano H. 81 86 286 299 Santa L.E. 105 Santaballa J.A. 67 68 Santelli M. 115 158 225 280 282 Santoni M.-J. 18 Sapino C. 197 233 Sargent M.V. 184 Sarkar D.C. 154 302 Sasaki K. 171 177 Sasaki M. 76 282 284 Sasaki S. 379 Saserman A. 348 Saso H. 195 Satake K. 207 219 Satge J. 256 Sato F. 266 294 Sato S. 172 256 275 Sato T. 150 164 Satoh T. 170 191 302 Satterwhite D.M. 330 Sauer R.36 Sauerbrey A.M. 59 Saunders M.R. 20 Saunders W.H. 47 58 63 Sauner C. 131 Saupe T. 64 Sauriol F. 332 Sauvage J.-P. 353 379 380 Savariar S. 99 145 166 254 Saveant J.-M. 174 175 Sawada M. 88 143 Sawaki Y. 171 Sawamura M. 120 232 265 269 Sawlewicz P. 301 Sawyer J.F. 250 264 Sawyer T.W. 185 Sax A.F. 32 Saxena A.K. 250 Sayo N. 238 Schaad L.J. 50 Schach T. 194 Schafer A. 250 257 Schafer H.F. 27 28 Schaefer V. 210 Schamp N. 133 141 194 Schauder J.-R. 348 Schaumann E. 192 Scheek R.M. 21 22 Scheetz M.E. 344 Scheffer J.R. 42 Schehlmann V. 100 Scheider J. 249 Scheinmann F. 98 Schepp N.P. 59 67 Scheuer P.J. 220 Schick H. 150 309 Schiess M.134 283 Schiesser C.H. 144 Schilf W. 251 257 Schlegel H.B. 22 34 37 41 Schlessinger R.H. 265 Schleyer P.von R. 22 54 101 241 242 243 Schlosser M. 111 179 275 Schlosser W. 249 Schmalz D. 188 Schmalz T.G. 186 Schrnidbaur H. 248 255 257 Schmidt F. 364 Schmidt M.W. 28 Schmidt N. 359 Schmidt R.R. 108 Schmidt T. 239 Schmidtchen F.F. 361 Schmitt R.J. 170 Schnatter W.F.K. 102 Schneider G. 132 Schneider H.-J. 188 362 Schneider M.J. 341 Schneider M.P. 302 307 Schobert F. 109 Schoellkopf U. 131 Schoemaker H.E. 379 Schoffstall A.M. 289 Schofield C.J. 134 272 343 344,345 Scholer P.A. 125 Schomburg D. 23 130 Schoonman J. 379 Schore N.E. 168 Schram J. 379 Schreer M.124 Schreiber S.L. 162 220 328 Schreuder H.A. 18 Schrock R.R. 95 Schroder G. 90 294 338 Schroder J. 131 338 Schroeder H.E. 353 Schuermann G. 361 Schulman J.M. 165 Schulte G. 11 162 328 Schultz A.G. 144 150 179 Schultz P.G. 319 320 Schulz M.W. 163 Schulz W.J. jun. 251 Schumann H. 247 248 255 257 Schurz K. 249 Schwab J.M. 322 Schwartz H. 132 Schwarz S. 150 309 Schwarzkopf B. 350 Schweiger E.J. 162 169 Schweizer E. 321 Schweizer M. 321 Schweltzer C.T. 11 Schwichtenberg M. 248 Sciacovelli O. 191 Scilimati A. 132 308 Scorrano G. 65 Scott A.I. 182 326 348 Scott F.E. 336 Scott L.T. 165 182 Scott R. 103 Scott W.J. 88 225 Scriven E.F.V. 191 Scuseria G.E.28 Searleman J.E. 24 Seaton P.J. 329 Sebald A. 15 273 Seconi G. 254 277 Sedaghat-Herati M.R. 56 Seddas A. 37 See K.A. 365 Seebach D. 102 109 111 117 129 134 135 241 273 283 303 Seeger R. 22 Seely F.L. 78 283 Segal I.D. 249 Segi M. 113 262 Seguineau P. 88 Seibel G. 22 Seijas J.A. 146 Seitz W.A. 186 Sekerak D. 216 Seki M. 35 Sekiguchi A. 95 250 251 Sekiguchi S. 62 Sekiguchi Y. 131 Sekine M. 179 Sellens R.J. 67 Selnick H.G. 147 Senanayake C.H. 156 Seo S. 335 Sera A. 43 278 Servin R. 167 Sessler J.L. 374 Seto H. 335 Sevestre H. 71 Seward E. 361 Seybold P.G. 85 Shah P. 167 Shah R.D. 152 Shah V.P. 174 Shahriari-Zavareh H. 378 Shaik S.S.34 65 Shankland N. 358 Shanklin M.S. 197 236 Share P.E. 46 Sharma R.D. 262 Sharma S.K. 171 Sharon R. 21 Sharpless K.B. 90 192 294 Shawe T.T. 145 Shea K.J. 43 Sheldrake G.N. 329 341 Sheldrick G.M. 291 Shellhamer D.F. 59 Shen W. 74 Shen Y. 141 Shepodd T.J. 362 Sheridan M.H. 333 Sheridan R.E. 364 Sheridan R.S. 51 Sherman D.H. 322 Sherman J.C.,370 371 Sherrod M.J. 360 Shevel A.B. 59 Sheves M. 46 Shevlin P.B. 41 Shibahara J. 297 Shibata K. 128 Shibata M. 275 Shibata S. 108 Shibato K. 167 Shibuya M. 341 Shibuya T.Y. 59 Shih M.-H. 134 Shih N.-Y. 373 Shillady D.D. 44 Shim C.S. 70 Shim S.C. 219 Shima K. 278 Shimada M. 152 283 Shimada S. 291 Shimagaki M. 129 Shimanouchi T.25 Shimizu H. 212 Shimizu M. 109 Shimizu T. 295 Shimizu Y. 330 Shimoda M. 255 Shimyozu T. 374 Shin D.-S. 305 Shin J.M. 355 Shine H.J. 47 62 63 Shinkai I. 195 Shinkai S. 366 Shinohara A. 253 Shinohara S. 253 Shinya T. 296 Shioiri T. 283 295 Shiokawa M. 129 Shiomi Y. 263 Shiori T.,114 Shipman M. 142 Shirai H. 168 Shiraishi H. 281 Shirakawa E. 232 269 Shirasaka T. 286 291 Shiro M. 269 302 Shiwaku S. 205 Shono T. 120 265 Shoup T.M. 107 Shultz D. 24 Shur V.B. 179 Sicheneder A. 136 294 Sicking W. 36 44 Siddhanta A.K. 53 105 Siddigi K.S. 257 Siddiq M. 171 Sidler D.R. 279 Siebert W. 210 Siegel J. 385 Siegel J.S. 163 Sielcken O.E. 379 Siggaard-Andersen M. 322 Siggel M.R.F.30 63 Sih C.J. 132 308 310 Sikorski J.A. 337 Silber J.J. 173 Silla E. 37 Silverton J.V. 188 Simandiras E.D. 27 Sime J.T. 345 Simig G. 179 Simig Y. 275 Simkin B.Y. 31 164 Simon E.S. 315 Simon R.A. 254 Simoni D. 92 Simons J. 28 Simova S. 362 Simpkins N.S. 199 Simpson T.J. 167 321 322 323 325 326 327 336 Sindoria G. 287 Author Index Singaram B. 86 113 Singaram S. 173 Singh H.B. 264 Singh J. 201 Singh J.O. 173 Singh P. 248 Singh S.B. 330 Singh U.C. 19 22 38 Sinnott M.L. 53 Sinou D. 109 299 Sirimanne S.R. 318 Sita L.R. 257 Skatrud P.L. 344 Skelton B.W. 263 Skowronska-Ptasinska M. 367 377 Skrabal P. 68 174 Slawin A.M.Z. 186 363 373 375 378 Slichter C.P. 15 Slisz M.L.344 Smalley R.E. 371 Smeets W.J.J. 244 376 Smit W.A. 44 286 Smith A.L. 205 Smith C.A. 100 162 Smith C.M. 28 Smith D.W. 28 Smith E.H. 324 Smith F.E. 302 Smith H.A. 319 Smith H.A. jun. 138 Smith I.C.C. 347 Smith J.R. 330 Smith K. 170 Smith L.M. 247 Smith M.F. 15 Smith P.E. 29 Smith R. 242 Smith V.A. 334 Smits G.F. 30 Snaith R. 242 Snider B.B. 42 290 Snieckus V. 178 Snyder E.J. 176 Soai K. 278 Sobey W.G. 343 Sock O. 175 Soderquist J.A. 55 Sodeyama T. 85 Soejima T. 120 265 Sogah D.Y. 253 Sohmiya H. 384 Soli A. 163 Soll R.M. 206 SolladiC G. 106 Solomon M. 152 Somoza J.R. 21 Soncini P. 370 Sonegawa M. 161 Song H. 160 178 Sonnenberg U. 259 Sonnet P.E. 307 308 Sonobe.H.. 45 Author Index Sonoda N. 113 172 Sooriyakumaran R. 251 Sorensen O.W. 6 Soteropoulos P. 51 Spagna R. 59 Spagnolo P. 101 Spang C. 259 Sparks S.W. 7 Spavold Z. 323 328 Speirs R.A. 261 Spek A.L. 244 376 Spellmeyer D.C. 37 49 Spelthann H. 365 Spencer C.M. 186 358 373 Spencer J.B. 324 Spencer N. 363 Spenser I.D. 341 Spero D.M. 78 199 Spiers K.J. 67 Spilling C.D. 239 Spina E. 56 Spirko V. 37 Sprague J.T. 19 Sprangers E.P.A.T. 317 Springer J.P. 156 265 Spritzer G.A. 24 Squires R. 251 Srebnik M. 109 113 300 Sridharan V. 201 203 236 Srivastava S. 40 Staab H.A. 64 Stader C. 255 Stadler R. 341 Stafford J.A. 142 Stagno d’Alcontres G. 374 Staley D.L. 384 Staley S.W.10 Stalick W.M. 98 Stambouli A. 113 Stang P.J. 66 99 Stanger A. 163 Stanley M.S. 59 Stanoeva E. 133 Stanzak R. 322 Stapleton A. 197 21 1 Stark W.M. 222 348 349 States D.J. 19 Stauffer D.A. 362 Staunton J. 327 Steckler R. 28 Stedman G. 68 Steele R.W. 212 Stefanidis D. 66 Steigel A. 40 Stein Z. 355 356 Steinhoff G. 255 Stephan D. 99 117 Stephens F.S. 259 Stephenson D.S. 3 Stem C.A. 204 Sternfeld F. 180 317 Stevenson P. 103 236 285 Stevenson P.J. 168 Stewart J.J.P. 28 Steyn P.S. 335 Stick R.V. 263 Still C. 23 Still W.C. 90 328 375 384 Stille J.K. 124 132 204 233 237 273 Stinn D.E. 236 Stinson E.E. 326 Stirling C.J.M. 69 Stocklin G. 171 Stockton G.W. 328 Stoddart J.F.186 353 354 358 359 363 373 374 375 376 378 Stolowich N.J. 348 Stolwijk T.B. 377 Stone M.P. 7 192 Storck W. 243 Stork G. 76 285 Storr A. 247 Stossel D. 183 Straathof A.J.J. 317 Stratmann D. 321 Stratton B. 70 Straub A. 124 313 Street G.B. 163 Streitweiser A. 30 63 Stremler K.E. 330 Strobl H. 12 Strohmeyer T.W. 291 Struthers R.S. 21 Stryker J.M. 296 Sturmer R. 11 1 Stull P.D. 43 Stults J.S. 44 126 Sturgess M.A. 195 225 Su Y. 153 Suarez E. 79 Subramanian K.K. 199 Sucholeiki I. 361 Suda H. 356 Sudha N. 264 Sudhakar A.R. 208 Sudholter E.J.R. 377 Sue R.E. 245 Suemitsu R. 117 Suemune H. 139 140 158 Suffert J. 162 Suga S. 119 262 Sugahara S. 371 Sugai K. 129 Sugai T.150 Sugasawara R. 320 Sugawara T. 71 Sugden D.A. 323 Sugg S. 113 Sugimori A. 171 Suginome H. 157 Sugioka H. 297 Sugita K. 300 Sugita N. 108 264 299 Suhr Y. 99 Sukata K. 254 Sukirthalingam S. 236 Sulmon P. 194 Sumiya R. 167 212 239 Sun D.-J. 92 153 Sundararaman P. 179 Sundermeyer W. 138 Sundin A. 23 Suppelt K. 243 Surcouf E. 23 Surendrakumar S. 44 Surleraux D. 144 Susens D.P. 176 Sussman J.L. 21 Sustmann R. 36 44 81 Sutherland LO. 105 374 Sutherland J.D. 343 Sutherland J.K. 212 Sutherland R.G. 173 Sutkowski A.C. 327 Suzukamo G. 299 Suzuki A. 178 Suzuki H. 111 260 261 Suzuki M. 269 Suzuki T. 62 95 164 188 200 Swager T.M. 96 Swaminathan S. 19 Sweeney J.B. 134 272 Sweers H.M.314 315 Swenson R.E. 150 Swinson J. 209 Switzer F.L. 206 Sworin M. 148 Symons M.C.R. 186 Syraeva I.N. 249 Szantay C. 44 Szejtli J. 357 Szeto W.T.A. 57 Szrnuszkovicz J. 154 Taagapera M. 64 70 Tabushi I. 358 Tada M. 81 Tadayoni B.M. 381 Taddei M. 217 271 Taft R.W. 64 70 Tagliavini G. 15 Tai J.C. 19 20 29 Tailhan C. 76 Tajima K. 297 Tajiri A. 279 Takabayashi K. 321 Takagi K. 278 Takagi S. 164 Takahara J.P. 229 272 Takahashi H. 264 276 299 Takahashi K. 188 205 283 311 Takahashi S. 359 Takahashi T. 225 Takahashi Y. 47 357 Takahata H. 200 Takai H. 278 Takai K. 272 Takai Y. 88 Takakis I.M. 88 Takakura T. 108 Takamatsu T. 200 Takami W. 379 Takamine K.281 Takamoto Y. 11 1 Takamura I. 164 Takano S. 131 193 Takase K. 188 Takasu M. 108 305 Takaya H. 89 238 296 Takeda K. 335 Takeda T. 81 86 157 299 Takei H. 153 Takeichi T. 108 Takemura H. 374 Takemura T. 187 Takenaka S. 324 Takenouchi K. 153 Takeshita H. 157 Takeuchi H. 173 300 Takeuchi S. 119 Takeuchi T. 309 Takeuchi Y. 255 Takeyasu T. 101 Takinami T. 171 Tamagawa H. 168 Tamao K. 103 150 237 Tamaru Y. 216 Tamm C. 106 308 Tamura R. 88 Tan S.-F. 164 Tan S.M. 4 Tanabe Y. 171 Tanaka I. 255 Tanaka K. 143 150 255 355 Tanaka M. 85 120 132 140 177 186 254 Tanaka S. 157 207 Tanaka T. 143 Tanaka Y. 371 Tang J. 5 Tang Q. 175 Taniguchi H. 281 Tanimoto S. 176 295 Tanino K. 140 Tanner D.D.80 Tao F. 90 Tapia O. 37 Tarbet B.J. 379 Tarti K. 188 Taschner M.J. 218 295 318 Tashiro M. 205 Tasumi M. 25 Taticchi A. 43 Tato J.V. 68 Tatsumi N. 109 Taube H. 179 Taunton J. 254 Taveras A.G. jun. 144 147 150 179 Taylor E.C. 198 Taylor J.M. 170 Taylor P. 260 363 Taylor R. 188 Taylor R.B. 86 Taylor R.J. 89 Taylor S.L. 332 Teague S.J. 181 Tee O.S. 62 Tejero T. 133 282 Tempesta M.S. 86 Tenaglia A. 218 Terada T. 270 Teranaka T. 129 Terao Y. 44 Terrier F. 65 Testaferri L. 112 Thea S. 300 Theil F. 150 309 Theis I. 362 Thianpatanagul S. 44 Thibaut D. 350 Thibblin A. 58 70 Thiboutot S. 119 Thiebault A. 175 Thiel M. 173 232 Thiel W. 28 29 Thiele G.F.188 Thiem H.-J. 360 Thiericke R. 338 Thivolle-Cazat J. 178 Thomas J.D.R. 363 373 Thomas P.J. 153 Thomas R.M. 154 Thomas S.D. 348 Thomas S.E. 231 279 309 Thomas T.D. 30 63 Thomason J. 22 Thompson A.M. 46 Thompson M.J. 170 Thomson C. 37 Thomson M.W. 277 Thorn K.-L. 252 Thornally M. 344 Thottathil J.K. 132 Thurston J. 153 Tibbels S.R. 186 Tidwell T.T. 66 Tiecco M. 112 136 Tietze L.F. 43 291 Tilley J.W. 233 Tilley T.D. 250 Timko J.M. 154 Timony P.E. 174 Tinant B. 194 Ting H.-H. 343 344 345 Ting P.C. 78 Tingoli M. 112 Tirado-Rives J. 20 38 Tite E.L. 371 Tittle F.K. 371 Tjivikua P.T. 381 Tkatchenko I. 112 Toczek J. 179 Toda F. 150 355 356 Todaro L. 48 Tollner F. 243 Author Index Togo H.72 203 Tohjo T. 269 Toi H. 371 Tokitoh N. 98 133 211 Tokunaga Y. 85 177 Tomaselli G.A. 56 102 Tomasi J. 37 tom Diek H. 89 Tomer K.B. ,186 Tometzki G.B. 239 Tomioka K. 266 Tommasi R. 93 Tomoda S. 255 263 Tonachini G. 35 37 41 Toone E.J. 307 Topliss J.G. 18 Torchia D.A. 7 Torreilles E. 116 Torres E. 94 Torrey G.M. 22 Toullec J.. 66 Tour J.M. 148 149 237 Tourwe D. 21 Townsend C.A. 325 326 345 346 Towson J.C. 193 Toy A. 102 Tozawa Y. 279 Trafton J.E. 378 Tramontano A. 319 Tramper J. 319 Treat M. 348 TrCcourt F. 213 275 Trevellick S. 63 Trevor D.J. 371 Trimble L.A. 325 336 Trimoto S. 93 Tripathy R. 40 Trost B. 239 Trost B.M. 136 137 138 148 160 208 218 240 289 295 Trost W.43 Trotter J. 42 247 Troupel M. 175 Trova M.P. 99 145 166 254 Truc V.C. 154 Trucks G.W. 27 Trueblood K.N. 370 Truhlar D.G. 28 Truter M.R.,353 Tsang R. 79 Tsay Y.-H. 186 Tschaen D.M. 195 Tson H.R. 328 Tsubaki T. 366 Tsuchihashi G. 121 Tsuchiya K. 187 Tsuchiya T. 110 Tsuda T. 167 202 212 239 Tsuji J. 272 Tsuji T. 35 180 Tsuji Y.,112 Tsukagoshi S. 205 Tsukube H. 384 Author Index Tsumuraya T. 256 Tsuno K. 385 Tsuruta T. 108 Tsuzuki T. 3 11 Tubul A. 158 Tuchihashi G. 276 Tucker H.P. 49 Tucker J.A. 370 Tuddenham D. 174 Tuncay A. 165 Tunstad L.M. 370 Turecek F. 68 Turnbull K. 191 Turner D.L. 328 Turner N.J. 343 Turner S.U. 102 Turowsky L.243 Turro N.J. 40 85 Twohig F.M. 156 Tycko R. 15 Uccella N. 287 Uccello-Baretta G. 118 Uchida Y. 119 238 Uchikawa O. 281 Udgaonkar J.B. 9 Udugawa A. 338 Ueda T. 71 Ueji S. 70 Uejima M. 75 Uemura M. 226 Uemura S. 108 264 299 Uesato S. 331 Ugajiu S. 278 Ugnozzoli F. 370 Ugrak B.I. 91 Uhl W. 246 Uhlen M. 322 Ukaji Y. 86 265 Ulibarri T.A. 247 Um I.-H. 65 Umano S. 296 Umeda S. 379 Urnekawa H. 257 Umezawa Y. 379 Undheim K. 215 Ungaro R. 365 367 Ungemach F.S. 341 Unkefer C.J. 350 Uomari A. 335 Ura T. 294 Urban M. 34 Urch C.J. 146 Ushio K. 129 297 Ustynyuk Y.A. 101 Utimoto K. 72 74 75 79 86 98 148 207 255 272 273 Uyeki M.A. 361 Vacher B. 78 82 Vagberg J.O. 96 Vaid B.K.300 Vaid R.K. 300 Valleau J.P. 22 Vallejo C.A. 344 Van Bekkum H. 317 van Binst G. 21 Van Boom J.H. 315 van Bruggen N. 338 Vance R.L. 47 van de Kuil L.A. 379 van den Berg K.J. 200 Van den Eijnden H. 315 van den Lieth C.W. 23 van der Gen A. 304 314 van der Heide F.R. 236 Van der Plas H.C. 67 Van der Velde D.G. 12 van der Wel H. 65 van Eerden J. 222 367 377 van Eikema Hommes N.J.R. 241 Van Engen D. 188 380 Van Epp J. 78 199 Vaney M.C. 23 van Frank R.M. 344 van Gunsteren W.F. 18 20 21,22 van Heerden F.R. 335 van Heteren A. 243 Vanhoye D. 113 van Hummel G.J. 365 van Lensen A.M. 200 van Loon J.-D. 365 van Middlesworth F. 331 332 van Staveren C.J. 377 van Veggel F.C.J.M. 377 van Zijl P.C.M.10 Van Zyl C.M.J. 383 Varela A. 68 Varma R.S. 296 Varvonnis G. 222 Vasil’eva G.A. 179 Vasojevic M. 294 Vasquez P.C. 107 Vasquez Tato M.,146 Veal L.E. 344 Veal W.R. 236 Vedejs E. 44 88 126 208 Vederas J.C. 325 327 336 Veeman W.S. 14 Veenstra S.J. 144 Vega A.J. 14 Veith M. 243 Ventrone J.A. 243 Venturello C. 90 294 Venturello P. 120 Venturini A. 36 44 Verboom W. 365 377 379 Verht R. 133 141 Verkruijsse H.D. 99 Verlhac J.-B. 275 Verlhac J.B. 113 Veselovsky V.V. 44 286 Vetter R. 34 Viala J. 115 280 Vicens J. 365 411 Vicent C. 363 378 Vicente M. 106 Vigneron J.-P. 364 Villa P. 55 Villani R. 130 Ville G. 109 Villeneuve P. 258 Villieras J. 88 Vinader M.V.216 Vining L.C. 344 Vinod T.K. 176 187 369 Vinson L.K. 29 Vinter J.G. 18 20 23 Vipond D. 44 Virgili A. 229 Viscariello A.M. 377 Vitali C.A. 376 Vite G.D. 79 Vleggaar R. 335 Vogtle F. 365 374 386 Vogelbacher U.J. 194 Vogt C.E. 178 234 Vogt W. 130 365 Voityuk A.A. 29 Volante R.P. 195 Volatron F. 33 Volk R. 351 Vollhardt K.P.C. 163 Vol’pin M.E. 179 Volpp W. 96 von der Bey E. 359 von Geldern T.W. 161 180 von Schnenng H.G. 212 264 von Wettstein-Knowles P. 322 Vonwiller S.C. 125 von Zelewsky A. 374 Vorbruggen H. 191 Voss E. 43 Voyle M. 231 Vrijenhoef J.P. 317 Vuister G.W. 6 Vuorinen E. 221 Vyankin N.S. 249 Vyazankina O.A. 249 Wada A. 234 Wada F. 257 Wada K. 177 Wada M. 267 Wade P.A.173 Wadman S. 87 234 278 Waegell,*B. 130 Waespe-SarEeviE N.; 308 Wagenaar A, 69 Waggoner K.M. 246 Wagle D.R. 291 Wagner C.K. 331 Wagner H.-U. 208 Wagner I. 261 Wagner O. 249 Wakabayashi T. 215 Wakasa M. 255 Wakatsuki K. 164 Wakita R. 378 412 Walba D.M. 376 Walder G.T. 242 Waldmann H. 286 Wali A. 43 Walker B.J. 88 Walker C. 379 Walker R.A.C. 56 Walkinshaw M.D. 363 Waller F.J. 289 Wallis J.M. 180 181 Wallis T. 344 Walter G.C. 146 Walters J. 258 Waltho J.P. 9 Wang D. 90 Wang J.T. 47 Wang K.T. 310 Wang W.-D. 251 Wang X. 30 63 Wang Y. 49 Wang Y.-F. 315 Wang Z.Y. 305 Ward D.E. 117 296 Ward M.D. 385 Ward T.J. 359 Warkentin J. 82 Warner C.D.186 Warner J.C. 188 380 Warren M. 323 Warren M.J. 348 Warren S. 129 Warshel A. 33 Wartz A.J. 343 Watanabe H. 253 Watanabe M. 171 Watanabe T. 117 Watanabe Y. 112 171 Watkin D. 154 Watson D.G. 25 Watt C.I.F. 53 Watt D.S. 71 125 Watt W. 102 154 Watts J.D. 27 Wear T.J. 212 Weaver D.F. 29 Webb K.S. 220 Weber E. 355 375 Weber L. 258 259 Webster G.R. jun. 24 Weerasuria K.D.V. 259 Weerawarna K.S. 187 Wege D. 183 Wehmeyer R.M. 277 Wei I.-C. 85 Wei Z.W. 310. Weidenbruch M. 250 252 257 Weidman T.W. 253 Weidmann H. 244 Weigand W. 134 283 Weinand A. 290 Weiner D.B. 18 Weiner P. 19 Weiner S.J. 19. 19 Weinhold F. 30 Weining J. 376 Weininger D. 25 Weinreb S.M. 130 159 Weiser J.370 Weiss B. 68 174 Weiss J. 369 379 Weissman S.A. 194 Welch M. 179 Welch M.C. 156 Welle R. 338 Wells R.L. 259 Welsh K.M. 85 251 Wender P.A. 156 157 161 162 180 289 Wengenroth H. 130 Wenkert E. 43 178 197 214 Wenz G. 89 359 Wermer J.R. 244 Werner H. 248 West J.B. 311 West R. 250 251 252 Westaway K.C. 302 Wester R.T. 132 Westheimer F.H. 66 Westhoff T. 260 Westlake D.W.S. 344 Westler W.M. 7 Westmoreland D.L. 248 Wetzel D.M. 251 Whalen D.L. 66 164 Whalley E. 54 Wheeler C.J. 330 Whipple W.L. 40 Whitby R. 234 White A.H. 221 246 263 289 White B.D. 377 378 White R.L. 347 Whiteside R.A. 22 Whitesides G.M. 177 307. 315 Whiting D.A. 71 175 211 338 339 Whitlock B.J. 364 Whitney S.E.183 Whittaker M. 226 Whittamore P.R.O. 326 Whittle Y.G. 333 337 Wiberg K.B. 30 36 50 63 Wiberg N. 249 Wickramasunghe W.A. 178 Widlanski T.S. 336 Wierda D.A. 246 Wiesner P. 321 Wiglesworth C. 125 Wijesekera T.P. 223 Wilcox C.S. 361 384 Wild S.B. 259 Wilde R.G. 44 126 Wilke G. 225 Wilking J.K. 255 Williams A.D. 161 Williams D.H. 9 Williams D.J. 186 328 363 373 375 376 378 Author Index Williams D.L.H. 59 60 68 Williams D.R. 127 295 Williams F. 47 Williams G.J.B. 25 Williams H.J. 182 326 348 Williams I.H. 31 33 Williams K. 381 Williams R.A. 246 Williams R.V. 32 99 273 Williams W.V. 18 Williamson J.M. 346 Willis P.A. 284 Willson T.M. 123 Wilson B.A. 346 Wilson B.E. 376 Wilson J.H.P.348 Wilson S.R. 94 Wilson T. 123 Wimmer E. 28 47 Wingert H. 99 Wintges H. 186 Wipff G. 376 Wirtz K.R. 145 Win J. 59 67 Wise W.B. 326 Witzel T. 301 Woggon W.-D. 331 Wojciechowski K. 173 Wolak R. 381 Wolczanski P.T. 177 Wolf J. 248 Wolfe J. 381 Wolfe J.F. 170 Wolfe S. 29 34 65 344 Wolfe T. 3 Wollowitz S. 80 Wong C.-H. 307 311 312 313 314 315 Wong H.N.C. 187 Wong T. 187 Wood B.F. 44 Wood C.Y. 312 Woolthuis G.K. 377 Wooster N.F. 75 Worakun T. 103 203 236 285 Woroniecki S.R. 345 Wrackmeyer B. 252 255 Wright D.S. 242 Wu A. 124 Wu G. 149 215 237 WU J.-P. 341 Wu T.C. 140 Wubbels G.G. 176 Xiao C. 116 Xie G. 90 Xie Z.-F. 139 Xu L. 90 Yadav J.S. 98 Yadav V.K.77 Yamabe S. 34 35 41 58 89 Yamada H. 43 278 294 Yamada J. 124 129 233 267 271 Author Index Yamada M. 358 Yamada T. 304 Yamada Y. 164 310 Yamaguchi M. 117 167,219 Yamaguchi R. 72 207 273 Yamaguchi Y. 253 Yamakawa K. 191 Yamamoto A. 143 229 301 Yamamoto H. 108 11 1 119 130 247 286 291 296 305 Yamamoto K. 186 Yamamoto Y. 117 124 129 233 261 267 271 323 Yamamura K. 358 Yamanaka H. 191 Yamaoka S. 200 Yamasaki T. 171 Yamashita A. 102 154 Yamashita D.S. 162 169 Yamashita H. 109 254 Yamashita M. 117 Yamashita O. 252 Yamataka H. 33 88 Yamawaki K. 294 Yamazaki T. 200 270 Yamochi H. 219 Yanagawa H. 385 Yanagisawa A. 283 Yang C.C. 65 323 Yang D. 80 Yang D.C. 141 Yang H.-Y.334 Yang K. 29 Yano T. 31 1 Yanovskaya L.A. 117 Yasuda H. 234 247 Yeah N.K. 344 Yeh M.C.P. 105 116 Yeoh B.L. 333 335 Yeske P.E. 44 Zarzycki R. 358 359 363 Yeung B.W.A. 79 375 Yi P. 158 Zawoiski S. 233 Yin Y. 56 66 67 164 Zax D.B. 15 Yoakim C. 305 Zeeck A. 338 Yodota K. 247 Zeegers P.J. 170 Yogai S. 161 Zefirov N.S. 91 101 Yokoyama S. 278 Zellmer K. 243 Yonemitsu T. 205 Zenk M.H. 331 341 Yoneyoshi Y. 299 Zevaart J.A.D. 334 Yoo H.K. 377 Zhang H. 366 377 Yoshida A. 343 Zhang Q. 371 Yoshida H. 195 251 256 Zhang Y. 178 236 Yoshida K. 295 Zhang Y.S. 134 Yoshida M.,170 220 302 Zhao C. 383 Yoshida T. 294 Zhao D.-C. 62 Yoshida Z. 216 Zhdankin V.V. 91 Yoshimura K. 283 Zhi-wei G. 132 Yoshimura Y. 335 Zhu J. 91 Yoshioka H.109 Zibuck R.,102 117 Yu G.X. 79 Zicmane I. 255 Yu Y. 239 Ziegler C.B. 99 Yu Y.-C. 182 Ziegler F.E. 132 Yue S. 323 Ziegler M.L. 210 Yuh Y. 19 Ziegler R. 124 Yun-Yu S. 21 Ziegler T. 313 314 Yura T. 125 270 Zielenkiewicz P. 18 Zagorski M.G. 330 Ziller J.W. 247 Zahradnik R. 34 Zimmermann J. 129 Zaidi S.A.A. 257 Zimmermann S.C. 383 Zaks A. 309 Zoghaib W.M. 296 Zalkow V.B. 29 Zollinger H. 68 174 Zamecka-Krakowiak D.J. ?176 Zuccarello F. 29 Zamir D. 171 Zuccarello G. 162 169 Zamir L.O.,332 zucco c. 53 105 Zani P. 253 Zucker P.A. 94 Zanirato V.,92 Zuckerman J.J. 248 255 Zanner I. 321 Zuiderweg E.R.P. 7 Zard S.Z.. 76 Zulicke L. 34

ISSN:0069-3030    

DOI:10.1039/OC9888500387

出版商:RSC    

年代:1988

数据来源: RSC