摘要:

7 Aromatic Compounds By R. McCAGUE Drug Development Section Institute of Cancer Research Sutton Surrey SMZ 5NG 1 General and Theoretical Studies Benzene.-The year 1987 has seen the appearance of articles that aim to consolidate the controversial casting aside of molecular orbital theory in favour of valence-bond theory to describe the electronic structure of benzene.’-3 It is using a valence-bond correlation model that Hiberty et al. have emphasized that electron delocalization in benzene occurs in spite of the nelectrons it being a consequence of imposed constraint by the cr-framew~rk.~ Thus the exceptional stability of benzene is because of the unusual property of its 7r-system in allowing the u-framework to achieve bond equality. However Kataska and Nakajuma point out that there is still a place for rr-electron delocalization energy since it correlates well with the experimental resonance en erg^.^ Regarding experimental determinations of the structure of ben- zene Ermer has given a caution; that a D6hstructure for benzene as opposed to a distorted Qhstructure cannot be deduced from an X-ray crystal structure owing to the effects of time and space averaging.6 This should be an important consideration when examining the structure of other delocalized species (e.g.higher annulenes) by X-ray crystallography. Indeed none of the present experimental evidence is considered rigorously to exclude a D3,,structure for benzene.6 In the light of this work new ab initio quantum mechanical calculations show a symmetrical D6, structure is preferred and that there is no minimum energy distorted structure although the amount of energy required for distortion to localized single and double bonds is only 8 kcal m01-l.~ [1,2-I3C2] Benzene prepared from 1,4-dichIorobutane and [13C]cyanide was subjected to high temperature automerization.A benzvalene mechanism has been proposed to explain the redistribution of the isotopic labels (Scheme 1).8 The thermal isomerization of benzocyclobutane to styrene is interesting because a proportion of carbon-13 label from a methylene group becomes incorporated into the aromatic ring. Cleavage to form an aryl radical is only a minor pathway; the principal J. Gerratt Chem. Brit. 1987 327. ’ L,.Pauling Nature (London) 1987 325 396.J. Maddox Nature (London) 1987,327 551. S. S. Shaik P. C. Hiberty J.-M. Lefour and G. Ohanessian J. Am. Chem. SOC.,1987 109 363. M. Kataoka and T. Nakajima J. Org. Chem. 1987 52 2323. 0. Ermer Angew. Chem. Znt. Edn. Engl. 1987 26 782. ’ R. Janoschek Angew. Chem. Znt. Edn. Engl. 1987 26 1298. L. T. Scott N. H. Roelofs and T.-H. Tsang J. Am. Chem. Soc. 1987 109 5456. 157 158 R. McCague * * * I Scheme 2 H H Scheme 3 mechanism has a cyclohepta-l,2,4,6-tetraeneas an intermediate (Scheme 2).9 The cycloheptatetraene can also be formed by thermolysis or photolysis of phenyl- diazomethane." Calculations on the cyclization of a dienyne radical to the phenyl radical (Scheme 3) reveal a high relative stability for the phenyl radical and an activation energy of only 19 kcal mol-'." The ring closure might be important in soot nucleation.A new dimer of benzene (1) has been isolated. It is thermally more stable than its anti-isomer.'2 Hexa-substituted benzenes of interest are hexakis(di-chloromethyl) benzene which is like hexaisopropylbenzene in having gear meshed groups around the ring,13 and tris(ethylenedithio)benzene which together with related compounds give conducting fluoroborate radical cation salts which might be candidates for an organic ferr~magnet.'~ 0. L. Chapman U.-P. E. Tsou and J. W.Johnson J. Am. Chem. SOC.,1987 109 553. 10 R. J. McMahon C. J. Abelt 0. L. Chapman J. W. Johnson C. L. Kreit J.-P. LeRoux A. M. Mooring and P. R. West J. Am. Chern. SOC.,1987 109 2456.I' M. J. S. Dewar W. C. Gardiner Jr. M. Frenklach and I. Oref J. Am. Chem. SOC.,1987 109 4456. l2 N. C. Yang B. J. Hrnjez and M. G. Homer J. Am. Chem. SOC.,1987 109 3158. B. Kahr S. E. Biali W. Schaefer A. B. Buda and K. Mislow J. Org. Chem. 1987 52 3713. 14 R. Lapouyade and J.-P. Morand J. Chem. SOC.,Chem. C'ommun. 1987 223. Aromatic Compounds 159 Homoaromaticity.-An example of three-dimensional homoaromaticity is the 27r 1,3-dehydr0-5,7-adamantanediyldication (2) which has been prepared by superacid- induced fluoride ion abstraction from 1,3-dehydr0-5,7-difluoroadamantane. It has a remarkable carbon-13 n.m.r. spectrum in which the bridged carbon atoms (6 6.6) are at lower frequency than the methylene carbons (6 35.6) despite the positive charges and in which the carbon-proton coupling constants indicate a strong deformation of the framework the bridgehead carbon atoms being drawn in towards the centre of the m~lecule.’~ The dication (3) is a sandwiched bis-homoaromatic system.It has highly shielded shifts in its carbon-13 n.m.r. spectrum.16 On the other hand studies with anionic systems have failed to provide evidence for homo- aromati~ity.’~”~ 2 Construction of the Benzene Ring from Non-aromatic Precursors uia Diels-Alder Cyc1oaddition.-Warrener et al. have advanced the concept of ‘Transfer Technology’.’’ They give as an example the use of quadricycline as an acetylene equivalent in the synthesis of 1 ,Cdisubstituted benzenes bearing electron- withdrawing groups (Scheme 4).C02Me C02Me C02Me I C02Me C02Me C02Me Scheme 4 The Diels-Alder approach is often chosen for the synthesis of highly substituted benzenes. Suitable heterocycles react with acetylenes to give benzenes directly. The most popular are the a-pyrones which yield the benzene ring on elimination of the carbon dioxide from the initial add~ct.~~~~ Since the synthesis of the a-pyrones can start from sodium acetate this methodology allows the preparation of heavily substituted products with specific isotopic labelling of the ring by 2H 3H 13C or 14c.24 An intramolecular Diels- Alder reaction to a 1,2-diazine (elimination of nitrogen) has been used in a synthesis of the components PDEI and PDEII of the c-AMP phosphodiesterase inhibitor CC-1065.The diazines are themselves prepared from an inverse electron demand Diels- Alder reaction of a 1,2,4,5-tetrazine-3,6- dicarboxylate (Scheme 5).24 l5 M. Bremer P. von R. Schleyer K. Schotz M. Kausch and M. Schindler Angew. Chem. Znt. Edn. Engl. 1987 26 761. 16 G. K. S. Prakash M. Farnia S. Keyanian G. A. Olah H. J. Kuhn and K. Schaffner J. Am. Chem. SOC.,1987 109 911. G. Jonsall and P. Ahlberg J. Chem. SOC. Perkin Trans. I 1987 461. l8 G. Trimitsis F.-T. Lin R. Eaton S. Jones M. Trimitsis and S. Lane J. Chem. Soc. Chem. Commun. 1987 1704. 19 R. N. Warrener R. A. Russell R. Solomon 1. G. Pitt and D. N. Butler Tetrahedron Lett. 1987,28,6503. 20 D. L. Boger and M. D. Mullican Org. Synfh. 1987 65 98. 21 S. A. Ahmed E. Bardshiri and T. J. Simpson J.Chem. SOC.,Chem. Commun. 1987 883. 22 A. Ichihara K. Murakami and S. Sakamura Tetrahedron 1987 43 5245. 23 T. Ziegler M. Layh and F. Effenberger Chem. Ber. 1987 120 1347. 24 D. L. Boger and R. S. Coleman J. Am. Chem. SOC.,1987 109 2717. 160 R. McCague Me2Bu'Si0 N-N N?N= -3 Me0,C-f \tCO,Me N=N VN COMe Me0 COMe 230 "C I OSiBu' Me2 \ COMe COMe Me0 COMe Me0 COMe Scheme 5 A particularly interesting synthesis is of a precursor of Fredericamycin A in which the substituted furan was itself prepared by a Diels-Alder cycloaddition and which demonstrates the use of an allene rather than an acetylene as the 2~-component (Scheme 6).25 ' N-o + Ill A -MeCN *Et &Me MeOX OEt 1Bu'OCH,CH=C=CHCO,Me 1.TiCI, u' LiAIH, Et,N. TH F 4 2. O, Me,& CH,CI C02Me EtO Scheme 6 Advances have been made in the use of acyclic dienes. In the reaction of l-acetoxy-3-methyl-(E)-buta-l,3-diene and p-phenylsulphonylacrylate esters the regiochemistry of addition depends on the stereochemistry of the acrylate the 2 and E acrylates give after aromatization of the adducts the meta-and para-toluates respectively.26 A useful diene which had been previously difficult to obtain is 2,3-dicarbomethoxy- 1,3-butadiene. It is conveniently prepared by flash vacuum thernolysis of its anthracene adduct and gives benzene-l,2-dicarboxylatesafter 25 A. V. R. Rao and D. R. Reddy J. Chem. SOC.,Chem. Commun. 1987 574. 26 A. D. Buss G.C. Hirst and P. J. Parsons J.Chem. Soc. Chem. Commun. 1987 1836. Aromatic Compounds Reagents i LiNPr; THF; ii PriSiCI; iii r-CO,Me 150 "C 4 h; iv KF MeOH Scheme 7 reaction with suitable acetylenes followed by ~xidation.~' Alkenyl ketimines have been used in a synthesis of anilines (Scheme 7).28 via Cyc1ocondensation.-Numerous methods have emerged for the synthesis of the benzene ring by cyclocondensation and sulphur substituents that are either lost on aromatization or later removed are particularly useful for activating one of the reacting component^.^^-^' Scheme 8 gives an example. Pyridinium substituents have been similarly employed in a synthesis of chalcone derivative^.^^ SMe ~ R'QSMe Et20 R'WSMe BF,.Et,O MeOH 1 OMe OMe Scheme 8 Frequently used components have extended conjugation such as a,p ;y,S-unsatur-ated aldehydes and An example is an intramolecular Wittig reaction that leads to benzenes bearing perfluoroalkyl groups (R,) (Scheme 9).36 The intramolecular cyclization of large ring dienynyl triflates on solvolysis gives benzo- cycloalkanes (Scheme 27 B.Tarnchompoo C. Thebtaranonth and Y. Thebtaranonth Tetrahedron Lett. 1987 28 6671. 28 E. Differding 0. Vandevelde B. Roekens T. T. Van and L. Ghosez Tetrahedron Lett. 1987 28 397. 29 A. K. Gupta H. Ila and H. Junjappa Tetrahedron Lett. 1987 28 1459. 30 L. W. Singh H. Ila and H. Junjappa Synthesis 1987 873. 31 Y. Ozaki and S.-W. Kim Chem. Lett. 1987 1199. 32 K. Eichinger P. Nussbaumer S. Balkan and G. Schulz Synthesis 1987 1061.33 M. H. Nantz and P. L. Fuchs Synth. Commun. 1987 17 761. 34 M. S. C. Rao and C. S. K. Rao Synthesis 1987 231. 35 D. Stossel and T. H. Chan J. Org. Chem. 1987 52 2105. 36 W. Ding P. Zhang and W. Cao Tetrahedron Lett. 1987 28 81. 37 M. Hanack and R. Rieth Chem. Ber. 1987 120 1659. 162 R. McCague C02Me Ph,P=CH-CH=CH-C0,Me + -ph31f('Jc02Me Rf-C=C-C02Me Rf \ / -Scheme 9 R = Et or CH2CF Scheme 10 Metal Complex Promoted Benzene Ring Formation.-Vollhardt et al. have demon- strated the synthesis of a 5-phenylene by cobalt complex catalysed co-cyclization (Scheme 1 l).38The central ring in the 5-phenylene is highly susceptible to cycloaddi- tion. The failure of an analogous approach to a 6-phenylene would indicate an upper limit to the stability of phenylene~.~~ A simple procedure for cyclotrimerization of alkynes uses a palladium catalyst activated by chlorotrimethylsilane.39 SiPr I Me3Si 51me3 Me3Si Reagents i + (C5H5)Co(CO), DMF; ii Bu4N+F-; iii Me3Si-C%C-SiMe3 (C5cH5)Co(CO)2 ,-THF CuCl-2Hz0 MeOCH,CH,OMe NEt3 Scheme 11 A malecylcobalt complex prepared from dimethyl squarate reacts with alkynes under Lewis acid catalysis to provide q~inones.~' Manganese(111) mediates the radical cyclization of methyl-3-0~0-6-heptenoateto give methyl salicylate in 94% 38 L.Blanco H. E. Helson M. Hirthammer H. Mestdagh S. Spyroudis and K. P. C. Vollhardt Angew. Chem. Int. Edn. Engl. 1987 26 1246. 39 A. K. Jhingan and W. F. Maier J. Org. Chem. 1987 52 1161.40 S. Iyer and L. S. Liebeskind J. Am. Chem. Soc. 1987 109 2759. Aromatic Compounds 0 OH (u" Mn(OAc) Cu(OAc) KOAc CO,Me 94% AcOH. 50 "C Scheme 12 yield (Scheme 12).41 If the terminus of the double bond in the substrate is substituted then a cyclopentenone becomes the preferred product. Other Methods.-A benzene ring annulation utilizing an electrocyclic ring closure has been used to convert tetralone into a 9,lO-dih~drophenanthrene.~~ 2-Bromo-3-methoxycyclohex-2-enone has been shown to be useful as a 3-hydroxyphenyl cation equivalent to arylate lactams in the synthesis of the analgesic drug meptazinol. Aromatization takes place on acid treatment of the add~ct.~~ 3 Substitution in the Benzene Ring Electrophilic Substitution.-Mechanistic Studies.Eberson and Radner have reviewed the matter of whether the a-complex (Wheland intermediate) in aromatic nitration is formed by way of electron transfer (Le. ArH + NO; -* ArH+' + NOz) followed by radical-pair ~ombination.~~ They conclude that in the nitration of naphthalene at least the radical pair does not lie on the pathway to the a-intermediate; an electron transfer mechanism being disfavoured because of the bond reorganization energy required to transform NO; (planar) into NO; (bent). When radical cations do form it is proposed that they do so by homolysis of the a-complex.& Interestingly the rearrangement of nitroanilines in sulphuric acid is suggested to involve migration of nitrogen dioxide rather than the nitronium ion.45 In this reaction it is the migration rate and not the protonation that is rate determining.When nitric oxide is present as a catalyst in nitration Eberson and Radner have noted that radical formation is favoured since bond reorganization is not required for this agent.& Indeed carbon-13 polarization has been demonstrated in the nitrous acid catalysed nitration of giving strong evidence for the intermediacy of the phenoxyl radical. In the reaction of arenes with nitrate radical prepared by photolysis of ammonium nitrate solution electron transfer is favoured because both the nitrate radical and anion are planar.47 However Kochi finds that radical pairs generated by laser flash photolysis of complexes formed between dialkoxybenzenes and tetranitromethane give rise to the same products as in nitration under classical conditions indicating that radical cations may be important for these electron-rich substrate^.^^'^^ 4' J.R. Peterson R.S. Egler D. B. Horsley and T. J. Winter Tetrahedron Lett. 1987 28 6109. 42 T. L. Gilchrist and R. J. Summersell Tetrahedron Lett. 1987 28 1469. 43 R. G. Shepherd and A. C. White 1. Chem. Soc. Perkin Trans. 1 1987 2153. 44 L. Eberson and F. Radner Acc. Chern. Rex 1987 20 53. 45 J. T. Murphy and J. H. Ridd J. Chem. SOC.,Perkin Trans. 1 1987 1767. 46 M. Ah J. H. Ridd J. P. B. Sandall and S. Trevellick 1. Chem. Soc. Chem. Commun. 1987 1168. 47 E. Baciocchi T. D. Giacco S. M. Murgia and G. V. Sebastiani J. Chem. SOC.,Chern. Comrnuri.,1987 1246. 48 S.Sankararaman W. A. Haney and J. K. Kochi J. Am. Chem. Soc. 1987 109 5235. 49 S. Sankararaman W. A. Haney and J. K. Kochi J. Am. Chem. Soc. 1987. 109 7824. 164 R. McCague In a theoretical study of the nitration of benzene the nitro a-intermediate is calculated to have biradicaloid character and to be favoured over the nitrito u-complex only because of s~lvation.~' However in a study of electrophilic aromatic nitration in the gas phase by protonated methyl nitrate this system is concluded to act as a well behaved electrophilic substitution in good analogy with the liquid phase reaction.51 Yet in the gas phase it has been observed that nitration of anisole is slow relative to that of toluene and this is explained by the formation of an early ion-molecule complex.52 In the gas phase alkylation of dihalogenobenzenes by free isopropyl cations peculiarities in the orientation of electrophilic attack are attributed to interactions between cations and radical^.'^ When mercuration is promoted by photolysis arene radical cations are formed as evidenced by mercury- 199 hyperfine coupling in the e.s.r.spectrum.54 Electron transfer has been discounted for elec- trophilic attack by Br+ C1+ CH3CO+ and HgR+ under solution conditions since the reaction rates depend on the stability of the o-c~mplexes.~~ Effenberger et al. have studied the structure and reactivity of some aromatic o-complexes that are particularly stable such as that obtained by bromination of 1,3,S-tripyrrolidinobenzene.The cyclohexadienylium ring in these complexes can be either planar or bent depending on the substituents and since when the ring is bent only the axial ligand can dissociate these complexes can have high stability owing to the high energy barrier to the proton taking up an axial position where it can leave.56 Tricarbonylchromium complexation of an arene has been shown to deactivate the ring only to a small extent towards Friedel-Crafts a~etylation.~'A tri-fluoromethoxy substituent is ortho-para directing by the resonance effect but electron withdrawing by the inductive effect resulting in a strong predominance for para-substitution since the inductive effect diminishes with distance.58 Synthetic Procedures.Regioselective 4-chlorination of anisole ( p/ o > 30) has been achieved with copper(r1) chloride on a neutral alumina support.59 With N-chlorodialkylamines where R,NH+Cl are the active electrophiles even more impress- ive regioselectivity (p/ o up to 500) has been accomplished.60 Halogenation of phenols and their ethers can be simply carried out with the potassium halide and meta-chloroperoxybenzoicacid in the presence of 18-Crown-6.Iodination is success- ful only if there is more than one substituent activating the ring.61 A potentially useful brominating agent for deactivated arenes is bromine monofluoride which is '' J. T. Gleghorn and G. Torossian J. Chem. SOC.,Perkin Trans. 2 1987 1303. 51 M. Attina F. Cacace and M. Yanez J. Am. Chem. SOC.,1987 109 5092. 52 M. Attina F. Cacace and G. de Petris Angew.Chem. Znt. Edn. Engl. 1987 26 1177. 53 B. Aliprandi F. Cacace and S. Fornarini Tetrahedron 1987 43 2831. 54 J. L. Courtneidge A. G. Davies P. S. Gregory D. C. McGuchan and S. N. Yazdi J. Chem. SOC.,Chem. Commun. 1987 1192. 55 E. Baciocchi and L. Mandolini Tetrahedron 1987 43 4035. 56 F. Effenberger F. Reisinger K. H. Schonwalder P. Bauerle J. J. Stezowski K. H. Jogun K. Schollkopf and W.-D. Stohrer J. Am. Chem. SOC.,1987 109 882. 57 J. L. von Rosenberg and A. R. Pinder J. Chem. SOC.,Perkin Tars. I 1987 747. 58 G. A. Olah T. Yamoto T. Hashimoto J. G. Shih N. Trivedi B. P. Singh M. Piteau and J. A. Olah J. Am. Chem. SOC.,1987 109 3708. 59 M. Kodomari S. Takahashi and S. Yoshitomi Chem. Lett. 1987 1901. 60 J. R. L. Smith L. C. McKeer and J.M. Taylor J. Chem. SOC.,Perkin Trans. 2 1987 1533. 61 M. Srebnik R. Mechoulam and I. Yona J. Chem. SOC.,Perkin Trans. 1 1987 1423. Aromatic Compounds 165 prepared from the elements. Ethyl benzoate is rneta-brominated in 95% yield at -45 "C; a Lewis acid not being required.62 Fluorination can be accomplished with N-fluoroperfluoroalkylsulphonimides[e.g. (CF3S02)*NF] but electron-deficient arenes do not react.63 Good para-preference in the nitration of halogenobenzenes is obtained with copper(I1) nitrate on K10 montmorillonite in the presence of acetic anhydride. The improved regioselectivity correlates with a lowering of dielectric constant of the medium.64 Useful agents for the nitration of highly activated substrates are nitrocyc- lohexadienes prepared by ipso-nitration of 2,4,6-trisubstituted phenols.These reagents give much less oxidation than nitric acid in the nitration of l-na~hthol.~~ Electrophilic amination is possible by photolysis with 1 -amino-2-methyl-4,6- diphenylpyridinium tetrafluoroborate. The reaction proceeds uia nitrene or nitrenium ion singlets causing poor positional selectivity owing to the high reactivity of these species.66 For the ethylation of benzene by ethylene trifluoromethanesul- phonic acid is better than aluminium chloride fluorosulphonic acid or sulphuric acid.67 Allylation can be carried out with the cationic iron complex (T~-allyl)Fe(CO)zBF as the electrophile. The method has been used to attach an isoprenyl side chain.68 A useful procedure for introducing a carboxylic acid function is to treat the arene with chloral in the presence of aluminium chloride and then to cleave the two-carbon chain with basic hydrogen peroxide.69 The normal tendency of Friedel-Crafts ring-closure to be directed para to an activating alkoxy substituent can be redirected ortho by incorporation of a trimethyl- silyl group into the position where ring closure is desired.70 The t-butyl group is useful for the blocking of sites on the aromatic ring to prepare 1,2,3-trisubstituted benzenes.An example is in a preparation of [2.2]meta~yclophanes.~~ The resin- supported superacid Nafion H is an alternative to Lewis acids for removal of the t-butyl group.72 Nucleophilic Substitution.-Mechanistic Studies. An encounter complex of the charge-transfer type has been invoked to explain the second-order dependence of rate on nucleophile concentration in substitution reactions of 1,2,3,5-tetranitroben-zene 2,4,6-trinitrofl~orobenzene,~~ 1,2-dinitroben~ene.~~ and When nucleophilic substitution is photoinduced the mechanism can be either classical nucleophilic substitution (S,Ar) on the activated arene or can involve initial electron-transfer from the nucleophile.Which mechanism occurs is dependent on the nucleophile. With 1 -methoxy-4-nitronaphthalene primary amines displace the nitro group by an S,Ar mechanism and the more electron-rich secondary amines displace the methoxy 62 S. Rozen and M. Brand J. Chem. SOC.,Chem. Commun. 1987 752. 63 S. Singh D. D. Desmarteau S. S.Zuberi M. Witz and H.-N. Huang J. Am. Chem. Soc. 1987,109,7194. 64 P. Laszlo and P. Pennetreau J. Org. Chem. 1987 52 2407. 65 M. Lamaire A. Guy J. Roussel and J.-P. Guette Tetrahedron 1987 43 835. 66 H. Takeuchi J. Chem. SOC.,Chem. Commun. 1987 961. 67 B. L. Booth M. Al-Kinany and K. Laali J. Chem. SOC.,Perkin Trans. 1 1987 2049. h8 J. W. Dieter Z. Li and K. M. Nicholas Tetrahedron Lett. 1987 28 5415. 69 P. Menegheli M. C. Rezende and C. Zucco Synth. Commun. 1987 17 457. '' M. P. Suhi K. Shankaran B. I. Alo W. R. Hahn and V. Snieckus Tetrahedron Lett. 1987 28 2933. 71 T. Yamato T. Arimura and M. Tashiro J. Chem. SOC.,Perkin Trans. 1 1957 1. 72 G. A. Olah G. K. S. Prakash P. S. Iyer M. Tashiro and T. Yamato J. Org. Chem. 1987 52 1881. 73 J.4.Hayami S. Otani F. Yamaguchi and Y. Nishikawa Chem. Left. 1987 739. 74 R. I. Cattana J. 0.Singh J. D. Anunziata. and J. J. Silber J. Chem. SOC.,Perkin Trans. 2 1987 79. 166 R. McCague OMe ,"':"" via 3"""' S,Ar* NO2 NMe2 NO2 \ via (CH,),NH electron transfer hv I NO2 Scheme 13 group uia electron tran~fer.~' 4-Nitroveratrole similarly undergoes displacement of either one of the methoxy groups depending on the nucleophile (Scheme 13).76 In the reaction of p-dinitrobenzene with basic hydrogen peroxide the hydroper- oxynitrobenzene is formed as an intermediate eighteen times faster than its conver- sion into p-nitr~phenol.~~ Polychloroarenes have been found to react readily with superoxide. It has been proposed that a similar action may take place in uiuo and account for the high toxicity of polychlorobiphenyl~.~~ Synthetic Procedures.Perhaps the most valuable recent developments in nucleophilic aromatic substitution are where overall it is a proton that is replaced allowing an increase in the number of ring substituents. A review has appeared on the vicarious nucleophilic substitution (VNS) reaction in which the chloromethylsulphone anion is a typical nucleophile which ultimately loses its chlorine atom. It is the elimination of hydrogen chloride that is the rate determining step -the initial addition is fast and rever~ible.'~ Manipulation of the products leads to a synthesis of nitroarylethyl- ene derivatives (Scheme 14).80 When trichloromethyl anion is the nucleophile i Et0,CC H Br -Scheme 14 75 N.J. Bunce S. R. Cater J. C. Scaiano and L. J. Johnston J. Org. Chem. 1987 52 4214. 76 A. Cantos J. Marquet and M. Moreno-Manas Tetrahedron Lett. 1987 28 4191. 77 R. A. Heller and R. Weiler Can. J. Chem. 1987 65 251. 78 H. Sugimoto S. Matsumoto and D. T. Sawyer J. Am. Chem. Soc. 1987 109 8081. 79 M. Makosza and J. Winiarski Arc. Chem. Rex 1987 20 282. 80 M. Makosza and A. Tyrala Synthesis 1987 1142. Aromatic Compounds 167 hydrolysis of the resulting dichloromethyl compound gives the aldehyde.81 The VNS reaction is successful only if the anionic a-complex is sufficiently stabilized. In 1 -cyanonaphthalene stabilization is insufficient and a bis-cyclopropane annelated product results.82 Tele-substitution para to the chlorine leaving group is observed with the tricar- bonylchromium complex of 2-chloro- m-xylene.After decomplexation the product is a 1,3,5-trisubstituted benzene.83 Direct displacement of halogen in 4-chloro- 4-bromo- and 4-iodo-benzene by amines takes place if a pressure of 7.2 kbar is applied.84 For the preparation of diphenyl ethers 1,4-dinitrobenzene has been shown to be better than 4-fluoronitrobenzene in its reaction with the phenoxide anion.85 An electron-transfer mechanism is likely since radical scavengers reduce the yield. Oxazoles as well as oxazolines are good at activating ortho leaving groups in nucleophilic aromatic substitution towards displacement by Grignard reagents.86 Substitution uia Aryl a-Radicals.-Abeywickrema and Beckwith have made a thorough study of the iododediazoniation reaction.Strong evidence for an SRNl mechanism is the observation of intramolecular ring-closure to a double bond revealing the intermediacy of an aryl radical (Scheme 15). The diiodine radical cation (11) is a key chain-transfer reagent in this pro~ess.~’ It has also been demonstrated that aryl radicals generated by tributyltin radical abstraction of bromine can intramolecularly abstract a cyano or acyl group if this group leaves a stabilized radical.88 I NaI -acetone Scheme 15 The approach can be used to synthesize benzonitriles from diazosulphides as an alternative to the Sandmeyer reaction. The radical is generated either by photochemical or electrochemical ind~ction.~~.~’ Electrocatalysis takes place on the cathode and examples are the electrochemical hydrogen-transfer oxidation by aryl halides whereby an alcohol is oxidized to a ketone 91 and in a synthesis of unsymmetrical biaryls by coupling between an aryl halide and phenolate anion.92 ” M.Makosza and 2.Owczarczyk Tetrahedron Lett. 1987 28 3021. a2 M. Makosza T. Glinka S. Ostrowski and A. Rykowski Chem. Lett. 1987 61. 83 F. Rose-Munch E. Rose and A. Semra J. Chem. SOC.,Chem. Cornmun. 1987 942. 84 T. Ibata Y. Isogami and J. Toyoda Chem. Lerf. 1987 1187. 85 P. G. Sammes D. Thetford and M. Voyle J. Chem. SOC.,Chem. Commun. 1987 1373. 86 D. J. Cram J. A. Bryant and K. M. Doxsee Chem. Lett. 1987 19. 87 A. N. Abeywickrema and A.L. J. Beckwith J. Org. Chem. 1987 52 2568. 88 A. L. J. Beckwith D. M. O’Shea S. Gerba and S. W. Westwood J. Chem. SOC.,Chem. Commun. 1987 666. 89 M. Novi G. Petrillo and C. Dell’Erba Tetrahedron Left. 1987 28 1345. 90 G. Petrillo M. Novi G. Garbarino and C. Dell’Erba Tetrahedron 1987 43 4625. 91 C. P. Andrieux J. Badoz-Lambling C. Combellas D. Lacombe J.-M. Saveant A. Thiebault and D. Zann J. Am. Chem. SOC., 1987 109 1518. 92 N. Alam C. Amatore C. Combellas A. Thiebault and J. N. Verpeaux Tetrahedron Lett. 1987,28,6171. 168 R. McCague Substitution tiu Aryl-Metal o-Complexes.-Direct Functionalization ofBenzene. The use of transition metal complex catalysis can enable substituted benzenes not obtain- able by electrophilic substitution to be synthesized.Direct hydroxylation of benzene is possible with palladium(1r) acetate and 1,lO-phenanthroline under 15 atmospheres pressure of oxygen.93 Highly efficient carbonylation of benzene takes place on irradiation with carbon monoxide.94 Curiously monosubstituted benzenes give mainly meta carbonylation irrespective of whether the substituent is electron donat- ing or electron ~ithdrawing.'~ Insertion of isonitriles into benzene to give aldimines takes place on irradiation with the complex Fe(PMe3)2(:CNR)3 obtained from the isonitrile and tetrakis(triphenylphosphine)iron(01.~~ Aryl-MetaZ a-Complex as the Nucleophile. A simplified classification is adopted here that divides aryl-metal a-complexes as behaving as essentially either electrophiles or nucleophiles.Thus in the coupling of an arylboronic acid -preparable from the aryl-lithium by lithium-boron exchange with an aryl palladium bromide generated from the aryl br~mide~~?~~ -the arylboronate is considered to be the nucleophile and the aryl palladium is the electrophile. For the introduction of radiolabelled halogen it has been suggested that aryltrimethylgermanes are preferred to the corresponding stannanes since the former are less sensitive to hydrolysis but more susceptible to electrophilic sub~titution.~~ Fluorine can be introduced by elemental fluorine or acetyl hypofluorite.'OO Arylhydrazines can be prepared by addition of aryllithiums or aryl Grignard reagents to di-t-butyl azodicarboxylate and subsequent acid treatment."' A simple procedure for specific hydroxylation of aromatics is via directed lithiation by s-butyllithium and then introduction of oxygen."* Functionalization adjacent to an aryl-ketone function can be achieved by forma- tion of the aryltetracarbonylmanganese complex which adds to the double bond of olefins that bear electron withdrawing groups (Scheme 16).'03 @CO,Me Scheme 16 Buchwald's zirconocene-benzyne complex (4) can be treated as a benzene-1,2- dianion.After addition of acetonitrile and iodine 2-iodoacetophenone is 93 T. Jintoku H. Taniguchi and Y. Fujiwara Chem. Lett.. 1987 1865. 94 T. Sakahura and M. Tanaka Chem. Lett. 1987 249. 95 T. Sakahura and M. Tanaka Chem. Lett. 1987 1113. 96 W. D. Jones G. P. Foster and J.M. Putinas J. Am. Chem. Soc. 1987 109 5047. 97 M. J. Sharp W. Cheng and V. Snieckus Tetrahedron Lett. 1987 28 5093. 98 W. Cheng and V. Snieckus Tetrahedron Lett. 1987 28 5097. 99 S. M. Moerlein J. Org. Chem. 1987 52 664. 1DO H. H. Coenen and S. M. Moerlein J. Nuorine Chern. 1987 36 63. 101 J. P. Demers and D. H. Klaubert Tetrahedron Lett. 1987 28 4933. 102 K. A. Parker and K. A. Koziski J. Org. Chem. 1987 52 674. I03 L. H. P. Gommans L. Main and B. K. Nicholson J. Chem. SOC.,Chem. Commun. 1987 761. Aromatic Compounds 169 obtair~ed.'~~.'~~ The zirconozene-benzadiyne complex (5) has also been prepared. It behaves as a tetraanion bromine yielding 2,3,5,6-tetrabromo-l,4-dimethoxyben-zene and it can be used for the preparation of a bis-cyclobutane-fused benzene.'06 A clever method for ring closure is shown in Scheme 17.'07 An aryldiethyl- aluminium complex is presumably an intermediate.Scheme 17 Aryl- Metal a-Complex as the Electrophile. Classical nucleophilic aromatic substitu- tion is largely limited to highly activated substrates -transition metal complexes are now playing an important role in overcoming this deficiency. The cyanation of aromatic halides under copper salt catalysis (Rosenmund von Braun reaction) has been reviewed. The mechanism remains uncertain.'08 Copper salts also catalyse the replacement of bromine by methoxy groups. This was used in the synthesis of the highly oxygen-substituted nucleus of ubiq~inone'~'and in the intramolecular dis- placement of bromine by an amine in the synthesis of azetidinones."' Cobalt complexes formed from aryl halides are equivalents of aryl radicals and can add intramolecularly to a nearby double bond.'" Barton et al.have published a series of papers on the use of bismuth (111) and (IV) and related lead(Iv) iodine( III) and antimony(v) for phenylation of alcohols phenols and amines.''2-'*6 Phenyl radicals are not thought to be intermediates in these reaction^."^ Pinhey has demonstrated the use of an aryl-lead triacetate to arylate a vinylogous P-ketoester in the synthesis of (*)-Iyc~ramine."~ 104 S. L. Buchwald B. T. Watson R. T. Lum and W. A. Nugent J. Am. Chem. SOC.,1987 109 7137. 105 S. L. Buchwald A. Sayers €3. T. Watson and J. C. Dewan Tetrahedron Lett.1987 28 3245. 106 S. L. Buchwald E. A. Lucas and J. C. Dewan J. Am. Chem. SOC.,1987 109 4396. 107 B. M. Trost and R. Walchli J. Am Chem. SOC.,1987 109 3487. I08 G. P. Ellis and T. M. Romney-Alexander Chem. Ret.. 1987 87 779. I09 E. Keinan and D. Eren J. Org. Chem. 1987 52 3872. 110 R. Joyeau L. D. S. Yadav and M. Wakselman J. Chem. SOC.,Perkin Trans. 1. 1987 1899. 111 V. F. Patel and G. Pattenden J. Chem. SOC.,Chem. Commun. 1987 871. D. H. R. Barton N. Yadav-Bhatnager J.-P. Finet J. Khamsi W. B. Motherwell and S. P. Stanforth Tetrahedron 1987 43 323. D. H. R. Barton J.-P. Finet C. Giannotti and F. Halley J. Chem. SOC.,Perkin Trans. 1 1987 247. 114 D. H. R.Barton J.-P. Finet W. B. Motherwell and C. Pichon J. Chem. SOC.,Perkin Trans.1 1987 251. I15 D. H. R. Barton J.-P. Finet and J. Khamsi Tetrahedron Lett. 1987 28 887. 116 D. H. R. Barton N. Yadav-Bhatnagar J.-P. Finet and J. Khamsi Tetrahedron Lett. 1987 28 3111. 117 D. J. Ackland and J. T. Pinhey J. Chem. Soc. Perkin Trans. 1. 1987 2695. 170 R. McCague Aryl trifluoromethanesulphonates readily preparable from phenols are proving increasingly valuable. Examples of procedures illustrating their utility that have appeared in 1987 are illustrated in Scheme 18. ArOS02CF3 Scheme 18 In the reaction that forms esters the use of 1,3-bis(diphenylphosphino)propane gave reaction rates 500 times those obtained using triphenylphosphine ligands.’” Coupling between aryl halides and diphenylphosphino-silanes or stannanes allows the introduction of the diphenylphosphino group.123 Vinyl stannanes can be coupled with aryl bromide^"^ as well as with the triflates. Aryldiazonium tetrafluoroborates can be coupled with vinyltrimethyl~ilanes~~~ and coupling is also successful between a tricarbonylchromium-complexed aryl chloride and a trialkylstannane to form the aryl-alkyl bond.’26 Miscellaneous Methods.-In substitutions via benzyne intermediates fing methoxy groups bring about regioselectivity by repelling nucleophiles ortho and para. Thus l-bromo-2,4-dimethoxybenzeneundergoes cine-halogen replacement to give a 1,3,5-trisubstituted An alternative route to 1,3,5-trisubstituted benzenes used in the synthesis of olivetol is by reductive removal of the 2-methoxy group in a 1,2,3-trimethoxy-5-substituted benzene by potassium in dimethylformamide.’28 Schultz et al.have elegantly demonstrated the synthesis of substituted phenols from benzoate esters via temporary removal of the aromatic conjugation (Scheme 19) Protected L-DOPA derivatives have been accessed by the benzylic hydroperoxide rearrangement [ArCH(OOH)CH3 -+ ArOH].’30 A method for hydroxylation a-to 118 A. M. Echavarren and J. K. Stille J. Am. Chem. Soc. 1987 109 5478. 119 G. A. Peterson F.-A. Kunng J. S. McCallum and W. D. Wuiff Tetrahedron Lert. 1987 28 1381. I20 R. E. Dolle S. J. Schmidt and L. I. Kruse J. Chem. SOC.,Chem. Commun. 1987 904. 12’ K. S. Petrakis and T. L. Nagabhushan J. Am. Chem. SOC.,1987 109 2831. 122 X. Lu and J. Zhu Synthesis 1987 726.123 S. E. Tunney and J. K. Stille J. Org. Chem. 1987 52 748. 124 D. R. McKean G. Parrinello A. F. Renaldo and J. K. Stille J. Org. Chem. 1987 52. 422. 12’ K. Ikenaga K. Kikukawa and T. Matsuda J. Org. Chem. 1987 52 1276. ‘26 W. J. Scott J. Chem. SOC.,Chem. Comrnun. 1987 1755. 127 A. Ruzzuk and E. R. Biehl J. Org. Chem. 1987 52 2619. 128 U. Azzana T. Denurra G. Melloni and G. Rassu 1. Chem. SOC.,Chem. Commun. 1987 1549. 129 A. G. Schultz R. E. Harrington M. Macielag P. G. Mehta and A. G. Taveras J. Org. Chem. 1987 52 5482. 130 D. L. Boger and D. Yohannes J. Org. Chem. 1987 52 5283 171 Aromatic Compounds R' + R C02Me R' Scheme 19 a ketone is by reaction of the tin enolate with benzoquinone in the presence of chlorotrimethylsilane.' 31 4 Benzene Derivatives for the Synthesis of Non-aromatic Compounds Reductions.-Birch reduction of m-anisic acid can lead to any one of four 3-oxocyclohexenecarboxylic acids by varying the treatment of the initial reduced product.'32 A trimethylsilyl substituent will override the regiochemical preference favoured by an alkyl group; in a substituted naphthalene the ring containing the trimethylsilyl group is preferentially reduced.'33 A protocol for electrochemical Birch reduction has been developed as an alternative to the use of alkali The photoreduction of aryl nitriles and halides by borohydride proceeds by an electron- transfer pathway but gives different 1,4-dihydro compounds than does the Birch reduction since protonation occurs in the radical anion rather than in the diani011.l~~ Photochemical Processes.-A thorough review of photocycloadditions of aromatic compounds has been pub1i~hed.I~~ Further evidence has appeared for ortho-and meta-cycloaddition proceeding via an initial photoinduced charge-transfer to the arene to give an exiplex ~witterion.'~~-'~' After intramolecular ortho-cycloaddition of olefins and acetylenes to the benzene ring thermal 6rr ring-expansion gives cyclo~ctatrienes'~~ respectively.A benzene derivative heavily sub- and tetraene~'~~ stituted with t-butyl groups undergoes photochemical isomerism not only to the I?l T. Mukaiyama N. Iwasawa T. Yura and R. S. J. Clark Tetrahedron 1987 43 5003. I32 F. X. Webster and R. M. Silverstein Synthesis 1987 922.133 P. W. Rabideau and G. L. Karrick Tetrahedron Lett. 1987 2481. 134 J. Chaussard C. Combellas and A. Thiebault Tetrahedron Lett. 1987 28 1173. 135 M. Kropp and G. R. Schuster Tetrahedron Lett. 1987 28 5295. 136 J. J. McCullough Chem. Rev. 1987 87 811. 13 7 J. Mattay J. Runsink J. A. Piccirilli A. W. H. Jam and J. Cornelisse J. Chem. SOC.,Perkin Trans. 1 1987 15. 138 J. Mattay Angew. Chem. Int. Edn. Engl. 1987 26 825. 139 G. Weber J. Runsink and J. Mattay J. Chem. Soc. Perkin Trans. 1 1987 2333. 140 J. Matray J. Runsink R. Heckendorn and T. Winkler Tetrahedron 1987 43 5781. 141 K. B.Cosstick M. G. B. Drew and A. Gilbert J. Chem. SOC.,Chem. Commun. 1987 1867. 142 M. C. Pirrung J. Org. Chem. 1987 52 1635.172 R. McCague Dewar benzene but further to the prismane. The prismane can revert thermally to a benzene derivative having a new substitution pattern.'43 4-Chlorobiphenyl under- goes photochemical conversion in water partly into the 3-chloro derivative; it has been suggested that the benzvalene (6) could be an intermediate in this process and that the chlorine transposition might have important environmental consequences.144 Thermal Cyc1oadditions.-Bis(trifluoromethyl)tetrazine the most reactive inverse electron-demand diene so far observed reacts thermally with benzene. The arene acts as the 2~-component and the product is a substituted phtha1a~ine.l~~ Phenol gives the 1 :1 cycloadduct (7) with N-(2,6-dimethylphenyl)maleimide in 63% yield.'46 Oxidations.-The oxidation of benzene by the bacteria Pseudornonas putida gives cyclohexa-3,5-diene- 1,2-cis-diol.The functionality thus introduced is ideal for the preparation of a range of natural products an example is the synthesis of (+)-pinit01 (Scheme 20).'47 Mutant strains of Pseudornonas putida can tolerate a wide range of functionality in the benzene nucleus whereupon the products obtained are optically a~tive.'~*-'~~ OH OH Scheme 20 The 2-hydroxyethoxy substituent promotes anodic oxidation of the aromatic nucleus in the presence of methanol to give a ketal of cy~lohexa-2,5-dienone.'~~ A curious anodic oxidation is in a synthesis of (*)-8,14-cedranoxine (Scheme 2l).'" The overall reaction is remarkably similar to the rneta-photocycloaddition reaction.143 H. Wingert H. Irngartinger D. Kallfass and M. Regitz Chem. Eer. 1987 120 825. 144 T. Moore and R. M. Pagni J. Org. Chem. 1987 52 770. 145 G. Seitz R. Hoferichter and R. Mohr Angew. Chem. Int. Edn. Engl. 1987 26 332. 146 D. Bryce-Smith. A. Gilbert I. S. McColl M. G. B. Drew and P.Yianni J. Chem. Soc. Perkin Trans. I 1987 1147. 147 S. V. Ley F. Sternfeld and S. Taylor Tetrahedron Lett. 1987 28 225. 148 J. T. Rossiter S. R. Williams A. E. G. Cass and D. W. Ribbons Tetrahedron Lett. 1987 28 5173. 149 S. J. C. Taylor D. W. Ribbons A. M. 2.Slawin D. A. Widdowson and D. J. Williams Tetrahedron Lett. 1987 28 6391. 1so M. P. Capparelli R. S. DeSchepper and J. S. Swenton J. Chem. SOC.,Chem. Commun. 1987 610.151 Y. Shizuri Y. Okuno H. Shigemori and S. Yamamura Tetrahedron Lett. 1987 28 6661. Aromatic Compounds 173 OMe anode _____. Me0 BU,N+BF,-'OAc Scheme 21 5 Condensed Polycyclic Aromatic Compounds Theoretical Studies.-Developments in computing power have naturally led to theo- retical methods being applied to large molecules. A molecular orbital based molecular mechanics (MOMM) approach is claimed to give greater accuracy than any previous method.'52 Stein and Brown have applied the HMO theory to large hexagonal condensed benzenoid systems of up to 2300 carbon atoms. At the edge of such molecules the properties are predicted to be similar to those in small polynuclear hydrocarbons whereas at the centre the carbon atoms have similar properties to those in graphite.Interestingly there was a calculated minimum resonance energy per electron at about 240 carbon atoms.'53 By Graphical Unitary Group methods the valence bond model has been applied to systems of up to 24 T-centres and gives good agreement with the HMO method.'54 An index of benzenoid character of polycyclic conjugated hydrocarbons has been proposed which entails partitioning the resonance energy into 4n + 2 (aromatic) and 4n (antiaromatic) circuits.'55 Elser and Haddon have predicted that icosahedral c60 (Footballene Buckminsterfullerine) will have a vanishingly small ring-current magnetic suscepti- bility; it may even be weakly paramagnetic. It would however have a very high electron affinity giving a strongly diamagnetic hexaanion which can be visualized as containing cyclopentadienyl anion units.Thus this spherical hydrocarbon is far removed from graphite.'56 Examination of carbon-13 shielding tensors can be used to evaluate bond orders and hence give a measure of ~-delocalization.*~~ This method has been applied to ~yrene.'~~ By high temperature vacuum thermolysis an equilibrium has been set up between aceanthrylene acephenanthrylene and fluoranthene (Scheme 22). The greater amount of aceanthrylene than acephenanthrylene was unexpected in view of the greater resonance energy of phenanthrene over anthracene. The proposed mechanism is a 1,2-carbon shift and then 1,2-hydrogen shift in the resulting ~arbene.'~~ Whereas in these compounds the double bond represents only a small perturbation in the 152 J.Kao J. Am. Chem. SOC.,1987 109 3817. 153 S. E. Stein and R. L. Brown J. Am. Chem. Soc. 1987 109 3721. 154 S. A. Alexander and T. G. Schmalz J. Am. Chem. SOC.,1987 109 6933. 155 M. Randic S. Nikolic and N. Trinajstic Gazz. Chim. Ztal. 1987 117 69. 156 V. Elser and R. C. Haddon Nature (London) 1987,325,792. See also R.B. Mallion Nature (London) 1987 325 760. 157 J. C. Facelli D. M. Grant and J. Michl Acc. Chem. Res. 1987 20 152. 158 C. M. Carter D. W. Alderman J. C. Facelli and D. M. Grant J. Am. Chem. Soc. 1987 109 2639. 159 L. T. Scott and N. H. Roelofs J. Am. Chem. Soc. 1987 109 5461. 174 R. McCugue \/ aceanthrylene acephenanthrylene fluoranthene 17 9 74 Scheme 22 dianions the pathway of electron delocalization is changed and the bridges become important.16' Synthesis of Condensed Aromatic Compounds.-By Diels- Alder Reactions.Reviews have appeared on the use of Diels-Alder strategy in the synthesis of natural products such as the anthracycline antibiotics,'61 and on orthoquinodimethanes which are useful 4.rr-cornponents in the construction of polycyclic systems.162 Regioselectivity in alkoxyisobenzofuran-aryne cycloaddition is at best only 4 :1 and this is attributed to the high reactivity of the partners.163 However some good regioselectivities have been obtained in the reaction of benzynes with 3-cyano-l(3H)isobenzofurans in what is probably a stepwise addition.'64 Useful 27~ components are the arene endoxides such as (8) which is prepared from furan and 1,2,4,5-tetrabromoben- zene.'6s Cycloaddition between anthracene-1,4-endoxide and 2-xylylene leads to a new synthesis of pentacene'66 and similar strategy leads to extended triptycene~.'~' The bicyclo(3.2.2)nonane (9) has been developed as a synthon in tandem Diels- Alder reactions to prepare linearly condensed ring systems.I6' A tandem Claisen rearrange- ment-intramolecular Diels-Alder cycloaddition strategy has been employed in a total synthesis of 1 1 -deoxydaunornycin~ne.'~~ 8 \ "ds c1' (9) Other Methods of Ring Construction.The traditional method for the synthesis of polycyclic ring systems -cycloalkylation of aldehydes and ketone -has been reviewed."' The ring opening of arylcyclobutenone to ketadienes which can undergo 160 Y.Cohen N. H.Roelofs G. Reinhardt L,. T. Scott and M. Rabinovitz J. Org. Chem. 1987 52 4207. 161 A. Ichihara Synthesis 1987 207. 162 J. L. Charlton and M. M. Alauddin Tetrahedron 1987 43 2873. 163 D. J. Pollart and B. Rickborn J. Org. Chem. 1987 62 792. 164 S. P. Khanapure R. T. Reddy and E. R. Biehl J. Org. Chem. 1987 52 5685. 165 H. Hart C.-Y. Lai G. C. Nwokogu and S. Shamouilian Tetrahedron 1987,43 5203. I66 J. Luo and H. Hart J. Org. Chem. 1987 52 4833. 167 W. C. Christopfel and L. L. Miller Tetrahedron 1987 43 3681. 168 B. Demarchi and P. Vogel Tetrahedron Lett. 1987 28. 2239. 169 G. A. Kraus and S. H. Woo J. Org. Chem. 1987 52 4841. 170 G. K. Bradsher Chem.Rev. 1987 87 1283. Aromatic Compounds electrocyclic ring closure is a useful route to highly substituted naphthalene^'^'-'^^ such as the 5-lipoxygenase inhibitor lonapalene (Scheme 23) and to various cyclopen- tene fused polycyclic systems such as a~eanthry1ene.l~~ p-xylene 138°C L Meono-Me0 0 Me0 HO I \ I THF -78 "C OAc OAc OH Scheme 23 A comparable process is the opening of arylcyclopropenones by metal carbonyls to form intermediate chelated carbenes. The additional carbon required for six- membered ring formation derives by carbon monoxide insertion. This method has been used to synthesize naphthols'74 and ring C of anthra~yclinone.'~~ Naphthols have also been prepared by palladium( ir )-catalysed cyclocarbonylation of cinnamyl alcohol acetates.'76 Preparation of Specifically Substituted Products.The weak interaction of the nitro group in 2-nitropyrene with the ring system leads to electrophilic attack at the adjacent 1 -position taking second preference after attack at the distant 6-positiqn. Thus 38% 1,2-dinitropyrene can be 0btair1ed.l~' Pyrenes with substituents at the 2- and 7-positions can be accessed via intramolecular cyclization and oxidation of 8-methoxy-[2.2]metacyclophanes.'7s Carcinogenicity of Polycyclic Aromatic Hydrocarbons (PAH).-Studies into the mechanism by which PAH exert their mutagenic/carcinogenic activity have now progressed to examination of PAH diol epoxide-DNA adducts. The sites of covalent attachment have been identified for benzo[ c]phenanthrene-3,4-diol-1,2-epoxides by n.m.r.Polydeoxyguanosine is particularly good at catalysing the 17' S. T. Perri and H. W. Moore Tetrahedron Lett. 1987 28 4507. I72 K. Chow and H. W. Moore Tetrahedron Lett. 1987 28 5013. 173 Y.3. Chung;H. Kruk 0. M. Barizo M. Katz and E. Lee-Ruff J. Org. Chem. 1987 52 1284. 174 M. F. Semmelhack S. Ho M. Steigerwald and h.C. Lee J. Am. Chem. SOC.,1987 109 4397. I75 K. H. Dotz and M. Popall Angew. Chern. Int. Edn. Engl 1987 26 1158. 176 Y. Koyasu H. Matsuzaka Y. Hiroe Y. Uchida and M. Hidai J. Chem. SOC.,Chem. Commun. 1987,575. 177 A. M. van den Braken-van Leersum J. Cornelisse and J. Lugtenburg J. Chem. Soc. Chern. Commun. 1987 1156. 17R M. Tashiro T. Yamato K. Kobayashi and T. Arimuro J.Org. Chem. 1987 52 3196. 179 S. K. Agarwal J. M. Sayer H. J. C. Yeh L. K. Pannell B. D. HiLon M. A. Pigott A. Dipple H. Yagi and D. M. Jerina J. Am. Chem. SOC.,1987 109 2497. 176 R. McCague hydrolysis of the epoxides'" and the monohydrogenphosphate group is responsible for the catalysis.'" Reduced tumourigenicity in 6-fluorobenz[ a]pyrene-7,8-diol-9,10- epoxide is explained by the fluorine atom causing the diol to adopt a pseudoaxial conformation whereas a diequatorial conformation is required for activity.lg2 Incor- poration of an isopropyl group into benz[ alpyrene distant from the metabolizable ring does not inhibit metabolism but renders the resulting diol epoxide only weakly active presumably because the isopropyl group sterically impedes intercalation.lg3 PAH epoxides such as triphenylene-l,2-oxide have some interesting properties. They undergo rapid racemization via the oxepin valence ta~tomer''~ and undergo an oxygen-walk rearrangement either an oxepin or epoxide tautomer being preferred in the product to retain the phenanthrene delocalization (Scheme 24). '85,186 Oxygen-walk does not take place in naphthalene-1,2-oxide because the energy barrier is too high,lg5 but a nitrogen-walk in the aziridine derived by methoxycarbonylnitrene attack on naphthalene has been rep~rted.'~' Scheme 24 Syntheses of various polyaromatic compounds possessing a fused indeno ring which are widespread environment mutagens using cyclohexane epoxide to add the indeno fragment have been reported.'88 Twisted Condensed Aromatic Hydrocarbons.-Polycyclic aromatic hydrocarbons twisted longitudinally by almost 70" have been Skeletal deformation in 4,5-disubstituted phenanthrenes results from steric overlap of the ~ubstituents'~' and helical twists of up to nearly 30" have been observed.In 3,4,5,6-tetramethyl- phenanthrene the 3-and 6-methyl groups exert a buttressing effect and raise the energy barrier for enantiomer interconversion from 16.1 to 23.1 kcal mol-'. Individual enantiomers are separable at low temperat~re.'~~ The effect of ring 180 N. B. Islam D. L. Whalen H. Yagi and D. M. Jerina J. Am. Chem. SOC.,1987 109 2108. 181 S. C. Gupta N. B. Islam. D. L. Whalen H. Yagi. and D. M. Jerina. J. Org. Chem.. 1987 52 3812. 182 H. Yagi J. M.Sayer D. T. Thakker W. Levin and D. M. Jerina J. Am. Chem. SOC.,1987 109 838. 183 J. Pataki and R. G. Harvey J. Org. Chem. 1987 52 2226. 184 D. R. Boyd D. A. Kennedy J. F. Malone G. A. O'Kane D. T. Thakker H. Yagi and D. M. Jerina J. Chem. SOC.,Perkin Trans. I 1987 369. '*' D. R. Boyd S. K. Agarwal S. K. Balani R. Dunlop G. S. Gadaginamath G. A. O'Kane N. D. Sharma W. B. Jennings H. Yagi and D. M. Jerina J. Chem. Soc. Chem. Commun. 1987 1633. D. R. Boyd and G. A. O'Kane Tetrahedron Lett. 1987 6395. 187 K. Satake H. Mizushima M. Kimura and S. Morosawa J. Chem. Soc. Chem. Commun. 1987 197. 188 B. P. Cho and R. G. Harvey J. Org. Chem. 1987 52 5668. 189 R. A. Pascal Jr. W. D. McMillan D. Van Engen and R. G. Eason J. Am. Chem. SOC.,1987 109,4660. 190 R.A. Pascal Jr. and D. Van Engen Tetrahedron Lett. 1987 28 293. 191 R. Cosmo T. W. Hambley and S. Sternhell J. Org. Chem. 1987 52 3119. 192 R. N. Armstrong H. L. Ammon and J. N. Darnow J. Am. Chem. SOC.,1987 109 2077. Aromatic Compounds distortions in such compounds increases their reactivity to electrophilic substitu- ti~n.'~~ Compound (10) is interesting because apart from having a high barrier (23 kcal mol-') for interconversion between the enantiomeric syn-forms the anti-isomer is considered to be a high energy intermediate of the con~ersion'~~ and therefore there must be some transmission of torsion through the anthracene system. (10) 6 Cyclophanes Distortion of the Benzene Ring.-Z-[6]Paracycloph-3-ene (11 )prepared by thermal valence isomerization of the corresponding Dewar benzene is more strained than [6]paracyclophane.The former undergoes 1,6methanol addition catalysed by tri- fluoroacetic acid whereas the latter is inert. Bending angles derived from X-ray crystal structures of dimethoxycarbonyl derivatives and defined according to Figure 1 are 4 =19.4" and a =20.2" for the [6]para~yclophanes,'~~ and 20.5 and 24.1" for the [6]para~ycloph-3-ene.'~~ Ab initio molecular orbital calculations on [51para-cyclophane give a value of about 23" for the distortion angle 4. The strain causes the molecule to be 78 kcal mol-' less stable than benzene but little variation in bond lengths around the benzene ring is ca1c~lated.l~' /-_ . Figure 1 Definition of bending angles in [n]paracycZophanes (11) (12) (13) (14) 193 A.P. Laws A. P. Neary and R. Taylor J. Chem. Soc. Perkin Trans. 2 1987 1033. 194 I. Agranat M. R. Suissa S. Cohen R. Isakasson J. Sandstrom J. Dale and D. Grace J. Chem. SOC. Chem. Commun. 1987 381. 195 Y. Tobe A. Nakayama K. Kaiuchi Y. Odaira Y. Kai and N. Kasai J. Org. Chem. 1987 52 2639. I 96 Y. Tobe K.4. Ueda T. Kaneda K. Kakiuchi Y. Odaira Y. Kai and N. Kasai J. Am. Chem. SOC. 1987 109 1136. 197 J. E. Rice T. J. Lee R. B. Remington W. D. Allen D. A. Clabo Jr. and H. F. Schaefer 111 J. Am. Chem. SOC.,1987 109 2902. 178 R. McCugue A range of substituted [S]paracyclophanes prepared by photochemical ring open- ing of Dewar benzenes decompose slowly at room temperature.19' Both Dutch and Japanese workers have intercepted [4]paracyclophane (12) pre- pared photochemically from 1,Ctetramethylene Dewar ben~ene.'~~-~'' It is stable at 77 K2O0and has a temporary existence at -20 0C.199It gives 1,4-adducts with trifluoracetic acid and with methanol. Unlike higher cyclophanes the protonated [4]cyclophane does not rearrange to the rnetu-cyclophane because increased bending reduces charge density ortho to the protonation site.'w Attempts to prepare the even more strained cyclophane (13) from a Dewar benzene were unsuccessful indicating that [4]paracyclophane may represent the limit of the synthetic methodology.200 [4]Metacyclophane (14) has been generated thermally but is not isolated; products arise from Diels- Alder dimerization.201 Attempted photochemical generation from the Dewar benzene gave only a prismane.Ring Interactions.-The in-[34~'0][7]metacyclophane (15) has been prepared by themolytic ring contraction of a trithio[9]cyclophane sulphone. In its n.m.r. spec- trum the bridgehead proton resonates at 6 -4.03.202In the [2.2]paracyclophane (16) non-bonded interactions between the rings result in the phenylene ring becoming deactivated to electrophilic substitution and acid-catalysed rearrangement and the tetracyanoethylene complex has lowered stability.203 Paracyclophanes bearing several cyano and dimethylamino groups have been studied as electron acceptors FF and donors respectively.2-206 [2.21Paracyclophanes bearing phenylmethylenyl car- bene substituents have been used as models for high-spin organic molecules that could lead to organic ferr~magnets.~" In the dianion of the paracyclophane (17) the protons shown resonate at S 8.62 and S 10.31; their deshielding results from the anisotropy of the 4n anion.208 Hence the benzene ring in paracyclophanes can be used to probe the electronic structure of its partner.198 G. B. M. Kostermans W. H. deWolf and F. Bickelhaupt Tetrahedron 1987,43 2955. 199 G. B. M. Kostermans M. Bobeldijk W. H. deWolf and F. Bickelhaupt J. Am. Chem SOC.,1987 109 247 1. 2oo T. Tsuji and S. Nishida J. Chem SOC Chem. Commun. 1987 1189. 20 1 G. B. M. Kostermans P. van Dansik W. H. deWolf and F. Bickelhaupt J. Am. Chem SOC.,1987 109 7887. 202 R. A. Pascal Jr. R. B. Grossman and D.Van Engen J. Am Chem. SOC.,1987 109 6878. 203 R. Filler G. L. Cantrell E. W. Choe 1. Org. Chem. 1987 52 511. 204 H. A. Staab G. Gabel and C. Krieger Chem. Ber. 1987 120 269. 205 H. A. Staab P. Wahl and K.-Y. Kay Chem. Eer. 1987 120 541. 206 H. A. Staab C. Krieger P. Wahl and K.-Y.Kay Chem. Ber. 1987 120 551. 207 A. Izuoka S. Murata T. Sugawara and H. Iwamura J. Am. Chm SOC.,1987 109 2631. *08 R. Frim M. Rabinovitz H. Hopf and J. Hucker Angew. Chem. Znt. Edn. Engl. 1987 109 232. Aromatic Compounds 179 Apart from the [2.2]paracyclophanes suitable [3.3]metacyclophanes have facing benzene rings which can interact and show characteristic spectral propertie~.~’’-~~~ Compound (18) which has rings 3.04 8 apart undergoes reversible 27r + 27r cyclo-addition between the rings.209 Even in systems where the benzene rings are not constrained to lie face to face favourable interaction between a neutral phenyl ring and a benzyl cation can influence the product f~rmation.~~~-~~~ 7 Non-benzenoid Aromatic Systems Non-alternant Ring Systems.-A heavy atom-microwave structure of cyclopropenone shows that it has closer bond lengths in the 3-membered ring than methylene- cyclopropene supporting a 27r-aromatic structure yet the molecule is stabilized by electron-pair donation from the oxygen to the unoccupied ring orbital.214 Evidence has been presented that despite its positive charge the tropylium ion can provide anchimeric assistance in the solvolysis of a nearby bromine atom.*” The oxidation of isopyrene (19) with bidentate oxidants takes place at the central bond to leave a [14]annulene perimeter in accord with electron density calcula- tiom216 Cyclohepta[a]phenylene (20) has been prepared and found to be a highly electron donating hydrocarbon (1st oxidation potential 0.39 V).*17 A study of the 209 W.-D.Fessner G. Sedelmeier P. R. Spurr G. Rihs and H. Prinzbach J. Am. Chem. SOC.,1987,109,4626. 210 S. Mataka K. Takahashi T. Mimura T. Hirota K. Takuma H. Kobayashi M. Tashiro K. Imada and M.Kuniyoshi J. Org. Chem. 1987 52 2653. 211 W.-D. Fessner G. Sedelmeier L. Knothe H. Prinzbach G. Rihs 2.-z. Yang B. Kovac and E. Heilbronner Helu. Chim. Acla 1987 70 1816. 212 J. Nishimura A. Ohbayashi Y. Horiuchi Y. Okada S.-i. Yamanaka and A.Oku J. Org. Chem. 1987 52 1409. 213 R. McCague J. Chem. SOC.,Perkin Trans. 1 1987 1011. 214 S. W. Staley T. D. Norden W. H. Taylor and M. D. Harmony J. Am. Chem. SOC.,1987 109 7641. 215 J. W. Wilt C. George and M. Peeran J. Org. Chern. 1987 52 3739. 216 E. Vogel L. Schamlstieg H.-J. Weyer and R. Gleiter Chem. LrL 1987 33. 217 Y. Sugihara H. Yamamoto K. Mizoue and I. Murata Angew. Chem. Znt. Edn. Engl. 1987 26 1247. 180 R. McCugue azulene-azulene rearrangement with carbon-13 labelled azulenes shows that all the atoms in the five-membered ring are rotated consistent with a mechanism proceeding via a sigmatropic rearrangement of the norcaradiene valence tautomer.218 Annu1enes.-Haddon has developed a combined .rr-orbital-axis vector (POAV) analysis-3 D Huckel molecular orbital theory to provide a generalized treatment for non-planar r-systems.The method is particularly applicable to bridged annulene~.~~~ A Pariser-Parr-Pople welectron model taking into account 7r-electron correlation predicts that calculated ring currents are higher in charged than in neutral systems in accord with experiment so that whereas large ring neutral 4n-systems (4n 3 16) become weakly aromatic the charged 4n species are antiaromatic irrespective of ring size.220 N.m.r. studies of the dianions of annulenes show that their properties are markedly dependent on the configuration of the periphery unlike the neutral species.221-222 Although compound (21) may be termed a homoanthracene position 7 has a hundred-fold lower electrophilic reactivity than position 2 unlike.in anthracene where the 9-position is the most reactive. The low reactivity of position 7 in (21) is attributed to the charge not being stabilized in the bis(n0rcaradiene) structure.223 By means of Wittig condensations and intramolecular oxidative alkyne coupling Ojima and co-workers have been able to prepare a substantial range of annulenes (22) having up to a 38-membered ring in order to establish the limiting ring size for dia- and para-tr~picity.~~~~~’ By comparisons of n.m.r. spectra with those of the precursor having uncoupled alkynes the [28]annulene (4n) and [34]annulene (4n + 2) were shown to sustain a paramagnetic and diamagnetic ring current respectively whereas the [32] and [38] annulenes were atropic.218 A. Wetzel and K.-P. Zeller 2. Naturforsch. Teil B 1987 42 903. 219 R. C. Haddon J. Am. Chem. Soc. 1987 109 1676. 220 S. Kuwajima and Z. G. Soos J. Am. Chem. SOC.,1987 109 107. 221 K.-U. Klabunde K. Miillen and H. Vogler Tetrahedron 1987 43 1183. 222 K. Mullen T. Meul P. Schade H. Schmickler and E. Vogel J. Am. Chem. SOC.,1987 109 4992. 223 A. P. Laws and R. Taylor J. Chem. SOC.,Perkin Trans. 2 1987 1691. 224 J. Ojima E. Ejiri T. Kato M. Nakamura S. Kuroda S. Hirooka and M. Shibutani J. Chem. SOC. Perkin Trans. 1 1987 831. 22s J. Ojima S. Fujita M. Masumoto E. Ejiri T. Kato S. Kuroda Y. Nozawa and H. Tatemitsu J. Chem. SOC.,Chem. Commun. 1987 534.

ISSN:0069-3030    

DOI:10.1039/OC9878400157

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

8 Heterocyclic Compounds By H. McNAB Department of Chemistry University of Edinburgh West Mains Road Edinburgh EH9 3JJ 1 Introduction A notable event during 1987 has been the award of the Nobel Prize for Chemistry to C. J. Pedersen J.-M. Lehn and D. J. Cram. Their work has established and developed the new area of host-guest chemistry. Although it is outside the traditional confines of heterocyclic compounds it is an area in which these materials often play an integral part (see Annu. Rep. Progr. Chern. Sect. B 1983,80 353). Appreci-ations in a historical context have appeared elsewhere' but the current status of the field may be gauged by full papers by Lehn2 and Cram3 in a recent issue of J. Am. Chern. SOC.In the first of these,* the hydrolysis of acetyl phosphate is studied under the influence of catalysis by the polyamine (1) and some eleven related macrocycles.An cNHHN3 O CNH 3 \O";" (1) The formation of pyrophosphate is a unique property of these catalyst systems made possible by (a) binding of the substrate by the receptor catalyst (b) formation of a N-phosphorylated intermediate (c) binding of a second substrate and (d) collapse to the pyrophosphate by intramolecular phosphoryl transfer. To work efficiently the catalyst therefore requires binding sites and transformation sites in correct relative orientation. The particular 'cavitands' which Cram reports3 do not possess heterocyclic nuclei but are composed of a cyclic array of eight meta-linked benzene rings with intermediate methoxy groups supplying the lone pairs needed for complex formation.By coincidence a monograph on the synthesis and design of macrocycles capable of selective cation complexing4 has been published. However it has not been a 'For example Chern. Br. 1987 23 1149. * M. W. Hosseini and J.-M. Lehn J. Am. Chem. Soc. 1987 109 7047. D. J. Cram R. A. Carmack M. P. deGrandpre G. M. Lein I. Goldberg C. B. Knobler E. F. Maverick and K. N. Trueblood J. Am. Chem. Soc. 1987 109 7068. 'Synthesis of Macrocycles The Design of Selective Complexing Agents' ed. R. M. Izatt and J. Christensen Wiley New York 1987. 182 H. McNab vintage year for heterocyclic texts and monographs though another volume of 'Advances in Heterocyclic Chemistry' is always welcome,' and a book on 'Hetero Diels- Alder Methodology' covers a wide range of heterodienes and heterodienophiles.6 The resurgence in free-radical chemistry was highlighted in the Introduction to last year's Annual Reports (Annu.Rep. Progr. Chem. Sec. B 1986 83 1) and this picture has been reinforced by a massive review in which many applications to the construction of heterocyclic rings are detailed.7More recent examples will be dis- cussed in the following sections. Two other reviews describe bifunctional reagents which are generally useful in ring synthesis. Breitmaier has surveyed the use of 3-alkoxyacrolein derivatives (2) in constructing 5-14-membered rings and has included typical experimental procedures,' while chlorosulphonylisocyanate(3) can be used to prepare a wide range of fused- and monocyclic lactams.' AHR 'But NHI (5) R = H (4) (6) R = OAc 2 Three-membered Rings There has been considerable activity in the formation and use of chiral aziridines.Significant asymmetric induction in the aziridine product is observed when the N-amino compounds (4) and (5) are oxidized by lead tetraacetate in the presence of alkenes," though improved preparations of chiral substrates will be required before these reactions can be used in synthesis. The stereoselectivity of such oxidative additions of the N-aminoquinazolinone (5) to a$-unsaturated carbonyl derivatives is much improved when trifluoroacetic acid is present allowing the reaction to be conducted at -60°C.'0c,d For years it has been assumed that N-nitrenes are the intermediates in these aziridinations but it now appears that the mechanism involves nucleophilic attack by the alkene on the N-acetoxy compound (6) in a manner similar to that of alkene peracid oxidation."' The preparation of chiral unsaturated 'Advances in Heterocyclic Chemistry' Vol.41 ed. A. R. Katritzky Academic Press Orlando 1987. D. L. Boger and S. M. Weinreb 'Hetero Diels-Alder Methodology in Organic Synthesis' Academic Press Orlando 1957. ' M. Ramaiah Tetrahedron 1987 43 3541. E. Breitmaier F.-W. Ullrich B. Potthoff R. Bohme and H. Bastian Synthesis 1987 1. A. Kamal and P. B. Sattur Heterocycles 1987 26 1051. lo (a) R. S. Atkinson and G. Tughan J. Chem. SOC.,Perkin Trans. 1 1987 2787; (6)R. S. Atkinson and G.Tughan J. Chem. SOC.,Perkin Trans. 1 1987 2797; (c) R. S. Atkinson and G. Tughan J. Chem. SOC.,Perkin Trans 1 1987 2803; (d) R. S. Atkinson and G. Tughan J. Chem. SOC.,Chem. Commun. 1987,456; (d) R. S. Atkinson and B. J. Kelly J. Chem. SOC.,Chem. Commun. 1987 1362. Heterocyclic Compounds amino acids" has been achieved by ring-opening of the readily available aziridine (7) using carbonyl-stabilized Wittig reagents (Scheme 1). Specific cleavage of the C(3)-N( 1) bond takes place to generate a new optically pure phosphorane which is subsequently trapped by aldehydes." A study of the reactions of the chiral bis-aziridines (9) (derived from mannitol) with C-nucleophiles has shown that bis-ring-opening mono-ring-opening and ring-opening-cyclization processes can all take place but the first is most common and can lead to enantiomerically pure amino acids." (7) Reagents i toluene reflux; ii paraformaldehyde toluene reflux 7h Scheme 1 FNY (9) Y = Ts or CH,Ph or C02CH,Ph The decomposition of thiiranium ions (10) with nucleophiles is still a matter of controversy since species generated in situ from alkenes and arenesulphenyl chlorides react at the less hindered carbon while stable thiiranium ions react at the more substituted carbon atom.The use of alternative precursors has shown that the former is indeed the kinetically controlled pathway in relatively non-polar solvents though considerable complexity is possible even under carefully con- trolled experimental conditions. l3 However intramolecular collapse of hydroxythiiranium ions generated from N-phenylthiomorpholine takes place by exo-attack at the more substituted carbon atom to give a useful synthesis of 5-7-membered ring ethers (1 1 ;70-90% ) (Scheme 2) l4 endo-cyclization occurs only -and in low yield -when n = 2.Remarkably in the presence of fluoride ion stable episulphuranes (12) can be isolated formed by nucleophilic attack at the sulphur J. E. Baldwin R. M. Adlington and N. G. Robinson J. Chem SOC Chem. Commun 1987 153. 12 A. Durkault I. Tranchepain C. Greck and J.-C. Depezay Tetrahedron Lett. 1987 28 3341. 13 (a) G. H. Schmid M. Strukelj S. Dalipi and M. D. Ryan J. Org. Chem 1987 52 2403; (b) G. H. Schmid M. Strukelj and S. Dalipi Can. 1. Chem. 1987 65 1945. 14 P.Brownbridge J. Chem. SOC,Chem. Commun. 1987 1280. 184 H. McNab -+ PhS-0 Scheme 2 F SMe I S-Me -H-+ A -H-fi-Me Me F v; Me Me H Reagents i CHC13 3 days 20 "C (12) Scheme 3 atom (Scheme 3).15 Though two epimers (differing in configuration at sulphur) are obtained these do not readily interconvert either by pseudorotation or by dissoci- ation-recombination. The isolation of the first selenirane has provided the first chemical evidence for the existence of selenirene intermediates (Scheme 4).16 Thus photolysis of the selenadiazole (13) in the presence of furan gave the cycloaddition product (14) in 12% yield. Although 1H-phosphirenes are relatively well known (see Annu. Rep. Progr. Chem. Sect. B 1985 82 184) the first 2H-isomer (15) has only now been obtained as an air-stable liquid by a photolytic route (Scheme 5).Its X-ray structure has been determined as a tungsten pentacarbonyl complex." The P=C bond is much shorter than expected for normal phosphaalkenes. The crystal structure of a related phosphasilirene (16; R = adamantyl) [also determined as its W(CO)5 com-plex] was also reported this year.18 The compounds (16) were obtained 'in a surprisingly straightforward fashion' by addition of di-t-butylsilylene to the appropri- ate phosphaalkyne." ' 0$se] &-e + other products 0 Reagents i hv; ii furan (14) Scheme 4 Reagents i hv pentane -40°C Scheme 5 l5 J. C. Carretero J. L. Garcia-Ruano and J. H. Rodriguez Tetrahedron Lett. 1987 28,4593.W. Ando Y. Kumamoto and N. Tokitoh Tetrahedron Lett. 1987 28 2867. " 0. Wagner G. Maas and M. Regitz Angew. Chem. Int. Ed. Engl. 1987 26 1257. A. Schafer M.Weidenbruch W. Saak and S. Pohl Angew. Chem. Int. Ed. Engl. 1987 26 776. Heterocyclic Compounds 185 The thermal stability of the triaziridine system can be dramatically improved by incorporating the N3 ring into a rigid framework." Both (17) and (18) were synthe- sized by photolytic decomposition of an appropriate azidoazo derivative; (17) in particular is thermally stable for several hours at 200 OC,190 while (18) having a hydrocarbon skeleton was used to study N-oxidation of the system.19' (16) R= But or adamantyl 3 Four-membered Rings Work on simple four-membered ring systems has been rather sporadic in recent years and this trend continues.However two more azetes [(19) and (20)] have been detected by i.r. and mass spectroscopy at -40 "C and below.20a A new route to their 1,2,3-triazine precursors was also developed.20b At normal temperatures the azete (19) polymerizes but the perfluoroalkyl compound (20) cleanly dimerizes by C=N cycloaddition to give the tricyclic derivative (21).20 In a detailed paper the complex reactions of Dewar pyrimidinones [e.g. (22)] in the presence of carboxylic acids are described.21 The major products (up to 76% yield) are pyrimidinium betaines [e.g. (23)]. It is a curious feature of their formation that the carboxyl carbon atom of the acid appears in the product at the 2-position. The mechanism shown in Scheme 6 involving protonation and successive ring opening is consistent with this and with 13C labelling experiments.21 RN "p" (19) R = F R (20) R = CF(CF3)2 (21) R = CF(CF,) Full details are now available of the preparation and chemistry of benzothiet-2-one (24) (stable below -40 "C) and the naphthothietones (sensitive but stable crystal- line solids at room temperature).22 A corresponding naphthooxetone (25) was also prepared by flash pyrolysis methods and found to be much less stable than its thietone analogue.22 19 (a)0.Klingler and H.Prinzbach Angew.Chem. In[. Ed. Engf. 1987,26,566; (b)W. Marterer H. Fritz and H. Prinzbach. Tetrahedron Lett.. 1987 28 5497. (a)R. D. Chambers M. Tamura T. Shepherd and C. J. Ludman J.Chem. SOC.,Chem. Commun. 1987 1699; (b)R. D. Chambers M. Tamura J. A. K. Howard and 0.Johnson J. Chem. SOC,Chem. Commun. 1986 1697. 21 S. Hirokami T. Takahashi M. Nagata and T. Yamazaki J. Org. Chem 1987 52 2455. 22 C. Wentrup H. Bender and G. Gross J. Org. Chem. 1987 52 3838. 186 H. McNab Me MeN\ Me MeN\ Me MeGre -+ANH c--MeC0OANH transfer acyl HOzC AcO-Bu' 0 But 0 But I Scheme 6 The challenge of synthesizing four-membered ring systems with two adjacent heteroatoms has been taken up by a number of groups. No special 'aromatic' stabilization is predicted to be associated with the 6welectron dioxetenes (26) or diazetines (27) and calculations suggest that conrotatory ring opening is highly exothermic with a lower activation energy than the corresponding cyclobutene- butadiene process.23 Nevertheless the parent 1,2-thiaselenete (28) and 1,2-diselenete (29) have been generated thermally and detected by photoelectron spectroscopy in the gas phase and by i.r.spectroscopy in an argon In contrast a fused-ring >:po$;;qq-k (26) X = Y = 0 0 0-0 0-0 (27) X = Y = NH (28) X = S,Y = Se (30) (32) (29) X = Y = Se (31) X = Y = PR 23 P. H. M. Budzelaar. D. Cremer M. Wallasch E.-U. Wurthwein and P. von R. Schleyer J. Am.Chem. SOC.,1987 109 6290. 24 (a)F. Diehl and A. Schweig Angew. Chem. Int. Ed. Engl. 1987,26,343; (b)W. Ando Y. Kumamoto and N. Tokitoh Tetrahedron Lett. 1987 28 5699. Heterocyclic Compounds 187 example generated in situ behaves as its 1,2-diselenone isomer (30)in cycloaddition reactions.24b A new route to 1,2,3,4-tetrasubstituted 1,2-dihydro-1,2-diphosphetes [cf.(31)] involves ring expansion of phosphirenes induced by dichlorophosphanes yields vary from 15-80% .25 At the fully saturated oxidation level the exotic trisdioxetane (32) can be generated by matrix photo-oxidation of tetramethylbutatriene it fragments to acetone and COz at 45 K.26Another exotic structure (33) contains the first stable 1,2-dithietane unit.” Its X-ray crystal structure is reported together with a number of intriguing reactions including transformation to the alkene (34) under a variety of conditions (Scheme 7). The thermal desulphurization is of particular interest in view of the report of the generation and trapping of diatomic molecular sulphur via in situ generation and thermolysis of the dithione (35)in which a 1,2-thietane is an obvious intermediate (Scheme 8).28 fli0 __* 0 OH 0 OH H H (33) (34) Reagents i hv or heat o r Bu,SnH Scheme 7 Q-c=s -P’ S I cs,i + S x (35) Scheme 8 P-Lactam.-A number of broad areas may be featured in this the most highly specialized section of heterocyclic chemistry in recent years.First a useful review of enantioselective syntheses of carbapenems emphasizes the increasing importance of this field (cf. Annu. Rep. Progr. Chem. Sect. B 1986,83 177; ibid. 1985,82 186).29 25 L. Ricard N. Maigrot C. Chamer and F. Mathey Angew. Chem. Int. Ed. Engl. 1987 26 548.26 W. Sander and A. Patyk Angew. Chem. Znt. Ed. Engl. 1987 26 475. 27 K. C. Nicolaou C.-K. Hwang M. E. Duggan and P. J. Carroll 1. Am. Chem Soc. 1987 109 3801. 28 K. Steliou P.Salama D. Brodeur and Y. Gareau J. Am. Chem. SOC.,1987 109 926. 29 T. Nagahara and T. Kametani Heterocycles 1987 25 729. 188 H. McNab Secondly the stability of the four-membered ring to free-radical conditions has been exploited by a number of groups in annelation reactions to give bicyclic p-la~tams.~' The general strategy involves generation of the radical by treatment of an appropriate halogeno-compound with tributyltin hydride followed by competitive em- and endo-cyclization onto an adjacent alkene (e.g. Scheme 9). Carbapenam and car- bacepham and their benzo-deri~atives~'~ have been created in this way.R I + + 0OR* 0OR OAAd R' Reagents i Bu3SnH AIBN Scheme 9 The use of p -1actams as intermediates in diastereoselective total syntheses has been highlighted recently31 and may be exemplified by applications to the preparation of amino acid32 and sugar33 derivatives. Such routes are attractive because the or availability of chiral sub~trates,~~' the possibility of efficient asymmetric induction,32b may be combined with a facile cleavage of the four-membered ring under reductive,32b or conditions. New p-lactams of novel structure include the first a-vinylidene derivatives [e.g. (36)],34 azetidine-2,3-diones (37)3' (which provide a route to cis-3p-amidoa~etidinones~'),and the fused p-lactam- y-lactam (38) .36a The development of active y-lactam antibiotics has also been reported.36b 4 Five-membered Rings As techniques become available the fundamental properties of small heterocycles in the gas phase are being investigated.Examples this year include the use of a 30 (a) J. Knight and P. J. Parsons J. Chem. SOC.,Perkin Trans. 1 1987 1237; (b) M. D. Bachi A. De Mesmaeker and N. S. De Mesmaeker Tetrahedron Lett. 1987 28 2637; (c) M. D. Bachi A. De Mesmaeker and N. S. De Mesmaeker Tetrahedron Lett. 1987,28,2887; (d)G. Just and G. Sacripante Can. J. Chem. 1987 65 104. 31 Chem. Ind. (London) 1987 796. '* (a) I. Ojima and H.-J. C. Chen J. Chem. SOC.,Chem. Commun. 1987; 625; (b) 1. Ojima and X. Qiu J. Am. Chem. SOC. 1987 109 6537. 33 (a) F.M. Hauser S. R. Ellenberger and R. P. Rhee J. Org. Chern. 1987 52 5041; (b) D.-C. Ha and D. J. Hart. Tetrahedron Lett. 1987 28 4489. 34 J. D. Buynak J. Mathew M. N. Rao E. Haley C. George and U. Siriwardane J. Chem. Soc. Chem. Commun. 1987 735. 35 J. J. Tufariello D. J. P. Pinto and A. S. Milowsky Telrahedron Lett. 1987 28 5481. 36 (a) J. T. Drummond and G. Johnson Tetrahedron Lett. 1987 28 5245. (b) L. N. Jungheim and S. K. Sigmund J. Org. Chem. 1987 52 4007. Heterocyclic Compounds pulsed electron-beam mass spectrometer to study clustering and hydration reactions of protonated species and radical cations derived from pyrrole furan thiophene and their tetrahydro derivative^,^^ and the use of radiolysis methods to study the gas-phase electrophilic substitution of pyrrole furan and thiophene derivatives by isopropyl cation.38 Whereas a-protonation of all the heteroaromatics is found,37 positional selectivity for the alkylation varies with the heteroatom being pre- dominantly a for furan and p for pyrroles while thiophene shows little discrimina- ti~n.~* In another fundamental paper the rate of isomerization of the 'homoazoles' (39A and B) uia the dipolar intermediate (40) was also found to be strongly dependent on the heter~atom~~ (Scheme 10) (relative rates X = S:NC02Me:0 = 63,100:72 l) thus demonstrating their substantially different influence on the stability of carbonyl ylide-like intermediates.(40) X = 0,S NC0,Me Scheme 10 Radical cyclization methods for generating the pyrrolidine nucleus have been de~eloped.~' The use of bulky dichloromethyl radical centres affects the transition state for cyclization to give much higher regio- and cis-stereo-selectivity than has previously been observed in N-ally1 cyclizations (Scheme 1l).40"The remaining halogen atoms can be removed if required by further treatment with tributyltin h~dride.~'"The generation and cyclization of aminyl radicals from the carbamates (41) is at a much earlier stage of development but useful cyclization yields can be obtained particularly under acidic condition^.^'^ P Phhd H H 79% H Reagents i Bu,SnH AIBN 70 "C 3h; ii 3Bu3SnH AIBN Scheme 11 Two more new methods for the synthesis of 2-arylpyrroles have appeared4' (cf Annu.Rep. Progr. Chern. Sect. B 1986 83 178) full experimental details for the key 4-oxoarylbutanals (42) should prove particularly useful and the methods are 37 K. Hiraoka H. Takimoto and S. Yamabe J. Am. Chem. SOC.,1987 109 7346. 38 G. Laguzzi and M. Speranza J. Chem. SOC.,Perkin Trans. 2 1987 857. 39 F.-G. Klarner and D. Schroer Angew. Chem. Inr. Ed. Engl. 1987 26 1294. 40 (a) T. Watanabe Y. Ueno C. Tanaka M. Okawara and T. Endo Tetrahedron Lett. 1987 28 3953; (b) M. Newcomb and T. M. Deeb J. Am. Chem. SOC.,1987 109 3163. 41 C. G. Kruse J. P. Bouw R. van Hes A. van de Kuilen and J. A. J. den Hartog Heterocycles 1987 26. 3141. 190 H. McNab suitable for large scale work. 2-Bromopyrroles have been little used in synthesis because of their instability.However they can be converted in situ into stable N-t-butyloxycarbonyl derivatives which readily undergo lithium-halogen exchange and conversion into a range of products (Scheme 12; E = TMS I C02H etc.) generally in yields in excess of 70% (Scheme 12).42 The anhydride of pyrrole-l- carboxylic acid (43),.and its indole analogue have been made and they react readily with nucleophiles (including pyrrolyl anions) to give N-carbonyl derivative^.^^",^ The general area of heterocyclic N-carboxylic acids has been reviewed.43cid Other substituted pyrroles described this year include simple N-protected 1 H-pyrrol- 3(2H)-ones (44) (prepared by a Wittig strategy,44 and used in the attempted synthesis of a~aazulenones~~~) and the related N-cations [e.g.(45)l."' r 1 BOC BOC Reagents i 1,3-dibromo-5,5-dimethylhydantoin; ii (BOC),O; iii BuLi -78 "C; iv E+ Scheme 12 In an extensive paper Battersby and co-workers describe the preparation and rearrangement reactions of some simple 2 H-pyrrole derivatives as well as more complex examples related to proposed porphyrin biosynthetic intermediate^.^^ Sig-matropic rearrangement of the 2,2-dibenzyl compound (46) to its 2,3-isomer takes place thermally or under acid conditions but no clean reactions occur if the 2H-pyrrole has substituents at the 3-and 4-positi0ns.~ However under 42 W. Chen and M. P. Cava Tetrahedron Lett. 1987,28 6028. 43 (a) D.L. Boger and M. Patel J. Org. Chem. 1987,52 2319; (b) D.L. Boger and M. Patel J.Org. Chem. 1987,52 3934; (c) A. R. Katritzky H. Faid-Allah and C. M. Marson Heferocycles 1987,26 1333;A. R. Katritzky C. M. Marson and H. Faid-Allah Heterocycles 1987,26 1657. 44 (a) W. Flitsch K. Hampel and M. Hohenhorst Tefrahedron Lett. 1987,28 4395;(b)W. Flitsch R. A. Jones and M. Hohenhorst Tetrahedron Lett. 1987,28 4397. 45 M. E. Jung and B. E. Love J. Chem. SOC.,Chem. Commun. 1987 1288. 46 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. Heterocyclic Compounds 191 intramolecular condition^,^' intermediate 3H-pyrroles (generated in situ from 2H-pyrroles) can be intercepted by cycloaddition to give the tricyclic products e.g. (47) and (48) (Scheme 13). The absence of 2H-pyrrole cycloaddition products is noteworthy and is rationalized by thermochemical analyses supported by ab initio ca~culations.~~ Reagents i benzene 210 "C 24h Scheme 13 New routes to furans include the condensation of P-dicarbonyl compounds with enol ethers in the presence of a manganese(II1) reagent,48 and a radical cyclization of propargyl ether derivatives also derived from enol both of these methods give 2,3-disubstituted examples (Scheme 14) and yields for the cyclization steps are typically >70%.3-Iodo-4-methylfuran is obtained in a one-pot procedure starting from 4-hydroxy-1-methoxybut-2-yne (Scheme 15) and the product can be further elaborated by metal-halogen exchange to give a general route to 3-substituted-4- methylf~rans.~~ COMe + MeCOCH2COMe i_ EtOoMe ($:ye OEt 0 0 Reagents i Mn,O(OAc), 40 "C 10 min; ii TsOH benzene 90 "C 4h Bun I + Ill I ii iii Buihb Bun Bun Br + + I\ OEt ,J Ph OEt Ph OH Ph Reagents i NBS -40 "C; ii Bu3SnCI NaBH,CN AIBN; iii TsOH benzene 20 "C Scheme 14 Work on the properties of the furan ring continues to be dominated by cycloaddi- tion reactions.Photo-oxidation reactions which generally involve the initial [4 + 21 cycloaddition of singlet oxygen to give endoperoxides [e.g. (49)] have been reviewed,'l and full details of cycloadditions of oxyallyl carbocations (50) with 47 A. Eddaif A. Laurent P. Mison N. Pellissier P.-A. Carrupt and P. Vogel J. Org. Chem. 1987,52,5548. 48 E. J. Corey and A. K. Ghosh Chem.Lett 1987 223. 49 A. Srikrishna and G. Sunderbabu Tetrahedron Lett. 15187 28 6393. 50 H. J. Reich and R.E. Olson J. Org. Chem. 1987 52 2315. 51 B. L. Feringa Red. Trav. Chim. Pays-Bas 1987 106 469. 192 H. McNab foMe Ill < OH Reagents i 2Bu'Li; ii MeI; iii I,; iv H30+ Scheme 15 polysubstituted furans have been published.52 'Furan transfer' methodology (cf Annu. Rep. Progr. Chem. Sect. B 1985 82 189) requires the generation and intramolecular cycloaddition of an intermediate allene and has been applied to the synthesis of the tricyclic derivative (51) which was further elaborated to the angular methyl compound (52) required for natural product syntheses (Scheme 16).s3 0 0-Rt/\ R2 '+' Reagents i BU'OK 83 "C 30 min Scheme 16 There is continued interest in the 3,4- and 2,3-dimethylene derivatives of furan and thiophene [(53) (54)].In the 3,4-~eries,~~ the singlet ground-state of the furan diradical (53; X = 0)has been directly observed in a matrix at 77 K by magic angle spinning n.m.r.,54a while competitive trapping experiments confirm the identity of (53; X = S) generated from two different In the 2,3-~eries,~~ the furan derivative (54; X = 0) has been identified in the gas phase by its photoelectron spectrum and photolytically isomerized to its cyclobuta-valence isomer (55),5sawhile the thiophene analogue (54; X = S) generated in solution was trapped by reaction with dienophile~."~ x = 0,s x = 0,s (53) (54) (55) 52 J. Mann H. J. Holland and T.Lewis Tetrahedron 1987 43 2533. 53 Y. Yamaguchi K. Hayakawa and K. Kanematsu J. Chem. SOC.,Chem. Comrnun. 1987 515. 54 (a) K. W. Zilm R. A. Merrill M.M. Greenberg and J. A. Berson J. Am. Chem. Soc. 1987 109 1567; (b) M. M. Greenberg S. C. Blackstock and J. A. Berson Tetrahedron Lett. 1987 28 4263. 55 (a) N. Munzel and A. Schweig Angew. Chem. Int. Ed. Engl. 1987 26 471; (b) D. J. Chadwick and A. Plant Tetrahedron Lett. 1987 28 6085. Heterocyclic Compounds 193 The highlight of phosphole chemistry during 1987 has been the mild cleavage of 1,2-bis( phospho1yl)ethanes by alkali metals to afford a particularly clean synthesis of simple phosphole anions and hence a route to P-unsuhstituted pho~pholes.~~ Spectroscopic characterization of the parent compounds (56) and (57) has also been reported.56b + IPh Two useful transformations have been discovered in indole chemistry.Treatment of the salt (58) with alkyl- or aryl-lithium reagents in the presence of boron trifluoride etherate gives the corresponding 3-alkyl or 3-aryl derivative in ca. 60% yield,57 while thallation of indole 3-carboxaldehyde has been found to take place exclusively at the 4-position." The bis-trifluoroacetate derivative so obtained can be transformed into a variety of simple 4-substituted products; conditions for removal of the 3-substituent are also reported.s8 Mechanistic work59 on the acid-catalysed rearrangement of 3,3-disubstituted 3 H-indoles (59) to their 2,3-disubstituted isomers has established migrating aptitudes for a range of alkyl substituents and also that the rearrangement of spiro-derivative (60) is some 7400 times faster than that of the simple dimethyl compound (59; R = The results have implications for the presence of a spiro-intermediate in the Pictet-Spengler rea~tion,'~" and this has indeed been established using deuterium labelling experiments for cyclization of an aza-analogue (Scheme 17).59' Deuterium scrambling in the product is thought to indicate that the ultimate cycliz- ation to the six-membered ring is slow with respect to the earlier equilibria shown in Scheme 17.59' cis-1,3 -Disubstituted P-carboline derivatives are formed stereo- and enantio-selectively from tryptophan methyl ester and aldehydes in the Pictet- Spengler reaction provided that the reaction is carried out at low temperature (0 oC).s9d 56 (a) C.Charrier N. Maigrot and F. Mathey Organometallics 1987 6 586; (b) C. Charrier and F. Mathey Tetrahedron Lett. 1987 28 5025. 57 R. M. Moriarty Y. Y. Ku M. Sultana and A. Tuncay Tetrahedron Lett. 1987 28 3071. 58 F. Yamada and M. Somei Heterocycles 1987 26 1173. 59 (a) A. H. Jackson and P. P. Lynch J. Chem. SOC. Perkin Trans. 2 1987 1215; (b)J. S. L. Ibaceta-Lizana A. H. Jackson N. Prasitpan and P. V. R. Shannon J. Chem. SOC. Perkin Trans. 2 1987 1221; (c) P. D. Bailey J. Chem. Res. (S) 1987 202; (d) P. D. Bailey S. P. Hollinshead and N. R. McLay Tetrahedron Left. 1987 28 5177. 194 H. MclL'ab MeNLNMe /- CD2O + W N ' H &DD H + other isotopomers + WMe ' N H Scheme 17 Stereocontrol is also a feature of modified intramolecular azatriene cycloadditions which give rise to hydroisoindoles:60 examples are shown in Scheme 18.The use of dichloromaleic anhydride (61) and related species is of particular interest,60b since the trans-adducts [e.g. (62)]can be reduced to give the cis-fused product (63) (Scheme 18). New fully unsaturated isoindole analogues include the parent pyr- rolopyridines (64) and (65):their syntheses and Diels- Alder reactions are reported.61 OCH2Sl.r)c \ -eNCH2Ph ref. 60a Reagents i heat (170 "C) H Reagents i 0°C; ii Zn HOAc (63) Scheme 18 60 (a) A. Guy M. Lemaire Y. Graillot M. Negre and J.-P.Guette Tetrahedron Lett.1987 28 2969; (b) J. M.Mellor and A. M. Wagland Tetrahedron Lett. 1987 28 5339. 61 C.-Y. Tsai and C.-K. Sha Tetrahedron Lett. 1987 28 1419. 195 Heterocyclic Compounds ~ (67) X = S Last year's activity in the isobenzofuran field has not been maintained (Annu. Rep. Progr. Chern. Sect. B 1986 83 182) though a comprehensive study of the reaction of the 1 -ethoxy-3-trimethylsilyl derivative with unsymmetrical arynes has established at best modest regioselectivity.62 The cyclopropisobenzofuran (66) and cyclopropisobenzothiophene (67) are the first heterocyclic cycloproparenes to be Both compounds decompose in the solid state and in solution the furan (66) is 4 times less reactive than isobenzofuran itself in the Diels-Alder reactions with dimethyl fumarate.The first benzoborole (68) has been generated using flash vacuum pyrolysis methods.64 It dimerizes to the diboradibenzazulene (69) at temperatures above -90 "C but it was successfully trapped with but-2-yne to give the first example of a 1-benzoborepin (70) (Scheme 19)64 (see also Section 6). c1 Reagents i -90°C; ii Me-=-Me (70) Scheme 19 A number of groups have studied cycloaddition reactions of novel a~oles.~~-~~ The isopyrazole (71) gives the expected azo-bridged cycloadduct with simple cyclo- alkenes though the reaction is best carried out at high pressure (7 kbar).65 Generation of the pyrazolone (72) in situ gives in 5 min a 77% yield of the cyclazine derivative (73) (Scheme 20).66 Deprotonation of 2-alkylimidazolidinium salts with base yields 62 D.J. Pollart and B. Rickborn J. Org. Chem. 1987 52 792. 63 I. J. Anthony and D. Wege Tetrahedron Lett. 1987 28 4217. 64 W. Schacht and D. Kaufmann Angew. Chem. Int. Ed. Engl. 1987 26 665. 65 K. Beck S. Hiinig F.-G. Klarner P. Kraft and U. Artschwager-Perl Chem. Ber. 1987 120 2041. 66 J. C. Medina R. Cadilla and K. S. Kyler Tetrahedron Lett. 1987 28 1059. 67 (a) U. Gruseck and M. Heuschmann Chem. Ber. 1987,120,2053; (b)U. Gruseck and M. Heuschmann Chem. Ber. 1987 120 2065; (c) U. Gruseck and M. Heuschmann Tetrahedron Lett. 1987 28. 6027. 68 W. L. Magee C. B. Rao J. Glinka H. Hui T. J. Amick D. Fiscus S. Kakodkar M. Nair and H. Shechter J. Org. Chem. 1987 52 5538. 196 H. McNab the 2-alkylidene derivatives [e.g.(74)],67" which act as ketene equivalents in the inverse-electron-demand Diels- Alder reaction,67 by cycloaddition (at room tem- perature or below) with electron deficient dienes followed by mild acid hydrolysis of the resulting aminal. The use of pyridazines and of 1,2,4-triazines as the diene component in this reaction gives new routes to benzene and pyridine derivatives re~pectively.~~' Shechter and co-workers have published an extensive paper on the 1,7-~ycloaddition reactions of diazoazoles (75) with electron-rich alkenes (e.g. enamines). The cyclization is usually followed by an elimination step (e.g. of the secondary amine in the enamine reactions) to give the fully conjugated fused heterocycle though in some cases tautomerization takes place preferentially.68 Me I "k (71) IMe x3 (74) (75) X = N and/or CR (72) (73) Reagents i Pb(OAc) Scheme 20 In two useful papers convenient recipes for 4(5)-acylimidazole~,~~ and 2- 4- and 5-formylthia~oles~~ are described.New stable 1,3-dioxolium salts [e.g. (76)] have been i~olated,~' and a new class of mesoionic system the tetrazolyliophenolates (77) have been prepared.72 A variety of phosphorus-containing five-membered rings are now available by dipolar cycloaddition to stable phosphaalkyne~.'~ Thus diazo- compounds give 1,2,4-diazaphospholes (78),'3a azides give 1,2,3,4-triazaphospholes (79),73b nitrilium betaines give the appropriate azaphospholes [e.g. (80) (81)];73d mesoionics can also act as dipolar reagents in these cy~loadditions.~~' Full experi- mental details are given in each of these paper^.^^^-^ 69 L.A. Reiter J. Org. Chem. 1987 52 2714. 70 A. Dondoni G. Fantin M. Fogagnolo A. Medici and P. Pedrini Synthesis 1987 998. " W. Lorenz and G. Maas J. Org. Chem. 1987 52 375. 72 S. Araki N. Aoyarna and Y. Butsugan Tetrahedron Lett. 1987 28 4289. 73 (a) W. Riisch U. Hees and M. Regitz Chem. Ber. 1987 120 1645; (b) W. Rosch T. Facklarn and M. Regitz; Tetrahedron 1987 43 3247; (c) W. Rosch H. Richter and M. Regitz Chem. Ber. 1987 120 1809; (d) W. Rosch and M. Regitz Sjwthesis 1987 689. Heterocyclic Compounds New examples of azapentalenes include the first 2,Sdiaza-derivatives (83) and (84) prepared conventionally from the readily available dione (82) (Scheme 21);74a their reactions with acids C-nucleophiles and with P0Cl3/ PC15 are described.In addition the 'spaced' analogue (85) (a 2,6-diaza-s-indacene) is rep0rted.7~~ The three diazapentalenones (86)-(88) are now available in two steps from the Reagents i P4SI0;ii EtI Me2C0 K,CO,; iii NaH DMF; iv ButMe2SiCl Scheme 21 appropriate azole ~arboxaldehyde;~~ their n.m.r. spectra show no evidence for cyclic delocalization to an 8n-electron system.75 A comprehensive paper on the 'hyper- valent pnictogens' (89) (cf:Annu. Rep. Progr. Chern. Sect. B 1985 82 193) covers their synthesis spectra chemical and electrochemical properties and X-ray crystal structure^.^^ Thirteen years have elapsed since the first preparation of tetraselenaful-valene (go) but it is only now that the parent tellurium analogue (91) has been synthesized to complete this series of welectron donors.77 The route combines organotin organopalladium and organolithium chemistry but the final step is (85) (86) (87) (88) (a) F.Closs and R. Gompper Angew. Chem. Int. Ed. Engl. 1987 26 552; (b) F. Closs R. Gompper U. Nagel and H.-U. Wagner Angew. Chem. Znt. Ed. Engl. 1987 26 1036. (a) H. McNab J. Chem. Soc. Perkin Trans. 1 1987 653; (b) H. McNab J. Chem. Soc. Perkin Trans. 1 1987 657. A. J. Arduengo 111 C. A. Stewart F. Davidson D. A. Dixon J. Y. Becker S. A. Culley and M. B. Mizen J. Am. Chem. Soc. 1987 109 627. R. D. McCullogh G. B. Kok K. A. Lerstrup and D. 0.Cowan J.Am. Chem. SOC.,1987 109 4115. 198 H. McNab Rcf>R +o-x-0 2-X =P As Sb (90) X =Se R =Ph But adamantyl (91) X =Te (89) simply the reaction of the dilithium salt of ethylene-l,2-ditelluride with tetra- chloroethylene." The first 3a,7a-dihydrobenzimidazolederivatives [e.g. (92)] have been made by cobalt-mediated [2 +2 +21 cycloaddition followed by demetallati~n~~ (Scheme 22) while the novel .fused pyrazoles (93) are formed by collapse of cyclooctatetraenyldiazomethane derivative^.'^ The first examples of the isomeric selenazolopyridine systems (94)-(96) have been synthesized using a selenoester as the key intermediate.80 SiMe3 SiMt N-HA ,SiMe3 N-HA ~ H I Co (HI Reagents i C~CO(CO)~, hv heat; ii CuCI, DME H20 0°C Scheme 22 Examples of complex indole-like systems include the benzodipyrroles (97)-(99) prepared in three efficient steps from appropriate dinitro-p-xylenes,8' and the anne- lated 18~-electron isoindoles (100) and (101) which can undergo cycloaddition and electrophilic substitution reactions.82 The complex anti-tumour antibiotic CC-1065 (102) has been the object of much synthetic effort in recent years.83" A total synthesis has now been reported by workers at the Upjohn company in which the labile spiro-cyclopropyl segment is introduced by treatment of the 'phenol chloride' [part structure (103)] with aqueous triethylamine as the final step of the sequence.836 78 R.Boese H.-J. Knolker and K. P. C. Vollhardt Angew. Chem. Inr. Ed. Engl. 1987 26 1035.79 D. C. Sanders A. Marczak J. L. Melendez and H. Shechter 1. Org. Chem. 1987 52 5622. 80 A. Couture P. Grandcloudon and E. Hugueme Synthesis 1987 363. 81 A. Berlin S. Bradamante R. Ferraccioli G. A. Pagani and F. Sannicolo J. Chem. SOC. Chem. Commun. 1987 1176. 82 R. P. Kreher and T. Hildebrand Angew. Chem. Int. Ed. Engl. 1987 26 1262. 83 (a) V. H. Rawal R. J. Jones and M. P. Cava Heterocycles 1987 25 701; (b) R. C. Kelly 1. Gebhard N. Wicnienski P. A. Aristoff P. D. Johnson and D. G. Martin 1.Am. Chem. SOC.,1987 109 6837. Heterocyclic Compounds fi H H H H H (97) (99) 5 Six-membered Rings Optically active 143-and 4-pyridy1)ethanols of R-configuration are required for alkaloid and pharmaceutical syntheses but only the S-enantiomers have previously been accessible (by microbial reduction of the corresponding acetylpyridines).Now a non-enzymatic reduction using lithium borohydride with dibenzoylcystine as chiral auxiliary gives the required isomers directly in >70% chemical yield and ca. 80% enantiomeric excess.84 There have been four notable 'firsts' in pyridine chemistry. The first pyridine Reissert compound (104) and related compounds can be made in low -but manipula- tively convenient -yield by reaction of pyridine with benzoyl chloride and trimethyl- silyl cyanide in the presence of aluminium tri~hloride.~~ The first cyclopropapyridine (105) was prepared by a photolytic method and its X-ray crystal structure deter- mined,86 while the first formyl onium salts (106) were obtained in >70% yield by decomposition of a dimethylaminopyridine-trimethylsilyl bromide complex with fiH N CN I COPh NHCOPh 84 K.Soai S. Niwa and T. Kobayashi J. Chem. SOC.,Chem. Commun. 1987 801. 85 F. D. Popp I. Takeuchi J. Kant and Y. Hamada J. Chem. SOC.,Chem. Commun.,1987 1765. 86 R. Bambal H. Fritz G. Rihs T. Tschamber and J. Streith Angew. Chem. Int. Ed. Engl. 1987,26,668. 200 H. McNab acetic formic anhydride." Decarbonylation takes place above 110 "C but the parent pyridine analogue is unstable even at room temperature. The first examples of 'effective' [4 + 21 cycloadditions of pyridin-2-ones with electron-rich dienophiles take place in respectable yield when 1,3-disulphonyl derivatives (107) are used as the substrate" (Scheme 23).The products may be useful in the synthesis of enan- tiomerically pure aminocyclohexanols.'' Reagents i heat or pressure (7 kbar) Scheme 23 An improved route to the dihydropyridin-4-one (108) has led to the synthetically useful salts (109) and (110) (Scheme 24).89 Reaction of either salt with Grignard reagents gives 2-substituted derivatives but the thio-compound ( 1 10) has the addi- tional flexibility of a subsequent thio-Claisen rearrangement to yield 2,3-disubstituted analogues (Scheme 24) which may be hydrolysed to piper id one^.'^' Comprehensive full papers on the iminium ion-vinylsilane cyclization route to tetrahydropyridines (Scheme 25)90cover the scope of the rea~tion,'~" its mechanism (with emphasis on the nature of the rate-determining step9'') and applications to natural product Addition of organo-cuprates to 2-siloxypyrylium salts proceeds with good regioselectivity to give the 4-alkyl-4H-pyrans (1 1 1) which react with electrophiles at the 3-position." The highly strained allene (112) has been generated in situ and trapped by [2 + 21 cycloaddition reactions with alkenes or diene~.~* The double Diels- Alder reaction of 2H-pyran-2-ones with maleic anhydride gives the syn-dianhydrides (113) after elimination of CO,; the electronic and steric influence of 87 R.Weiss and R. Roth J. Chem. SOC. Chem. Commun. 1987 317. aa G. Posner and C. Switzer J. Org. Chem. 1987 52 1642. 89 (a) F. Tubtry D. S. Grierson and H.-P. Husson Tetrahedron Left.,1987,28,6457;(6) F.Tubiry D. S. Grierson and H.-P. Husson Tetrahedron Lett. 1987 28 6461. 90 (a) C. Flann T. C. Malone and L. E. Overman J. Am. Chem. SOC.,1987 109,6097; (b)S. F. McCann and L. E. Overman J. Am. Chem. Soc. 1987 109 6107; (c) C. J. Flann and L. E. Overman J. Am. Chem. Soc. 1987 109 6115. 91 T. Kume H. Iwasaki Y. Yamamoto and K. Akiba Tetrahedron Lett. 1987 28 6305. 92 M. Schreck and M. Christl Angew. Chem. Int. Ed. Engl. 1987 26 690. Heterocyclic Compounds 0 I I Me Me (109) fi N I Y' Me Me (1 10) Reagents i AcCI -50 "C; ii RMgX; iii Lawesson's reagent; iv ally1 bromide; v heat Scheme 24 fiR3 hR3 NH SiMe + R~CHO2 N R2 I I R' R' Reagents i RS03H 100°C Scheme 25 substituents on this reaction has been studied in detail.93 Of the many new examples of six-membered ring syntheses by hetero-Diels- Alder reaction (CJ Annu.Rep. Progr. Chem. Sec. B 1986 83 192) the following may be quoted the formation of 2,3-dihydropyran-4-ones [e.g. (1 14)] by Lewis acid catalysed cycloaddition of elec- tron-deficient ketones with electron-rich dienes? the synthesis of selenapyrans [e.g. (115)] in >90% yield from selenoflu~renone,~~ and further examples of the gener- ation and cycloaddition reactions of simple ph~sphaethylenes,~~ including the parent compound (CH2=PH).96b Further synthetic elaboration of thiopyrans derived from thioaldehydes and dienes has given sulphur-bridged cyclodecenones [e.g. (1 16)19' and full details have appeared of the completed elaboration to indole alkaloids of functionalized hydroisoquinolines obtained by intramolecular Diels- Alder reaction of 6-carboxamide derivatives of 2-pyrones ( 117).98 93 F.Effenberger and T. Ziegler Chem. Ber. 1987 120 1339. 94 P. C. B. Page P. H. Williams E. W. Collington and H. Finch J. Chern. SOC., Perkin Trans. 1 1987 756. 95 P. T. Meinke G. A. Krafft and J. T. Spencer Tetrahedron Lett. 1987 28 3887. 96 (a)L. D. Quinn A. N. Hughes and B. Pete Tetrahedron Lett. 1987,28,5783; (b)B. Pellerin P. Guenot and J.-M. Denis Tetrahedron Left. 1987 28 581 1. 97 E. Vedejs C. L. Fedde and C. E. Schwartz J. Org. Chem. 1987 52 4269. vx S. F. Martin H. Rueger S. A. Williamson and S. Grzejszczak J. Am. Chem. SOC., 1987 109 6124.202 H. McNab Isochromene (1 18) is now available in a neat three-step synthesis starting from indan-2-0ne,~~ while a 'simple synthesis of coumarins' (Scheme 26) utilizes 3- ethoxyacryloyl chloride (1 19) as the key reagent.'" OEt (119) Reagents i 1,2-dichloroethane reflux; ii H2S04/S03 Scheme 26 From a detailed mechanistic investigation of the reverse electron-demand Diels- Alder reaction of isoquinolinium salts with vinyl ethers,'" Gupta and Franck conclude that the reaction probably proceeds in stepwise fashion. Nevertheless the products can be transformed easily and stereoselectively to tetralins with up to four stereogenic centres. lo' Unusually for 2-benzopyran-3-ones the 1 -aryl derivative ( 120) is isolable and has a good shelf life''* -its diene character in cycloaddition reactions is unimpaired however and transformation to podophyllum lignans has been accomplished.'02 Full details of the synthesis and cycloaddition reactions of the parent member of the isomeric 2-benzopyrylium-4-olate series (121) have also been p~blished."~ The cyclic ylide (122) is the first example of a stable selenabenzene analogue.'04 A useful review emphasizes free-radical substitution methods for introducing carbon functional groups to the pyridazine nucleus.'05 Details of the synthesis of stable tetra-aryl-l,4-dihydropyrazines(123) have also been published.'06 Reverse 99 F. Cottet L. Cottier and G. Descotes Synrhesis 1987 497. 100 T. Ziegler H. Mohler and F. Effenberger Chem. Eer.1987 120 373. 101 R. B. Gupta and R. W. Franck J. Am. Chem. Soc. 1987 109 5393. 102 D. W. Jones and A. M. Thompson J. Chem. Soc. Chem. Commun. 1987 1797. 103 P. G. Sarnrnes and R. J. Whitby J. Chem. SOC.,Perkin Trans. 1 1987 195. 104 M. Hori T. Kataoka H. Shirnizu K. Tsutsurni and S. Irnaoka Heterocycles 1987 26 2365. 105 G. Heinisch Heterocycles 1987 26 481. 106 J.-L. Fourrey J. Beauhaire and C. W. Yuan J. Chem. SOC.,Perkin Trans. 1 1987 1841. Heterocyclic Compounds electron-demand cycloadditions continue to dominate triazine and tetrazine chemistry (cf ref. 67c) and full details of Taylor's work in this area are now available.lo' In these reactions intramolecular alkyne cycloadditions have been exploited to make fused pyridine~"~"~' (cf:Annu.pyrimidine^,"^^ and pyra~ines"~~ Rep. Progr. Chem. Sect. B 1985 82 202). Indole has been found to react with the tetrazine (124) (but not with related hetero-dienes) to give 50-80% yields of the pyrazinoindole (125) (Scheme 27). The dehydrogenation step requires an excess of the tetrazine and is apparently the driving force for the reaction.lo8 An ihtramolecular heterocycloaddition is the key stage in the multi-step synthesis of deoxyloganin (127) from the Meldrum's acid derivative (126) (Scheme 28).lo9 r 1 C02Me (124) - NbN R C02Me R R L -J (124) Scheme 27 OYOY +x Me OH -lo OH Scheme 28 Now that 1,2,4-trioxanes are readily accessible their potential as synthetic inter- mediates is being explored."' Thus non-aqueous aminolysis gives a 'mild and efficient preparation of cis-1,2-diols' -yields of this 'inherently unstable arrangement' are certainly in excess of 80% 'lob -whereas quantitative ring-contraction can take place in the presence of electrophiles (Scheme 29)."O" 107 (a) E.C. Taylor and J. E. Macor J. Org. Chem. 1987 52,4280; (b) E. C. Taylor and J. L. Pont J. Org. Chem. 1987 52 4287; (c) E. C. Taylor J. E. Macor and J. L. Pont Tetrahedron 1987 43 5145; (d) E. C. Taylor J. L. Pont and J. C. Warner Tetrahedron 1987 43 5159. 108 S. C. Benson C. A. Palabrica and J. K. Snyder J. Org. Chem. 1987 52 4610. I09 L. F. Tietze H. Deuzer X.Holdgriin and M. Neumann Angew. Chem. Int. Ed. Engl. 1987. 26 1295. I10 (a) C. W. Jefford J.-C.Rossier and J. Boukouvalas 1.Chem. Soc. Chem. Cornrnun. 1987 713; (b) C. W. Jefford J.-C. Rossier and J. Boukouvalas J. Chem. Soc. Chem. Cornrnun. 1987 1593. 204 H.McNab '0H Reagents i (R = R1 = H) Pr;NH CH2C12 20°C; ii TMSOTf 24"C 10 rnin Scheme 29 The first 1,3- and 1,2-A3-azaphosphinines (128) and (129),"' the first 1,3,5,2,4- trithiadiazines (13O),Il2 and the remarkable BP heterocycle (131)113 are amongst the more exotic six-membered rings to be reported in 1987. The X-ray crystal structure of (131) shows an essentially planar B3P3C3 array in which all the BP bonds are equal and show partial double-bond ~haracter."~ Mes Reaction of 2,3-dimethylquinoxaline N-oxide with propiolates takes place with elimination of water to give pyrroloquinoxaline derivatives (132) (Scheme 30).The same process can happen twice when the corresponding dioxide is used as the substrate. The previously unknown acridine 1-,2-,3- and 4-carboxaldehydes have now been synthe~ized,"~ but the most unusual application of the acridine ring system this year is a detailed study of rotation barriers in the 4-methyl derivative (133) which has enabled the side-on steric bulk of the lone-pair electrons of the nitrogen atom 'I' (a) G. Mark1 and G. Dorfmeister Tetrahedron Lett. 1987 28 1093; (b)C. Bourdieu and A. Foucaud Tetrahedron Lett. 1987 28 4673. 112 R. M. Bannister R. Jones C. W. Rees and D. J. Williams J. Chem. Soc. Chem. Commun. 1987 1546. 113 H. V. R. Dias and P. P. Power Angew. Chem.Inr Ed. Engf, 1987 26 1270. 114 G. Kaupp H. Voss and H. Frey Angew. Chem. Znt. Ed. Engl 1987 26 1280. 11s K. Takahashi R. N. Castle and M. L. Lee J. Heterocycl. Chem. 1987 24 977. 205 Heterocyclic Compounds Reagents i heat (I 15 "C),3 days Scheme 30 to be estimated in terms of van der Waals radii (1.1 A).'16 The n.m.r. spectra of the related anions (134) show that only one (134; X = Se) maintains a detectable paramagnetic ring current.' '' Me 0 @g@l (133) II X = Se PPh AsPh PPh ( 134) The synthesis of a variety of heterophenalenes has been ac~omplished"~~~'~ including the triaza-derivatives (135) and (136) (from isoquinoline and quinoline respectively),"8a and the thiaza-compound (137) (from naphtha1ene).'lgb The parent benzonaphthyridine (138; R = H) has been synthesized for the first time (from tetrahydrois~quinoline),~~~ as has the dimethoxy derivative (138; R = OMe) which is an unusual marine alkaloid.(135) X = CH Y = N (136) X = N Y = CH 6 Seven-membered Rings Mention has already been made of new borepin systems,64 and the year has also seen reports of the first C-alkyl and C-unsubstituted derivatives (139) and ( 140).120 The key step in both routes was the exchange reaction of the stannepins (141) and (142) with dibromomethylborane (Scheme 31). The B-methyl compound (142) is stable to heat but decomposes to benzene in degassed chloroform even at -20 "C owing to the presence of traces of acid.120b Ilb F. Imashiro K. Takegoshi K. Hirayama T. Tereo and A.Saika J. Org. Chem. 1987 52 1401. H. S. Kasmai J. F. Femia L. L. Healy M. R. Lauria and M. E. Lansdown J. Org. Chem. 1987,52 5461. I I8 (a) P. D. Woodgate J. M. Herbert and W. A. Denny Heterocycles 1987 26 1029; (b) J. M. Herbert P.D. Woodgate and W. A. Denny Heterocycles 1987 26 1037. 1I9 J. C. Pelletier and M. P. Cava J. Org. Chcm. 1987 52 616. I20 (a) A. J. Ashe Ill and F. J. Drone J. Am. Chem. SOC.,1987 109 1879; (b) Y. Nakadaira R. Sato and H. Sakurai Chem. Lett. 1987 1451. 206 H. McNub (141) R-R = -(CHZ)3-(139) R-P (142) R = H (140) R = H Scheme 31 Current interest in molecular S2 has been mentioned previously.28 The dithiadiselenacycloheptane (143) is also a source of this species 12’ decomposition takes place in refluxing chlorobenzene and [4 + 21 cycloadducts of S2 with dienes can be isolated in cu.50% yield. The tricycle (144) is also of interest not only because of its easy synthesis (200g scale in one step from triethylenetetramine ammonium chloride and malonodinitrile),”’“ but also because of its remarkable basicity which is rather greater than that of DBU. The utility of (144) and related derivatives as ‘proton sponges’ has been studied.122b 1,7-Electrocyclization of appropriate dipolar intermediates can give rise to diben~azepines”~ In the first of these methods the nitrile or benzotriazepine~.’~~ ylide (145) was generated by reaction of an imidoyl chloride with base (Scheme 32).’23 In the second method the required nitrile imines [e.g. (146)] were obtained by thermolysis of the tetrazoles [ e.g.(147)] and the cyclization proceeded in 40-75% yield to give the first N-unsubstituted benzotriazepines (148) (Scheme 33).’24 ,g. HH ‘Cl 60-80% Reagents i KOBu‘ 0 “C 121 M. Schmidt and U. God Angew. Chem. Znr. Ed. Engl. 1987 26 887. 122 (a) R. Schwesinger Angew. Chem. Znt. Ed. Engl. 1987 26 1164; (b) R. Schwesinger M. Missfeldt K. Peters and H. G. von Schnering Angew. Chem. Int. Ed EngL 1987 26 1165. 123 P. Groundwater C. Struthers-Semple and J. T. Sharp J. Chem. SOC. Chem. Commun. 1987 1367. 124 G. V. Boyd J. Cobb P. F. Lindley J. C. Mitchell and G. A. Nicolaou J. Chem. SOC.,Chem. Commun. 1987 99. Heterocyclic Compounds (147) MezN (146) Reagents i heat (xylene) -N2 Scheme 33 A variety of azepinones and diazepinones have been reported this yea^-.'^'-'^^ Simple N-substituted lH-azepin-3(2H)-ones (149) can be made by a thermolysis method in which 1,7-electrocyclization is again thought to be involved.'25" The products (149) react with electrophiles and behave as dienes in Diels-Alder reactions.125 The dihydrodiazepin-5-ones (150) are formed regiospecifically by cycloaddition of the N-aryl sydnones (15 1) and isopropylidenecyclobutenone (Scheme 34) though a mixture of 4-ones and 5-ones is formed when N-alkyl analogues are used.'26 The 'ring expanded cytidine' (152) has been synthesized in five steps from the saturated nucleoside ( 153),'27 while Tsuchiya has utilized his ring expansion method (cJ Annu.Rep. Progr. Chem. Sect. B 1986 83 197; ibid. 1985 82 206) to give the 1,4-diazepinone (154) and oxazepinone (155).12' Fully unsaturated diazepine and oxazepine derivatives were obtained by 0-alkylation using triethyloxonium tetrafluoroborate while thermolysis resulted in ring contrac- tion to pyridine derivatives.128 0 Ho(1 N 0 0 I RI I Ho R R (152) (153) (154) X = NC0,Et I(155) X = 0 R = p-D-ribofuranose 0-n ,R k-9 Ph Me Me (151) (150) Reagents i heat (toluene) Scheme 34 125 (a) H. McNab L. C. Monahan and T. Gray J. Chem. Soc. Chem. Cornrnun. 1987 140; (b) H. McNab and L C. Monahan J. Chem. SOC.,Chern. Commun. 1987 141. 126 F.-J. Mais H. Dickopp B. Middlehauve H.-D. Martin D. Mootz and A. Steigel Chem. Ber.1987 120 275. I27 C.-H. Kim and V. E. Marquez J. Org. Chem. 1987 52 1979. I28 J. Kurita T. Yoneda N. Kakusawa and T. Tsuchiya Heterocycles 1987 26 3085. 208 H. McNab 7 Eight-membered and Larger Rings With the exception of the specialized literature on 'host-guest' chemistry which is largely outside the scope of this survey very little novel work on medium and large heterocyclic rings is being published in the late 1980s. However Prinzbach's group has made the non-planar dihydroazocines (156) and oxocin ( 157)129"which can be transformed into their planar diatropic 10~ anions in the presence of non-ionic phosphinimine bases.'29b The halogen substituents in the stable 1,2-diazocine ( 158) are readily replaced by nucleophiles to give for example arylthi~,'~'" arylsulphonyl I3Ob and imido-substit~ted'~'' derivatives.Ring contraction to pyridines is generally observed on thermolysis of these diazocines in ~ylene,'~'~*~~~ though hydrolysis of acetoxy- and phthalimido-diazocines gives pyrazoles. 130d (156) X = NR (157) X = 0 I29 (a) B. Zipperer M. Fletschinger D. Hunkler and H. Prinzbach Tetrahedron Lett. 1987 28 2513; (6) M. Fletschinger B. Zipperer H. Fritz and H. Prinzbach Tetrahedron Lett. 1987 28 2517. (a)S. Yogi K. Hokama and 0. Tsuge Bull. Chem. SOC.Jpn. 1987 60 335; (6) S. Yogi K. Hokama and 0.Tsuge Bull. Chem. SOC.Jpn. 1987,60,343; (c) S. Yogi K. Hokama S. Takayoshi and 0.Tsuge Bull. Chem. SOC.Jpn. 1987 60 731; (d) S. Yogi K. Hokama and 0. Tsuge Chem. Lett.1987 157. Heterocyclic Compounds Interest in new conjugated systems related to porphyrins continues with the synthesis of a tetra-alkyl 'porphycene' (1 59)13'= and the planar dihydro-derivative (160) which is the porphycene analogue of ~hlorin.'~'~ "N-CPMAS-N.m.r. has been used to study the tautomerism of porphyrin and porphycene systems in the solid The novel platyrin dication (161) has a 26~-electron periphery and is strongly diatropic but decomposes in the solid state or in solution even at low temperatures. 132 Applications of free-radical methods to macrolide synthesis include the prepar- ation of 9-1 1-membered examples in excellent yield by a ring cleavage sequence (e.g. Scheme 35)133" and a further use of tributyltin hydride (Scheme 36) which is particularly efficient for large (> 15-membered) rings.'33b 76'/o 82% Reagents i HgO-I2 pyridine hu; ii Bu,SnH Scheme 35 Reagents i Bu,SnH Scheme 36 The evolution of synthetic routes to catenanes (interlocked rings) and their coordination chemistry is discussed in an interesting article in Chemical It is always refreshing when authors conclude that 'the interest in catenanes and related systems originates to a large extent in their aesthetic 131 (a) E.Vogel M. Balci K. Pramod P. Koch J. Lex and 0. Ermer Angew. Chem. Int. Ed. Engl. 1987 26 928; (6) E. Vogel M.Kocher M. Balci I. Teichler J. Lex H. Schmickler and 0. Ermer Angew. Chem. Znt. Ed. Engl. 1987,26,931; (c)B. Wehrle H.-H. Limbach M. Kocher 0.Enner and E. Vogel Angew.Chem. Int. Ed. EngL 1987 26 934. 132 E. Le Goff and 0.G. Weaver. J. Org. Cbem. 1987 52. 710. 133 (a) H. Suginome and S. Yamada Tetrahedron 1987,43 3371; (b) N. A. Porter and V. H.-T. Chang J. Am. Chem. Soc. 1987 109 4976. 134 C. 0. Dietrich-Buchecker and J.-P.Sauvage Chem. Rev. 1987 87 795.

ISSN:0069-3030    

DOI:10.1039/OC9878400181

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

9 0rganometaI I ic Ch em istry 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 30Y 1 Introduction With each succeeding year publications on the applications of organometallic chemistry to organic synthesis have increased. Of necessity therefore the references described in this report are restricted for the most part to demonstrating the major trends and advantages conferred by the use of organometallic chemistry to organic synthetic problems. The growth in the application of organometallic chemistry to stereospecific synthesis is particularly noticeable. A number of useful reviews have appeared this year including applications of higher order mixed organocuprates to organic synthesis,' early transition-me'tal complexes of dienes alkynes alkenes and alkyl complexes,* the use of metal reagents in stereo- and regio-selective functionalization of conjugated diene~,~ new palladium-catalysed synthetic reactions of ally1 P-keto carboxylates and form ate^,^ homogeneous palladium-catalysed carbon-carbon bond f~rmation,~ formation of cyclopropanes from the reaction of transition-metal-carbene complexes with olefins; synthesis and stereoselective reactions of a$-unsaturated acyl ligands bound to the chiral auxiliary [( q5-C5H,)Fe(C0)(PPh3)],' the application of tetra-cyanoethylene in organometallic chemistry,8 and the transition metal promoted cyanation of aromatic halides.' The useful book entitled 'Principles and Applications of Organotransition Metal Chemistry' by Collman Hegedus Norton and Finke has appeared as a revised and extended version of the well-known previous edition by the first two authors." Some reactions of coordinated ligands are reviewed in the first of a new series edited by Braterman." ' B.H. Lipshutz Synthesis 1987 325. ' H. Yasuda and A. Nakamuro Angew. Chem. Int. Ed. Engl. 1987 26 723. J. E. Backvall Bull. SOC.Chim. Fr. 1987 665. J. Tsuji and T. Takahashi Takugaku Zasshi 1987 107 87. H. M. Colquhoun Chem. Ind. (London) 1987 612. M. Brookhart and W. 9. Studabaker Chem. Rev. 1987 87 411. ' S. G. Davies 1. M. Dordor-Hedgecock R. J. C. Easton S. C. Preston K. H. Sutton. and J. C. Walker Bull. SOC.Chim. Fr. 1987 608. * A.J. Fatiadi Synthesis 1987 959. G. P. Ellis and T. M. Romney-Alexander Chem. Rev. 1987 87 779. J. P. Collman L. S. Hegedus J. R. Norton and R. G. Finke 'Principles and Applications of Organotransi- tion Metal Chemistry' OUP Oxford 1987. l1 'Reactions of Coordinated Ligands' Vol. 1 ed. P. S. Braterman Plenum London 1987. 211 S. G. Davies and I. M. Dordor-Hedgecock 2 Organometallics as Nucleophiles The use of chiral organometallic nucleophiles as intermediates in natural product synthesis is attracting increasing attention. The highly stereoselective benzylic func- tionalization of (S)-( -) -N,N-dimethylamphetamine has been demonstrated via n-butyl lithium removal of the pro-R-benzylic proton from its chromium tricarbonyl complex (1).Using MoOPH as the electrophile (1 S,2S) -N-methylpseudoephedrine (2) was obtained after decomplexation as depicted in Scheme 1.'' Racemic ephedrine analogues have also been prepared by Solladii and co-workers via the useful diastereoselective addition to (ortho-toI~aldehyde)Cr(CO)~ (Scheme 2).13 Highly stereoselective ortho deprotonation/substitution of chiral chromium tricarbonyl complexes containing a coordinating benzylic substituent has been a~hieved.'~ /@nNMe2 Cr (C0)3 (1) Reagents i BuLi ii MoOPh; iii Et,O 02,hv Scheme 1 0 90% yield I I Cr Cr (C0)3 (CO) Reagents i MeNOz HO- -40 "C Scheme 2 The key step in the asymmetric synthesis of (+)-corynoline (3) involved the condensation of the chiral 1-ferrocenyl-2-methylpropylamine Schiff base (4) with racemic homophthalic anhydride (5) to afford the required chiral intermediate (6) in 81% yield (Scheme 3).The chiral auxiliary influences both the relative and absolute configuration of two asymmetric centres.I5 (q4-Isoprene)Fe(CO)3(7) can be deprotonated at low temperature to give the isoprene anion equivalent (8) an attractive synthon for isoprenoid natural product synthesis.I6 Semmelhack has reacted (8) with series of electrophiles. Reaction of l2 J. Blagg and S. G. Davies Tetrahedron 1987 43 4463. l3 A. Solladi&Cavallo G. Lapitajs P. Buchert A. Klein S. Colonna and A. Manfredi J. Organomet. Chem. 1987 330 357. J. Blagg S. G. Davies C. L. Goodfellow and K. H. Sutton J. Chem. SOC.,Perkin Trans. I 1987 1805.l5 M. Cushman and J. K. Chen J. Org. Chem. 1987 52 1517. l6 M. F. Semmelhack and E. J. Fewkes Tetrahedron Len. 1987 28 1497. Organometallic Chemistry -Part (i) The Transition Elements L- I Fe CHO I H (3) Reagents i C,H, A Scheme 3 OH (10) 91% \ Reagents i LDA ii H202 base Scheme 4 (8) with the aldehyde (9) followed by decomplexation with hydrogen peroxide gave the bark beetle sex pheromone (10) (Scheme 4). Davies’ asymmetric synthesis of the angiotensin converting enzyme inhibitor (-)-captopril using the iron chiral auxiliary [( q5-C5H5)Fe(CO)( PPh3)] in 59% overall yield has demonstrated the practical potential of this synthetic method.” ” G. Bashiardes and S. G. Davies Tetrahedron Lett. 1987 28 5563.S. G. Davies and I. M. Dordor-Hedgecock Otsuji has reported the use of ~3-l-trimethylsilyloxyallylic iron complexes (1 1) as a P-acyl carbanion equivalent of a$-unsaturated ketones and esters.18 Complex (11) may be readily prepared from (12) using trimethylsilyl iodide followed by treatment with tetrabutylammonium tricarbonylnitrosyl ferrate. The allylic iron complexes reacted regioselectivity with 3-bromopropyne giving the corresponding 5-hexynyl ketone and 5-hexynoic ester derivatives in a one-pot reaction (Scheme 5). TMSO I TMSO I II -4 Ph3 Ph AJ A Ph I 95% Fe TMSO 81 Yo Reagents i TMSI; ii Bu,NFe(CO),NO; iii P(OPh),; iv HCGCCH,Br Scheme 5 3 Organometallics as Electrophilev Organometallic allyl complexes continue to provide the basis of novel reaction methods.Complexes such as the allyl iron tetracarbonyl cation (13) undergo nucleophilic addition with electron-rich aromatic nucleophiles in the presence of carbon monoxide to afford allylated aromatic products ( 14).19The observed aromatic regioselectivity is that expected based on attack by the allylic complexes at the site of greatest combined electrophilicity and accessibility (Scheme 6). A general method for the synthesis of a-methylene lactones has been developed by Tsuji2' Ally1 a-acetoxymethylcarboxylates which have an electron-withdrawing Scheme 6 I' K. Ito S. Nakanishi and Y. Otsuji Chem. Lett. 1987 2103. 19 J. W. Dieter Z. Li and K. M. Nicholas Tetrahedron Lett. 1987 28 5415. 20 J.Tsuji M. Nisar and I. Minami Chem. Lett. 1987 23. Organometallic Chemistry -Part (i) The Transition Elements 215 (15) (16) 93% Reagents i Pd,(dba),.CHCI, PPh Scheme 7 group at the a-position undergo smooth palladium-catalysed decarboxylation- deacetoxylation. The exo-methylene lactone (16) was obtained in 93% yield from (15) (Scheme 7). Hayashi etal. have extended the asymmetric allylic alkylation of racemic 2-propenyl acetates to examples substituted with two different aryl groups at the 1 and 3 positions.2' Little regioselectivity but high enantioselectivities are observed (Scheme 8). The reaction is catalysed by palladium in the presence of the chiral ferrocenylphosphine ligand ( 17). qphL %ph+q+ CH(COMe)2 Ph OAc CH( COMe)2 92 yo IL 34 52 YPh2 ,Me 95% e.e.80% e.e. (17) Reagents i NaCH(C0Mel2 Pd/L* Scheme8 Molybdenum catalysts show excellent regioselectivity for alkylation at the more hindered end of ally1 fragments with dimethyl malonate anion regardless of the regioisomeric nature of the starting material or the presence of strong directing substituents.22 Stoicheiometric mixtures of copper(11) perchlorate/copper metal have been shown to be an inexpensive alternative to palladium-catalysed activation of allylic chlorides and acetates towards nucleophilic ~ubstitution.~~ Substitution 21 T. Hayashi A. Yamamoto and Y. Ito Chem. Lett. 1987 177. 22 B. M. Trost and M. Lautens Tetrahedron 1987,43,4817. 23 J. B. Baruah and A. G. Samuelson J. Chem. Soc.Chem. Commun. 1987 36. S. G. Davies and I. M. Dordor-Hedgecock occurs without rearrangement and at rates comparable or better than the palladium- catalysed reaction. The Pdo-catalysed cyclization of 2-butylene dicarbamates gave 4-vinyl-2-oxazolidones.24The cyclization did not occur when palladium complexes such as Pd(OAc) PdC12 and Pd2( dba)3 were lacking phosphine ligands. 0-Aryl oximes are useful intermediates for the synthesis of benzofurans. However the known synthetic methods generally allow the preparation only of compounds carrying electron-withdrawing substituents on the aryl moiety. A new general syn- thesis of 0-aryl oximes by chromium tricarbonyl-promoted S,Ar substitution of halogenoarenes allows entry to a broad range of substituted benzofurans (Scheme 9).25 CI c1 I 6+ HONG Iii c1 Reagents i KOH (C8H,7)4N+Br-; ii I2 Scheme 9 0 Me Ph 75% yield 80% e.e.Reagents i KOH (C,H,,),NBr; ii 30% Reports of asymmetric synthesis on q6-(arene)Cr(CO) complexes are appearing with increasing frequency. ortho-Disubstituted q6-(arene)Cr( CO) complexes have been used as chiral auxiliaries in Darzens condensations giving optically active oxiranes with high diastereoselectivity (Scheme The reaction of Fe(CO) complexes of a$-unsaturated ketones with nucleophiles has been investigated. Reaction of (benzylidene acetone) iron tricarbonyl (18 R = Me) with organolithium and Grignard reagents gave 1,4-diketones2’ The reaction 24 T. Hayashi A. Yamamoto and Y. Ito Tetrahedron Lett.1987 28 4837. 2s A. Alemagna C. Baldoli P. D. Buttero E. Licandro and S. Maiorana Synthesis 1987 192. 26 C. Baldoli P. D. Buttero E. Licandro S. Maiorana and A. Papagni J. Chem. SOC.,Chem. Cornmun. 1987 762. 27 S. E. Thomas J. Chem. Soc. Chem. Commun. 1987 226. Organometallic Chemistry -Part (i) The Transition Elements probably proceeds through a metal acyl intermediate. Acyl-transfer to the a$-unsaturated ketone and protonation presumably occur whilst the a$-unsaturated ketone is attached to the metal atom (Scheme 11). Similarly 4-keto esters may be prepared from a$-unsaturated esters.28 Ph H - 0 Of(+? R ' h R Fe- Ph H 0 oc' CI 0 R = Me Bun Bu' Bu' OMe Reagents i R'Li or R'MgBr (R' = Me Bu) Scheme 11 Activated nickel powder is known to react with aryl and benzyl halides to yield the corresponding biaryls and bibenzyls.Surprisingly non-activated nickel powder stable in air selectively catalyses the aromatic halide exchange between aryl halides and alkali metal halides without producing coupled by-product^.^^ 4 Coupling-cyclization Reactions Cross-coupling reactions are a very versatile method for carbon-carbon bond forma- tion and continue to attract increasing interest. Trialkyl manganate derivatives have been shown to react similarly to organoaluminium derivatives effecting the alkyla- tions of enol phosphates; in the presence of a catalytic amount of Pd(PPh3) they give a regioselective synthesis of alkyl substituted 01efins.~' Kosugi has found that 2-ethoxy-2-propenyldiethylphosphateis a much more efficient halogenoacetone equivalent than the corresponding acetate or carbonate in the Pdo-catalysed reaction with organotin compounds to give the corresponding coupled (E)-(2-Bromoethenyl)dibromoborane prepared readily from acetylene and boron tribromide can be used as an effective preccrsor for the stereoselective synthesis of (E)-l,2-disubstituted ethene~,~~ as shown in Scheme 12.Suzuki reports the HC-CH Reagents i BBr Scheme 12 28 D. Rakshit and S. E. Thomas J. Organomet. Chem. 1987 333 C3. 29 S. H. Yang C. S. Lj and C. H. Cheng J. Org. Chem. 1987 52 691. 30 K. Fugami K. Oshima and K. Utimoto Chem. Lett. 1987 2203. 3' M. Kosugi K. Ohashi K. Akuzawa T. Kawazoe H. Sano and T. Migita Chem.Lett. 1987 1237. 32 S. Hyuga Y. Chiba N. Yamashina S. Hara and A. Suzuki. Chem. Left. 1987 1757. 218 S. G. Davies and I. M. Dordor-Hedgecock preparation of stereo-defined 1,3-alkadienyl and 1,3,5-alkatrienyl sulphides through the palladium-catalysed cross-coupling of (E)-or (2)-1-alkenylboronates with (E)-or (2)-2-bromo- 1 -phenylthio-1 -alkene~.~~ The products are useful intermediates for the synthesis of conjugated polyenes via sulphide displacement with Grignard reagents in the presence of a Ni catalyst (Scheme 13). Kishi has shown that thallium hydroxide greatly enhances (1000-fold) the rate of the Suzuki diene synthesis involving the Pd( PPh,),-catalysed coupling of vinyl boronic acids with vinyl iodides.34 He has applied this to a synthesis of palytoxin.97% Reagents i 3 mol% Pd( PPh,), KOH C6H Scheme 13 The synthesis of conjugated dienones by means of palladium-catalysed cross- coupling reaction between (E)-l-alkenyl-l,3,2-benzodioxaboronates( 19) or-di-isopropyl (2)-1 -hexenylboronate (20) with 3-halogeno-2-alken- 1-ones was described by Suz~ki.~~ Thus the cyclic dienone (21) was obtained in 98% yield following this procedure (Scheme 14). R R 4 B 0 n Bu B(OPr')2 L/ (21) 98% Reagents i Pd(OAc) NaOAc Scheme 14 Oxidative homo coupling of 1 -alkenylstannanes catalysed by Pd( 0Ac)J Bu'OOH has been shown to give 1,3-dienes in good yield while cross-couplings with 2-alkenylstannanes provide a useful route to 1,4-dienes giving the E -isomers exclus- i~ely.~~ Nickel catalysis has also been used for the synthesis of aryl acetonitriles from aryl zinc chlorides and brom~acetonitrile.~' The palladium-catalysed cross- coupling methodology has been extended to the heteroarylation of pyridinone and quinoline ~ysterns.~' The cross-coupling reaction between pyridinyl zinc chloride 33 T.Ishiyama N. Miyaur and A. Suzuki Chem. Lett. 1987 25. 34 J.-I. Uenishi J.-M. Beau R. W. Armstrong and Y. Kishi J. Am. Chem. SOC.,1987 109 4756. 35 N. Satoh T. Ishiyama N. Miyaura and A. Suzuki Bull. Chem. SOC.Jpn. 1987 60 3471. 36 S. Kanemoto S. Matsubara K. Oshirna K. Utirnolo and H. Nozaki Chem. Lett. 1987 5. 37 T. Frejd and T. Klingstedt Synthesis 1987 40. 38 A. S. Bell D. A. Roberts and K. S. Ruddock Synthesis 1987 843. Organometallic Chemistry -Part (i) The Transition Elements (22) and the halogenoquinolinone (23) in the presence of Pdo provides a direct synthesis of 6-pyridinyl-2-( 1 H)-quinolinone (24) in which ortho-substituted pyridinyl components are tolerated (Scheme 15).Reagent i Pd( PPh3)4 Scheme 15 Facile and selective syntheses of symmetrical and unsymmetrical diary1 sulphides from aryl halides and aromatic thiols by the aid of an in situ generated Nio catalyst -from nickel( II)bromide 1,l'-bis(diphenylphosphino)ferrocene and zinc powder -have been reported.39 Vinyl triflates easily prepared from the corresponding ketones have been widely used in coupling reactions with organocopper reagents and organostannanes. Palladium(0)-mediated cross-coupling reaction between Refor- matsky reagents such as BrZnCH2C02But and vinyl triflates provide a new procedure for the synthesis of p,y-unsaturated esters.40 In search of a mild method for the preparation of acyclic a-methyl and a-phenyl substituted a$-unsaturated ketones Renaldo investigated the Pdo-catalysed coup- ling of acid chlorides with trimethyl (1-methyletheny1)stannane(25) and trimethyl- (1 -phenylethenyl)stannane (26).41a-Methylene ketones were formed under neutral conditions in moderate to good yields (Scheme 16).Reagents i Pd(PPh3)4,CO Scheme 16 Methods for the a-alkenylation and a-arylation of cyclic ketones that permit introduction of a stereo-defined alkenyl group (E or 2)in high yield with essentially complete retention (>98%) of the alkenyl stereochemistry have been reported.42 The introduction of an alkenyl group in an a-position of a cyclopentanone derivative with approaching 100% control of regio- and stereo-chemistry is outlined in Scheme 17.Similar conditions can be used for the a-alkylenation of cyclic unsaturated ketones. As an approach to macrolide synthesis the intramolecular coupling of an ester bearing vinyl triflate and vinyl stannane groups at the termini has been 3Y K. Takagi Chem. Lett. 1987 2221. 40 F. Orsini and F. Pelizzoni Synth. Cornmun. 1987 17 1389. 41 A. F. Renaldo and H. Ho Synth. Commun. 1987 17 1823. 42 E. Negishi and K. Akiyoshi Chern. Lett. 1987 1007. S. G. Davies and I. M. Dordor-Hedgecock It C6H,3 Reagents i MeNH 1-ZnCI,; iv,iii,BuLi;ii,;NMe2 Pd(PPh,),(l%); v H30+ Scheme 17 explored.43Tetrakis(tripheny1phosphine)palladiumin the presence of LiCl catalysed the cyclization with no E-to 2-isomerization or rearrangement of exocyclic double bonds.The ability of Pd"-catalysed intramolecular carbametallation to form quaternary and vicinal quaternary centres in the anti-Markovnikov sense has been demonstrated in the synthesis of the picrotaxane skeleton.44 A template-induced [2 + 2 + 13 condensation of an alkyne or allene and carbon monoxide uia an iron carbonyl complex intermediate gives P-methylenecyclo-pentenones in a one-pot procedure (Scheme 18).45 L Ir/' H Ill'I + CPhII C 0 0 56% Reagents i Fe2(C0)9or Fe(CO),/hv Scheme 18 The five-ring annulation method originally described by Trost which employs the transient trimethylenemethane (TMM) complex prepared from [2-(acetoxy-methyl)-3-allyl]trimethylsilane/Pd' worked reasonably well with 2-cyclopentenones but poorly if at all with the 6-and 7-membered ring homologues.Paquette has shown that introduction of a 2-carbomethoxy group to the enone gives a dramatic improvement in the yield with cyclohexenones and octenones and extends considerably the utility of this ann~lation.~~ The nickel-catalysed intramolecular [4 + 41 cycloaddition of bis-dienes has been successfully applied to the preparation of the taxane ring system.47This methodology provides the basis for a general and efficient route to angularly substituted alkyl bicyclo[6.4.0]dodecanes and to tricyclo[5.3.l]undecanes.43 J. K. Stille and M. Tanaka J. Am. Chem. Soc. 1987 109 3785. 44 B. M. Trost and D. J. Jebaratnam Tetrahedron Lett. 1987 28 1611. 45 R. Aumann and H.-J. Weidenhaupt Chem. Ber. 1987 120 23. 46 D. G. Cleery and L. A. Paquette Synth. Commun. 1987 17 497. 47 P. A. Wender and M. L. Snapper Tetrahedron Lett. 1987 28 2221. Organometallic Chemistry -Part (i) The Transition Elements 22 1 Excellent stereo-control of the ene-type coupling between cyclic diene-Fe(C0)3 groups and alkenes4* can be achieved by appropriate substitution at C(5) of the diene ring.49 The use of this reaction in the preparation of asymmetric quaternary centres and enantiomerically pure spirolactams and spirolactones has been demon- strated by Pearson.5 Carbonylation Reactions Nucleophilic olefins such as simple alkyl vinyl ethers serve as good substrates in the palladium-catalysed aroylation of 01efin.s.~' Aroylation takes place exclusively at the /3-carbon atom affording useful l-aryl-l,3-dicarbonyl equivalents when the reaction is carried out at moderate temperatures; decarbonylation occurs at elevated temperatures. The intermolecular acylpalladation of activated alkenes such as acrylonitrile with bridgehead acid chlorides (e.g. 1 -adamantanecarbonyl chloride) leads to the forma- tion of acylated alkenes regio- and stereo-~electively.~' The exclusive formation of acylated alkenes contrasts with the palladium-catalysed reaction of aroylchlorides with activated alkenes where a highly efficient decarbonylative alkene arylation occurs.It was envisaged that the bridgehead acid chlorides would not be de- carbonylated due to the instability of olefins that would be formed. Palladium(0) catalyses the carbonylation of methylene aziridines (27) to a-methylene-P-lactams (28) in high yield (Scheme 19).52 Alper had shown that metal complex-catalysed carbonyl insertion occurred into the saturated carbon-nitrogen bond of a-lactams. Replacement of the carbonyl function of an a-lactam by a carbon-carbon double bond Le. rnethylene aziridine alters the regiochemistry of the ring expansion-carbonylation since the unsaturated moiety being a stronger donor than the carbonylation group can 7r-complex to the metal. (27) (28) 72% Reagents i Pd(PPh3)4 CO Scheme 19 The palladium-catalysed oxycarbonylation c f 4-pentenols gives tetrahydrofuran-2- acetic esters.Tamaru has extended this reaction to 3-butenols. Intramolecular di-alkoxy carbonylation of 3-butenols catalysed by Pd" under an atmosphere of CO gives y-butyrolactone-2-acetic esters.53 Thus di-alkoxy carbonylation of l-allyl- cyclohexanol (29) gave the spirobutyrolactone (30) (Scheme 20). The reaction is dependent on the kind and amount of additives used. Ethyl orthoacetate and propylene oxide were found to increase the turnover number of the catalyst system giving high yields. 421 A. J. Pearson M. W. Zettler and A. A. Pinkerton J. Chem. SOC.,Chem. Commun. 1987 264. 49 A. J. Pearson and M. W. Zettler J. Chem. Soc.Chem. Commun. 1987 1243. 50 C.-M. Andersson and A. Hallberg Tetrahedron Lett. 1987 28 4215. 51 K. Hori M. Ando N. Takaishi and Y. Inamoto Tetrahedron Lett. 1987 28 5883. 52 A. Alper and N. Hamel Tetrahedron Lett. 1987 28 3237. 53 Y. Tamaru. M. Hojo and Z. Yoshida Tetrahedron Left. 1987 28 325. S. G. Davies and I. M. Dordor-Hedgecock (29) (30) 70% Reagents i PdCI, CuCI, CO MeC(OEt), (Me,N) CO Scheme 20 The cobaltocene (CoCp ; Cp = cyclopentadienyl) catalysed reaction of carbon dioxide with propargyl alcohols has been st~died.’~ a-Ethynyl tertiary alcohols such as 2-methyl-3-butyn-2-01 (31) underwent cycloaddition with carbon dioxide yielding the a-methylene cyclic carbonate (32) in good yields in the presence of CoCp and trimethylamine added as co-catalyst (Scheme 21).a-Ethynyl primary or secondary alcohols gave non-cyclic alkyl carbonates in only fair yields. Reagents i (C,H,),Cb Et,N C02 Scheme 21 Cobalt carbonyl catalyses the carbonylation of thiirane to P-mercapto acids using methyliodide and phase-transfer ~atalysis.’~ The reaction is regiospecific with the acid function attached to the more substituted carbon. Under these conditions treatment of 2-phenylthiirane yielded the P-mercapto acid (33) in 78% yield. The proposed mechanism for this reaction via a thietan-2-one is depicted in Scheme 22. .. ... MYPh Co~(c0)~2 CO2H R = Me,PhCH CO(CO)4 (33) 41% S Reagents i KOH PEG-400; ii RX; iii CO; iv Ph-; v KOH Scheme 22 Simple methods for the conversion of amines into carbamate esters in good yields using PdC12 di-t-butyl hydroperoxide have been reported.56 Conversion of allenic bromides into alkoxy esters in high yield via Pdo carbonylation has been demon- strated.” 54 Y.Inoue J. Ishikawa M. Taniguchi and H. Hashimoto Bull. Chem. SOC.Jpn. 1987 60,1204. 55 S. Calet H. Alper J.-F. Petrignani and H. Arzoumanian Organometallics 1987 6 1625. 56 H. Alper G. Vasapollo and F. W. Harstock M. Miekuz D. J. H. Smith and G. E. Morris Organornetallics 1987 6 2391. 57 N. D. Trieu C. J. Elsevier and K. Vrieze J. Organomet. Chem. 1987 325 C23. Organometallic Chemistry -Part (i) The Transition Elements 3-Hydroxy-4-pentenes are known to undergo palladium-catalysed cyclization to provide bicyclic lactones tetrahydropyridines or dihydropyranes.Tsuji's carbonate method was used in order to isolate the postulated intermediate (34) to explain the formation of the by-product. However 3-vinyl-l-oxo-2,6-dioxacyclohexanone was found to undergo a decarboxylation-carbonylation in the presence of Pdo to give a new product 2-vinyl-y-butyrolactone (35) in high yield (Scheme 23).j8 The reaction shows high solvent dependence. Butyrolactones were obtained only if the reaction was carried out using aprotic solvents. OH [Pdl' 0 (34) (35) 53% Reagents i Pd(PPh,),; ii CO Scheme 23 78'/a 0 (37) Reagents i Pd(PPh,), Ph2PCH2CH2PPh2 Scheme 24 The elimination of carbon oxysulphide from allylic dithiocarbonates (36) or (37) is promoted by palladium complexes and provides a convenient preparation of allylic sulphides (Scheme 24).59 Pd( PCy,) (PCy = tricyclohexylphosphine) was found to catalyse the decarbonylation of thiol esters to give sulphides quantitatively.60 The rhodium complex RhC1( PPh3)4 also caused decarbonylation but the reaction was stoicheiometric.Asymmetric hydroformylation of a variety of olefins using a transition metal complex has so far been achieved with low enantiomeric excess. Stille has reported the first asymmetric hydroformylation of styrene catalysed by the homogeneous chiral platinum complex [(-)-BPPMIPtCl (38):' The reaction gave a mixture of aldehydes since the addition is not regioselective but the chiral aldehyde (39) was obtained with 78% enantiomeric purity (Scheme 25).The first example of carbonylation of alkane C-H bond assisted by transition metal complex RhCl( CO) PMe3) has been reported.62 58 Y. Tamaru T. Bando M. Hojo and Z. Yoshida Tetrahedron Lett. 1987 28 3497. 59 X. Lu and Z. Ni Synthesis 1987 66. 60 K. Osakada T. Yamamoto and A. Yamamoto Tetrahedron Lett. 1987 28 6321. 61 G. Parrinello and J. K. Stille J. Am. Chem. SOC.,1987 109 7122. 62 T. Sakakura and M. Tanaka J. Chem. SOC.,Chem. Commun. 1987 758. S. G. Davies and I. M. Dordor-Hedgecock (39) 70% e.e. Reagents i HJCO SnCI, 2650 p.s.i. Scheme 25 6 Oxidation and Reduction Two mild catalysts for the oxidation of alcohols tetra-n-propylammonium per- ruthenate (TPAP reagent) and tetra-n-butylammonium per-ruthenate (TBAP) using N-methylmorpholine-N-oxideas co-oxidant have been reported.63 Most notably oxidation of alcohols containing adjacent chiral centres give products without any detectable racemization (Scheme 26).Primary alcohols give aldehydes and secondary alcohols give ketones. The reagents have an additional advantage of a relatively simple work-up procedure and may be used in the presence of labile functional groups. OH 0 nt-70‘7’’ Reagents i 0.5 mol% (Pr;N)Ru04 0 WN-Scheme 26 Progress towards the enantiospecific chemical epoxidation of simple olefins has been demon~trated~~ using the chiral diphosphine modified palladium( 11) complex (40). Thus propylene was converted into propylene oxide with a 41% e.e. the highest reported so far for a catalytic system (Scheme 27).The asymmetric epoxidation conditions originally reported by Sharpless et al, although excellent for allylic alcohols give only modest to poor enantiomeric excesses with homoallylic alcohols. Up to 77% e.e. have now been achieved65 for some homoallylic alcohols using a Zr(OPr’) ,dicyclohexyltartaramide and t-butyl- hydroperoxide system. The larger Zr-0 bond length compared to Ti-0 may explain the improved enantioselectivity. It was found that asymmetric induction 63 W. P. Griffith S. V.Ley G. P. Whitcombe and A. D. White J. Chern. SOC.,Chern. Comrnun. 1987 1625. 64 R. Sinigalia R. A. Michelin F. Pinna and G. Strukul Orgunornefallics 1987 6 728. 65 S. Ikegami T. Katsuki and M. Yamaguchi Chern. Lefr. 1987 83. Organometallic Chemistry -Part (i) The Transition Elements 41% e.e.Reagent i H202 Scheme 27 increased with the steric bulk of the alkyl groups on the amide. Zirconium- and titanium-mediated epoxidations showed the same sense of asymmetric induction. Practical methods for the synthesis of useful polyhydroxylated chiral building blocks continue to be developed. Sat0 et al. have extended the kinetic resolution of y-trimethylsilyl allylic alcohols to y-tributyl-stannyl allylic alcohols using the Sharp- less asymmetric epoxidation reaction (Scheme 28).66 Rate differences were not as high for the two enantiomers as for the corresponding trimethylsilyl case but these derivatives should have ready application in natural product syntheses. 0. I Bu3Sn*CsH11 + BuJnqC.Hll II -Bu3Sn+YCsH11 OH OH OH >99% e.e.84% e.e. 3842% Reagents i Bu'OOH Ti(OPr') D-(-)-diisopropyitafirate Scheme 28 If the Wacker reaction -the Pd"-catalysed oxidation of terminal olefins -is carried out in alcohols the corresponding acetals are obtained. However terminal olefins bearing electron-withdrawing substituents such as (41) are regioselectively acetalized at the terminal carbon by diols in the presence of PdC12 and CuCl in dimethy- oxyethane under an O2 atmosphere. Homochiral cyclic acetals (42) of aldehyde precursors are obtained in good yield when optically active (R,R)-2,4-pentanediol is used (Scheme 29).67 The addition of Na2HP04 prevents formation of the Michael- type by-product. (42) 79% Reagents i PdCI, CuCI O2 Scheme 29 A novel heterobimetallic catalyst (43) for asymmetric hydrogenation based upon a chiral rhenium template in a chelating 'diphosphane' backbone has been developed.68 Hydrogenation of the enamide (44) gives (45) in 98% enantiomeric purity (Scheme 30).66 Y. Kitano T. Matsumoto S. Okamoto T. Shimazaki Y. Kobayashi and F. Sato Chem. Lett. 1987 1523. 67 T. Hasokawa T. Ohta S. Kanayama and S. I. Murahashi J. Org. Chem. 1987 52 1758. 6X B. D. Zwick A. M. Arif. A. T. Patton and J. A. Gladysz Angew. Chem. Int. Ed. EngL 1987 26 910. S. G. Davies and I. M. Dordor-Hedgecock (44) (45) 82% (98% e.e.1 PPh3 (+)-(R ) -(43) Reagents i H, THF Scheme 30 Halogen-containing BINAP-coordinated Ru" complexes unlike the dicarboxylate complexes used for the enantiomeric hydrogenation of olefins have been shown to reduce P-ketocarboxylic esters to P-hydroxy esters in high enantiomeric Further examples of the use of chiral (R) and (S) BINAP Ru" dicarboxylate complexes were illustrated by the enantioselective hydrogenation of 3,3-disubstituted allylic alcohols and 4,4-disubstituted homoallylic alcohols.70 Directed homogeneous hydrogenation of olefins has been comprehensively reviewed this year by Br~wn.~' He has also reported a highly stereoselective homogeneous hydrogenation of 3-substituted itaconate esters using the (R,R)-DIPAMP-derived rhodium catalyst (46).72 This has been extended to a useful kinetic resolution of N-substituted a-(aminoalkyl) acrylates providing a simple route to optically active p-amino acids with defined configuration at both the a and p carbon atoms (Scheme 31).73 Hayashi et a!.have demonstrated the high stereoselectivities obtainable in the asymmetric hydrogenation of tri- and tetra-substituted acrylic acids using a rhodium complex of the chiral phosphine ligand (47) (Scheme 32).74 A conveniently mild method for the preparation of 1,2-dienes involves the palladium-catalysed hydrogenolysis of 3-methoxycarbonyloxy-1-alkyneswith ammonium formate (Scheme 33).75 7 Cycloadditions Carbenes and Miscellaneous Reactions A new and highly stereoselective iron-catalysed carbocyclization of triene ethers via a formal [4 + 4lene reaction provides a useful route to 1,2-substituted cyclopent- ane~.~~ Similarly (48) undergoes a highly stereoselective ene reaction catalysed by 69 R.Noyori T. Ohkuma M. Kitamura H. Tokaya N. Sayo H. Kumobayashi and S. Akutagawa J. Am. Chem. SOC.,1987 109 5856. 70 H. Takaya T. Ohta N. Sayo H. Kumobayashi S. Akutagawa S. Inoue I. Kasahara and R. Noyori J. Am-. Chem. Soc, 1987 109 1596. 71 J. M. Brown Angew. Chem. Int. Ed. EngL 1987 26 190. 72 J. M. Brown and A. P. James J. Chem. Soc. Chem. Commun. 1987 181. 73 J. M. Brown A. P. James and L. M. Prior Tefrahedron Lett. 1987 28 2179. 74 T. Hayashi N. Kawamura and Y. Ito J. Am. Chem. SOC.,1987 109 7876. 75 J. Tsuji T. Sugiura and 1. Minami Synthesis 1987 603. 76 J. M.Takacs and L. G. Anderson J. Am. Chem. Soc. 1987 109 2200. Organometallic Chemistry -Part (i) The Transition Elements 58% conversion Me02C% A (46) Me02CY 96% ex.NHCOMe NHCOMe Reagents i H2 1 atm 20 "C Scheme 31 (97%e.e.> (471 Reagents i RhCI(NBD) AgBF, (47) Et,N; ii H2 Scheme 32 0 OKO/Me R ii R >.= *o 2">( __* R' + R' R' R = C8H,9;R' = H 87% Reagents i HC=CMgBr CIC0,Me; ii HCO,NH, Pd,(dba) .CHC13 Bu,P Scheme 33 palladium(0); the intermediate (49) eliminates the exocyclic Hb preferentially over Ha as might be expected for a syn-P-elimination process (Scheme 34)." Zirconium methodology may also be employed in the preparation of five-membered rings. Bicyclization of enynes such as (50) promoted by 'Zr"Cp,' has previously been demonstrated where X = TMS and Y = CH2. This has now been extended to W.Oppolzer and J. M. Gaudin Helu. Chem. Acta 1987 70 1477. --goJol S0,Tol i_ SOzTol __* SOzTol H*j-jso2Tol~Ts02T01 AcO [Pdl (48) - Hh - 91 Yo Reagents i Pd(dba), PPh3 AcOH (49) Scheme 34 x>.. ydH Y -LY& 'Cp,Zr' ZrCp (50) Y = CH,; NCH,Ph; X = alkyl aryl alkenyl SiMe, SnMe Reagents i Cp2ZrC1, Bu"Li; ii H,O+; iii CO Scheme 35 examples where X is a carbon or trialkyltin substituent Y = CH2 or where X = TMS and Y = NCH2Ph (Scheme 35).78 Cobalt maleoyl species have been used in a [4+ 13 process via a metal-catalysed terminal alkene/vinylidene rearrangement to give moderate to good yields of 5-aIkylidene-cy~lopent-2-enones.~~ Vollhardt has reported the first synthesis of the 3a,7a-dihydrobenzimidazole nucleus via a cobalt-mediated [2 + 2 + 21 cycloaddition of alkynes to the imidazole 4,Sdouble bond further extending the application of this process in heterocyclic chemistry.80 Additional useful examples of carbene ligands coordinated to transition metals have been reported.Dotz has demonstrated the intramolecular metal-assisted cycliz- ation of alkynols leading to 2-oxacycloalkylidme complexes of chromium tungsten and manganese suitable for conversion into butyrolactones and 2-thiobutyro- lactones.*' Hegedus has extended the use of chromium carbene complexes to the synthesis of the important 3-amino p-lactams using (CO)&r=CHNR2 complexes to give in most cases the trans stereochemistry in moderate to good yields.82 Barrett reports improved yields in his route to p-lactams with the cationic vinylidene complex (51).The reaction of this complex with some imines and thiazolines produces the corresponding [2 + 21 azetidinylidene cycloadducts (Scheme 36).83 7x E. Negishi D. R. Swanson F. E. Cederbaum and T. Takahashi Tetrahedron Lett. 1987 28 917. 79 L. S. Liebeskind and R. Chidambaram J. Am. Chem. SOC.,1987 109 5025. xo R. Boese H.-J. Knolker and K. P. C. Vollhardt Angew. Chem. In!. Ed. Engl. 1987 26 1035. " K. H. Dotz W. Sturm and H. G. Alt Organometallics 1987 6 1424. x2 C. Borel L. S. Hegedus J. Krebs and Y. Satoh J. Am. Chem. Sdc. 1987 109 1101. 83 A. G. M. Barrett and M. A. Sturgess J. Org. Chem. 1987 52 3940. Organometallic Chemistry -Part (i) The Transition Elements H P(OMe) (51) Reagent i PhIO CO2Et Scheme 36 Photolytic homolysis of carbon-bonded cobalt species in radical cyclization reac- tions have been investigated extensively by various groups in recent years.Pattenden describes the use of cobalt salophen reagents photolytically to generate al kyl radicals which add to activated carbon-carbon double bonds producing new alkenes in good yields (Scheme 37).84A cobalt-catalysed reaction of nitric oxide with aryl substituted olefins involving a radical intermediate gave aryl oximes in the presence of tetra-hydroborate ion.85 A cobalt(sa1ophen) complex has been used in the conversion of hydrazones into cis-alkenes.86 ii Reagents i 1% Na/Hg; ii hv qo Scheme 37 Further examples of stereocontrol in transition metal-catalysed reactions which are not listed under previous headings are for example the diastereocontrolled Claisen rearrangement with cyclic enol ethers using 2,6-dimethylphenol (mainly anti) or palladium-catalysed (mainly syn) control (Scheme 38).87 84 V.F. Patel and G. Pattenden J. Chem. SOC.,Chem. Commun. 1987 871. 115 T. Okamoto K. Kobayashi S. Oka and S. Tanimoto J. Org. Chem. 1987 52 5089. n6 A. Nishinaga S. Yamazaki and T. Matsuura Tetrahedron Lett. 1987 28 6309. 117 K. Mikami K. Takahashi and T. Nakai Tetrahedron Lett. 1987 28 5879. S. G. Davies and I. M. Dordor-Hedgecoci F+\ ___ \ catalyst @JC fJJj OH Me0 catalyst anti syn yield 2,6-dimethylphenol 94 6 94% (PhCN),PdCI 13 87 >95% Scheme 38 Noyori has applied the cationic Rh-BINAP complex (52) to an interesting kineti resolution of the racemic ketoalcohol (53) which when exposed to the (R)-(-catalyst selectively isomerized the S-enantiomer to the diketone (Kfa,,/ = 5/ 1; The key prostaglandin intermediate (R)-(-) ketoalcohol(53) was recovered in 910/ e.e.at 72% conversion (0.5 mol ‘10 catalyst) (Scheme 39).88 0 0 0 (53) R-(53) 3::::j;.e~72% conversion c10; OMe Phz H \/ Scheme 39 M. Kitamura K. Manabe R. Noyori and H. Takaya Tetrahedron Lett. 1987 28 4719.

ISSN:0069-3030    

DOI:10.1039/OC9878400211

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

9 Organometallic Chemistry Part (ii) The Main-Group Elements By P. D. LlCKlSS The School of Chemistry and Molecular Sciences University of Sussex Brighton BN19W 1 Group I11 Dialkylaluminium cations have been stabilized in two ways. The AlMe2+ cation can be stabilized by crown ethers (either 18-crown-6 or 15-crown-5) in com-pounds of type [A1Me,~crown][A1Me2C12]'while use of a bulky alkyl substitusd pyridine as a ligand allows intramolecular coordination to stabilize [A1{2 C( Me,Si),C,H,N},][ AlC1J2 The macrocyclic amine 1,4,8,1l-tetraazacyclotetradecanereacts with [Me,&] to give methane and [AlMe]2[CloH20N4][AlMe3]2 which has an A12N2 four-membered ring in the cavity of the macr~cycle.~ Treatment of [Me,Al] with the crown thioether 1,4,8,1l-tetrathiacyclotetradecaneaffords the complex [AlMe,],[ C10H20S4] in which the four AlMe groups all lie around the periphery of the ring.Photolysis of the aluminium ethyltetraazamacrocycle (1) with visible light in CDC1 solution leads to cleavage of the Al-ethyl bond to give ethane and a product formulated as Al(C22H22N,)Cl.5 The reaction between AlMe and diethylenetriamine affords com- plex (2) in quantitative yield which contains two 5-coordinate aluminium atoms in square pyramidal environments -the first time that such an environment has been found in an organoaluminium compound.6 ' S. G. Bott A. Alvanipour S. D. Morley D. A. Atwood C. M. Means A. W. Coleman and J. L. Atwood Angew. Chern. Int. Ed. Engl. 1987 26 485. L. E. Engelhardt U. Kynast C.L. Raston and A. H. White Angew. Chern. Int. Ed. EngL 1987,26,681. G. H. Robinson A. D. Rae. C. F. Campana. and S. K. Bryan Organornetallics 1987,6 1227. G. H. Robinson. H. Zhang and J. L. Atwood Organomeraffics,1987 6 887. ' H. Oshio S. Tero-Kubota and T. Ito Bull. Chem SOC.Jpn. 1987 60,3047. G. H. Robinson and S. A. Sangokoya J. Am. Chern. SOC.,1987 109 6852. 231 232 P. D. Lickiss Treatment of Me2AlC1 with (PMe2),XCLi (X = PMe2or Me,Si) gives monomeric tetrahedral phosphine complexes Me2Al[ (PMe2),CX] which contain AlPCP four- membered rings. On heating these give the hexacoordinate aluminium compounds Al( PMe2)CX]3.7 Condensation of aluminium atoms onto ethylene in a hydrocarbon matrix affords alumino-cyclopentane which is stable in a matrix to 343 K.8 The cyclodimerization of alkenes is usually performed with transition-metal complexes with other ligands present and this appears to be the first report of such a reaction involving a naked metal atom.The use of bulky alkyl and aryl ligands attached to Group I11 metals has as in Groups IV and V provided compounds with interesting structures. The mesityl gallium chlorides MesGaC1 and Mes2GaC1 (Mes = 2,4,6-trimethylphenyI) have been prepared and characterized. The structure of the dichloride has been determined by X-ray crystallography and is a one-dimensional polymer in which chloride ions bridge between planar GaMesCl units with a Ga. -Ga distance 3.781(1) A.' Several new compounds containing Ga-As bonds have been prepared reaction of (Me,SiCH,),AsSiMe with GaBr MeGaCI, and PhGaC1 gives [(Me3SiCH2),AsGaBr2] and {[ (Me3SiCH,),As],GaBr}, [(Me3SiCH,),AsGaMeC1] (n = 2 or 3) and [(Me3SiCH2),AsGaA1Ph] (n = 2 or 3) respectively." The bulky organolithium reagents (Me,Si),CLi and (PhMe,Si),CLi react with GaCI InCI and TICI to give (Me,Si)3CGaC13Li(thf)2 (PhMe2Si),CGaCl3Li(thf),,(Me,Si),CInCI,Li(thf), (PhMe2Si),CInC13Li(thf)3 and (Me,Si),CTlCI,Li(thf) rather than simple RMCI2 species.These chlorides can be reduced with LiAlH4 giving alkyltrihydride species including the first structurally characterized alkylindium hydride (3). Hydrolysis of hydride (3) affords an unusual indium hydroxide oxide-cage compound (4)." C(Si Me3)3 Pentabenzylcyclopentadienylthallium is formed when pentabenzylcyclopenta-diene reacts with thallium ethoxide.It has a Tl.-.Tl distance of 3.632A which although not of bond length does indicate some metal-metal interaction giving the molecule some 'dimeric' nature.' ' H. H. Karsch A. Appelt J. Riede and G. Muller Organomerallics 1987 6 316. J. H. B. Chenier J. A. Howard and B. Mile J. Am. Chem. SOC. 1987 109 4109. 0. T. Beachley jun. M. R. Churchill J. C. Pazik and J. W. Ziller Orgunometullics 1987 6 2088. A. P. Purdy R. L. Wells A. T. McPhail and C. G. Pitt Organometallics 1987 6 2099. 'I J. L. Atwood S. G. Bott P. B. Hitchcock C. Eaborn R. S. Shariffudin J. D. Smith and A. C. Sullivan J. Chem. SOC.,Dalton Trans. 1987 741. l2 H. Schurnann. C. Janiak J. Pichardt and U. Borner Angew. Chem. In?. Ed. Engl.1987 26 789. Organometallic Chemistry -Part (ii) The Main-Group Elements 2 Group IV A new journal Applied Organometallic Chemistry containing some interesting Group IV chemistry appeared in 1987. The chemistry of the silicon-carbon bond was extensively reviewed for 198513 while a review of the preparations reactions properties and structures of disilenes (Si=Si compound^)'^ shows how this area has grown dramatically in the past six or seven years. The large number of polycarbosilanes and their various preparations and potential as precursors to silicon carbide has also been re~iewed.'~ The interest in stable compounds containing multiple bonds to silicon continues. The T bond strengths for Si=C Si=Si Si=N Si=P Si=O and Si=S bonds have been estimated by several methods and recommended values are 159 105 151 121 209 and 209 kJ mo1-'.16 The synthesis of the first stable tetraalkyl disilene (5) as a bright yellow solid was achieved by reduction of [( Me,Si)2CH],Si12 with lithium naphthalenide.It is thermally stable (melting with decomposition at 224-226 "C) and although it reacts with both water and oxygen is appears to undergo no reaction with hot methanol in 24 h." (Me3Si)2CH\ /CH(SiMe3)2 / Si=Si P=Si p,R \ \ (Me3Si)2CH CH(SiMe3)2 R' Several phosphasilenes of the general form (6) (e.g. R = R' = mesityl R = Ph R' = 2,4,6-triisopropylphenyl,R = But R' = 2,4,6-triisopropylphenyl)have been prepared'* by treatment of (2,4,6-But3C6H2)PHLi with the corresponding dichlorosilane RR'SiCl and subsequent elimination of HCl.These compounds are highly reactive and could not be isolated pure. Evidence has also been published for the generation of the acetate ion analogue Me(0-)Si=O during the cleavage of m-C1C6H4CH2SiMe(OH) by NaOH in Me2SO-H20.'9 It is postulated that on photolysis at 254 nm ( Et2SiSe)3 loses diethylsilaneselone (Et,Si=Se) .,' which can be trapped as an insertion product into (Me,SiO) This appears to be the first report of the preparation of a silaneselone. After many unsuccessful attempts to prepare transition-metal silylene complexes two compounds (7) and (8) have been made and characterized crystallographically by different groups.21,22 Iminosilanes (Si=N- species) are formed on loss of lithium fluoride from lithi- ated aminofluorosilanes.If the substituents around the Si=N bond are large e.g. l3 G. L. Larson J. Organomet. Chem. 1987 337 195 containing 532 refs. 14 R. West Angew. Chem. Int. Ed. Engl. 1987 26,1201 containing 75 refs. Is G. Fritz Angew. Chem. Znt. Ed. Engl. 1987 26 1111 containing 87 refs. 16 M. W. Schmidt P. N. Truong and M. S. Gordon J. Am. Chem. SOC.,1987 109 5217. S. Masamune Y. Eriyama and T. Kawase Angew. Chem. Int. Ed. Engl. 1987 26,584. C. N.Srnit and F. Bickelhaupt Organometallics 1987 6 1156. 19 J. Chmielecka J. Chojnowski C. Eaborn and W. A. Stahcyzk J. Chem. SOC.,Chem. Commun. 1987,1337. 20 D. P. Thompson and P. Boudjouk J. Chem. SOC.,Chem. Commun. 1987 1466. 21 D. A. Straus T. D. Tilley A. L. Rheingold and S. J. Geib J.Am. Chem. SOC.,1987 109 5872. 22 C. Zybill and G. Muller Angew. Chem. Inr. Ed. Engl. 1987 26,669. 234 I? D. Lickiss Me I CO Do OC I 1,OBu' Fe=Si, oc/ I OBu' PMe3 co Do = THF or HMPT (7) (8) in But2Si=N-(2,4,6-But3C,H2) the product is stable but with smaller substituents dimerization occurs.23 The availability as starting materials of stable compounds containing multiple bonds to silicon has led to more detailed studies of their reactions being carried out and several highly unusual types of products have been formed in such reactions. Relatively stable 1,2-siloxetanes that can be isolated as solids are produced when non-enolizable ketones are added to stable silenes; the structure of one (9) has been confirmed by X-ray crystallography and has 0-Si-C and C-0-Si angles in the ring of 79.2 and 98.5" re~pectively.~~ Addition of (2,6-dimethylphenyl)isocyanideto tetra(2,6-dimethylphenyl)disilene gives a novel disilacyclopropanimine ( 10) as a bright red solid,25 and hydrolysis of C1[ (Bu'CH~)~S~],CI gives the novel hexaneopen- tyltrisiloxetane which in contrast to the folded-ring structures of cycloterasilanes has a planar Si30 ring.26 Tetramesityldisiloxetane has also been prepared and has a Si-0-Si angle of 80.0°.27Phosphasilirenes have been prepared by addition of Bu'Si to phosphaalkynes RCEP (R = But or adamantyl).28 Although alcohols have been used widely as efficient regiospecific trapping reagents for silenes the stereochemistry and mechanism of such reactions has been studied relatively little.It has now been shown that the addition of methanol to thermally generated E or 2 PhMeSi=CSiMe3But leads to a stereospecific addition which is thought to be syn by analogy with the addition of alkoxysilanes to ~ilenes.~' Although many reactive intermediates containing multiple bonds or small rings have now been isolated and structurally isolated proof of the existence of a ,XY lY1 OSiMe3 N I II (Me3Si)zSi-CCloHls I t /"\ 0-CPh2 (xylyl),Si-Si( xylyl)2 23 D. Stalke N. Keweloh U. Klingebiel M. Noltemeyer and G. M. Sheldrick Z. Naturforsch. Teil B 1987,42 1237. 24 A. G. Brook W. J. Chatterton J. F. Sawyer D. W. Hughes and K. Vorspohl Organometallics 1987 6 1246. 25 H. B. Yokelson A. J. Millevolte K.J. Haller and R. West J. Chem. SOC. Chem. Commun. 1987 1605. 26 H. Watanabe E. Tabei M. Goto and Y. Nagai J. Chem. SOC.,Chem. Commun. 1987 522. 27 H. B. Yokelson A. J. Millevolte G. R. Gillette and R. West J. Am. Chem. SOC.,1987 109 6865. 28 A. Schafer M. Weidenbruch W. Saak and S. Pohl Angew. Chem. Int. Ed. Engl. 1987 26 776. 29 P. R. Jones and T. F. Bates J. Am. Chem. SOC.,1987 109 913. Organometallic Chemistry -Part (ii) The Main-Group Elements 235 silicocation (R3Si+ species also known as siliconium silicenium or silylenium ion) in solution remains a matter of some debate and the prospect of a new area being opened up as mentioned in the Introduction to this volume last year remains unrealized. A detailed investigation using multinuclear NMR spectroscopy and X-ray crystallography of the solution and solid-state structure of Ph,SiOC103 by Olah and co-~orkers~~~ concluded that under normal conditions the compound is covalent with no evidence for the ionic structure Ph,Si+ClO,- previously proposed by other workers.30b The solvolysis of trimethylsilyladamantane derivatives in hexa- fluoroisopropanol (HFIP) has been proposed to involve a silicocationic intermedi- ate31 that had apparently unusual reactivity towards water and HFIP.This anomaly has been commented on and the products rationalized in terms of the cations present reacting with solvent at the solvent-separated ion-pair stage., Treatment of (Me3Si),(SiMe2CH=CH2)CSiEt21 with AgBF gives a mixture of unrearranged (Me&),( SiMe,CH=CH,)CSiEt,F and rearranged (Me3Si),C(SiEt2CH=CH2)(SiMe2F) in approximately 1 :2 ratio while (Me,Si),C( SiMe,OMe)( SiPh,Br) gives a 4 :1 mixture of the rearranged (Me,Si),C( SiMe,F)( SiPh,OMe) and unrearranged (Me,Si),C(SiMe,OMe)-(SiPh,F).Such migrations of vinyl and methoxy groups respectively are interpreted in terms of bridging uia a 1,3-silicocationic intermediate by the migrating groups which also provide anchimeric as~istance.~~-~’ The 1,3-migration of a phenyl group uia a silicocation has also been observed in the reaction of (Me,Si),C(SiMe,P@)- (SiEt,I) with AgBF which gives the rearranged (Me,Si),C(SiMe,F)(SiEt,Ph) as the major product.36 The 1,3-migration of a phenyl group between carbon centres appears to be unknown but the demonstration of such a reaction between silicon centres should encourage further work in this area.Further evidence for the stabiliz- ation of carbonium ions by a y-silicon has been presented for the solvolysis of 4-(trimethylsilyl)-2-butyl-p-bromobenzenesulphonate~.~~ Several new small-ring polysilanes have been prepared. Decaisopropyl-hexasilabicyclo[ 2.2.0lhexane is the first compound containing the bicyclo[2.2.0]hexasilane ring system to be made and is formed in low yield by treating a mixture of C12RSiSiRC12 and ClR2SiSiR2C1 (R = Pr’) with lithium.,* Several new cyclotri- and tetra-silanes bearing t-butyl cyclohexyl trimethylsilyl- methyl or i-propyl groups have been prepared and their structures determined by X-ray cry~tallography.~~,~~ The rates of reaction of several cyclic polysilanes (from ’O (a) G.K. S. Prakash S. Keyanigan R. Aniszfeld L. Heiliger G. A. Olah R. C. Stevens H.-K. Choi and R. Bau J. Am. Chem. SOC.,1987 109 5123; (b)J. B. Lambert J. A. McConnell and W. J. Schulz jun. J. Am. Chem. SOC.,1986 108 2482. 31 Y. Apeloig and A. Stanger J. Am. Chem. SOC.,1987 109 172. 32 D. N. Kevill J. Chem Res. (S) 1987 272. 33 G. A. Ayoko and C. Eaborn J. Chem. SOC.,Perkin Trans. 2 1987 1047. 34 N. H. Buttrus C. Eaborn P. B. Hitchcock P. D. Lickiss and S. T. Najim J. Chem. SOC.,Perkin Trans. 2 1987 891. 35 N. H. Buttrus C. Eaborn P. B. Hitchcock P. D. Lickiss and S. T. Najim J. Chem. SOC.,Perkin Trans. 2 1987 1753. 36 C. Eaborn P. D. Lickiss S. T. Najim and W. A. Stanczyk J. Chem.SOC.,Chem. Commun. 1987 1461. 37 V. J. Shiner jun. M. W. Ensinger and R. D. Rutkowske J. Am. Chem. SOC.,1987 109 804. 38 H. Matsumoto H. Miyamoto N. Kojima and Y. Nagai J. Chem. SOC.,Chem. Commun. 1987 1316. 39 M. Weidenbruch K.-L. Thorn S. Pohl and W. Saak J. Organornet. Chem. 1987 329 151. 40 H. Watanabe M. Kato T. Okawa Y. Kougo Y. Nagai and M. Goto Appl. Organornet. Chem. 1987 I 157. 236 P. D. Lickiss three- to six-membered rings) with iodine have been measured and as might be expected the smaller rings react faster than the larger ones.41 Polysilanes of various types are becoming increasingly important for industrial applications as precursors to ceramics e.g. Sic and Si3N4 as photoinitiators and as photoresists. The general subject of soluble poiysilane polymers has been revie~ed?~,~~ The relatively new route to as have polysilazanes and their US~S.~’~~ polysilanes i.e.dehydrogenative coupling of silicon hydrides (by for example dimethylzirconocene) has also been reviewed.46 Polysilanes have been shown to photoinitiate the polymerization of vinyl monomers such as styrene and methyl metha~rylate.~’ Although the initiation efficiency is low the polysilanes have high extinction coefficients and the polymerization is not very sensitive to oxygen which gives the method potential for example for the polymerization of thin films. Recent work on siloxane co-polymers has been reviewed,48 as has the stereochemistry and mechanism of group-transfer polyrnerizati~n.~~ A series of liquid crystalline polysiloxanes containing spiropyran groups have been shown to undergo remarkable colour changes depending on light and temperat~re.~’ Films of the polymers appear yellow under visible light but turn deep red on irradiation with ultraviolet light or blue if the irradiation is carried out at -20°C.The variety of functional groups on silicon that are finding use in organic synthesis continues to grow. The disilanes C13SiSiMe3 and Cl,PhSiSiMe silylate optically active .rr-allylpalladium complexes with retention of configuration giving optically active allylsilanes in good yield.51 Trimethylsilylisothiocyanate reacts with acetals and aldehydes in the presence of ZnC1 or SnCl to give a-isothiocyanato and a,a’-diisothiocyanato ethers re~pectively.~ For the first time a system [ -94% ( Bu‘O)~S~CN, -6% (Bu‘O),SiNC] containing a high enough concentration of a silylisocyanide species for comparison of the chemical reactivity of silylcyanide and silylisocyanide has been prepared.53 Unlike silylcyanides the silylisocyanide is a poor silylating agent and does not coordinate readily to platinum.A new reagent for organic synthesis H2Si12 can be prepared readily from PhSiH3 and iodine.54 It cleaves and deoxygenates ethers and alcohols readily and shows a reversed reactivity i.e. secondary >> methanol > primary compared with HI or Me3SiI. The ease of preparation of H2Si12 and its complementary reactivity to that of Me,SiI should make it a useful reagent. 41 H. Watanabe H. Shimoyama T.Muraoka Y. Kougo M. Kato and Y. Nagai Bull. Chem. SOC.Jpn. 1987 60,769. 42 L. D. David Chem. Brit 1987 23 553 containing 20 refs. 43 R. West J. Maxka R. Sinclair and P. M. Cotts folym. Prepr. 1987 28 387 containing 16 refs. 44 D. Seyferth G. H. Wiseman. and C. A. Poutasse. Pol-vm. Prep. 1987 28. 389 containing 2 refs. 45 R. M. Laine Y. D. Blum A. Chow R. Hamlin K. B. Schwartz and D. J. Rowecliffe Polym. frepr. 1987 28 393 containing 11 refs. 46 J. F. Harrod Polym. Prepr. 1987 28 403 containing 10 refs. 47 A. R. Wolff and R. West Appl. Organomet. Chem. 1987 1 7. 48 S. Kilic J. D. Summers C. S. Elsbernd C. A. Arnold J. Pullockaran and J. E. McGrath folym. Prepr. 1987 28 398 containing 36 refs. 49 Y. Wei and G. E. Wrek folym. Prepr.1987 28 252 containing 21 refs. so 1. Carera V. Krongauz and H. Ringsdorf Angew. Chem. Int. Ed. Engl. 1987 26 1178. ” T. Hayashi A. Yamamoto T. Iwata and Y. Ito J. Chem. SOC.,Chem. Commun. 1987 398. 52 K. Nishiyama and M. Oba Bull. Chem. SOC.Jpn. 1987 60 2289. 53 W. R. Herther D. A. Dixon E. W. Matthews F. Davidson and F. G. Kitson J. Am. Chem. SOC.,1987 109,6532. 54 E. Keinan and D. Perez J. Org. Chem. 1987 52 4846. Organometallic Chemistry -Part (ii) The Main-Group Elements 237 Co-condensation of germanium atoms with alkyl halides gives a germanium tetrahalide and alkyl germanes in low yield. For example CHCI with Ge gives GeCI and CHCI2GeCl3 while Pr'I gives GeI and PriGe13 .55 The cyclic organoger- mane 1,1,3,4-tetramethylgermoleacts (like doles) as a good q4-ligand to transition metals and is not displaced by pho~phines.~~ Treatment of bis( dimethylger- my1)methane with di-t-butylmercury affords in 74% yield compound (1 l) which is a good precursor to several unusual types of germanium heterocycle e.g.(12) and (13).57 Me2Ge-GeMez -Me2Ge-GeMe2 \ Me2GenGeMe2 I~OT I Hg H2O II \ d 0 Me2Ge, GeMez Me2Ge,,GeMez A convenient method for preparing a-trimethylgermyl ketones involves addition of Me,GeCI to a lithium enolate of a ketone (a reaction which gives silyl enol ethers when Me,SiCI is used in place of Me3GeC1). With two equivalents of lithiating reagent a,a-bis(trimethylgermy1)-substituted ketones can be ~repared.~' A 1,3- migration of a methyl group from germanium to silicon was observed when (Me,Si),C(GeMe,)(SiMe,Br) was treated with AgX (X =02CCF3or 03SCF3) to give (Me,Si),CGeMe,X as the major product^.'^ The migration is thought to occur via a cationic intermediate with the migrating methyl group bridging between germanium and silicon in a similar manner to the better studied silicon analogues.Interest continues to grow in compounds containing multiple bonds to germanium and small germacycles. The first compounds containing a C=Ge bond (14) and (15) have been isolated although (15) could not be obtained in a pure form.60,61 The germaethene (14) has a Ge=C bond length of 1.827(4) 8 and a I3C n.m.r. chemical shift of 115 p.p.m. for the double-bond carbon. But B N(SiMe3)z /\ / (Me3Si),C C=Ge \/ \ B Several aspects of the reactivity of the (2,4,6-Me3C6H2)2Ge=P(2,4,6-But3c6H2) have been explored.For example protic species such as alcohols and amines add across the double bond to give secondary phosphines and reduction with LiAIH 55 K. Mochida and K. Tashiro Chem. Lett. 1987 1105. 56 G. T. Burns E. Colomer R. J. P. Corriu M. Lheureux J. Dubac A. Laporterie and H. Iloughmane Organometallics 1987 6 1398. 57 J. Barrau N. B. Hamida A. Agrebi and J. Satge Organometallics 1987 6 659. 58 S. Inoue and Y. Sato Organometallics 1987 6 2568. 59 C. Eaborn and A. K. Saxena J. Chem. SOC. Perkin 2 1987 779. 10 H. Meyer G. Baum W. Massa and A. Berndt Angew. Chem. Int. Ed. Engl. 1987 26 798. 61 C. Couret J. Escudie J. Satge and M. Lazraq J.Am. Chem. Soc. 1987 109 4411. 238 P. D. Lickiss gives (2,4,6-Me3c6H2),GeHPH( ~,~,~-BU',C~H,).~~ Heating the germaphosphene at 140 "C for 40 h leads to loss of isobutene and formation of the first stable germaphos- phetene the structure of which has been determined by X-ray ~rystallography.~~ Reductive coupling of R2GeC12 (R = aryl or alkyl) with magnesium and mag- nesium bromide is a convenient route to cyclotri- and tetra-germanes in 10-60°/~ yield depending on R. For example Ph,GeCl and Pr',GeC12 give (Ph,Ge) and (Pr',Ge) respectively and (2,4,6-Me3C6H2),GeC1 and (2,4,6-Me3C6H,)( Bu')GeC12 afford [(2,4,6-Me3C6H2)GeI3 and [(2,4,6-Me3C6H,)( Bu')Ge] re~pectively.~~ The Ge-aryl bond in aryltrimethylgermanes is rapidly cleaved by Cl, Br, I, or ICl to give good yields of arylhalides; the best solvent for the reaction is acetic acid.65 This route to aryl halides may be of use in cases where a reactivity between that of the highly reactive arylstannanes and the comparatively unreactive arylsilanes is needed.The germylene bis(2,4,6-tri-t-butylphenyl)germanium(11) reacts with sulphur at -10°C to give an unstable germathione which undergoes an addition of a C-H bond from one of the But methyl groups to give a cyclic germanethiol. At room temperature the germylene itself undergoes a self-insertion into a But methyl group to give a cyclic germylhydride.66 A book concerning the use of tin in organic synthesis reviews the extensive literature of this expanding area.67 The toxicology and biomedical applications of organotin compounds have also been reviewed.68 Extracts of (Bu,Sn),O-impregnated natural and neoprene rubbers have been investigated by lI9Sn n.m.r.and Mossbauer spectroscopy. Extracts from natural impregnated rubbers were found to contain (Bu3Sn),S and tributyltin stearate while those from neoprene contained Bu3SnC1 tributyltin stearate and dibutyltin distear- ate. The implications of these results for formulating rubbers is discussed.69 A new method for the analysis of organotin species e.g. R,SnX involves the preparation of volatile hydrides on a gas chromatography column by doping the top of the column with sodium tetrahydroborate rather than the usual hydride formation outside the column.70 This method can detect Bu3SnC1 at 50 ng dm-3 in aqueous solution and may find use in the analysis of environmental samples.The first six-coordinate tetraorganotin compound bis[3-(2-pyridyl)-2-thienyl-C N]diphenyltin(IV) has been prepared and characterized by n.m.r. and Mossbauer spectroscopies and X-ray crystallography. The compound exists as discrete molecules in the solid state with the tin atom in a distorted octahedral en~ironment.~' In line with the successful preparations of compounds containing Si=C and Ge=C bonds the first stannaethene (Sn=C-containing compound) ( 16)has been prepared.72 62 J. Escudie C. Couret M. Andrianarison and J. Satge J. Am. Chem. Soc. 1987 109 386. 63 M. Andrianarison C. Couret J.-P.Declercq A. Dubourg J. Escudie and J. Satge J. Chem. Soc. Chem. Commun.1987 921. 64 W. Ando and T. Tsumuraya J. Chem. Soc. Chem. Commun. 1987 1514. 65 E. M. Moerlaein J. Org. Chem. 1987 52 664. 66 L. Large B. Meyer and W.-N. du Mont J. Organomet. Chem. 1987 329 C17. 67 M. Pereyre J.-P. Quintard and A. Rahm 'Tin in Organic Synthesis' Butterworths London 1987. 68 A. K. Saxena Appl. Organomet. Chem. 1987 1 39 containing 280 refs. 69 S. J. Blunden A. J. Crowe and A. W. Monk Appl. Organomet. Chem. 1987 1 57. 70 S. Clark J. Ashby and P. J. Craig Analysr 1987 112 1781. 71 V. G. K. Das L. K. Mun C. Wei and R. C. W. Mak Organometallics 1987 6 10. 72 H. Mayer G. Baum W. Massa S. Berger and A. Berndt Angew. Chem. Int. Ed. Engl. 1987 26 546. 239 Organometallic Chemistry -Part ( ii) The Main-Group Elements But Me3Si B C H( SiMe3)2 \/\ / C C=Sn /\/ \ Me3Si B C H( SiMe3)2 But (16) The stannaethene is a deep red solid with a S 13C and S lt9Sn of 142 and 835 p.p.m.respectively for the C=Sn atoms and a Sn=C bond length of 2.025(4) A. Mono- and bi-cyclic macrocycles of type (17) and (18) containing two ring tin atoms bind two and one chloride ions respectively. The rates of binding are slower for the bicyclic compounds and the rate decreases with ring size. The bicyclic compounds can thus act as selective hosts for the chloride anion as cryptands do for the binding of cation^.^^'^^ (CH2)n f\ C1Sn-(CH 2) ,,-SnC1 \/ (CH,)n n = 8 10 or 12 n = 6 8 10 or 12 (17) (18) A I3C and Il9Sn n.m.r. study of a variety of substituted dioxastannolanes shows that both intra- and inter-molecular processes occur in solution.The intramolecular process an inversion of configuration at tin has a high energy barrier which is thought to be due to the dioxastannolanes having a dimeric structure in ~olution.’~ As has been demonstrated for silicon and germanium analogues a 1,3-migration of a methyl group from tin to silicon can occur via a cationic intermediate in sterically hindered molecules. Thus treatment of (Me,Si),C( SnMe3)( SiMe,I) with AgX (X = O,CMe 02CCF3 or 03SCF3) gives (Me3Si)3CSnMe2X as the sole product. Reactions of compounds of this type have often been found to give mixtures of rearranged and unrearranged products but the greater space around the tin atom in this case presumably favours exclusive attack at tin rather than silicon by the incoming nucleophile X-.76 The use of the bulky alkyl groups (Me3Si)3C and (PhMe2Si),C has enabled the preparation of tin fluorides which are discrete monomers with four-coordinate tin.The structures of the compounds (Me3Si),CSnPh2F and (PhMe2Si)3CSnMe2F were both determined by X-ray crystal- lography the latter structure enabling the first accurate measurement to be made of the Sn-F bond length [1.965(2) A] for a four coordinate tin fluoride in the solid state.77 The direct synthesis of triorganotin compounds using tin metal an alkyl halide and a catalyst such as Bu4NBr gives about 95% yield of R3SnX with very little 73 M. Newcomb J. H. Homer and M. T. Blanda J. Am. Chem. Soc.1987 109 7878. 74 M. Newcomb A. M. Madonik M. T. Blanda and J. K. Judice Organometallics 1987 6 145. 75 C. Luchinat and S. Roelens J. Org. Chem. 1987 52 4444. 76 S. M. Dhaher C. Eaborn and J. D. Smith J. Chem. Soc. Chem. Commun. 1987 1183. 77 S. S. Al-Juaid S. M. Dhaher C. Eaborn P. B. Hitchcock and J. D. Smith J. Organomet. Chem. 1987 325 117. 240 P. D. Lickiss R2SnX2 formed. The by-product from the reaction a quaternary salt (e.g. Et,NSnBr,) can be broken down by electrolysis leading to recovery of tin and catalyst.78A new route to aryl tin compounds which involves no other organometallic reagents has been dem~nstrated.~' Treatment of a Schiff base with SnCl leads to formation of an orthometallated product for example SnC1 and Ph2C=NMe afford 2-C1,SnC,H4C(Ph)=NMe in >75% yield.The cleavage by iodine of mixed- functionality tetraorganotin compounds shows that tin-alkyl bonds can be broken in preference to tin-vinyl or tin-aryl bonds (the reverse of normal reactivity) for example in reaction 1 the tin-alkyl bond is broken in preference to the tin-vinyl bond. This unexpected reactivity is thought to be due to intramolecular coordination and assistance by the oxygen (or nitrogen in other analogous compounds) when the iodine approaches. This constrains the vinyl (or benzyl or aryl group in other examples) to be equatorial at tin and the leaving R group to be in an apical position where attack by incoming iodine can then occur.*o COR COR R = Me or OMe The effects of organolead compounds on algae" and chromosomal length in human lymphocytes82 have been investigated.It was found that tetraalkyl leads were not toxic to algae and that their decomposition products trialkylleads were responsible for their apparent toxicity. Organolead derivatives e.g. Et,PbCl were found to have a much greater effect than inorganic lead salts and were found to induce a gradual reduction in length of chromosome with increasing concentration. Tetraalkyl leads &Pb (R = Et Bu or cyclohexyl) have been found to react readily with aldehydes in the presence of Lewis acids such as TiCl or BF to give secondary alcohols in moderate to good yield. For example Et,Pb and benzaldehyde in the presence of TiC14 gave 96% PhCH(0H)Et. The reagents react only with aldehydes in the presence of ketones and the alkylation also occurs with a high degree of diastereoselectivity.These previously overlooked reagents for organic synthesis are stable can be stored easily and may find considerable use as alkylating reagents.83 F. S. Holland AppL Organomet. Chem. 1987 1 185. 79 W. Clegg C. M. J. Crievson and K. Wade J. Chem. SOC.,Chem. Commun. 1987,969. 80 B. Jousseaume and P. Villeneuve J. Chem. Soc. Chem. Commun. 1987 513. 81 A. W. P. Jarvie and S. J. Marshall Appl. Organomet. Chem. 1987 1 29. 0. Andersen and P. Grandjean Appf. Organomet. Chem. 1987 1 15. 83 Y. Yamamoto and J. Yamada J. Am. Chem. SOC.,1987 109. 4395.

ISSN:0069-3030    

DOI:10.1039/OC9878400231

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

10 Synthetic Methods By P. A. CHALONER School of Chemistry and Molecular Sciences University of Sussex Falmer Brighton 8N19QJ 1 Introduction The format of this report remains broadly the same as in previous years with a division of the material considered into two sections. The first details reactions in which new carbon-carbon bonds are formed or broken and new carbon skeleta are constructed. The second section is concerned with functional group transformations. As always such a review must be extremely selective and whilst every effort has been made to include contributions of general interest the author expresses her regret that some valuable material must be excluded. 2 C-C Connection and Disconnection Connection of Separate Fragments.-Endures and their Equivalents.Again this year enolates figure strongly in C-C bond-forming methodology and again stereoselec- tive reactions have proved to be among the most interesting. Reviews of tin(r1) enolates in synthesis,' stereoselective aldol reactions of a-unsubstituted chiral eno- lates,2 and cross-couplings based on acetals3 have been published. The preparation of activated zinc for Reformatsky reagents using trimethylsilyl chloride has been noted! Reaction of the enolates of chiral hydrazones such as (1) with Knoevenagel or Michael acceptors has been achieved in a very stereoselective manner (Scheme l).5 The asymmetric synthesis of alcohols and carboxylic acids may be accomplished by the alkylation of the enolates of piperazine-derived chiral diamides (Scheme 2).6 a-Alkylation of P-aminobutanoates (2) proceeds with good asymmetric induction giving diastereoisomer excesses up to 98% (Scheme 3).7 There has been continued progress and extensive interest in the area of diastereoselective aldol condensations.In the reaction of (3) the nature of the protecting group R was able significantly to change the diastereofacial selectivity ' T. Mukaiyama and N. Iwasawa Nippon Kagaku Kaishi 1987 1099. ' M. Braun Angew. Chem. Int. Ed. Engl. 1987 26 24. T. Mukaiyama and M. Murakami Synthesis 1987 1043. G. Picotin and P. Miginiac J. Org. Chem. 1987 52 4796. D. Enders and B. E. M. Rendenbach Chem. Ber. 1987,120,1223; D. Enders A. S. Demir and B. E. M. Rendenbach Chem. Ber. 1987 120 1731. K. Soai H. Hayashi A.Shinozaki H. Umebayashi and Y. Yamada Bull. Chem. SOC.Jpn. 1987,60,3450. ' D. Seebach and H. Estermann Tetrahedron Left. 1987 28 3103. 241 P. A. Chaloner H JJQOOMe >96% e.e. Reagents i MeCHO 25 "C; ii LDA THF 0 "C; iii Me/\\/COOMe -78 -+ 0 "C; iv O, CH2C12 -78 "C Scheme 1 iv v I R3 H &OH R2 Reagents RZCH2COCI Et,N 0 "C; ii base THF -78 "C; iii R3X; iv Li[HBEt,] THF 30 "C; v HCl H20 Scheme 2 0 PhA NHCOPh 2)yCOOR1goR R2 R2 E (2) 50-98% d.e. Reagents i LDA THF -78 "C; ii E' (alkyl halide or RCHO) -78 -+ 0 "C Scheme 3 of aldol reactions.* Stereoselective aldol reactions were achieved uia titanium eno- lates such as (4)(Scheme 4); the ratio of diastereoisomers in this case ranged from 79:21 to 98:2.The zirconium analogue gave syn-adducts with better than 90% selectivity.' The stereoselective aldol reactions of chiral halogenoethanoate enolates have been studied by Evans' group. The 2-enolate reacts rapidly and with high P. A. McCarthy and M. Kageyama J. Org. Cfiern. 1987 52 4681. P. J. Murphy G. Procter and A. T. Russell Tetrahedron Lett. 1987 28 2037. Synthetic Methods OLi OR ++ OTiCpzCl Nb CNb -C 64-77% (4) 58-96% d.e. Reagents i LDA THF -78 "C; ii Cp2TiC12 -78 +25 "C; iii RCHO -95 +-78 "C; iv [NH,]Cl H@ Scheme 4 i ii iii ____ C1 67% ,. Ph 'Me 95 YO diastereoselective Ph 'Me 1iv v vi NH2 Reagents i Bu2BOTf Et,N Et20 -78 "C; ii MeCHO -78 +0 "C; iii H202 MeOH H20 0 "c; iv ",I-; v LiOH H20; vi Hlr Pd/C CF,COOH Scheme 5 selectivity whereas the E-enolate reacts very slowly and with lower selectivity.The products have been converted into chiral amino acids and monobactams (Scheme 3.'' Condensation of the protected amino acid (5) with aldehydes proceeds in a very stereoselective manner being controlled not only by steric but also by stereoelectronic effects (Scheme 6). Alkylation is similarly selective and after debenzylation the products may readily be hydrolysed to threo-amino alcohols." New catalysts for aldol reactions have emerged this year. Lanthanide salts have been used as Lewis acids in aldol addition cyanohydrin formation and oxirane ring opening (Scheme 7)." Lanthanide-assisted electrochemical aldol condensations were shown to be very selective for aldehydes over ketones; this allowed the cross-aldol condensation of Scheme 8 to proceed in good yield.13 By contrast cerium enolates generated from a-halogenoketones by reaction with cerium(III) halides D.A. Evans E. B. Sjogren A. E. Weber and R. E. Conn Tetrahedron Lett. 1987 28 39. D. Seebach E. Tuaristi D. D. Miller C. Schickli and T. Weber Helv. Chim. Acta 1987 70 237. A. E. Vougioukas and H. B. Kagan Tetrahedron Lett. 1987 28 5513. l3 A. J. Fry M. Susla and M. Weltz 1. Org. Chem. 1987 52 2496. P. A. Chaloner i,i-FHNr; n R2 R' I R' OH Ph Ph X = 0or NMe (5) Reagents i base; ii R'CHO Scheme 6 OSiMe3 . .. OSiMe3 COOMe COOMe 12-5 1 O/o 1146% Reagents i RCHO; ii LnCI or Eu(fod), CH2CI, 25T 1 week Scheme 7 PhCOCH(Br)Me + PhCHO --* PhCOCH(Me)CH(OH)Ph Reagents LaBr, Li[C104] THF 0.2 8 ceramic anode carbon cloth cathode Scheme 8 OSiMe3 4 OH 81-93% 84-93 Oh 96-99% d.e.Reagents TiC14 CH2Cl,; ii [pyH][OOCCl] CH,CI, 25 "C dark; iii (PhCH2),NH CF,COOH 50 "C C6H6 Scheme 9 react successfully with both aldehydes and ketones.14 Rhodium diene biphosphine complexes better known for their activity as hydrogenation catalysts have proved useful in promoting aldol rea$tions between silyl enol ethers and either aldehydes or acetals. 15,16 Aldols have been prepared using butane-l,3-diol acetals as templates by the sequence of Scheme 9.17 Triphenylmethyl perchlorate was used to activate silyl enol ethers towards Michael reactions with CqP-unsaturated orthoesters to give 1,5-dicarbonyl compounds 14 S.Fukuzawa T. Tsuruta T. Fujinami and S. Sakai J. Chem. SOC.,Perkin Trans. I 1987 1473. S. Sato I. Matsuda and Y. Izumi Tetrahedron Lett. 1987 28 6657. 16 M. T. Reetz and A. E. Vougioukas Tetrahedron Lett. 1987 28 793. I. R. Silverman C. Edingon J. D. Elliot and W. S. Johnson J. Org. Chem. 1987 52 180. Synthetic Methods (Scheme 10).I8The stereoselective construction of adjacent tertiary and quaternary carbon atoms has been achieved by Michael addition; the diastereoisomers (6a) and (6b) were obtained in the ratio of 20 1 (Scheme 11). However the selectivity was a little capricious; using the pyrrolidine derivative gave equal amounts of the possible diastereoi~omers.'~ An approach to an enantioselective Michael addition was provided by the reactions of Scheme 12.Condensation of a P-ketoester with a chiral amino acid ester followed by deprotonation provided a potent nucleophile for conjugate addition to an appropriate acceptor; (7) was in general the sole product after hydrolysis and was obtained enantiomerically and diastereomerically pure.*' Hydride abstraction from acetals by triphenylmethyl tetrafluoroborate gives the dioxalynium cation (8). Reaction with a silyl derivative such as (9) allows the Reagents i [Ph,C][ClO,] CH,CI2 -78 "C; ii H20 Scheme 10 (6a) 80'/o (6b) Reagents i LDA THF -78 "C; ii WCOOEt THF -78 "C Scheme 11 i ii 0 R' (7) Reagents i L-ValOCMe,; ii LDA; iii x)=/ -78 "C X Scheme 12 l8 S.Kobayashi and T. Mukaiyama Chem. Lett. 1987 1183. M. Yamaguchi M. Hamada H. Nakashima and T. Minami Tetrahedron Lett. 1987 28 1785. *' K. Tornioka K. Yasuda and K. Koga J. Chem. SOC.,Chem. Commun. 1987 1345. 246 P. A. Chaloner preparation of ketoesters and diketones (Scheme 13).21 Reaction of a ketone enol with the related cation derived from a dithioacetal (lo) led to the formation of an a-oxoketene dithioacetal (Scheme 14).22 Methallyl magnesium chloride has been used as a synthon for the enolate of propanone. The process (Scheme 15) corresponds to an aldol type reaction and should be used in cases in which traditional methods 0-0 n + 40SiMe2CMe3 n __* 0 /O OMe PhCH2CH2-C-CH2COOMe 7 Ph (9) 80% (8) Reagents CH2C12 -45 "C 2.5h Scheme 13 S + asp"U:l - (10) 48-99Oh Reagents CH2C12 25 "C 1.5-24 h Scheme 14 .....II 111 %+ LMgCl * * 100% 1iv ' 74% Reagents i THF 0 +20 "C; ii O, CH2Clz -70 "C; iii DMSO 20 "C; iv HOOCCOOH H20 A Scheme 15 The silyl enol ethers of arylmethyl ketones were oxidatively coupled to the corre- sponding butanediones in modest yields using iodosobenzene/boron trifluor- ide etherate. The key step appears to be attack of the silyl enol ether on ArCOCH21Ph(OBF2).24 a-Methylenated ketones (1l) may be obtained from silyl enol ethers by reaction with bromomethylmethyl ether (Scheme 16); the reaction was used to prepare an intermediate for the synthesis of ~arkomycin.'~ " Y.Hayashi K. Wariishi and T. Mukaiyama Chem. Lett. 1987 1243. 22 J. Nakayama Y. Sugie and M. Hoshino Chem. Lett. 1987 939. 23 W. H. Bunnelle M. A. Rafferty and S. L. Hodges J. Org. Chem. 1987 52 1603. 24 R.Moriarty 0. Prakash and M. P. Duncan J. Chem. SOC.,Perkin Trans. 1 1987 559. 25 M. Hayashi and T. Mukaiyama Chem. Lert. 1987 1283. Synthetic Methods Reagents i MeOCH2Br SnBr, CH2CI2 25 "C 1.540 h; ii DBU CH2C12 25 "C 2 h Scheme 16 Allyl Alkynyl and Alkenyl Anions and their Equivalents. Reviews of the uses of allyltin compounds in organic synthesis and of routes to acyclic stereocontrol via allylic organometallic compounds have been A regiocontrolled syn- thesis of allyl stannanes has been described (Scheme 17). Although several steps are required both stereoisomers could be obtained with good selectivity.28 Allyllead compounds have been generated in situ using catalytic lead(I1) bromide and stoicheiometric aluminium; these were used for the allylation of imine~.~' A similar process was reported using bismuth( 111) chloride; conversion of aldehydes into homoallyl alcohols could then be accomplished in excellent yield in aqueous solvents.30 Selective allylation of ketones in aqueous media was also achieved by reaction of tin or zinc metal with an allyl halide3' (Scheme 18).SnMe3 . .. I I1 - iii - ,COOH I A.R2 OHIiv SnMe3 SnMe3 R' R' L,2 ti4-8m0 1 vi ii 4 1-78 Yo Reagents i Me,SnLi THF -78 "C; ii R'CHO; iii Me,CuLi; iv Me2NCH(OMe), CH2C12 25 "C; v MeOH H,O 25 "C; vi LDA THF -78 "C Scheme 17 26 Y.Yamamoto Aldrichimica Acra 1987 20 45. 27 Y. Yamamoto Acc. Chem. Res. 1987 20 243. I. Fleming and M. Rowley J. Chem. Soc. Perkin Trans. I 1987 2259. 29 H. Tanaka S. Yamashita Y. Ikemoto and S. Torii Chem. Lett. 1987 673. 'O M. Wada H. Ohki and K. Akiba J. Chem. SOC. Chem. Commun. 1987 708. 31 C. Einhorn and J. L. Luche J. Organomet. Chem. 1987,322 177. P. A. Chaloner R' OH 0 R3?X iorii R2+ R' R4 R3 R4 30-90% Reagents i Zn [NHJCI THF H20 25 "C 10-60 min; ii Sn ultrasound THF H,O 15-18 "C 30-60 min Scheme 18 Addition of crotyldiisopinocampheylboranes to aldehydes has again been achieved with good diastereofacial selectivity (Scheme 19).32 The stereoselectivity of the addition of crotylboronates (12a) and (12b) to oximes was shown to depend mainly on the geometry of the boronate and not significantly on that of the oxime (Scheme 20).33 OH OH Reagents -78 "C,<3 h N2 96 4 Scheme 19 NHOH From (12a) 95 5 64% From (12b) 12 98 38% Reagents i B") 9 kbar 46°C; ii /-?iB:O] 9 kbar 45 "C -\ 0 0 (12b) Scheme 20 Allyltin reagents have again figured prominently this year.The stereoselective synthesis of Z-homoallyl alcohols (13) from a-methylcrotylstannanes was accom- pli~hed,~~ whilst in addition to a,P-epoxyaldehydes the products of non-chelation controlled addition (14) were principally obtained.35 Enantioselective allylation has been achieved using a new chiral allylating agent formed from tin(r1) triflate a chiral diamine and an allylaluminium (Scheme 21).36 There have been further reports of the conjugate addition of ally1 silanes to enones catalysed by triphenylmethyl perchlorate; the intermediate silyl enol ether may readily be intercepted by an electrophile (Scheme 22).37 32 H.C. Brown K. S. Bhat and R. S. Randad J. Org. Chem. 1987 52 319 3701. 33 R. W. Hoffmann and A. Endesfelder Liebigs Ann. Chem. 1987 215. 34 C. Hull S. V. Mortlock and E. J. Thomas Tetrahedron Lett. 1987 28 5343. 35 G. P. Howe S. Wang and G. Procter Tetrahedron Lett. 1987 28 2629. 36 N. Minowa and T. Mukaiyama Bull. Chem. SOC.Jpn. 1987 60,3697. 37 M. Hayashi and T. Mukaiyama Chem. Letr. 1987 289. Synthetic Methods RCHO i ii iii R up to 84% e.e. Reagents i Sn(OTf),; ii N I Me ...; 111 AIBu'~ CH2CI2. -78 "C Scheme 21 Reagents i Me3SiCH2CH=CH2 [Ph3C][C104]; ii PhCHO Scheme 22 H-C C-0Et 70% ClCH,CH(OEt) LiCEC-OEt 111 IV RR'C (0H ) -CGC-0Et 7 1-9 5'/o Reagents i LDA THF 0 "C; ii NaCI H,O -78 "C fast addition; iii RCOR'; iv [NH4]CI Scheme 23 New and appreciably improved syntheses of ethoxyethyne and ethoxyethynyl alcohols have been reported (Scheme 23).38Useful ally1 silanes and trimethylsilyl ketones have been prepared via alkynyl boron compounds (Scheme 24).39Interest in the coupling of alkynyl anions with vinyl halides in the presence of palladium(0) complexes has continued (e.g. Scheme 25); (15) was used in a synthesis of the sex pheromone of the processionary moth.40 Selective monosubstitution of 1,l-dichloroethene by either a l-alkyne or a vinylalane was also shown to be catalysed by [Pd( PPh3)J .41 38 S.Raucher and B. L. Bray 1. Org. Chem. 1987 52 2332. 39 K. K. Wang K. E. Yang and S. Dhumrongvaraporn Tetrahedron Lett. 1987 28 1003 1007. 40 J. K. Stille and J. H. Simpson J. Am. Chem. SOC.,1987 109 2138. 41 V. Ratovelomanana A. Harnrnond and G. Linstrurnelle Tetrahedron Lett. 1987,,28 1649. P. A. Chaloner i ii RIB R1 R' -R'-C=C-Li RK!3iMe3 R/-LCSiMe3 \SiMe3 Reagents i R,B THF 0 "C 30 min; ii F,CSO,CH,SiMe, 25 "C; iii MeCOOH H,O; iv H20 NaOH Scheme 24 SiMe3 X // Me3Sn-CEC-SiMe3 + Bu-Bu-~ (15) Reagents [Pd(PPh,),] THF 50 "C or [Pd( MeCN),CI,] Scheme 25 Further reactions of vinylcuprates (readily prepared by alkyne carbocupration) have been described.Coupling with alkynyliodonium tosylates gave enynes with excellent stereoselectivity (Scheme 26).42Reaction with chiral acetals such as (16) proceeded with relatively low diastereoselectivity; the product on hydrolysis was a y,S-unsaturated aldehyde (Scheme 27) which was used in the synthesis of a precursor of the California Red Scale pheromone.43 R-CGC-iPh + )-7 R2 -Rk --0Ts R' CU R' =-R Reagents Et20 -78 -* 25 "C Scheme 26 CuLi 24% d.e (16) )=)-CHO Reagents i CuI.BF,.Et,O; ii H,O+ Scheme 27 42 P. J. Stang and T. Kitamura J. Am. Chem. SOC., 1987 109 7561. 43 P. Mangeney A. Alexakis and J. F. Normant Tetrahedron Left. 1987 28 2363. Synthetic Methods 25 1 Stannylation of trimethylsilyldiynes (17) gave initially distannylalkeneynes (Scheme 28); these undergo a variety of metallation and substitution reactions to give enynes dienes and alkenes.44 Deprotonation of styryl sulphone yields a lithiated alkene (18) (Scheme 29); this may be regarded as a synthon for an acyl anion?5 ........R)J R-C=C-C=C-SiMe3 11 111 II IV A RHSnMe3 +, (17) Me3Sn B' SiMe, '$, SiMe3 86% Reagents i Me,SnCu.SMe, LiBr THF -50 +0 "C; ii MeLi; iii Mel; iv BuI Scheme 28 . Ph Ph+ -2 qLi -phvo SOzPh SO2Ph S02Ph PhSOz (18) Reagents i BuLi THF -78 "C 30 min; ii MeI; iii 3-CIC6H4C03H CCI, A 48 h Scheme 29 Other Anions and their Equiualents. The use of higher order mixed organocuprates in organic synthesis has been reviewed.46 The reduction of magnesium chloride by lithium metal at 0°C to give very activated magnesium has been described?' The use of ultrasound in accelerating the formation of alkyllithiums under rather mild conditions has found applications in the reaction of Scheme 30 as well as in aldol and alkylation rea~tions.~~,~~ .HO R ArCH2C1 + Ar'COR -CAr A ArCH=CHAr' Ar' 100% E Z = 70:30-98:2 Reagents i Li sand 2% Na Et,O 0 "C ultrasound; ii 4-MeC6H4S03H Scheme 30 Many workers continue to report examples of the addition of organometallic reagents to carbonyl compounds. A particular favourite this year has been the enantioselective addition of diethylzinc to aldehydes in the presence of chiral catalysts generally amino alcohols including ephedrine derivatives and (19).50,51 44 G.Zweifel and W. Leong J. Am. Chem. Soc. 1987 109 6409. 45 M. Yamamoto K. Suzuki S. Taneka and K. Yamada Bull. Gem. SOC.Jpn. 1987 60,1523. 46 B. H. Lipshutz Synthesis 1987 325. 47 T. P. Burns and R. D. Rieke 1. Org. Chem. 1987 52 3674. 48 1. C. Burkow L. K. Sydnes and D. C. N. Ubeda Acta Chem. Scand. Ser. B 1987,418 235. 49 J. Einhorn and J. L. Luche J. Org. Chem. 1987 52 4124. 50 P. A. Chaloner and S. A. R. Perera Tetrahedron Letr. 1987 28 3013. '' K. Soai S. Yokoyama K. Ebihara and T. Hayasaka J. Chem. SOC.,Chem. Cornmun. 1987 1690. P. A. Chaloner In the asymmetric addition of Grignard reagents to benzaldehyde in the presence of chiral diamines such as (20) the addition of aryloxyaluminium dihalides enhances the optical yield; the function of the aluminium is thought to be to coordinate the oxygen of the aldehyde.52 The chiral amide (21) effected enantioselective deproto- nation of (22) with about 70% optical efficiency (Scheme 31).The products of the reaction with ethanal were used in a synthesis of (+)-~itrinin.’~ I I OMe OMe li + “‘O@JO OMe 0 OMe 0 70% e.e. 74% e.e. 3 1 Reagent i MeCHO Scheme 31 Two new reactions involving lanthanide organometallics have proved interesting. Alkyl and aryl lanthanum triflates may be generated in situ from La(OTf) and RLi; they react readily with tertiary amides to give excellent yields of ketones.54 Addition of organocerium compounds to SAMP hydrazones (23) proceeds with good diastereoselectivity (Scheme 32) leading to a general synthesis of chiral arnine~.~~ Tetraalkyllead compounds are proving to be a new class of stable storeable and selective alkylating agents.Coupling with chiral aldehydes in the presence of titanium( IV) chloride gives good diastereoselectivity (Scheme 33),56whilst coupling with acyl halides in the presence of a palladium(0) complex gave ketones.57 52 K. Tomioka M. Nakajima and K. Koga Tetrahedron Lett. 1987 28 1291; Chem. Lett. 1987 65. 53 A. C. Regan and J. Staunton J. Chem. Soc. Chem. Commun. 1987 520. 54 S. Collins and Y. Hong Tetrahedron Lett. 1987 28 4391. 55 S. E. Denmark T. Weber and D. W. Piotrowski J. Am. Chem. SOC.,1987 109 2224. 56 Y.Yamamoto and J. Yamada J. Am. Chem. Soc. 1987 109 4395. 57 J. Yamada and Y. Yamamoto J. Chem. SOC.,Chem. Commun. 1987 1302. Synthetic Methods 93% d.e. (23) Reagents i BuLi CeCI, THF -78 "C; ii CICOOMe 20 "C Scheme 32 Phx CHO -Ph %Et P h L Et OH OH 93?'a 7% Reagents Et,Pb TiCI4 -78 4 -60 "C Scheme 33 Zinc homoenolate esters may be generated by reaction of zinc(rr) chloride with (24). The intermediate (25) is a three carbon nucleophile with general synthetic utility.'& Direct geminal dimethylation of aryl aldehydes may be accomplished using Me2TiC12. The addition of two different alkyl groups by the sequence of Sch6me 34 should prove val~able.'~ XZn noR Reagents i BuLi; ii Me,TiC12 Scheme 34 Two new and rather general syntheses of amines have been described.In the first organolithiums are reacted with benzylmethylene hydroxylamine which acts as a synthon for +CH2NH+.60 Primary amines were synthesized by the reaction of Grignard reagents with a bis(trimethylsily1)aminomethylating agent (Scheme 35).61 58 E. Nakamura S. Aoki K. Sekiya H. Oshino and I. Kuwajima J. Am. Chem. SOC.,1987 109 8056. 59 M. T. Reetz and S.-H. Kyung Chem. Ber. 1987 120 123. 6o A. Basha and D. W. Brooks J. Chem. SOC.,Chem. Commun. 1987 305. 6L H. J. Bestmann G. Wolfel and K. Mederer Synthesis 1987 848. P. A. Chaloner . .. ... CH,=NOCH,Ph -R'CH2NR2R3 MeOCH,N(SiMe,) -% RCH,N(SiMe,) 2RCH,NH,+CI-Reagents i R'Li Et20 -40 "C; ii R'Li Et20 -40 +0 "C; iii R3X THF 25 "C; iv RMgX Et,O 0 440 "C; v HCI H20 Scheme 35 Methyleneation and Alkylideneation.Two new metals have been added to the armoury of those involved in methyleneation of carbonyl compounds. The use of the uranium derivative (26) was extremely effective even for readily enolizeable ketones giving readily isomerized alkenes.62 Methyleneation of enolizeable carbonyl compounds was also catalysed by ceriurn(Ir1) chloride in a modification of the Peterson reaction (Scheme 36).63 R R . R OH ii iii or iv '>-R''O R1cSiMe3 R' 6 1-98 Yo Reagents i Me3SiCH2Li CeCl, THF -78 "C; ii HF MeCN HzO;iii HF MeCN py H,O; iv KH THF Scheme 36 The Wittig and Wittig-Horner reactions have also seen considerable activity this year. In particular workers have been seeking methods to carry out the reaction under milder conditions or to force unwilling reactions (Scheme 37); techniques used include high pressures,64 gas-liquid phase-transfer catalysis,65 and the use of ultrasound-activated barium hydroxide as the base.66 Ph3P= CHCOOEt -&cooEt + A 96Yo PhCH(R')CHO + (EtO),P(0)CH,COR2 -% PhCH(R')CH=CHCOR' Reagents i 9 kbar xylene 50 "C 30 h; ii K2C03 MeOH polyethylene glycol carbowax 6000 130 "C 5 torr 1.5 h; iii Ba(OH)2 ultrasound dioxan Scheme 37 62 A.Dormond A. El Bouadili and C. Moise J. Org. Chem. 1987 52 688. 63 C. R. Johnson and B. D. Tait J. Org. Chem. 1987 52 281. 64 N. S. Isaacs and G. N. El-Din Tetrahedron Lett. 1987 28 2191. 65 E. Angeletti P. Tundo and P. Venturello J. Chem.SOC.,Perkin Trans. I 1987 713. 66 J. V. Sinisterra A. Fuentes and J. M. Marinas J. Org. Chem. 1987 52 3875; C. Alvarez-Ibarra S. Arias G. Banon M. J. Fernandez M. Rodriguez and V. Sinisterra J. Chem. Soc, Chem. Commun. 1987 1509. Synthetic Methods 255 Stereoselectivity has also been to the fore. The E-selective alkylideneation of aldehydes by RCHI is accomplished via gem-dichromium reagents derived from reduction by chromium( 11) chloride.67 E-Selectivity was also high in reactions of P-diphenylphosphino propanoic acid (Scheme 38) the stereoselection being explained by steric interactions in the betaine.68 Ph2hCH2CH,COOH -RCH=CHR' + Ph2P(0)CH2CH2COO-LR Reagents i base CH,CI,; ii R'CHO Scheme 38 Miscellaneous. Several new pinacol-type reactions of carbonyl compounds have been reported.Titanium on graphite prepared from titanium( 11) chloride and lamellar potassium/graphite proved to be a universal reducing agent for the coupling of carbonyl compounds to give alkenes or diols (Scheme 39).69The complex formed R' R2 I "& 7&96% R2)=o R2 R' \i i R2 R2 or R1-t-+R1 Rg2 R2 R' OH OH 80-95'/! 64-9 1 '/o R' R2 = Ar H R',R2 = H alkyl Reagents i TiCI, CsK THF A; ii TiC14 C8K THF 0°C Scheme 39 from Cp,TiCl and Bu'MgCl was selective for the pinacolization of aromatic and a,S-unsaturated aldehydes to give mainly threo- products.'' The use of ytterbium metal gave selectively either reduction or coupling according to the mole ratio of the reactants7' Solvent complexes of niobium( 111) chloride were useful in coupling imines with carbonyl compounds with moderate diastereoselectivity (Scheme 40).72 Vicinal diamines could be obtained from nitriles or N-trimethyl~ilylimines.~~ Several one-carbon homologations of carbonyl compounds have been described.Substitution on (27) followed by reduction gave a homologated aldehyde in good to excellent yields (Scheme 41).74A samarium iodide-induced masked formylation of carbonyl compounds (Scheme 42) is thought to proceed via a radical process.75 67 T. Okazoe K. Takai and K. Utimoto J. Am. Chem. SOC. 1987 109 951; K. Takai K. Kataoka T. Okazoe and K. Utimoto Tetrahedron Lett. 1987 28 1443. 68 H. Daniel and M. Le Corre Tetrahedron Lett. 1987 28 1165. 69 A.Furstner and H. Weidmann Synthesis 1987 1071. 70 Y. Handa and J. Inanaga Tetrahedron Lett. 1987 28 5717. 71 Z. Hou K. Takamine Y. Fujiwara and H. Taniguchi Chem. Lett. 1987 2061. 72 E. J. Roskamp and S. F. Pedersen J. Am. Chem. Soc. 1987 109 6551 73 E. J. Roskamp and S. F. Pedersen J. Am. Chem. SOC.,1987 109 3152. 74 M. Ceruti 1. Degani and R. Fochi Synthesis 1987 79. 75 M. Matsukawa J. Inanaga and M. Yamaguchi Tetrahedron Lett. 1987 28 5877. P. A. Chaloner R' R HO threo erythro = 3 1-83 1 Reagents i NbCl, dme THF 1 min; ii R2COR3 30 min Scheme 40 ask CHRlR2 R2 S RZ Reagents i BuLi THF -78 "C; ii H[BF4] Et,O MeCN 25 "C; iii Na[BH4] 0 "C; iv HgO H20 H[BF4] Scheme 41 73-77% Reagents SmI, C,H, HMPT 25 "C 5 min Scheme 42 Cyc1ization.-Free radical cyclizations continue to attract considerable attention and the use of such reactions in synthesis has been reviewed.76 Samarium(I1) iodide has been particularly useful as the initiator of such processes and a new and convenient preparation has been described.77 For example the samarium iodide-mediated cyclization of iodoalkyl ketoesters and ketoamides proceeds with good stereoselec- tivity (Scheme 43);the kinetically favoured ring closure from the more accessible face of the chelated ketyl intermediate is supposed to ~redominate.~~ Asymmetric induction was also noted in intramolecular Reformatsky-type reaction^.^' Eneynes have been a topic of considerable investigation over the last year and several new cyclizations have emerged.In the presence of a nickel/chromium 76 M. Ramaiah Tetrahedron 1987 43 3541. 77 T. Imamoto and M. Ono Chem. Lett. 1987 501. 78 G. A. Molander J. B. Etter and P. W. Zinke J. Am. Chem. SOC.,1987 109,453; G. A. Molander and J. B. Etter Synth. Commun. 1987 17 901; G. A. Molander and C. Kenny Tetrahedron Lett. 1987 28 4367. 79 G. A. Molander and J. B. Etter J. Am. Chem. SOC.,1987 109 6556. Synthetic Methods 0 Srn 3+ I - OH COOEt.-ttPhvia 'R' Y d.e. = >200:1 I Reagents SmI, THF -78 "C Scheme 43 Reagents [ Ni(PPh,),Cl,] CrCl, THF 25 "C Scheme44 catalyst (28) was cyclized to (29) the chromium(I1) salt acting as a one-electron reducing agent (Scheme 44). Five- and six-membered rings could be produced with equal facility.80 Reductive cyclization of 1,6- and 1,7-eneynes occurs in the presence of a palladium(0) catalyst with polymethylhydrosiloxase acting as the reductant (Scheme 45).81 Stereospecific dicobalt octacarbonyl-mediated eneyne cyclization was used in an enantiospecific synthesis of an analogue of 6a-carbocycline (Scheme 46).82 Sequential intramolecular Michael addition followed by alkylation of /3-ketoester ynones resulted in the synthesis of tricyclic compounds shown in Scheme 47.83 Reagents [ Pd(dba),] polymethylhydrosiloxane MeCOOH CaHa 25 "C Scheme 45 %Me3 SiMe3 '.p + HO' H3$-J$o 'H R iR HO Reagent [co,(co)8] Scheme 46 80 B.M.Trost and J. M. Tour J. Am. Chem SOC.,1987 109 5268. 81 B. M.Trost and F. Rise J. Am. Chem. Soc. 1987 109 3161. a2 P. Magnus and D. P. Becker J. Am. Chem. Soc. 1987 109 7495. 83 J.-F. Lavellee and P. Deslongchamps Tetrahedron Left 1987 28 3457. P. A. Chaloner A"'" -& OTS H H 60% 15 Reagents Cs,[CO,] DMF 65 "C Scheme 47 Cycloadditions and Annu1ations.-Reactions Forming Six-membered Rings. The gener- ation and uses in Diels- Alder reactions of orthoquinodimethanes have been reviewed.84 The Diels- Alder reactions of 1,3-dienyl boronates have provided a new route to functionalized carbocycles such as (30) (Scheme 48); stereoselection was m~derate.~' An inverse type of hetero-Diels- Alder reaction has been used in the synthesis of 3-deoxy-2-glyculosonatesand C-aryl glycosides (Scheme 49).86 0 P i_ J3 OOMe 1 1.8 endo exo Reagents i C,H,Me 100 "C,100 h; ii Me,NO Scheme 48 A one-pot four-component annulation of cyclohexanone has been described (Scheme 50).The initial product (31) was readily cleaved using lead(1v) ethanoate as the ~xidant.~' Biomimetic syntheses of polycyclic quinones have been noted; the polyketide intermediate (32) (Scheme 51) closely resembles the intermediates pro- posed in the biosynthetic pathway.88 84 J. L. Charlton and M. M. Alauddin Tetrahedron 1987 43 2873. M. Vaultier F. Trichet B. Carboni R. W. Hoffrnann and I. Denne Tetrahedron Lett. 1987 28 4169. 86 R. R. Schmidt W. Frick B. Haag-Zeino and S. Apparao Tetrahedron Lert. 1987 28 4045. 87 G. H. Posner E. Asirvatharn K. S. Webb and S.-S.Jew Tetrahedron Lett. 1987 28 5071. 88 M. Yamaguchi K. Haseba M. Uchida A. Irie and T. Minami Tetrahedron Lert. 1987 28 2017. Synthetic Methods foBn / foBn RK P h S h OMe A. 0 *COOMe OCOMe R f7-*,0'0 Ph C-aryl glycosides = Me or 3-deoxy-2-heptulosonates OMe COOMe Reagents i MeCOO-Ar 5.2 kbar 60 "C 30 h; ii ==( 5.2 kbar 48 h 60 "C OMe Scheme 49 77% trans cis = 0.7 (31) Reagents i LiSnBu3 THF -78 "C; ii CH,=CHCOEt THF -78 "C; iii MeCHO THF DMF -65 "C; iv Pb(OCOMe), C6H6 A 3.5h Scheme 50 COOMe COOMe i ii iii COOMe COOMe 0 00 COOMe COOMe (32) Reagents i ACOOMe Li+ Na+ THF HMPT 25°C; ii Ca(OCOMe), MeOH 25°C; iii K2[C03] MeOH 25 "C Scheme 51 I? A. Chaloner Chiral non-racemic cyclohexanediols have been prepared by the pathway shown in Scheme 52; the Lewis acidity of the tin is the controlling factor in determining the diastereo~electivity.~~ R,' RZ OH R2 CHO H R R' R2 = H or alkyl 4 1-50 :1 diastereomer ratio Reagents SnF, THF 25 "C Scheme 52 Reactions Forming Fivemembered Rings.Cycloaddition reactions of nitrones have been much in vogue this year and both intra" and intermolecular reactions have proved useful'' (Scheme 53). Nitrile oxides (33) gave similarly successful results in reaction with the acetaldehyde enolate anion produced by treatment of tetrahy- drofuran with butyl lithium and cycloreversion (Scheme 54).92 An enantioselective reaction (Scheme 55) occurred between (34) and Me,C-CrN+-O-; L-Selectride reduction allowed release of the chiral auxi1ia1-y.~~ Oximes are known to react readily with Michael acceptors; in the reaction of (35) (Scheme 56) the process was intramolecular and the product nitrone could be trapped both intra- and inter- molecularly.94 96 4 0 Reagents i MeNHOH.HC1 K,[C03] PhMe A Scheme 53 89 G.A. Molander and D. C. Shubert J. Am. Chem. SOC.,1987 109 576. 90 R. Annunziata M. Cinquini F. Cozzi and L. Raimondi Tetrahedron 1987 43 4051. 91 R. L. Funk and J. U. Dagget Heterocycles 1987 26 2175. 92 L. D. Nunno and A. Scilimati Tetrahedron 1987 43 2181. 93 D. P. Curran B. H. Kim H. P. Pujasena R. J. Loncharich and K. N. Houk J. Org. Chem. 1987,52,2137. 94 P. Armstrong R. Grigg W.J. Warnock and S. Surendrakumar J. Chem. SOC.,Chem. Commun. 1987 1325 1327. Synthetic Methods 26 1 OH 83-100% Reagents i THF 25 "C; ii Na[OMe] MeOH; iii Na[OH] EtOH Scheme 54 Reagents i 25 "C 6 h; ii L-Selectride Scheme 55 Dihydrofurans have been synthesized by reaction of dibromodeoxybenzoin with alkenes in the presence of samarium(11) iodide. The reaction (Scheme 57) is formally a 1,3-dipolar cycloaddition to a ketocarbenoid but the mechanism is not clear since the zinc carbenoid was not a suitable s~bstrate.~' Atom-transfer cycloaddition led to an unusual synthesis of methylenecyclopentanes; the ratio between 5-ex0 and 6-end0 processes ranged from 7 1 to 100 0 (Scheme 58).96 COOMe COOMe + NMe -Hh,oeo NMe H HO (jOH (35) 90% Reagents PhMe 110 "C 3 h Scheme 56 Ph Ph Ph 80O/O Reagents SmI, THF HMPT Scheme 57 95 S.Fukuzawa T. Fujinami and S. Sakai J. Chem. SOC. Chem. Commun. 1987 919. 96 D. P. Curran and M.-H. Chen J. Am. Chem. Soc. 1987 109 6558. P. A. Chaloner R = H or SiMe,; R' = H or alkyl; R2 = carbonyl CN or SOzPh Reagents Bu,SnSnBu, hv C,H6 70-80 "C Scheme 58 <OR' + Me3Si-=-R2 -!+ BrZn ZnBr R'O R'O' " 51-91°/o Reagents i 100 "C 30 h; ii [Pd(PPh3)J 65 "C 24 h Scheme 59 A one-pot synthesis of methylenecyclopentenes has been achieved via an allyl-metallation of 1-silylalkynes by 2-bromozincmethyl-2-propenyl ether followed by palladium-catalysed cyclization (Scheme 59).97Manganese( 111)-promotedannula-tion of enol ethers and esters to fused or spiro cyclopentenones has proved very efficient and a closely related process was used in furannulation (Scheme 60).98 76Yo OMe 92% Reagents i Mn(OCOMe), MeCOOH 23 "C 5 min then 40 "C 30 min; ii NaH PhMe A; iii HCl HzO; iv [Mn,0(OCOMe)7]; v H+ Scheme 60 Other Ring Sizes.The preparation of cyclopropanes by reactions of transition metal carbene complexes with alkenes has been reviewed.99The cyclopropanation of allylic alcohols is promoted by samarium metal or samarium amalgam; the degree of stereocontrol obtained is dependent on the substituents but is generally high."' 97 J. van der Louw J. L. van der Baan F. Bickelhaupt and G. W. Klumpp Tetrahedron Left.,1987,28,2889. 98 E. J. Corey and A. K. Ghosh Tetrahedron Lett.1987,28 175; Chem. Lett. 1987 223. M. Brookhart and W. B. Studabaker Chem Rev. 1987 87 411. 100 G. A. Molander and J. B. Etter J. Org. Chem. 1987 52 3942. Synthetic Methods 263 a$-Unsaturated acetals from dibenzyl threitol(36) undergo diastereoselective cyclo- propanation under Simmons-Smith conditions (Scheme 61)."' Two stereoselective syntheses of p-lactams have been reported by Dutch workers (Scheme 62). In the first an a-iminoester is reacted with diethylzinc to give exclusively the trans-product (37).'02 The reaction of zinc enolates with imines gave (38).'03 Preparative scale syntheses of bicyclobutylidene methylenecyclobutane and cyclo- butanone have been described (Scheme 63); the one-pot procedure compares favour- ably with previously reported rneth~ds."~ P hCH 2 OCH 2 ,C H 2 OCH 2 Ph P hCH 2 OCH 2 ,CH2 OCH2 Ph PhCH20C H 2 ,C H2OC H 2 Ph 7-7 77 77 0 + &>.9 1ii 1 75 % A>. 51% e.e. Reagents CH212 I, Zn/Cu Et,O A; ii HCl H20 MeOH Scheme 61 R'O R iii iv v vi Et2 NCH2COOEt Reagents i Et2Zn; ii -80 -+25 "C;iii LDA C6H6 25 "C; iv ZnC1,; v PhCH=NMe A; vi H,O Scheme 62 101 E. A. Mash and K. A. Nelson Tetrahedron 1987 43 679. 102 M. R. P. van Wet J. T. B. H. Jastrzebski W. J. Kaver K. Goubitz and G. van Koten Red. Trau. Chim. Pu~s-Bus,1987 106 132 103 J. T. B. H. Jastrzebski F. H. van der Steen and G. van Koten Recl. Trau. Chim. Pays-Bas 1987,106,516. L. Fitjer and U. Quabeck Synthesis 1987 299. 264 P.A. Chaloner 67-7 1Yo Reagents i K[OCMe3]; ii 02,50°C; iii (CH20),; iv 0, MeOH CH,CI,; v (NH2)2CS Na[OH] Scheme 63 Several new and high yielding syntheses of medium ring compounds have been reported this year. The [6 + 31 cycloaddition shown in Scheme 64 gave a nine- membered ring presumably via a trimethylenemethane complex.'o5 The [3 + 41 and [3 + 51 annulations of Scheme 65 involve a dianion synthon.lo6 Intramolecular nickel-catalysed cycloadditions of bis-dienes may lead to the formation of eight-membered rings with high yield and excellent diastereoselectivity. The reaction was used in an approach to the taxane ~keleton."~ ( + -m SiMe3 R R 68% Reagents Pd(OCOMe)2 P(OCHMe2)3 PhMe 80-85 "C,3-10 h Scheme64 11 SiMe X2Sn0 + Me3SiX + RQRl SnX, -hR1 Ill 1" n = lor2 Reagents i SnF,; ii RCOCH2(CH2),COR' Scheme65 B.M. Trost and P. R. Seoane J. Am. Chem. SOC.,1987 109 615. 106 G. A. Molander and D. C. Shubert J. Am. Chem. SOC. 1987 109,6877. 107 P. A. Wender and M. L. Snapper Tetrahedron Lett. 1987 28 2221. Synthetic Methods Rearrangements and Fragmentations.-The enantioselective [2,3] Wittig ring con- traction induced by chiral bases was applied in the synthesis of (+)-aristolactone (Scheme 66)."' 82% 65% e.e. Reagents Ph ANAPh THF -20°C I Li Scheme66 Lewis acid-catalysed rearrangement of epoxysilyl ethers such as (39) gave aldols (Scheme 67). The catalytic reaction generally gave superior yields of the aldol to the analogous stoicheiometric version.'o9 The ring expansion of ketones to a-methoxy and a-phenylthioketones was also achieved in the presence of a Lewis acid (Scheme 68).'lo A radical-promoted rearrangement of bromomethyl p-ketoesters was also instrumental in promoting ring expansion generally in good yield (Scheme 69)."' RZ i ii or iii R3 OH 0 R14&3 OSiMe3 12-100% (39) Reagents i Me,SiI; ii Me,SiOTf; iii TiCl Scheme 67 SOzPh 11 _.WSPh a0 + clir H 92% \ iii iv 79'/o Reagents i PhSO,CH(Li)SPh Et,AICl hexane; ii Et,AlCI CH>Cl, -20 "C; iii PhSO,CH( Li)OMe Et,AICl THF -78 "C; iv Et,AlCl CH,Cl, -78 "C Scheme68 108 J. A. Marshall and J. Lebreton Terrahedron Lett. 1987 28 3323. 109 K. Suzuki M. Miyazawa and G. Tsuchihashi Tetrahedron Lett.1987 28 3515. 110 B. M. Trost and G. K. Mikhail J. Am. Chem. SOC.,1987 109 4124. 111 P. Dowd and S.-C. Choi J. Am. Chem. SOC.,1987 109 3493. 266 P. A. Chaloner COOMe 7 1O/O trace Reagents i NaH; ii CH2Br2 A; iii Bu,SnH AIBN C6H, A Scheme 69 Insertion of the metal carbonyl into the three-membered ring of a cyclopropene to give a metallocyclobutene is the first step in the catalytic rearrangement of these compounds to highly substituted naphthols (40) (Scheme 70).' '*An entirely novel synthetic approach to biphenyls has been described (Scheme 71). Two arenes are initially joined by a Wittig reaction to give a stilbene derivative which is then coupled to give a phenanthrene (41) using iodine. The biphenyl is released by ozono~ysis.''~ OH ph'pOMe Ph __* 40 yo aPh Ph Ph OH (40) Reagents [Cr(CO),] Bu,O 3 h A Scheme 70 Reagents (CH,),N, MeCOOH A; ii (EtO),P Na[OMe]; iii hv 1,; iv 03,MeOH; v KI MeCOOH Scheme 71 3 Functional Group Modifications Oxidation.-Additions to C=C.There have been further reports of new methodology for the conversion of alkenes into epoxides. Epoxidation of a,@-unsaturated carbonyl compounds by hydrogen peroxide or alkyl hydroperoxides is 112 M. F. Semmelhack S. Ho M. Steigerwald and M. C. Lee J. Am. Chem. SOC.,1987 109 4397. I I3 T. Ho C. Shu M. Yeh and F. Chen Synthesis 1987 795. Synthetic Methods promoted by fluoride ion; the method is also applicable to unsaturated nitriles and nitro compounds.' l4 Sulphamyl oxaziridines (42) have been used in the preparation of a-siloxyepoxides and a-hydroxycarbonyl compounds.Enantioselective versions of the reaction gave rather modest optical yields.' l5 A modified version of the Sharpless reagent has been shown to give excellent enantioselectivities in asymmetric epoxidation with a much reduced reaction time (Scheme 72). The epoxidation of methyl gibberellate fails with the normal Sharpless conditions but succeeded with the modified reagent.' l6 The kinetic resolution pro- cedure effected by Sharpless epoxidation has been used to resolve E-fluoroalkyl ally1 alcohols such as (43)."' i ii iii iv 71% -OH OH 95% e.e. Reagents i [Ti(OCHMe2)4],L-(+)-DET,CaH, SiOz CH2C12 -20 "C 10 min; ii Me3COOH -40 "C 1 h; iii tartaric acid H20 -20 -* 25 'C; iv Na[OH] H,O Et20 0 "C 30 min Scheme 72 Further enantioselective cis-dihydroxylations of alkenes by osmium(vrI1) oxide have been reported.In the presence of the chiral diamine (M),optical yields up to 99% were achieved.lI8 Oxidation of alkenes to 1,2-diethanoates was accomplished using benzenetellurinic anhydride in ethanoic acid."' Other Oxidations. The salts tetrabutylammonium and tetrapropylammonium perruthenate have been prepared and used as new catalysts for alcohol oxidation using NMO as oxidant. Primary alcohols are converted into aldehydes and sec- ondary alcohols into ketones whilst epoxides alkenes indoles and trimethylsilyl- or tetrahydropyranyl-protected alcohols are unaffected.12' The Swern reagent Me,SO/ClCOCOCl oxidizes the trimethylsilyl ethers of primary and secondary alcohols to carbonyl groups.However a useful selectivity difference on steric grounds has emerged in that 1,l -dimethylethyldimethylsilyl ethers are unaff ected.121 Amines have been dehydrogenated to imines under mild conditions by the Swern reagent.'*' This year has been marked by the emergence of a number of practical and high yielding procedures for the oxidation of unfunctionalized benzylic methylene groups. 114 M. Miyashita T. Suzuki and A. Yoshikoshi Chem. Letr. 1987 285. 115 F. A. Davis and A. C. Sheppard J. Org. Chem. 1987 52 954. 116 Z.-M. Wang and W.-S. Zhou Tetrahedron 1987 43 2935. 117 Y. Hanzawa K. Kawagoe M. Ito and Y. Kobayashi Chem. Pharm. Bull 1987 35 1633.118 K. Tomioka M. Nakajima and K. Koga J. Am. Chem. SOC.,1987 109 6213. I19 N. Kambe T. Tsukamoto N. Miyoshi S. Murai and M. Sonoda Chem. Lett. 1987 269. 120 W. P. Griffith S. V. Ley G. P. Whitcombe and A. D. White J. Chem. SOC.,Chem. Commun. 1987 1625. 121 C. M. Alfonso M. T. Barros and C. D. Maycock J. Chem. SOC.,Perkin Trans. 1 1987 1221. 122 D. Keirs and K. Overton J. Chem. SOC.,Chem. Commun. 1987 1660. P. A. Chaloner Reagents have included chromium(v1) oxide/ alkyl hydr~peroxide'~~ and per- manganate under phase-transfer condition^.'^^ Methyl groups were oxidized to methanoyl groups using cerium( IV) methane sulphonate or trifluoromethane sul- phonate'25 or iron(11) chloride and 2-methyl-2-iodopropane in dimethylsul-phoxide/ trifluoroethanoic acid.'26 lodine(II1) reagents have been used (Scheme 73) for the oxidation of silyl enol ethers to a-methoxyketones (45).12'Related species were used in the procedure of Scheme 74 to prepare alkynyl methane sulphonates and 4-methylphenyl sulphonates; these are the first acetylenic esters of any kind to be synthesized.'28 Reagents {PhIO}, BF .Et,O MeOH -70 "C Scheme 73 PhI(OCOMe) + RSO,H.H,O OHII Ph-I-OS0,R ii +-Ph-I-CEC-R' R-CrC-0,SR RS03- Reagents i MeCN 25 "C 30 min; ii R'-CZC-H THF desiccant; iii Cu[OTfl Scheme 74 Oxidation of N-acylpyrrolidines and piperidines with iron(1x) and hydrogen peroxide or an iron oxygen complex has been described in detail and the pro- cedure has been extended to tetrahydroquinolines to allow the synthesis of cyclic hydroxamic acids."' Reduction.-Hydrogenation of Carbon-Carbon Multiple Bonds.The stereoselective hydrogenation of alkenes using cationic rhodium or iridium complexes as catalysts has been reviewed with particular reference to reductions the stereochemistry of which is directed by the presence of a polar functional The enantioselective reduction of substrates other than dehydroamino acids has been a long-standing problem and some progress in this area has been made this year. Unsaturated carboxylic acids such as (46) were reduced in the presence of a ruthenium complex of BINAP (47) with up to 88% optical efficiency (Scheme 75)I3l and 123 J. Muzart Tetrahedron Lett. 1987 28 2131 2133. 124 S. M. Cannon and J.G. Krause Synthesis 1987 915. 125 R. P. Kreh R. M. Spotzitz and J. T. Lundquist Tetrahedron Left. 1987 28 1067. 126 E. Vismara F. Fontana and F. Minisci Gazz. Chim. Ital. 1987 47 135. 127 R. M. Moriarty 0. Prakash M. P. Duncan R. K. Vaid and H. A. Musallam J. Org. Chem. 1987 52 150; R. M. Moriarty M. P. Duncan and 0. Prakash J. Chem. SOC.,ferkin Trans. I 1987 1781. I28 P. J. Stang B. W. Surber Z.-C. Chen K. A. Roberts and A. G. Anderson J. Am. Chem. SOC.,1987 109 228. 119 S. Murata M. Miura and H. Narnura J. Chem. SOC.,Perkin Trans. I 1987 1259; S.-I. Murahashi T. Oda T. Sugahara and Y. Musui J. Chem. SOC.,Chem. Commun. 1987 1471. 130 J. M. Brown Angew. Chem. Int. Ed. Engl. 1987 26 190. 131 H. Kawano Y. Ishii T. Ikariya M. Saburi S.Yoshikawa Y. Uchida and H. Kurnobayashi Tetrahedron Lett. 1987 28 190.5. Synthetic Methods 269 PArz TOoH -YOOH 86-88% e.e. (S) PArz COOH COOH (46) (47) Reagents H, Et3N [(47),Ru2CI4] Scheme 75 Reagents H2 [{(R)-(47)}Ru(OCOMe),] Scheme 76 MeOzClc....e R (49) [(BINAP)Ru(OCOM~)~] was an effective catalyst for reduction of (48) in 99% enantiomer excess (Scheme 76).'32 Diastereoselectivity in the reduction of itaconate esters (49) was excellent in the presence of an achiral rhodium(1) complex and racemic starting material underwent quite effective kinetic resolution in the presence of a chiral cata1y~t.I~~ Hydride reduction of a,/?-unsaturated carbonyl compounds generally occurs at the carbonyl group but again this year a number of contrary examples have been reported.The addition of organolanthanide complexes such as [CpSmC13(THF),] or [CPE~C~~(THF)~] to sodium borohydride gave a particularly selective reagent,'34 and [BH4]- gave efficient reduction of (50) when bound to an ion exchange resin (Scheme 77). In this latter case isolation of the reduced products required only filtration and e~aporati0n.l~~ The conjugate reduction of enones by phenylsilane in the presence of a molybdenum(o) catalyst was also applicable to unsaturated nitriles esters acids and amide~.'~~ 132 H. Takaya T. Ohta N. Sayo H. Kumobayashi S. Akutagawa S. Inoue I. Kasahara and R. Noyori J.Am. Chem. SOC.,1987 109 1596. 133 J. M. Brown and A. P. James J. Chem. SOC.,Chem. Commun.1987 181. 134 S. Komiyama and 0.'isutsumi Bull. Chem. SOC.Jpn. 1987 60,3423. 135 A. Nag A. Sarkar S. K. Sarkar and S. K. Palit Synth. Commun. 1987 17 1007. 136 E. Keinan and D. Perez J. Org. Chem. 1987. 52 2576. P. A. Chaloner 95% I::I -Q54% cis NC COOEt COOEt NCk NC COOEt NC COOEt (50) Reagents [BH4]-/resin seralite SRA-400 EtOH 25 "C Scheme 77 The synthesis and selected reductions of conjugated nitroalkenes has been reviewed.'37 The asymmetric reduction of 2-aryl-1 -nitropropenes has been effected by fermenting baker's yeast (Scheme 78). The optical purity of the product (51) was assessed as between 89 and 98'/0.'~* R RflNo2 R\yrNH2 -R\yrNHMTPA )-?-NO2 H H H (51) Reagents i Baker's yeast; ii Li[AIH4]; iii MTPACI Scheme 78 Hydrogenation of Carbonyl Compounds.In general it has proved easier to reduce aldehydes than ketones but a contrary example has been noted this year. Magnesium metal in methanol reduces 2-hydroxyphenylethanone efficiently in the presence of 2-hydroxyben~aldehyde.'~~ Facile conversions of carboxylic acids into aldehydes have been noted using thexylbromoborane/dimethylsulphide in carbon disul-phide.14' Esters were reduced to aldehydes using lithium aluminium hydride in the presence of diethylamine; the aluminium hydride generated in the initial attack is held in a stable amine/alane c~mplex.'~' Stereoselective reactions have again been widely reported. Synthesis of optically pure amino alcohol derivatives by yeast reduction of (52) has been and the sulphur functionality of (53) did not affect efficiency.In the latter case the product was used in a synthesis of the pine saw-fly pher0m0ne.l~~ A novel reaction using 'non-fermenting' baker's yeast without nutrients and in tap water proved equally successful (Scheme 79).14j 137 G. W. Kabalka and R. S. Varma Org. Prep. Proc. Int. 1987 19 283. 138 H. Ohta K. Ozaki and G. Tsuchihashi Chem. Lett. 1987 191. 139 M. Bordoloi and P. Sarmah Chem. Ind. (London) 1987 459. 140 J. S. Cha J. E. Kim S. Y. Oh J. C. Lee and K. W. Lee Tetrahedron Lett. 1987 28 2389; J. S. Cha J. E. Kim and K. W. Lee J. Org. Chem. 1987 52 5030. 141 J. S. Cha and S. S. Kwon J. Org. Chem. 1987 52 5486. 142 T. Fujisawa H. Hayashi and Y.Kishioka Chem. Lett. 1987 129. 143 T. Itoh T. Sato and T. Fujisawa Nippon Kagaku Kaishi 1987 1414. 144 D. Seebach S. Roggo T. Maetzke H. Braunschweiger J. Cercus and M. Kreiger Helu. Chim. Acta 1987 70 1605. Synthetic Methods 271 0 EtOzC EtozcQU U 86‘/o >99’/0 diastereoselective >99% enantioselective Reagents Baker’s yeast tap water 30 “C 10 h Scheme 79 Chiral additives for or chiral complexes of known reducing agents have continued to be popular and (54) (55) and (56) have shown some excellent selec- tivjty. 145-147 Asymmetric hydrogenation of P-ketoesters in the presence of [(BINAP)Ru(OCOMe)2] gave p-hydroxy esters in 98-100% enantiomer excess.14* ,;-a. K+ N>B’ /BH \ R (541 (55) CHz-S-S-CHl HtC-NH Ph/Li[BH4] I I COOH COOH (56) 145 H.C. Brown B. T. Cho and W. S. Park J. Org. Chem. 1987 52 4020. 146 E. J. Corey R. K. Bakshi S. Shibata C. Chen and V. K. Singh J. Am. Chem. Soc. 1987 109 7925; E. J. Corey R. K. Bakshi and S. Shibata J. Am. Chem. Soc. 1987 109 5551. 147 K. Soai S. Niwa and T. Kobayashi J. Chem. Soc. Chem. Commun. 1987 801. 148 R. Noyori T. Ohkurna M. Kitamura H. Takaya N. Sayo H. Kumobayashi and S. Akutagawa J. Am. Chem. Soc. 1987 109 5856. I? A. Chaloner Other Reductions. The reduction of secondary and tertiary benzylic alcohols to hydrocarbons was accomplished using Me3SiC1/NaI/ MeCN; the method was applied in a short synthesis of (*)-art~rmerone.'~~ A mild and convenient reduction of organic halides occurs using a solution of samarium(11) iodide in THF containing HMPT.Aryl alkyl and steroidal halides were reduced.15' Denitrohydrogenation of nitro compounds is effected by triethylsilane in the presence of a Lewis acid such as S~CI,or AICI~.'~~ Methods for the stereospecific deoxygenation of epoxides to alkenes have been reviewed.15*Samarium(11) iodide may be used either for regioselective reduction of epoxides to alcohols,153or for complete deoxygenation (Scheme 80).'54 Mixed-solvent systems were crucial in the chemo-and regio-selective reductions using borohydride; the reaction tolerated carbamoyl carboxyl nitro cyano and bromo fun~tionalities.'~~ >2OO 1 regioisomeric excess I I Reagents i Sml, HMPT Me2NCH2CHzOH THF 25"C 1 min; ii SmJ,X; iii Me,NCH,CH,OH or glutaric anhydride; iv 2 SmI Scheme 80 Deoxygenation of pyridine N-oxides may be effected using a titanium(0) reagent even in the presence of a halogen s~bstituent.'~~ Both sulphoxides and pyridine N-oxides were reduced using either WCl,/BuLi or [MOO,(S,CNEt,),]/ PPh .1577158 a-Chelation-controlled hydride addition to acyclic alkoxy ketone oximes proceeds with anti-selectivity in a useful preparation of chiral primary amines (Scheme 81).159 .$ ,+ JH iorii + NH2 OMOM OMOM OMOM anri SY n Reagents i AIH, anti syn = 86 14 ii Li[AIH,] anti:svn = 81 19 Scheme 81 149 T. Sakai K. Miyata M. Utaka and A. Takeda Tetrahedron Lett. 1987 28 3817. 150 J. Inanaga M. Jshikawa and M.Yarnaguchi Chem. Lett. 1987 1485. 151 N. Ono T. Hashimoto T. X. Jun and A. Kaji Tetrahedron Lett. 1987 28 2277. 152 H. N. C. Wong C. C. M. Fok and T. Wong Heterocycles 1987 26 1345. 153 K. Otsubo J. Inanaga and M. Yamaguchi Tetrahedron Lett. 1987 28 4437. 154 M. Matsukawa T. Tabuchi J. Inanaga and M. Yarnaguchi Chem. Lett. 1987 2101. 's5 A. Ookawa H. Hiratsuka and K. Soai Bull. Chem. Soc. Jpn. 1987 60,1813. 146 M. Malinowski and L. Kaczmarek Synthesis 1987 1013. 157 T. Wen-Ming L. Ji-Sheng and T. H. Chan Huaxue Xuebao 1987,45 472. 158 X.-Y. Lu X.-C. Tao and J.-H. Sun Youji Huaxue 1987 376 378. I59 H. Iida N. Yamazaki and C. Kibayashi J. Chem. Soc. Chem. Commun. 1987 746. Synthetic Methods Ph (57) Acetophenone oxime 0-alkyl ethers were reduced enantioselectively (4&100% ) by lithium aluminium hydride in the presence of the amino alcohol borane complex (57) as catalyst.16' Non-redox Conversions.-Substitutions af sp3-Hybridized Carbon.The functionaliz- ation of chiral enolates has continued to be an area of much activity and silylation azidination and bromination have all been achieved with good enantioselectivity (Scheme 82).161*162 Phenyldimethylsilyl groups may be converted into hydroxyl groups with good retention of stereochemistry using Br,/ MeC02H/ MeC0,H or Hg(OCOMe),/MeCOOH/MeC03H at 25 0C.163 18-96% d.e. 67-86% 95- 100% 78-95% d.e. 99% e.e. OMe - OMe 0 NHN R' li-siMe2R iv v VI + R2 >96% e.e. R2 R2 Reagents i Bu,BOTf CH2CI2,NBS -78 "C; ii tetramethylguanidinium azide CH2C12 0 "C; iii Li[OH] THF H20; iv LDA Et20 0 "C; v RMe2SiOTf -78 "C 2 h -25 "C 10 h Scheme 82 A number of new routes for the conversion of alcohols into halides have been reported.Halides were prepared using [(Ph2PCX2)2]'64 and fluorides from primary halides using methanesulphonylfluoride caesium fluoride and 18-crown-6.16' A one-pot conversion of alcohols into amines was accomplished by the pathway of Scheme 83.'66 Primary alkyl halides were converted into fluorides using either copper( I) fluoride or tetrabutylammonium difl~oride.'~' 160 S. Hsuno Y. Sakurai K. Ito A. Hirao and S. Nakahama Bull. Chem. SOC.Jpn. 1987,60 395. 161 D. A. Evans J. A. Ellman and R. L. Dorow Tetrahedron Lett. 1987 28 1123; D.A. Evans and T. C. Britton J. Am. Chem. Soc. 1987 109 6881. 162 D. Enders and B. B. Lohray Angew Chem. Int. Ed. EngL 1987 26 351. 163 I. Fleming and P. E. J. Sanderson Tetrahedron Lett. 1987 28 4229. 164 S. P. Schmidt and D. W. Brooks Tetrahedron Lett. 1987 28 767. 165 K. Makino and M. Yoshida J. Fluorine Chem. 1987 35 677. 166 E. Fabiano B. T.Golding and M. M. Sadeghi Synthesis 1987 190. 167 N. Yoneda T. Fukuhara K. Yamagishi and A. Suzuki Chem Lett. 1987 1675. P. A. Chaloner PhCH,OH 2PhCH,N=PPh -!!+ PHCH2NH3+CI-68% Reagents i HN, C6H6 PPh, Me2CH02CN=NC0,CHMe2 THF 50°C; ii H20 50°C Scheme 83 The stereoselective synthesis of methyl- 1,2-thioglycosides (58) was accomplished using MeSSiMe3/BF,. The synthetic utility of the product has been greatly increased by recently developed methods for activation of the anomeric thioalkyl group (e.g.Scheme 84).'68,'69 AcO /OAc AcofioAc AcO OAc OAc BnO& BnO OBn SEt ii BnO Brio? + -0 /OH 87'/o a:p = 3.5:l 00 00 X X Reagents i MeSSiMe3 BF, CH,C12 ; ii Me03SCF3 4 A sieves Et20 Scheme 84 Substitution at sp2-Hybridized Carbon. Various routes to the preparation of aryl-amines have been noted this year. N-Phenylation of amines may be achieved using either Ph3Bi/Cu(OCOMe)2 or PhPb(OCOMe) with either Cu(OCOMe) or CU(OCOCF~)~ .'" Iodination of aromatic compounds by Lewis acid (AlCl or better GaCl,) catalysed transiodination with 2,6-diiodo-4-methylphenolhas been described.17' N-Fluoro(perfluoroalky1)sulphonimides were prepared in high yield from the sulphonimides and elemental fluorine.They were stable for long periods at room temperature in a fluoropolymer plastic container and proved to be excellent 168 P. Bosch F. Cambs E. Chamorro V. Gasel and A. Guerrero Tetrahedron Lett. 1987 28 4733; V. Pozsgay and H. J. Jennings Tetrahedron Lett. 1987 28 1375. 169 H. Lonn J. Carbohydr. Chem. 1987,6 301. I70 D. H. R. Barton N. Yadav-Bhatnagar J.-P. Finet and J. Khamsi Tetrahedron Lett. 1987 28 3111; D. H. R. Barton J.-P. Finet and J. Khamsi Tetrahedron Lett. 1987 28 887. 171 M. Tasturo T. Makashima and S. Hone J. Chem. Rex S 1987 342. Synthetic Methods OMe R (59) The fluorinating agents towards arene~.~~~regioselective demethoxylation of alkyltrimethoxybenzenes such as (59) to (60) was used in a synthesis of 0liveto1.”~ More examples of the enantioselective formation and hydrolysis of acid derivatives catalysed by enzymes have been reported this year.The uses of enzymes as reagents for organic synthesis have been ~eviewed.”~’ Particularly prominent have been reactions (Scheme 85) of meso-compounds such as (61).17’ In a strictly chemical process chiral( *)-carboxylic anhydrides such as (62) underwent kinetic resolution catalysed by diphenylboryl trifluoromethane ~u1phonate.l~~ H 1iii,iv 0 Reagents i Pig liver esterase pH 7 H,O; ii BH,.Me,S THF -10-20 “C 6 h; iii Li[BF,] Et,O A 2 h; iv MeOH A 0.5 h Scheme 85 0 OBPhz LOMe 2az 0 + Ph YOMe (62) Ph 90‘/o 99% d.e.(1 S 2R) Reagents i Ph,BOTf PhMe 0°C; ii CH2N2 Scheme 86 172 S. Singh D. D. DesMarteau S. S.Zuberi M. Witz and H.-N. Huang 1.Am. Chem. SOC.,1987,109,7194. 173 U. Azzana T. Denurra G. Melloni and G. Rassu J. Chem. SOC.,Chem. Commun. 1987 1549. 174 A. Akiyama M. Bednarski M.-J. Kim E. S. Simon H. Waldmann and G. M. Whitesides Chem. Brit. 1987 23 645. 175 G. Sabbioni and J. B. Jones J. Org. Chem. 1987. 52 4565. 176 M. Ohshima and T. Mukaiyama Chem. Left. 1987 377; M. Ohshima N. Mioshi and T. Mukaiyama Chem. Letf. 1987 1233. l? A. Chaloner New processes for the interconversions of carboxyl derivatives continue to be reported. Acids were easily converted into anhydrides amides esters and thioesters using 1,l '-oxalyldiimidazole (63) and 1,l '-oxalyldi( 1,2,4-triazole) (64); 177p178 (65) was also useful as an esterification reagent.'79 Selective deacetylation of anomeric sugar ethanoates was accomplished using tin alkoxides.'80 Guanidine effected instantaneous deacetylation of acetylated carbohy- drates.Using this method phenolic ethanoates are cleaved in the presence of benzylic ethanoates whilst ethanamides benzoates and 2,2-dimethylpropanoates remain unchanged.181 Addition to Carbon- Carbon Multiple Bonds. Supported reagents have been used in a facile and selective two-phase addition to carbon-carbon double bonds (Scheme 87).lg2 Stereospecific iodofluorination of alkenes in the presence of polymer- supported HF was achieved in useful ~ie1ds.l~~ Reagents K[SCNl Na[N,] or K[OCOMe] CaF, SiO or A1203 I, CH,C12 2-72 h Scheme 87 An improved general synthesis of amines from alkenes via organoboranes has been described by Brown (Scheme 88); the major problem is that all the R groups are not used.'84 Boranes may be converted into primary amines using hydrazoic acid; this rather hazardous substance is best generated insitu from sodium azide and hydrochloric acid.lg5 Ph ph>= i ii iii or i iv iii ' WNH2 Reagents i BH, THF 1h; ii H,NCI Na[OH] H,O 25 "C 1 h; iii HCI H20; iv NH20S03H THF A,3h Scheme 88 177 T.Kitagawa H.Kuroda H. Sasaki and K. Kawasaki Chem. Pharm. Bull. 1987 35,4294. 178 T. Kitagawa H. Kuroda and H. Sasaki Chern. Pharrn. Bull. 1987 35 1262. 179 K.Takeda K. Tsuboyama H. Takayangi and H.Ogura Synthesis 1987 560. 180 A. Nudelman J. Jerzig H. E. Gottlieb E. Keinan and J. Sterling Carbohydr. Res. 1987 165 145. 181 N. Kunesch C. Miet and J. Poisson Tetrahedron Lett. 1987 28 3569. 182 T. Ando J. H. Clark D. G. Cork M. Fujita and T. Kimura J. Chem. Soc. Chern. Commun. 1987 1301. A. Gregorcic and M. Zupan Bull. Chem. SOC.Jpn. 1987 60,3083. H. C. Brown K.-W. Kim M. Siebnik and B. Singaram Tetrahedron 1987 43 4071. 185 G. W. Kabalka D. A. Henderson and R. S. Varma Organometallics 1987 6 1369. Synthetic Methods Oxazolidinones were prepared from alkenes in an organotellurium-mediated process (Scheme 89).'86 This process is equivalent to a cis-hydroxyamination and was also observed on the reaction of vinyl epoxides with isocyanates in the presence of palladium(0) catalysts.In this case the mechanism involves a palladium ally1 complex as an ir~termediate.'~~ 0 Ph-II 92% + PhTe02CCF3 -Phh HNKo 0 Reagents BF,.Et20 NH,COOEt CICH,CH,CI A 6-20 h Scheme 89 Miscellaneous. A modified procedure for the preparation of Schwartz's reagent [ HZrCp,Cl] has been described. It does not require expensive reducing agents can be accomplished in 3-4 hours and does not require the use of a glove box.'88 Triorganotin halides were synthesized directly (Scheme 90); the quaternary tin halide and halide ion may be recovered from the by-product and re-u~ed.'~~ 3RX + R',QX + 2Sn -+ R3SnX + R',QSnX Q = N P As or Sb R R' = alkyl Reagents 120-140 "C no solvent Scheme 90 The dioxolanation of a,P-unsaturated aldehydes using (66) and trimethylsilyl trifluoromethylsulphonate has been described.The conditions used are mild and aprotic alkenes do not isomerize and tetrahydropyranyl and vinyl ether moieties survive.'9o Anhydrous iron(II1) chloride on silica is known to be a mild reagent for deacetalization and has been used in a convenient preparation of the useful inter- mediate (67) in 55% yield from the bis-acetal.'" 186 N. X.Hu Y. Aso T. Otsubo and F. Ogura J. Chem. Soc, Chem. Commun. 1987 1447. 187 B. M. Trost and A. R. Sudhaker J. Am. Chem. SOC.,1987 109 3792. 188 S. L. Buchwald S. J. LaMaire R. B. Nielsen B. T. Watson and S. M. King Tetrahedron Lett. 1987 28 3895. 189 F.S. Holland Appl. Organomet. Chem. 1987 1 185. 190 J. R. Hwu L.-C. Leu J. A. Rohl D. A. Anderson and J. M. Wetzel J. Org. Chem. 1987 52 188. 191 A. Fadel R. Yefsah and J. Salaun Synthesis 1987 37. I? A. Chaloner Cleavage of 1,l-dimethylethyldimethylsilyl ethers occurs in the presence of 1,l-dimethylethyl hydroperoxide with dioxo bis(pentanedionato)molybdenum(vr) as the catalyst. The mild conditions avoid the formation of a basic alkoxide ion.19* Tetrahydropyranyl ethers could be selectively cleaved in the presence of 1,l-dimethylethyldimethylsilyl ethers using magnesium bromide in ether. Under these conditions MOM ethers were cleaved slowly but MEM ethers were inert.'93 RNHXNH RN(2)-XNHZ -!!+ RN(2)-XN(Z)BOC 1 liv RNHXNHBOC -RN(Z)XNBOC 2 = PhCH2OCO-BOC = Me3CCO-R = Et X = CH,CH, or R = Me X = 0 Reagents i ZCI pyridine; ii (BOC),O DMAP MeCN 25 "C; iii [HC00][NH4] HCOOMe Pd/C; iv TMG MeOH 25 "C 1.5 h; v Z,O CH2CI2or ZC1 pgridine Scheme 91 The azepine derivative (68) was used for the efficient resolution of ketones the hydrazones being separated chromatographically.'94 Selective protection of primary and secondary amines led to a simple preparation of spermidine derivatives (Scheme 91).195 192 T. Hanamoto T. Hayama T. Katsuki and M. Yamaguchi Tetrahedron Left. 1987 28 6329. I93 S. Kim and J. H. Park Tetrahedron Lett. 1987 28 439. 194 F. Fernandez and C. Perez Heterocycles 1987 26 2411. 195 M. L. S. Almeida L. Grehn and U. Raguarsson J. Chem. SOC. Chem. Commun.1987 1250.

ISSN:0069-3030    

DOI:10.1039/OC9878400241

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

11 Enzyme Chemistry By D. GANl Department of Chemistry The University Southampton SO9 5NH 1 Introduction As in previous years,**’ the objective of this review is to highlight some of the more important findings of the recent past with special emphasis on published work which increases our understanding of enzyme mechanism and on recent progress in the design and production of catalytic antibodies. These new synthetic entities are enzymes of a sort and offer enormous potential for the future design of sequence- specific endo-proteases the protein-cutting equivalents of the DNA restriction enzymes or functional group specific hydro-lyases e.g. esterases and phosphatases. Before embarking on this review it might be interesting and informative to read Kornberg’s article relevant to the foundations of Enzyme Chemistry ‘The Two Cultures Chemistry and Bi~logy’.~ The article is adapted from a lecture presented at a meeting of the American Association for the Advancement of Science.2 DNA Polymerase I Research on the mechanism of E. coli DNA polymerase I Klenow fragment was reviewed last year.2 Benkovic and co-workers have now determined the minimal kinetic scheme of the DNA polymerization reaction using short DNA oligomers of defined sequence The key feature of the scheme is a minimal two-step sequence that interconverts the ternary E.DNA;dNTP and E.DNA,+I.PP complexes. The rate is not limited by the actual polymerization but by a separate step which is probably important in ensuring fidelity. Wallace and co-workers have shown that the Klenow fragment accepts both (5R)-and (5s)-5,6-dihydrothymidine triphosphates as substrates for DNA polymeriz- ation.Using exonuclease 111-activated DNA (salmon testes) as a template the two diastereomers ofdihydrothymidine phosphate were incorporated into the synthe- sized DNA in a manner which reflected the ratio of the isomers present in the nucleotide ~001.~ Modak has shown that pyridoxal5’-phosphate (PLP) is a substrate binding site directed reagent for E. coli pol I.6 The covalent attachment of PLP ‘ D. Gani Ann. Rep. Prog. Chem. Sect. B 1985 82 287. D. Gani Ann. Rep. Prog. Chem. Sect. B 1986 83 303. A. Kornberg Biochemistry 1987 26 6888. R. D. Kuchta V. Mizrahi P. A. Benkovic K. A. Johnson and S. J. Benkovic Biochemistry 1987,26,8410.H. Ide R. J. Melamede and S. S. Wallace Biochemistry 1987 26 964. A. Basu and M.J. Modak Biochemistry 1987,26 1704. 279 280 D. Gani causes inactivation of the enzyme and loss of substrate binding ability. The inactiva- tion is dependent upon the presence of a divalent metal ion. The enzyme reacts with 4 mols of PLP in the absence of substrate and with 3 mols of PLP in the presence of substrate. In order to identify the substrate binding region of the protein the PLP-lysine imines were reduced with borotritide and the resulting labelled protein was subjected to tryptic digestion. The peptides were analysed and Lys-758 was identified as the site for PLP binding within the substrate binding region. It was concluded that Lys-758 is the site of binding for the metal chelate form of nucleotide substrates in E.coli DNA pol I. 3 Amino Acyl tRNA Synthetases The mechanism of the reaction catalysed by tyrosyl-tRNA synthetase has been reviewed recently.'.2 Fersht and co-workers have continued to investigate the reaction in detail.'-'' The enzyme catalyses the aminoacylation of tRNA in a two-step reaction (Scheme 1). E + Tyr + ATP + E.Tyr-AMP + PP E.Tyr-AMP + tRNA + Tyr-tRNA + AMP Scheme 1 Fersht has used the gradient (p values) of linear free energy plots obtained by studying the kinetics of mutant enzymes to determine the fraction of the overall binding energy used in stabilizing particular complexes during catalysis. The forma- tion of E-Tyr-AMP from E-TyrSATP results in an increase in binding energy between the enzyme and the side-chain of tyrosine and the ribose ring of ATP.Linear free energy plots of enzymes modified at these positions give the fraction of the binding energy change that occurs on formation of the transition state for the chemical reaction and various complexes. Fersht showed that groups that specifically stabilized the transition state are characterized by p values >> 1. These elegant studies which are derived from a vast amount of kinetic and thermodynamic data for several series of mutant enzymes are accompanied by strong warning^.^ These mainly concern the nature of specific mutations which Fersht has categorized into six groups according to the 'disruptive' effect of the mutation.Following on from these studies Fersht showed that Thr-40and His-45 provide a binding site for the pyrophosphoryl portion of the transition state for the formation of tyrosyl adenylate from tyrosine and ATP and for pyrophosphate in the reverse direction. Deletion of the side chains in mutant enzymes destabilized the transition state by 4.9 kcal mol-' (His-Ma-40) or by 4.1 kcal mol-' (His-Ma-45) confirming the loss of charged hydrogen-bonding interactions? In order to examine the role of His-45 further potentially conservative Gln-45 and Asn-45 mutants were constructed. Both mutant enzymes were debilitated compared to the wild-type enzyme but Gln-45 was more ' A. R. Fersht R. J. Leatherbarrow and T. N. C. Wells Biochemistry 1987 26 6030. * D.M.Lowe G.Winter and A. R. Fersht Biochemistry 1987 26,6038. R.J. Leatherbarrow and A. R. Fersht Biochemistry 1987 26,8524. Enzyme Chemistry 28 1 active and Asn-45 less active than Ala-45 indicating that asparagine causes des- tabilization of the transition state compared to alanine. Fersht considered that the location of the amide NH2 group of glutamine was similar to that of the imidazole E-NH of histidine whereas the amide NH2 of asparagine is comparable to the imidazole 8-NH2 in the wild-type enzyme. The results are used to suggest that the E-NH rather than the 8-NH group of His-45 is involved in transition-state stabiliz- ation in the reaction catalysed by the wild-type enzyme (Figure 1). The unexpected low activity of the Asn-45 mutant is used to illustrate the dangers of introducing groups into positions which cause alternative interactions.Figure 1 (Reproduced by permission from Biochemistry 1987 26 6030) Fersht has also examined heterodimeric tyrosyl-tRNA synthetase by altering the two Phe-164 residues of the wild-type hornodimeric enzyme which are on the axis of symmetry and interact in a hydrophobic region at the subunit interface to aspartate (or glutamate) and lysine." The salt bridges engineered into the hydrophobic subunit interface are weak but sufficient to direct specificity in dimerization when the separately produced inactive monomers Asp-164 (or Glu-164) and Lys-164 are mixed in equimolar amounts. A method for the kinetic analysis of dimeric enzymes which reversibly dissociate into inactive subunits is also presented." Fersht has recently compared the deduced amino acid sequence of Bacillus stearothermophilus valyl-tRNA synthetase with isoleucyl-tRNA synthetase from E.lo W. H.J. Ward D. H.Jones and A. R.Fersht Biochemistry 1987 26 4131. 282 D. Gani coli and reports that there is 25% homology. There are several regions which are highly conserved." One region the HIGH region His-Ile-Gly-His near the N- terminus is conserved in many aminoacyl-tRNA synthetases although Ile is some- times replaced by other hydrophobic residues Leu or Met. In tyrosyl-tRNA syn- thetase the first histidine residue is His-45 which has been shown to form part of a binding site for the y-phosphate of ATP in the transition state for the reaction vide supra.Using site-specific mutagenesis Fersht has shown that for B. stearother-mophilus valyl-tRNA synthetase Thr-52 and His-56 serve similar functions to residue Thr-40 and His-45 in tyrosyl-tRNA synthetase and are involved in binding to the transition state for the reaction but not to either of the substrates valine and ATP or the product.12 Leon and S~hulman'~ have covalently coupled the minor base 3-(3-amino-3- carboxypropyl) uridine of the variable loop of the elongator methionine tRNA to lysine-596 of E. coli methionyl-tRNA synthetase. To date five peptides in the primary sequence of native methionyl tRNA synthetase that are covalently coupled to methionine tRNA have been identified. The 'molecular recognition' of isoleucine and valine by energy dissipation for isoleucyl tRNA synthetase has been reviewed by Cramer and Frei~t.'~ 4 Dihydrofolate Reductase Dihydrofolate reductase catalyses the NADPH-dependent reduction of dihydrofolic (H2F) acid to give tetrahydrofolic acid (H4F).The kinetics of E. coli reductase have been investigated by Benkovic and co-workers and a scheme that predicts the steady-state kinetic parameters and full time course kinetics under a variety of conditions has been pre~ented'~ (Scheme 2). The binding kinetics suggest that during steady-state turnover product dissociation follows a specific preferred pathway in which H4F dissociaton occurs after NADPH replaces NADP+ in the ternary complex. The dissociation is thought to be the rate-limiting step at low pH because k, = V,, .The transfer of hydride from NADPH to H2F shows a deuterium isotope effect of 3 and is rapid essentially irreversible and pH-dependent; the pK = 6.5 reflects the ionization of a single group in the active site. The scheme accounts for the apparent pK = 8.4 observed in the steady state which may be attributed to a change in the rate-determining step from H4F release at low pH to hydride transfer at high pH. The role of Phe-3 1 was assessed by preparing Tyr-3 1 and Val-3 1mutant enzymes.16 Phe-31 is a strictly conserved residue which interacts with the pteroyl portion of H2F in a hydrophobic pocket. The kinetic properties of the mutant enzyme were similar to those of the wild-type enzyme. The rate of hydride transfer was slightly decreased and the rate of H4F dissociation increased in the mutant proteins so that V,, was increased twofold over the wild-type enzyme.T. J. Borgford N. J. Brand T. E. Gray and A. R. Fersht Biochemistry 1987 26 2480. 12 T. J. Borgford T. E. Gray N. J. Brand and A. R. Fersht Biochemistry 1987 26 7246. l3 0. Leon and L. H. Schulman Biochemistry 1987 26 1933. 14 F. Cramer and W. Freist Acc. Chem. Res. 1987 20 79. l5 C. A. Fierke K. A. Johnson and S. J. Benkovic Biochemistry 1987 26 4085. 16 J. Chen K. Taira C. D. Tu and S. J. Benkovic Biochemistty 1987 26 4093. Enzyme Chemistry 5 pM-' 11 50 I1 3 ENADPH -EH~F-950 H~F 0.6 1.7 20 g M-' L ENADPH ENADPH -85 . EH4F 1.4 E-H4F 3.5 12.5 8 MM-' 25 gM-' pH-Independent kinetic scheme for E.coli dihydrofolate reductase at 25 "C rate constants s-l Scheme 2 In order to explore the substrate protonation mechanism of the reductase Howell and co-workers constructed a double mutant in which the usual proton donor Asp-27 was replaced by serine and in which a nearby threonine residue 113 was replaced by the alternative proton donor glutamic acid.I7 The double mutant was threefold more active than the single mutant Ser-27,I8 but k,, was 25-fold lower than for the wild-type enzyme. It was concluded that the double mutant does not stabilize the transition state for the hydride reduction through initial protonation at 0-4 of the substrate" and that the most likely site for protonation is N-1. wild-type D27S + T113E mutant Scheme 3 Mutant enzymes with specific amino acid replacements in two helices and in two strands of the central @-sheet of dihydrofolate reductase have also been used to probe the folding and stability of the E.coli 5 PLP-Dependent Enzymes Site-specific mutagenesis has now been extensively used to study the mechanism of aspartate aminotransferase. Substitution of Arg-292 which normally binds the p-and y-carboxyl groups of aspartic and glutamic acid respectively for aspartic acid gave an a-transaminase capable of acting upon ornithine and arginine albeit slowly.22 Replacement of the active site Lys-258 by alanine gave an inactive enzyme '' E. E. Howell. M. S. Warren C. L. J. Booth. J. E. Villefranca and J. Kraut Biochemisrry 1987 26 8591. E. E. Howell J.E. Villefranca M. S. Warren S. J. Oatley and J. Kraut Science 1986 231 1123. 19 J. E. Gneady Biochemistry 1985 24 4761. 20 N. A. Touchette K. M. Perry and C. R. Matthews Biochemistry 1986 25 5445. 'I K. M. Perry J. J. Onufper N. A. Touchette C. S. Herndon M. S. Gittelman C. R.Matthews J. Chen R. J. Mayer K. Taka S. J. Benkovic E. E. Howell and J. Kraut Biochemistry 1987 26 2674. 22 C. N. Cronin B. A. Malcolm and J. R. Kirsch J. Am. Chem. Soc. 1987 109 2222. 284 D. Gani Tyr-70 Lys-258 I / + H-0 HZN Arg-292 ...02c~C02-+Arg-386 Figure 2 which acted as an oxaloacetate decarboxylase when pyridoxamine S'-phosphate (PMP) was used as the coenzyme.23 Unlike the mitochondria1 and E. coli wild-type enzyme the Ala-258 E. coli mutant is unable to labilize the C-4' pro-S hydrogen of PMP.24Kirsch has shown that the replacement of Tyr-70 (the other possible candidate of the active-site base) by alanine gives an enzyme which retains 17% of the activity of the wild-type enzyme.Collectively these results strongly support the notion that Lys-258 is the proton abstracting-donating group in physiological transamination reactions. Kuramitsu et al. have shown that the replacement of Lys-258 by arginine gives an enzyme which is 3% active,25 and Metzler and co-workers have shown that 3'-0-methyl- pyridoxal 5'-phosphate functions as a poor coenzyme for aspartate aminotransferase- catalysed transamination half-reactions.26 Walsh has studied the time-dependent inactivation of PLP-dependent 1 -aminocyc- lopropanecarboxylate deaminase and alanine racemase by 1 -aminocyc- lopropanepho~phonate~'( 1).The physiological role of the deaminase is to catalyse H$.@ ACPP -0.,P=0 -0 (1) the formation of a-ketobutyrate and ammonia from 1-aminocyclopropanecarboxylic acid' and the role of alanine racemase is well established.',2 The enzymes were inactivated with KM/Ki ratios of 500 and 2000 respectively and in each case inhibition was characterized by a slow-binding slow-dissociating behaviour. Analysis 23 B. A. Malcolm and J. F. Kirsch Biochem. Biophys. Res. Cornmun. 1985 132 915. 24 S. Kochhar N. L. Finlayson J. F. Kirsch and P. Christen J. Biol. Chern. 1987 262 11446. 25 S. Kurarnitsu Y. Inoue S. Tanase Y. Morino and H. Kagarniyama Biochem.Biophys. Res. Commun. 1987 146 416. 26 V. J. Chen D. E. Metzler and T. W. Jenkins J. Biol. Chem. 1987 262 14422. 27 M. D. Erion and C. T. Walsh Biochemistry 1987 26 3417. Enzyme Chemistry k, E + ACPP F= E.ACPP E = ACPC deaminase k2 ki = 5pM Scheme 4 k, E + ACPP & E.ACPP eE.ACPP* kz k4 E = alanine racemase k = 8mM KF = 2pM Scheme 5 of the pre-steady-state kinetics revealed a kinetically detectable intermediate E.1 complex in the inhibition mechanism for the racemase but not for the deaminase. 6 Other Enzymes Blundell and Szelke and co-workers have recently reported on the modes of binding of transition-state inhibitors at the active-site of the aspartic protease endothiapep- sin.28 The most potent inhibitor H261 contains the grouping -CHOH-CH2-in place of the scissile carboxamide functionality of the substrate.The compound binds so that the hydroxyl group occupies a spatial position similar to that occupied by the small molecule (probably water) which is hydrogen bonded to the two aspartate residues in the native protein. As yet it is not known which hydroxyl group Figure 3 (Reproduced by permission from Biochemistry 1987 26 5585) T. L. Blundell J. Cooper S. I. Foundling D. M. Jones B. Atrash and M. Szelke Biochemistry,1987 26 5585. 286 D. Gani carbonyl-derived or water-derived in the transient geminal aminodiol is mimicked by the inhibitor. and also Polgar3’ have recently discussed the mechanism of aspartic proteases while COI-VO~~~ and co-workers and Pals32 and co-workers have investigated the kinetics of the inhibition of human renin and other aspartic proteases using statine and hydroxyethylene containing peptide analogues.Knowles has studied enzyme relaxation in the reaction catalysed by triosephos- phate is~merase.~~ Using the tracer perturbation method of Britton which involves measuring the time-dependent distribution of radio-labelled substrate and product after the system is perturbed from an initial equilibrium by the addition of a relatively large amount of unlabelled material it was shown that the enzyme exists in two forms. One form binds and isomerizes (R)-glyceraldehyde 3-phosphate and the other form binds and isomerizes dihydroxyacetone 3-phosphate. The rate of the interconversion of free (unbound) forms of the enzyme is lo6s-’.Knowles points out that it is improper and possibly erroneous to presume that the rates of the interconversion of the unliganded substrate-binding and product-binding forms of an enzyme ( k4 and kP4) are not kinetically significant. ‘SOH Y OP Scheme 6 Gani and co-~orkers~~-~~ have shown that in the presence of ammonia 3-methylas- partase converts a range of halogeno- and alkyl-fumaric acids into the corresponding 3-substituted L-aspartic acids via anti-addition. Further mechanistic studies of the enzyme revealed that the deamination of the physiological substrate (2S,3S) -3-methylaspartic acid showed a primary isotope effect upon both V,, and V of 1.7 while the substrates (2S,3S)-3-ethylaspartic acid and aspartic acid showed ”( V/K) and ”(V) effects of 1.15 and 1.0 respectively.The results were rationalized in terms of transition-state binding where the transition states for non-physiological substrates would interact with the active-site weakly. It was argued that this would cause C-N bond cleavage to become kinetically more important than for the physiological substrate and thus obscure the deuterium isotope effects. 29 L. H. Pearl FEBS Lett. 1987 214 9. 30 I-. Polgar FEBS Left. 1987 219 1. 3’ F. Cumin D. Nisato J. Gagnol and P. Corvol Biochemistry 1987 26 7615. 32 W. M. Kati D. T. Pals and S. Thaisrivongs Biochemistry 1987 26 7621. 33 R. T. Raines and J. R. Knowles Biochemistry 1987 26 7014. 34 M. Akhtar M.A. Cohen and D. Gani Tetrahedron Lett. 1987 28 2413. 3s M. Akhtar M. A. Cohen N. P. Botting and D. Gani Tetrahedron 1987 43 5899. 36 N. P. Botting M. A. Cohen M. Akhtar and D. Gani J. Chem. SOC.Chem. Commun. 1987 1371. Enzyme Chemistry Enz A H H u R =H,Et Scheme 7 7 Catalytic Antibodies Over the past two years the ability of antibodies to catalyse chemical reactions in an almost analogous fashion to enzymes has been realised. Antibodies bind biological macromodels as well as small synthetic molecules with enzyme-like affinities and specificities. Also antibodies can be generated selectively towards any molecule of theoretical interest. The large rate enhancement observed for enzyme-catalysed reactions over and above the rate for the corresponding chemical reactions is ascribed to the ability of enzymes to bind the transition state for the reaction more tightly than the reactants or products.Hence the activation energies for chemical steps are lowered compared to reactions where the medium interacts essentially equally with each of the species. This analysis of enzymic catalysis led to the advent of transition-state inhibitors which are now well established as potent tight-binding competitive inhibitors. With this background and the availability of transition-state inhibitors Lerner and co- workers and others investigated the possibility of raising antibodies to transition-state analogue haptens. Lerner and ~o-workers,~~~~~ chose to create and investigate esterase activity and therefore prepared phosphonate monoesters [e.g.(2)] for incorporation into antigens. It was reasoned that the transition state for potential ester hydrolysis with its developing negative charge would be accurately mimicked by the tetrahedral phosphate monoester anion. The phosphonate was conjugated with keyhole limpet hemocyanin to produce the actual antigen which was used to immunize mice. The monoclonal antibodies were prepared and were assayed for esterase activity using compound (2). Some of the antibodies reacted stoicheiometrically to release the fluorescent phenol (7-hydroxycoumarin) and under basic condition acted catalytically (Scheme 8). The observed reaction rates were very small but the haptenic phosponate monester (2) was found to be a potent competitive inhibitor.It is proposed that the antibody catalyses transacylation of itself but that deacylation is not catalysed. 37 A. Tramontano K. D. Janda and R. A. Lerner Roc. Nafl.Acad. Sci. USA 1986,83 6736. 38 A. Tramontano K. D. Janda and R. A. Lerner Science 1986 234 1566. 288 D. Gani 0 H R=COMe or N-Keyhole limpet hemocyanin 0 Schultz and co-w~rkers~~~~~ have also used tetrahedral phosphonate transition- state analogues to raise antibodies. The antibodies catalyse carbonate hydrolysis at appreciable rates and show the expected kinetic properties in the presence of transition-state analogue inhibitors. Finally Benkovic4' has used a cyclic phosphon- ate ester (4) to elicit the production of a S-lactone synthase antibody (Scheme 9).Higher pH CFSCONH HOa. I 3 COzH + IgG Scheme 8 39 S. J. Pollack J. N. Jacobs and P. G. Schultz Science 1986 234 1570. 40 J. Jacobs and P. G. Schultz J. Am. Chem. Soc. 1987 109 2174. 41 A. D. Napper S. J. Benkovic A. Tramontano and R. A. Lerner Science 1987 237 1041. Enzyme Chemistry The antibody catalysed the cyclization of the racemic hydroxyester to give the lactone in 94% enantiomeric excess. The rate acceleration factor was 167. S-o OPh ___ 24811 H NHAC NHAc OH (*I) 94% e.e. kc,,lk,,c,t = 167 Scheme 9 Clearly the full potential of catalytic bodies is enormous and given that only half a dozen or so papers have been published so far the immediate future promises to be extremely exciting.

ISSN:0069-3030    

DOI:10.1039/OC9878400279

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

12 Carbohydrates By J. F. KENNEDY and D. L. STEVENSON Department of Chemistry University of Birmingham P.0. Box 363 Birmingham B 15 277 1 Introduction This inevitably selective chapter covers the literature since the previous report' in 1984 with some emphasis on work described in 1987.For reasons of space it has had to be restricted to the monosaccharides and to the use of carbohydrates as chiral templates. For a more comprehensive coverage the reader is referred to the Specialist Periodical Report on the Carbohydrates. 2 Monosaccharides G1ycosides.-The stereoselective formation of glycosides continues to be one of the central goals of carbohydrate chemistry. The preparation of C-glycosides has attrac- ted attention. The synthesis of 0-(a-g1yco)-peptides has been achieved2 by treating unsaturated monosaccharides such as (1) with peptides containing serine and threonine in the presence of N-iodosuccinimide to give the 2-iodoglycosides from which the glycopeptides [e.g.(2)] were then obtained by hydrogenolysis with Bu3SnH. The formation of acetal-P-D-glucosides from cytotoxic aldehydes has been examined in the context of cancer ~hemotherapy.~ Compounds such as (3) may act as pro-drugs liberating the aldehyde by acidic or enzymic hydrolysis at the required site. The glucosides were obtained by reaction of trimethylsilyl2,3,4,6-tetra-O-acetyl-p-D-glucopyranoside and an acetal (R'O)2CHR2 in the presence of catalytic amounts of CF3S03SiMe3 followed by deacetylation. The preparation of C-glucopyranosyl derivatives from the readily available 2,3,4,6-tetra-0-benzyl-a-D-glucopyranosyl chloride (4)has been de~cribed.~ Treatment of compound (4)with for example Et02CCH=C(OSiMe3)OEt in the presence of silver triflate gave C-glucopyranosyl derivatives with the a-configuration (5).The synthesis of C-glucosides has also been achieved' using the reaction between O-glycosylimidates [e.g. (6)]and electron- rich heterocycles such as furans and thiophenes to give the P-D-C-glucosides. A novel and stereoselective carbon-carbon bond-forming reaction at the anomeric centre of carbohydrates has been developed by means of a carbenoid displacement reaction with phenylthioglycosides.6 The reaction may proceed via an oxonium ion ' J. Thiem Annu. Rep. Bog. Chem. Secf. B. 1984 81 31 1.H. Kessler M. Kottenhahn and C. Kolar Angew. Chem. 1987 99,919; (Int. Ed. Engl. 1987 26 888). L. F. Tietz R. Fischer H. J. Guder and M. Neumann Liebigs Ann. Chem. 1987 847. P. Allevi M. Anastasia P. Ciuffreda A. Fiecchi and A. Scala J. Chem. SOC.,Chem. Commun. 1987 101. R. R. Schmidt and G. Effenberger Liebigs Ann. Chem. 1987 825. T. Kametani K. Kawamura and T. Honda J. Am. Chem. Soc. 1987 109 3010. 29 1 J. F. Kennedy and D. L. Stevenson CHzOAc AcO &AJ CHzOH HOa0& OI"' Z.PrO.NH C0.Ala.0CH2Ph HO OH OMe AcOEc H (1) (2) (3) CH2OR' vH20R @-l;c13 &J2 R'O RO OR' OR (4) R' = CH,Ph R2 = CI (6) (5) R' = CH2Ph,R2 = CH(CO,Et) intermediate and has the following advantages (i) the preferential participation of a carbenoid with a sulphur atom can restrict the reaction site; (ii) the reaction can be carried out under neutral reaction conditions; and (iii) the introduction of various functionalities can be accomplished by manipulation of the organosulphur groups of the products.This synthetic strategy was successfully applied to the synthesis of the antitumour agent (+)-showdomycin (7). HO OH (7) The conjugate addition of glucosylcopper reagents to enones such as cyclo- hexenone has been applied7 to the stereospecific synthesis of C-glycosides. Some C-glycoside derivatives [ e.g. (9)] of 3-deoxy-~-mannooctulosonic acid (KDO) have been prepared' by reacting the enolate of (8) with a series of electrophiles. The P-configuration predominated in the C-glycosides which were formed.The stereocontrolled synthesis of four C-disaccharides [(lo)-( 1l)] has been rep~rted.~ The reduction of hemiketals such as (12) with (Pr"),SiH gave pre- dominantly the equatorially substituted C-glycosides. C-Alkylation by displacement ' D. K. Hutchinson and P. L. Fuchs J. Am. Chem. SOC.,1987 109 4930. K. Luthman M. Orbe T. Waglund and A. Claesson J. Org. Chem. 1987 52 3777. S. A. Babirad Y. Wang and Y. Kishi J. Org Chem. 1987 52 1370. 293 Carbohydrates Me 0 Mexoq @COzMe Me Me (10) (8) R = H R,R' = H OH (9) R = CH,OH Ho&;p..oMe "* 'OH HO PhCH2O 'OCH2Ph OH R 'R1 OH OCH2Ph Me0 (11) R R' = H OH (12) of the p-nitrobenzoate (13) gave axially substituted C-glycosides as the major product.Deoxy Branched and Higher Sugars.-There continues to be considerable interest in the synthesis of deoxy-sugars. In a new synthesis" of 2-deoxy-sugars glycosyl bromides [e.g. (14)] underwent reductive dehalogenation with Bu,SnH. This was accompanied by rearrangement of the adjacent acetoxyl group to give (15). OAc -0 A c -Br AcOb -OAc AcOb-AcO OAc AcO lo B. Giese K. S. Groeninger T. Witzel H. G. Korth and R.Sustmann Agnew. Chem. 1987,99,246; (Int. Ed. Engl. 1987 26 233). 294 J. E Kennedy and D. L. Stevenson D-Cordycepose (16) has been prepared with useful levels of diastereoselection by treatment of the glycerol allyl ether (17) with ozone dimethylsulphide and Amberlyst 15." The reaction proceeds via a Wittig rearrangement of the p-D-alkoxyalkyl allyl ether.Some deoxy-KDO derivatives [e.g. (8)] have been prepared in a stereospecific manner starting with the diacetonide of D-mannose.'2 Deprotec- tion of (8) gave an acid (18) that was a potent inhibitor of CMP-KDO synthetase. These derivatives were also useful in the formation of C-glycosides of KDO (see above). CHO I H-C-OH CH20H I Reduction of an a-acetoxyketone [e.g. (19)] with baker's yeast gave predominantly the 2S,4S,5R,6R-carbinol (20). This and some related examples of multiple enzy- matic stereoselectivity permittedt3 the synthesis of chiral synthons such as (21) 4-deoxymannose derivatives and the higher sugar derivative (22) in enantiomerically pure forms.OAc lp ia \ HO 0-/\ }-OH Addition of the 2-and E-alkoxyallylboronates (23) to 0-benzyl-lactaldehyde led,14 with some assymetric induction to various 3,4,5-trioxygenated 1-hexenes (24) of the arubino xylo ribo and lyxo configurations. The synthesis of dideoxy-sugars has been achieved" using triflate rearrangements. Reaction of 2,6-dideoxy- a-D-arabino-hexopyranoside (25) with triflic anhydride [(CF,SO,),O] gave the corresponding triflate which rearranged at room temperature S. L. Schreiber and M. T. Goulet Tetrahedron Left. 1987 28 1043. A. Claesson J. Org. Chem. 1987 52 4414. l3 G. Fronza C. Fuganti P. Grasselli and S. Semi J. Org. Chem. 1987 52 2086.. 14 R. W. Hoffmann R. Metternich and J. W. Lam Liebigs Ann. Chem. 1987 881. R.W. Binkley and M. A. Abdulaziz J. Org. Chem. 1987 52 4713. Carbohy dra tes 295 Me OH (23) OTf OMe OMe (25) (27) to another extremely reactive triflate (26) which on hydrolysis gave the 3- and 4-benzoates of 2,6-dideoxy-a- ~-lyxo- hexopyranoside (27). A new branched-chain monosaccharide 3,6-dideoxy-4C-(1-hydroxyethy1)-D-xylo-hexose (yersiniose) has been isolated16 from the Yersinia enterocolitica 0:4.32 lipopolysaccharide and is the second representative in a new class of monosac-charides. Some axially methyl-branched pyranosiduloses have been ~ynthesized.'~ The allyldeoxyglucose (28) can be cyclized to the oxabicyclooctane (29) in a radical chain reaction.'* However the isomer (30) did not cyclize confirming the boat conformation for glucosyl radicals.Dipeptide derivatives of 8-amino-D-glycero-D-talo-octanoate (3 1) have been synthesized" and shown to be effective antibacterial agents against Gram-negative bacteria. The glycopeptides [e.g. (32)] which are KDO analogues interfere with lipopolysaccharide biosynthesis. OAc Me fH2 16 R. P. Gorshkova V. A. Zubkov V. V. Isakova and Y. S. Ovodov Bioorg. Khim. 1987 13 1146. " A. Klemer and W. Klaffke Liebigs Ann. Chern. 1987 759. 18 K. S. Groeninger K. F. Jaeger and B. Giese Liebigs Ann. Chem. 1987 731. 19 A. Claesson A. M. Jansson B. G. Pring and S. M. Hammond. J. Med. Chem. 1987 30,2309. J. F. Kennedy and D. L. Steuenson The extension of the carbohydrate template via the secondary positions C-2 to C-4 and the primary position C-6 ('pyranosidic homologation') continues to attract attention.In one such example Robinson annulation of the hexopyranosidulose (33) with 3-trimethylsilyl-3-buten-2-one gave the tricyclic sugar derivative (34).20 In two papers Fraser-Reid and colleagues describe the preparation of di- [e.g. (36)12' and tri- [(e.g. 37])22 -pyranosides from the readily obtainable dianhydro-sugar (35). These compounds are precursors of the ansamycins such as rifamycin and strep- tovaricin A. PhTO phTo%0 Me '@OMe OMe 0 (33) (34) Halogeno- and Thio-sugars.-The interest in the preparation of fluorinated sugars continues. One recent efficient preparation involved treatment of anhydropen- topyranoside triflates [e.g. (38)] with tetrabutylammonium fluoride in acetonitrile to fluorodeoxy sugars [e.g.(39)] with inversion of configuration. 'H 19F and I3C n.m.r. studies of these compounds provided strong evidence for OH5conformation^.^^ Some other fluorinations that have been reported proceed via a galactal derivative. Thus 2,2-Difluorodaunosamine (40) was prepared24 by treating the galactal (41) with FOCF3 in C13CF in the presence of CaO. In a variation of the procedure "F-labelled 2-fluoro-2-deoxy-~-galactopyranosewas prepared25 by treatment of a galactal with acetyl hypofluorite. The first example of a naturally occurring 5-thiosugar 5-thio-~-mannose has been isolated26 from the marine sponge Clathria pyrurnida. The synthesis of 6-thio-N-*' R. V. Bonnert and P. R. Jenkins J. Chern.SOC.,Chern. Cornrnun. 1987 6. 21 B. Fraser-Reid L. Magdzinski B. F. Moho and D. R. Mootoo J. Org. Chern. 1987 52 4495. 22 B. Fraser-Reid B. F. Moho L. Magdzinski and D. R. Mootoo J. Org. Chern. 1987 52 4505. 23 F. Latif A. Malik and W. Voelter Liebigs Ann. Chern. 1987 617. 24 A. Dessinges F. Cabrera Escribano G. Lukacs A. Olesker and T. T. Thang J. Org. Chern. 1987,52,1633. 25 M. Tada T. Matsuzawa K. Yamaguchi Y. Abe H. Fukuda M. Itoh M. Sugiyama T. Ido and T. Takahashi Carbohydr. Res. 1987 161 314. 26 R. J. Capon and J. K. MacLeod J. Chern. SOC.,Chern. Cornrnun. 1987 1200. 297 Carbohydrates R' "'QOC H2Ph BzO Q 0 CFSCONH F (38) R' = OSO,CF, R2 = H (411 (39) R' = H,R2 = F acetyl-D-neuraminic acid has been achieved.27 Aldol condensation of mannothiazo- line (42) with potassium di-t-butyloxaloacetate gave the two 6-thiosialic acids (43).However the reaction between the thiofuranose (44) and Ni" oxaloacetate gave the 6-thio-N-acetyl-~-neurarninicacid (45). Substitution of oxygen by sulphur in the pyranose ring drastically changed the biological properties. The first synthesis of 2,5-anhydro-5-thio-~-allononitrile (46) has been accomplished.28 During this work a large-scale synthesis of 3,4,5,7-tetra-O-acetyl-2,6-anhydro-~-glycero-~-~a~o-heptanonitrile (47) and an improved synthesis of 2,5-anhydro-3,4,6-tri-O-benzoyl-~-gulononitrile (48) were developed. (7) Ho*co2H A HO' AcO "OAc AcNH OH (42) (43) HO HO' C O Z H G OH AcNH HOCH2 HO OH OBz Amino-sugars.-Many unusual amino-sugars are found in antibiotics and this has provided the stimulus for synthetic efforts.A simple method for the preparation of 2-amino-sugars involving the cycloaddition of azodicarboxylate to glycals has been 21 H. Mack and R. Brassmer Tetrahedron Lerr. 1987 28. 191 28 G. D. Kini C. R. Petrie W. J. Hennen N. K. Dalley B. E. Wilson and R. K. Robins Curbohydr. Res. 1987 159 81. 298 J. E Kennedy and D. L. Stevenson de~cribed.'~ Thus the glycal(49) gave in high yield the dihydrooxidiazine (50) which was in turn converted into the 2-aminoglycoside (51). There have been several new routes to the synthesis of 3-amino- and 3-amino-3-C-methyl sugars reported recently. The diastereoselectivity of epoxidation of the (2)-ally1 amides (52) depend3' both on the amide functionality and the reagent.The formation of the threo-epoxide (53) was highly favoured (95:5) with m-chloroperbenzoic acid as oxidant and when (52;R = NHPh) was used as the substrate. High threo selectivity (88 12) was also realized in the Mo(CO),-catalysed epoxidation of (52; R = CC13). However the stereochemistry of epoxidation of the (E)-allylic amide series was much less sensitive to the reagent and amide functionality. This method was applied to the synthesis of N-benzoylristosamine and to precursors of N-benzoyldaunos- amine and N-benzoyl-3-amino-2,3,6-trideoxy-xylo-hexose. M eOC H 2OC €4 'y 0 0i.(OC H2 P h MeOCH20CH2a Me ,C Ph Si0' NHN I Me3CPh2Si0 C02CH2Ph (49) (50) (51) (52; R = CCl, Ph OMe NHPh) (53) A new synthesis of 3-amino-3- C-methyl hexoses involved the stereoselective C-alkylation of the substrates (54) and (55) to give the 3-C-methylated products which were then reduced with sodium borohydride to give the equatorial alcohols.The resultant 3-amino-2,3,6-trideoxy-3-C-methyl-L-lyxo-hexopyranoses were con- verted into antibiotic A355 12B L-vancosamine and D-rubranitrose. The intermedi- ates were also precursors of L-decilonitrose and D-kijano~e.~' 2,3-Dideoxy-3- aminopentoses and 2,3-dideoxy-3- C-methyl-3-aminopentoses have been prepared32 from the azetidinone (56). A highly diastereoselective synthesis of L-N-acety-lacosamine (58) and L-N-benzoylristosamine (59) has been achieved33 by utilizing the conjugate addition of a carbamate group in the Z-a,P-unsaturated esters (57).4-Amino-sugar derivatives have been prepared34 by treating anhydropentopyrano- side triflates [e.g. (60)]with esters of p-aminobenzoic acid. The total syntheses of (+)-nojirimycin and (+)-1-deoxynojirimycin in which the amino is in the 5-position and therefore appears in the pyranose ring have been reported.35 An efficient 29 B. J. Fitzsimmons Y. Leblanc and J. Rokack J. Am. Chem. SOC.,1987 109 285. 30 W. R. Roush J. A. Straub and R. J. Brown J. Org. Chem. 1987 52 5127. 31 A. Klemer and H. Wilbers Liebigs Ann. Chem. 1987 815. 32 F. M. Hauser S. R. Ellenberger and R. P. Rhee J. Org. Chem. 1987 52 5041. 33 M. Hirama T. Shigemoto and S. Ito J. Org. Chem. 1987 52 3342.34 F. Farzana A. Malik and W. Voelter Liebigs Ann. Chem. 1987 717. 35 H. Lida N. Yamazaki and C. Kibayashi J. Org. Chem. 1987 52 3337. Carbohydrates ~2 OMe R'NH OMe R2 (54) R' = CO,CH,Ph; R' = H R' = CO,CMe,; R' = H ?R .:&OH OCONH2 NHAc (57) R = CONH,; SiEt (58) (59) synthesis of 6-amino-6-deoxy-sugars involved the reaction of galactopyranose triflate with the methyl esters of several amino-a~ids.~~ 4,8-Anhydro-N-acetylneuraminic acid (61) has been isolated3' from the edible bird's nest following mild acid hydrolysis which supports an earlier finding that in the glycoprotein at least a proportion of N-acetylneuraminic acid (NANA) is acetylated at HO-4. Attempts have been made3* to correlate the side-chain conforma- tion of NANA and its epimers at C-7 and C-8 with activation by NANA-CMP- synthetase.The synthesis of the side-chain epimers of 2-deoxy-2,3-dianhydro-NANA has been Both the conformation and stereochemistry of the side chains influenced the action of sialidase from Vibrio cholerae. Anhydro-sugars.-Since anhydro-sugars have considerable synthetic utility this sec- tion reports some preparations and properties of these compounds. An efficient synthesis of anhydroalditols has been reported4' involving the silylation of glycosides followed by reductive cleavage with triethylsilane in the presence of trimethylsilyltri- flate. The method was also an efficient means to prepare ally1 C-glycosides by simply replacing Et3SiH with Et,SiCH,CH=CH,. Mono- (62) and di-oxetanes (63) of coy HOCH2 36 A.Malik Z. Ahmed N. M. Kazmi and A. Q. Khan. 2. Naturjorsch. Teil B 1987 42 514. 37 V. Pozsgav H. Jennings and D. L. Kasper Eur. J. Biochem. 1987 162 445. 38 R. Christian G. Schulz H. H. Btandstetter and E. Zbiral Carbohydr. Rex 1987 162 1. 39 E. Zbiral H. H. Brandstetter R. Christian and R. Schauer Liebigs Ann. Chem. 1987 781. 40 J. A. Bennek and G. R. Gray J. Org. Chem. 1987 52 892. 300 J. F. Kennedy and D. L. Stevenson 2,5-anhydroalditols have been prepared4' from the appropriate 2,5-anhydroalditols by the selective mono- and ditosylation of the primary hydroxyl groups and sub- sequent treatment with base. Nucleophilic ring-opening of some of these oxetanes gave new derivatives of 2,5-anhydrohexitols with the L-ido and D-gluco configur-ation.Treatment of tosylated anhydrosugars with trimethylsilylazide in the presence of BF3Et20 gave the azidodeoxy-sugars without disp€acement of the toluene-p-~ulphonate.~~ The anionic ring-opening and polymerization of 1,6 :2,3-dianhydro-4-0-allyl-D-mannopyranose has been reported43 to give a polymer with intact ally1 groups. The polymerization of anhydro-sugars has been reviewed.44 Ethers Isotopic Labelling and Epimerization.-Some 3-0-alkyl-~-glucose and D-allose derivatives have been found to be cytotoxic agents against cultured leukemia L-5178Y cells.45 The butylation of pyranoses by phase-transfer and the preparation of 2- 0-allyl-D-glucose derivatives4' has been reported. Chiral deuteriation of 1,5-anhydropentofuranosederivatives at C-5 has been simply achieved48 by photobromination followed by metal deuteride reduction.Aldoses and ketoses have been labelled with carbon-13 at a number of sites by using '3C-pyruvate and the enzymes from the glycolytic pathway.49 The aldolase-catalysed reaction between a labelled aldopentose 5-phosphate and dihydroxyacetone has been used5' to prepare ''C-~~t~lo~e mono- and diphosphates. The epimerization of aldoses at C-2 by combinations of divalent metal ions and diamines have been examined in a number of st~dies.~'-~~ 3 Chiral Synthons This area of carbohydrate chemistry involves the synthesis of chiral non-carbohydrate structures from carbohydrate starting materials. Cyclitols are chiral polyhydroxy- cyclohexane derivatives which have many applications in organic synthesis.Three cyclitols [(64)-(Mi)] have been synthesized from D-glucurono-6,3-lactone by a synthetic strategy which involved an efficient conversion of the D-gluco configuration into the L-ido configuration and reductive cyclization of dials to cy~litols.~~ Cyclitols which are currently enjoying much interest are the so-called pseudo- sugars which resemble sugars but lack the ring oxygen. 41 P. Koell and M. Oelting Liebigs Ann. Chem. 1987 205. 42 G. Janairo W. Kowollik and W. Voelter Liebigs Ann. Chem. 1987 165. 43 A. A. Gorkovenko E. L. Berman and V. A. Ponomarenko Vysokomol. Soedin. Ser. B. 1987 29 134. 44 N. K. Kochetkov Terrahedron 1987 43 2389. 45 T. Ikekawa.K. Irinoda K. Saze T. Katori H. Matsuda M. Ohkawa and M. Kosik Chem. Pharm. Bull. 1987 35 2894. 46 R. Nouguier and C. Medani Tetrahedron Letr. 1987 28 319. 47 M. K. Gurjar and S. M. Pawar Carbohydr. Res. 1987 159 325. 48 H. Ohrui T. Misawa H. Hori Y. Nishida and H. Meguro Agric. Bid. Chem. 1987 51 81. 49 W. J. Goux US. Patent 4,656,133. so K. K. Arora J. K. MacLeod and J. F. Williams J. Labelled Comp. Radiopharm. 1987 24 205. " T. Tanase F. Shimizu M. Kuse S. Yano S. Yoshikawa and M. Hidai J. Chem. SOC. Chem. Commun. 1987 659. 52 R. E. London J. Chem. SOC. Chem. Commun. 1987 661. 53 B. Klaic Z. Raza M. Sankovic and V. Surjic Helu. Chim. Acra 1987 70 59. 54 Y. Watanabe M. Mitani and S. Ozaki Chem. Lett. 1987 123. Carbohydrates 301 PhCH2O OH PhCH20 OH PhCHzO ROQH RoQ OH Ro@H OCHzPh OCH2Ph OCHzPh (64) (65) (66) R = CH2Ph Several such pseudo-pyranoses [e.g.(70)] have been prepared5' by treatment of D-glucose diethylthioacetal with lithium dimethylmethyl phosphonate to produce (67). Conversion of (67) into (68) followed by Swern oxidation produced a ketone (69) which on stereospecific hydrogenation yielded (70). 0'BDPSi OX0 OCH2Ph PhC HzO' C H( 0H)C H2POJMe OCHzPh% OCHzPh P03Me2PhCH20' PhCH20 OH (67) (68) 7H2OR' CHZOH R200 0 "-OH HO OH OR2 (69) R' = SiMe,CMe, RZ= CH2Ph Other pseudo-monosaccharides which have been prepared include (71)56 and (72).57Some pseudo-disaccharides containing an ether linkage between a cyclitol and a sugar component have been synthe~ized.~' The condensation reaction of a cyclitol derivative carrying a free hydroxyl group with a sugar triflate occurred in the presence of sodium hydride.Both primary and secondary triflate groups were substituted to yield (1 + 6) and (1 + 4) linked pseudo-disaccharide analogues of isomaltose maltose and cellobiose. New water-soluble trans-butadienyl ethers [e.g. (73)] have been prepared from D-gl~cose.~~ Cycloaddition reactions with a variety of dienophiles in an aqueous medium showed both rate and stereoselectivity enhancements when compared to the reactions of similar peracetylated dienes in organic solvents. The sugar moiety may subsequently be removed enzymatically to give highly functionalized chiral cyclohexanes.( 1 S,2S)-2-(Hydroxymethyl)-2-methylcyclohexanolwas prepared this way. 55 H. Paulsen and W. von Deyn Liebigs Ann. Chem. 1987 125. 56 H. Paulsen and W. von Deyn Liebigs Ann. Chem. 1987 133. 57 K. Tadano H. Maeda M. Hoshino Y. Iimura and T. Suami J. Org. Chem. 1987 52 1946. 58 H. Paulsen and W. von Deyn Liebigs Ann. Chem. 1987 141. 59 A. Lubineau and Y. Queneau J. Org. Chem. 1987 52 1001. J. E Kennedy and D. L. Stevenson AcO OAc (71) R = CH,Ph (72) CH20H OH (73) (74) Enantiomerically pure L-and D-muscarine halides (74) have been prepared6' on the one hand from (R)-2,3-0-isopropylidineglyceraldehyde, and on the other from D-glucose. Diastereoselective Diels- Alder reactions have been carried out on carbohydrates.Addition of cyclopentadiene to the protected glucofuranose (75) gave the norbor- nenecarboxylate (76) and its (1'S,2'S)diastereoisomer in the ratio 93 :7.61 D-Mannitol has found particular application as a chiral synthon. Thus the chiral butenolide (77) which is readily available from D-mannitol has been used a 'replicating lactone template' affording structural sub-units such as (78) in natural Me3SiOCH2 I HO HOCHz 1 I 02CCH=CHI 0 +Me Me OH OH Ph 2( Me3C)SiO Ro+Co,H Me (77) (78) 60 J. Mulzer A. Angermann W. Muench G. Schlichthoerl and A. Hentzschel Liebigs Ann. Chem. 1987,7. 61 H. Kunz N. Muller and D. Schanzenbach Angew. Chem. 1987,99 269; (In?.Ed. Engl. 1987 26,267). Carbohydrates 303 product synthesis.62 cis-Caronaldehyde an intermediate in the production of the pyrethroid insecticides has been prepared63 by a route involving the periodate cleavage of 1,2:5,6-di-0-isopropylidene-~-mannitolto (R)-0-isopropylidenegly-ceraldehyde followed by a Horner-Emmons reaction with (EtO),P(O)CHMeCO,Et.Some new chiral macrocylic ethers [e.g. (79)] have been prepared64 via the condensa- tion of 2,3,4,5-tetra-O-benzyl-D-rnannitol with tetraethyleneglycol ditoluene-p- sulphonate in the presence of sodium hydride. The synthesis of diepoxides and diaziridines of D-mannitol as precursors of enantiomerically pure a-hydroxy and a-amino-aldehydes and acids has been reported.65 A short practical synthesis of the (2S,5S)-bis-hydroxymethyL(3R4R)-bis-hydroxypyrrolidine (80) from D-man- nitol has also been achieved.66 D-and L-Arabinose have also been used as the chiral starting points for some syntheses of y-la~tones,~~*~* whilst levoglucosan (81) formed the starting material for a synthesis of the diolide (82).69 Some building blocks for the total synthesis of the antibiotics amphotericin B and amphoteronolide B have been synthesized using (+)-and (-)-xylose as the starting material.70 Me 62 S.Hanessian and P. J. Murray J. Org. Chem. 1987 52 1170. 63 S. Takano A. Kurotaki M. Takahashi and K. Ogasawara J. Cbem. Soc. Perkin Trans. 1 1987 91. 64 M. Alonso-Lopez M. Martin-Lomas S. Penades C. Bosso and S. Ulrich J. Carbohydr. Chem. 1986 5 705. 65 Y. Le Merrer A. Dureault C. Greck D. Micas-Languir C.Gravier and J. C. Depezay Heterocycles 1987 25 541. 66 T. K. M. Shing J. Chem. SOC.,Chem. Commun. 1987 262. 67 A. B. Reitz A. D. Jordan jun. and B. E. Maryanoff J. Org. Chem. 1987 52 4800. 68 Y. Nishida M. Konno M. H. Hori H. Ohrui and H. Meguro Agric. Biof. Cbem. 1987 51 635. 69 T. Wakamatsu S. Yamada H. Nakamura and Y. Ban Heterocycles 1987 25 43. 70 K. C. Nicolaou R. A. Daines J. Uenishi W. S. Li D. P. Papahatjir and T. K. Chakraborty J. Am. Chem. Soc. 1987 109 2205. J. F. Kennedy and D. L. Stevenson Several amino-acid derivatives have been obtained in an enantiomerically pure form starting from carbohydrate precursors. Thus the 4,5,6-trihydroxylated nor-leucines [(83)-(85)] have been prepared” from vitamin C and isovitamin C deriva-tives.The Schiff bases from the protected D-galactodialdehyde (86) and the amino- OH NH2 OH NH2 HO &C02H acid methyl esters of valine leucine and isoleucine were diastereoselectively alky- lated uia their lithium derivatives. Hydrolysis gave the optically active a-alkylated methyl (S)-valinates leucinates and i~oleucinates.~~ Finally C-glycosides are useful chiral synthons a point which is illustrated in the total synthesis of the antibiotic pseudomonic acid (87).73 ” J. A. J. M. Vekemans R. G. M. de Bruyn R. C. H. M. Caris A. J. P. M. Kokx J. J. H. G. Konings E. F. Godefroi. and G. J. F. Chittenden J. Om. Chem. 1987 52 1093. ’’ U. Schoellkopf R. Toelle E. Egert and M. Nieger Liebigs Ann. Chem. 1987 399. 73 J. C. Barrish H.L. Lee E. G. Baggiolini and M. R. Uskokovic J. Org. Chem. 1987 52 1372.

ISSN:0069-3030    

DOI:10.1039/OC9878400291

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Author Index Abbott D.E. 114 Abdulaziz M.A. 294 Abe Y. 296 Abell C. 11 Abelt C.J. 158 Abeywickrama A.N. 167 Abraham M.H. 79 Abraham W.D. 134 Acheson S.A. 77 Ackland D.J. 169 Adam W. 33 Adegoke E.A. 93 Adlington R.M. 183 Agami C. 39 Agarwal S.K. 175 176 Agmon I. 109 Agmon N. 35 Agrafiotis D.K. 38 Agranat I. 177 Agrebi A. 237 Ahlberg P 159 Ahmed S.A. 159 Ahmed Z. 299 Ajaz A.A. 8 Akasaka T. 44 Akhtar M. 286 Akiba K. 66 200 247 Akimoto K. 44 Akiyama A. 275 Akiyoshi K. 219 Akutagawa S. 99 226 269 27 1 Akuzawa K. 217 Alagona G. 27 Alam N. 167 Alauddin M.M. 45 174 258 Alderman D.W. 173 Alemagna A. 216 Alexakis A. 250 Alexander S.A. 173 Alfonso C.M.267 Ali M. 69 163 Aliprandi B. 164 Al-Juaid S.S. 239 AI-Kinay M. 165 Allen A.D. 67 Allen L.C. 29 Allen W.D. 29 32 177 Allerhand A, 4 5 Allevi P. 291 Allinger N.L. 26 27 Allison J. 20 Almeida M.L.S. 278 Almlof J. 33 No B.I. 165 Alonso-Lopez M. 303 Alpegiani M. 126 Alper H. 221 222 Alster J. 29 Alston P.V. 38 Alt H.G. 228 Alty A.C. 108 Alvanipour A. 231 Alvarez-Ibarra C. 254 Amatore C. 167 Ambrosetti R. 72 Amick T.J. 195 Ammann A. 112 Ammon H.L. 176 Amorebieta V.T. 112 Amos R.D. 25 A,mster I.J. 21 Anastasia M. 291 Andersen O. 240 Anderson A.G. 110 268 Anderson D.A. 277 Anderson L.G. 137 226 Anderson C.-M. 221 Ando K. 125 Ando M.121 221 Ando T. 99 276 Ando W. 44 109 184 186 238 Andreini B.P. 107 Andrew R.C. 146 Andrianarison M. 238 Andrieux C.P. 167 Andro A. 121 Anet F.A.L. 4 10 Angeletti E. 254 Angermann A. 302 Angermund K. 101 Angoh A.G. 155 Aniszfeld R. 235 Annunziata R. 49 260 Anthony I.J. 195 Anthony N.J. 153 Anunziata J.D. 72 165 305 Aoki S. 253 Aoyama N. 196 Aped P. 27 Apeloig Y. 27 34 62 75 235 Apparao S. 258 Appelt A. 232 Arad D. 75 Arai K. 125 Arai Y. 41 145 Araki S. 196 Arase A. 104 106 Ardisson J. 82 Arduengo A.J. 111 197 Argile A. 77 Arias S. 254 Arif A.M. 225 Arimura T. 165 175 Aristoff P.A. 198 Armistead D.M. 153 Armstrong P.48 260 Armstrong R.N. 176 Armstrong R.W. 218 Amett E.M. 74 Arnold C.A. 236 Arnold L.D. 124 Arora K.K. 300 Arregey San Miguel B. 83 Artschwager-Perl U. 195 Arvanaghi M. 132 Arzoumanian H. 222 Asai Y. 33 Asao N. 125 Asaoka M. 142 Asensio G. 110 Ashby E.C. 63 Ashby J. 238 Ashcroft A.E. 17 Ashe A.J. 111 205 Ashton P.R. 16 Asirvatham E. 142 258 Aso Y.,277 Atkinson R.S. 182 Atrash B. 285 Attina M. 69 72 164 Atwood D.A. 231 Atwood J.L. 231 232 Aube J. 128 Audia J.E. 46 Aumann R. 44 109 220 306 Avramovitch B. 68 Axelsson B.S. 78 Ayoko G.A. 235 Azzana U. 170 275 Baba S. 103 Babirad S.A. 292 Bachi M.D. 81 188 Bachrach S.M. 28 Baciocchi E.68 163 164 Bader R.F.W. 28 Badoz-Lambling J. 167 Backvall J.-E. 36 107 108 136 211 Baettig K. 46 146 Bauerle P. 164 Baggiolini E.G. 304 Bagna A. 59 Bahr U. 19 Bahsas A, 42 Bailey A.R. 55 Bailey P.D. 193 Bailey W.F. 134 Baillie T.A. 15 Baker J. 26 33 Baker M.G. 190 Baker M.V. 94 Baker R. 143 Bakker B.H. 101 Bakouetila M. 101 Bakshi R.K. 271 Balasubramian P.N. 101 Balch A.L. 6 Balci M. 209 Bald R. 6 Baldoli C. 216 Baldridge K.K. 33 Baldwin J.E. 51 52 111 126 183 Baldwin M.A. 15 23 24 Baldwin S.W. 128 Balkan S. 161 Baloni S.K. 176 Baltzer L. 11 12 Bambal R. 199 Ban Y. 303 Banait N. 67 Bando T. 223 Bannister R.M. 204 Banon G.254 Bar-Adon R. 29 33 Baran J. 49 Barasch D. 126 Barbeaux P. 139 Barber M. 15 16 17 Barber S.E. 61 Barchi J. jun. 155 Bardshiri E. 159 Bargon J. 6 Barizo O.M. 175 Barluenga J. 110 Barrau J. 237 Barrett A.G.M. 228 Barrish J.C. 304 Barron C.A. 55 Barros M.T. 267 Barta M. 129 Barton D.H.R. 87 93 169 274 Baruah J.B. 215 Barz M. 112 Ba-Saif S. 77 Basak S. 112 Basavaiah D. 94 Bash P.A. 40 Basha A. 253 Bashiardes G. 213 Bassett K.E. 98 Bastian H. 182 Basu A. 279 Bates T.F. 234 Battersby A.R. 190 Bau R. 235 Bauer W. 10 Bauld N.L. 43 46 Baum G. 237 238 Baumstark A.L. 101 Bauschlicher C.W. 31 Bax A. 7 Beachley O.T. jun. 232 Beau J.-M.218 Beauhaire J. 202 Beaulieu P.L. 87 Beck K. 195 Becker, D.P. 257 Becker J.Y. 197 Beckhaus H.-D. 91 Beckwith A.L.J. 83 90 167 Bedford C.D. 110 Bednarski M. 275 Behling R.W. 6 Bell AS. 218 Bell D. 17 Bellucci G. 66 72 99 Bellville D.J. 43 Beloeil J.C. 93 Bender H. 185 Benetti M. 107 Benkovic P.A. 279 Benkovic S.J. 279 282 283 288 Bennek J.A. 299 Bennett P.A.R. 11 1 Bennett S.M. 155 Benson S.C. 203 Bentley T.W. 61 Berchtold G.A. 143 Bergbreiter D.E. 119 Berger S. 9 79 238 Berlin A. 198 Berman E.L. 300 Bernardi F. 26 34 38 48 Bernasconi C.F. 67 Bernatchez M. 137 Berndt A. 237 238 Berson J.A. 12 192 Bertran J. 38 39 40 Bertrand.R. 61 Author Index Berube G. 46 146 Bestmann H.J. 107 253 .Beynon J.H. 23 24 Bhat K.S. 248 Bhupathy M. 134 Biali S.E. 158 Bianchini R.,66 72 Bickelhaupt F. 29 133 178 233 262 Bidd I. 93 Biehl E.R. 170 174 Biemann K. 21 22 Biller J.E. 22 Biller S.A. 87 Billington D.C. 143 Billion A. 93 Binkley R.W. 294 Binzet S. 35 Birbaum J.L. 89 Birkhofer H. 91 Bitha P. 17 Blackstock S.C. 192 Blagg J. 212 Blaho J.K. 51 Blake J.F. 39 Blanchet D. 87 Blanco L. 162 Blanda M.T. 239 Blandamer M.J. 60 Blanton J.R. 119 Bliznyuk A.A. 27 Blomberg M.R.A. 36 Bloodworth A.J. 82 Bloom A.J. 45 107 Blotny G. 76 Blum Y.D. 236 Blundell T.L. 285 Blunden S.J. 238 Boatz J.A.33 36 39 Bobeldijk M. 178 Bodenshausen G. 3 Bohme R. 182 Borner U. 232 Boese R. 198 228 Boesl U. 20 Boger D.L. 159 170 182 190 Boivin J. 93 Boivin T.L.B. 132 Boldeskul I.E. 132 Bonaccorsi R. 40 Bonnert R.V. 44 103 142 296 Booth B.L. 165 Booth C.L.J. 283 Borak G. 64 Bordas-Nagy J. 24 Borden W.T. 31 36 Bordoli R.S. 15 Bordoloi M. 270 Bordwell F.G. 63 Borel C. 228 Borgford T.J. 282 Bosch P. 274 Bosso C.. 303 Author Index 307 Bott S.G. 231 232 Bryce-Smith D. 172 Carlacci L. 32 Bottaro J.C. 110 Buchert P. 212 Carmack R.A. 181 Botting N.P. 286 Buchwald S.L. 101 169 277 Carpenter B.K. 53 Bottorff K.J. 127 Buckner J.K. 40 60 Carpita A. 107 11 1 Bouchoux G.34 Buda A.B. 158 Carr R.C. 46 Boudjouk P. 233 Budzelaar P.H.M. 33 186 Carretero J.C. 184 Boukouvalas J. 203 Burgi H.-B. 35 Carroll P.J. 187 Boulanger R. 137 Bunce N.J. 166 Carrupt P.-A. 191 Bouma W.J. 24 34 Buncel E. 59 Carter C.M. 173 Bourdieu C. 204 Bundy G.L. 22 Carter E.A. 31 Bouw J.P. 189 Bunnelle W.H. 122 246 Casado J. 73 Bowen J.P. 27 Bunton C.A. 59 66 72 Casadonte D.J. 98 Bowers C.R. 5 Burford N. 9 Cass A.E.G. 172 Bowers J.L. 12 Burgers P.C. 34 Castellino S. 114 Boyd D.R. 176 Burgess K. 136 Castle R.N. 204 Boyd G.V. 55 206 Burggraf L.W. 26 Castro A. 70 73 Boyd R.J. 29 Burke L.D. 46 Castro M.E. 21 Boyd R.K. 23 Burkow I.C. 251 Cater S.R. 166 Bradamante S. 198 Burlingame A.L. 15 Catrousse A.-P. 73 Bradsher G.K. 174 Burnell D.J.27 38 41 Cattana R.I. 165 Brady W.T. 137 Bums G.T. 237 Caufield C.E. 27 Brand M. 119 165 Burns T.P. 251 Cava M.P. 190 198 205 Brand N.J. 282 Burshtein K.Ya. 40 Cederbaum F.E. 112 228 Brandstetter H.H. 299 Burton D.J. 55 Celerier J.P. 135 Brassmer R. 297 Bury A. 65 Cercus J. 270 Brauers F. 11 Buss A.D. 95 144 160 Cerfontain H. 101 Brauman J.I. 77 Buss D. 97 Cerichelli G. 66 Braun M. 132 241 Butler D.N. 159 Ceruti M. 120 255 Braunschweiger H. 270 Butsugan Y. 196 Cha J.S. 119 270 Bray B.L. 249 Buttero P.D. 216 Cha Y. 48 Brazier J.L. 23 Buttrus N.H. 235 Chadwick D.J. 45 192 Breitmaier E. 106 182 Buynak J.D. 188 Chait B.T. 21 Bremer M. 30 159 Chakraborty T.K. 303 Brenton A.G. 23 24 Cabaleiro M.C. 65 Chaloner P.A. 251 Brereton R.G. 3 Cabrera Escribano F.296 Chamberlin A.R. 38 66 Briggs J.M. 40 74 Cacace F. 69 164 Chambers R.D. 185 Britton T.C. 124 273 Cadilla R. 46 195 Chamorro E. 274 Broadbent H.A. 190 Cagnol J. 286 Chan C. 110 Broadbent T.A. 150 Cai Z. 103 Chan T.H. 118 142 161 272 Broadway D.E. 9 79 Cairns P.M. 42 Chan Y.-Y.,33 Brodbelt J.S. 21 Calet S. 222 Chandrakumar N. 3 Brodeur D. 187 Cambs F. 274 Chang C.-T. 83 Brook A.G. 234 Brookhart M. 21 1 262 Brooks D.W. 139 253 273 Cammi R. 27 Campana C.F. 231 Campi E. 11 1 Chang J.-W.A. 39 Chang T.T. 17 Chang V.H.-T. 209 Brown E.G. 108 Brown F.K. 27 38 41 Campos P.J. 110 Canonne P. 137 Chapman J.R. 17 Chapman K.T. 41 Brown H.C. 94 101 113 248 271 276 Cantos A. 166 Cao W. 161 Chapman O.L. 158 Charles G. 119 Brown J.M. 98 132 226 268 Capdevielle P.126 Charlton J.L. 45 174 258 Brown M.J. 134 269 Capon B. 62 Capon R.J. 296 Charpentier M. 33 Charrier C. 187 193 Brown P.A. 103 Brown P.H. 44 Caporusso A.M. 108 Capparelli M.P. 172 Chary K.V.R. 6 Chatterton W.J. 234 Brown R.J. 298 Brown R.L. 173 Caprioli R.M. 17 18 Caputo R. 122 Chattopadhyaya J. 19 Chaudhuri N.C. 134 Brown R.S. 17 77 Carboni B. 45 144 258 Chaussard J. 171 Brownbridge P. 183 Browne M.E. 155 Cardellicchio C. 119 Cardenas C. 34 Chau-Yu-King R. 135 Chavan S.P.. 42 Bruice T.C. 101 Cardona R. 38 Chen C. 271 Bruins A.P. 22 Carera I. 236 Chen F. 266 Bryan S.K. 231 Carey A.R.E. 77 Chen H.-J.C. 188 Bryant J.A. 167 Carey P.R. 34 Chen J. 212 282 283 Bryant T. 73 Caris R.C.H.M. 304 Chen M.-H. 83 261 Author Index Chen V.J.284 Chen W. 190 Coates M. 53 Cobb J. 55 206 Cramer C.J. 36 Cramer F. 282 Chen 2.-C. 110 268 Cody R.B. 23 Crandall J.K. 109 Cheng C.H. 217 Cheng H.J. 123 Coenen H.H. 168 Coerver J.M. 102 Creary X. 51 Cremer D. 25 33 186 Cheng M.-C. 122 123 Cohen M.A. 286 Crich D. 82 88 118 Cheng W. 168 Cohen S. 177 Crievson C.M.J. 240 Chenier J.H.B. 232 Cherrah Y. 23 Cohen T. 106 134 Cohen Y. 174 Crimmins M.T. 83 137 Crisco L.V.T. 139 Chiacchiera S.M. 72 Colclough E. 97 Cronin C.N. 283 Chiang Y. 74 76 Coleman A.W. 231 Crowe A.J. 238 Chiappe C. 66 99 Chiba Y. 95 217 Chidambaram R. 228 Coleman R.S. 159 Collington E.W. 201 Collins M.J. 12 Culley S.A. 197 Cullis P.M. 9 Cumin F. 286 Child R.G. 17 Collins S. 33 119 252 Curran D.P. 41 53 83 260 Chiou H.-S. 43 Collman J.P.21 1 26 1 Chirlian L.E. 29 Chittenden G.J.F. 304 Chmielecka J. 233 Cho B.P. 176 Colomer E. 237 Colonna S. 212 Colquhoun H.M. 211 Colussi A.J. 112 Cushman M. 212 Cyr D.R. 115 Dabard R. 98 Cho B.R. 64 65 Combellas C. 167 171 Dad M.M. 137 Cho B.T. 113 271 Choe E.W. 178 Choi H.-K. 235 Conn R.E. 124 243 Connolly M.J. 16 Contrell G.L. 178 Dagget J.U. 260 Daines R.A. 303 Dale J. 177 Choi S.-C. 83 134 265 Chojnowski J. 233 Chong W. 32 Cook B.R. 107 Cooke M.P. jun. 134 Cooks R.G. 21 Dalipi S. 183 Dallaire C. 46 146 Dalley N.K. 297 Choong J.M. 115 Chou S.-S.,44 Cooney B.T. 79 Cooper D.K. 46 Dalton D.R. 99 Danheiser R.L. 136 Chou T. 44 108 Cooper D.L. 26 29 31 Daniel H. 96 255 Chow A. 236 Cooper J. 285 Danis P.O. 24 Chow K. 110 175 Cooper P.J. 102 Danishefsky S.J. 82 117 153 Chowdhury A.K.64 Christen P. 284 Copley S.D. 53 Corbel B. 139 Dannheim J. 97 Dantanarayana A.P. 153 Christensen J. 181 Corey E.J. 114 139 140 147 Dappen M.S. 155 Christian R. 299 155 191 262 271 Darba P. 35 Christiansen J.W. 18 Cork D.G. 99 276 Darnow J.N. 176 Christl M. 200 Cornelisse J. 171 175 Daruwala K.P. 147 Christofides J. 9 Correia C.R.D. 50 146 Das V.G.K. 238 Christopfel W.C. 174 Corriu R.J.P. 119 237 David L.D. 236 Chuchani G. 61 64 Corvol P. 286 Davidson E.R. 28 Chuche J. 112 Cosmo R. 176 Davidson F. 197 236 Chung Y.-S. 175 Cossar J. 74 Davies A.G. 164 Churchill M.R. 232 Costello F. 99 Davies D.B. 9 Cieplak P. 40 Costick K.B. 50 171 Davies H.M.L. 139 Cinquini M. 49 260 Cipiciani A. 72 Ciuffreda P. 291 Cotter R.J. 22 Cottet F.202 Cottier L. 202 Davies J.W. 88 Davies S.G. 211 212 213 Davis. F.A. 267 Ciufolini M.A. 155 Cottrell C.E. 51 Davis L.P. 26 Clabo D.A. 29 32 177 Cottrell J.S. 16 17 20 Davoust D. 143 Claesson A. 292 294 29 5 Cotts P.M. 236 Dax S. 48 Clark G. 149 Couret C. 237 238 de Bruyn R.G.M. 304 Clark J.H. 99 119 276 Court J.J. 142 Decker O.H.W. 56 Clark R. 26 171 Clark S. 238 Courtneidge J.L. 164 Couture A. 198 Declercq J.-P. 238 Dedopoulou D. 77 Clark T. 37 51 Clarke T. 53 153 Clavero C. 38 Coveney D.J. 88 Covey T.R. 22 Cowan D.O. 197 Deeb T.M. 189 Defauw J. 145 Degani I. 120 255 Cleery D.G. 220 Clegg W. 240 Clemens G.B. 51 Cox R.A. 79 Coy M.G. 42 Cozzi F. 49 260 deGrandpre M.P. 181 DeHoff B.S. 146 Deiters J.A. 39 Clemett C.J. 101 Clive D.L.J. 155 Closs F. 197 Craig D.143 Craig P.J. 238 Cram D.J. 167 181 de Kanter F.J.J. 29 Deker P.B. 113 de Koning L.J. 64 Author Index Del Bene J.E. 27 Delguzzo L. 61 Dell C.P. 152 Dell’Erba C. 167 Delmond B. 83 Demarchi B. 174 Demers J.P. 168 De Mesmaeker A. 81 188 De Mesmaeker N.S. 188 Demir AS. 241 Demirev P. 22 den Hartog J.A.J. 189 Denis A. 136 Denis J.-M. 201 Denmark S.E. 36 118 129 Denne I. 45 144 258 Denny W.A. 205 Denurra T. 170 275 de Petris G. 164 Depezay J.-C. 183 303 Derome A.E. 3 de Roop J.S. 6 Derrick P.J. 15 18 DeSchepper R.S. 172 Descotes G. 202 DeShoong P. 121 Deslongchamps P. 46 141 146 257 DesMarteau D.D. 165 275 deSolms S.J. 143 149 Dessage M.,23 Dessinges A.296 DeTar D.F. 35 Deutsch P.P. 6 Deuzer H. 203 Devia A.H. 98 Dewan J.C. 169 Dewar M.J.S. 26 33 35 39 53 158 Dewinter A.J. 134 de Wolf W.H. 29 133 178 Deycard S. 90 Dhaher S.M. 239 Dhanoa D.S. 87 Dhumrongvaraporn S. 249 Dias H.V.R. 204 Dickopp H. 207 Dickson J.K. 82 Diehl B.W.K. 9 79 Diehl F. 186 Diehl J.W. 23 Dieter J.W. 165 214 Dietrich-Buchecker C.O. 209 Dietze P.E. 67 94 Differding E. 161 Difiore K.F. 44 Ding W. 161 Dipple A. 175 Disanayaka B.W. 149 Dixon D.A. 197 236 Dobbs K.D. 26 Doherty R.M. 79 Dolata D.P. 26 Dolbier W.R. 55 108 Dolle R.E. 124 170 Domelsmith L.N. 29 Dominguez R.M. 64 Dondoni A. 195 Dopp D. 145 Dordor-Hedgecock I.M.21 1 Dorfmeister G. 204 Dorigo A.E. 35 37 Dormond A. 254 Dorow R.L. 118 273 Dotz K.H. 175 228 Doubleday C. 32 Doubleday W. 106 Dougherty D.A. 30 Douglas T.A. 63 Dowd P. 32 83 134 265 Doxsee K.M. 167 Doyle M.P. 98 Dreiding A.S. 112 Drew M.G.B. 50 171 172 Drone F.J. 205 Drover J.C.G. 124 D’Rozario A.P. 72 Drummond J.T. 188 Du P. 31 36 Dubac J. 237 Dube D. 155 Dubourg A. 238 Duggan M.E. 187 Duhaime R.M. 52 76 Duhamel C. 143 Dujardin R. 10 Dumont W. 134 du Mont W.-N. 238 Duncan M.P. 111 246 268 Dunitz J.D. 34 35 Dunlap N.K. 140 Dunlop R. 176 Dupre B. 155 Dupuis M. 29 Duran M. 38 Duran R.P. 112 DurCault A. 183 303 Durst T.45 Dutler R. 33 Dykstra C.E. 36 Eaborn C. 232 233 235 237 239 Eagles J. 16 Earl H.A. 65 Eason R.G. 176 Easton R.J.C. 211 Eaton R. 159 Ebata K. 98 Eberson L. 68 163 Ebihara K. 114 251 Echavarren A.M. 170 Eddaif A. 191 Edgecombe K.E. 29 Edington C. 244 Effenberger F. 159 164 201 202 309 Effenberger G. 291 Egert E. 304 Egler R.S. 163 Eichinger K. 161 Einhorn C. 247 Einhorn J. 251 Eisenberg R. 6 Eisenschmid T.C. 6 Eisenstein O. 39 Ejiri E. 180 El-Alaoui M. 67 El Bouadili A. 254 El-Din G.N. 254 El-Dusouqui O.M.E. 70 Elecko P. 108 Ellenberger S.R. 188 298 Ellencweig A. 27 Elliot G.J. 15 16 Elliot J.D. 244 Ellis G.P. 169 211 Ellman J.A.118 124 273 Elsbernd C.S. 236 Elser V. 173 Elsevier C.J. 11 1 222 Enders D. 127 241 273 Endesfelder A. 248 Endo T. 86 189 Engelhardt L.E. 231 Engelke F. 19 Engelke U. 6 Englander S.W. 7 Ensinger M.W. 235 Ephraim Bassey H. 93 Epiotis N.D. 32 Epstein I.R. 72 Erdmann V.A. 6 Eren D. 169 Erion M.D. 284 Eriyama Y. 98 233 Ermer O. 157 209 Emst I. 109 Ernst R.R. 3 6 Escudie J. 237 238 Essenfeld A.P. 46 Esteban N.V. 23 Estermann H. 123 241 Etter J.B. 126 135 137 256 262 Euranto E.K. 79 Evans D.A. 41 118 124 243 273 Evans R.D. 100 Evans S. 20 Evanseck J.D. 39 Everett J.R. 6 Evershed R.P. 22 Fabiano E. 129 273 Facelli J.C. 173 Facklam T.196 Fadel A. 277 Fadel R. 99 Faghih R. 155 Faid-Allah H. 190 Falconnet J.B. 23 Falorni M. 11 1 Fan T. 17 18 Fantin G. 195 Farnia M. 159 Farrell P.G. 73 Farzana F. 298 Fasold E. 29 Fatiadi A.J. 21 1 Fausto R. 34 Fedde C.L. 44 201 Feller D. 28 Femia J.F. 205 Feng R. 24 Fennessey P.V. 16 Fenselau C. 22 Fenstel M. 112 FtrCzou J.P. 82 Feringa B.L. 191 Fernandez F. 278 Fernandez M.J. 254 Ferraccioli R. 198 Ferre E. 109 Ferreri C. 122 Fersht A.R. 280 281 282 Fessner W.-D. 179 Fewkes J.K. 212 Fiandenese V. 119 Fiecchi A. 291 Field F.H. 21 Field L.D. 7 94 Field M.J. 31 37 40 78 Fierke C.A. 282 Fife T.H. 78 Filler R. 178 Finch H.201 Findeis A.F.F. 16 19 Findlay P. 67 Finet J.-P. 169 274 Finke R.G. 211 Finlayson N.L. 284 Fischer R. 291 Fiscus D. 195 Fitjer L. 81 263 Fitzmaurice N.J. 11 1 Fitzpatrick F.A. 22 Fitzsimmons B.J. 298 Flann C. 200 Fleck T. 95 Fleming A. 136 Fleming I. 106 125 247 273 Fletschinger M. 208 Flies F. 82 Flinn A. 126 Flitsch W. 190 Fobare W.F. 42 Fochi R. 120 255 Fogagnolo M. 195 Fok C.C.M. 272 Fontana F. 89 90 268 Fookes C.J.R. 190 Forbes J. 12 Ford G.P. 35 39 Forman. J.D. 7 Formosinho S.J. 35 Fornarini S. 164 Forrest A.K. 11 1 Fortt S.M. 118 Fossey J. 33 Foster G.P. 168 Foucaud A. 96 101 204 Foundling S.I. 285 Fourrey J.-L. 202 Fox M.A.38 Fozum T.Z. 109 Fracassini M.C. 72 Francisco C.G. 84 Franck R.W. 202 Francl M.M. 29 Fraser-Reid B. 82 155 296 Frechet J.M.J. 114 Freeman R. 3 Freer A.A. 44 Freire R. 84 Freist W. 282 Frejd T. 149 218 Frenklach M. 158 Frey H. 204 Frick W. 258 Friederichs M.G. 39 Frirn R. 178 Fritz G. 233 Fritz H. 109 185 199 Fronza G. 294 Fruscella W.M. 46 Fry A.J. 243 Fuchs B. 27 Fuchs P.L. 161 292 Fuentes A. 254 Fugami K. 217 Fuganti C. 294 Fujimoto H. 35 Fujimoto I. 106 Fujinarni T. 244 261 Fujisawa T. 270 Fujita M. 99 130 276 Fujita S. 180 Fujiwara Y. 168 255 Fukuda H. 296 Fukuhara T. 273 Fukui K. 33 Fukui M. 155 Fukurnoto K. 87 141 Fukutome H.35 Fukuzawa S. 244 261 Funk R.L. 260 Furlani T.R. 32 Furlong J.J.P. 21 Furstner A. 255 Furuta K. 145 Gabel G. 178 Gadaginamath G.S. 176 Gad El Karim I.A. 37 Gadwood R.C. 134 Gajewski J.J. 41 53 Gal C. 93 Games D.E. 17 Author Index Gande M.E. 53 Ganem B. 53 Gani D. 279 286 Cannon S.M. 268 Gano D.R. 39 Gao J. 40 74 Gao Y. 101 Garay R.O. 65 Garbarino G. 167 Garcia J. 129 Garcia-Ochoa S. 127 Garcia-Ruano J.L. 184 Gardiner W.C. jun. 158 Gareau Y. 187 Garlaschelli L. 94 Gasel V. 274 Gaskell S.J. 22 Gassman P.G. 42 127 Gateau-Olesker A. 87 Gaudin J.M. 227 Gaul M.D. 113 Gaumann T. 20 Gauss J. 25 33 Caw J.F. 25 Gazit A. 68 Gazovi J.108 Gebhard I. 198 Geib S.J. 233 Gellene G.I. 24 Genarri C. 49 Genet J.P. 136 George C. 61 179 188 Gerba S. 83 167 Germani R. 72 Gero S.D. 87 Gerratt J. 26 29 31 157 Gessner R. 6 Ghio C. 27 Ghosal S. 111 Ghosez L. 161 Ghosh A.K. 147 191 262 Ghosh S. 137 Giacco T.D. 163 Ciacornelli G. 111 Giang Y.-S.F. 137 Giannotti C. 169 Gibson B.W. 16 19 Giese B. 85 86 98 293 295 Giguere R.J. 145 Gil G. 109 Gilbert A. 50 171 172 Gilchrist T.L. 56 163 Gillette G.R. 234 Gingras M. 131 Giordano C. 90 Girardin A. 130 Gittelman M.S. 283 Gladysz J.A. 225 Glaser R. 29 Gleghorn J.T. 164 Gleiter R. 30 133 179 Glendening E.D. 34 Glinka J. 195 Glinka T.167 Author Index Glover S.A. 90 Gneady J.E. 283 Goddard J.D. 34 Goddard W.A. 3 1 Godefroi E.F. 304 Gorl U. 44,206 Goldback M. 107 Goldberg I. 27 181 Goldblum A. 27 Golding B.T. 129 273 Goldsmith D.J. 27 Gololobov Y.G. 132 Gommans L.H.P. 168 Gompper R. 197 Gonzalez J.M. 110 Gonzilez-G6mez J.A. 98 Goodfellow C.L. 212 Goodman J.M. 27 Gordon M.S. 33 36 39 233 Gore P.M. 72 Gorenstein D.G. 39 Gorkovenko A.A. 300 Gorshkova R.P. 295 Goss C.H. 16 Goto M. 17 234 235 Gottlieb H.E. 276 Goubitz K. 263 Could L.D. 137 Goulet M.T. 116 294 Goux W.J. 300 Govil G. 6 Grace D. 177 Graff J.L. 121 Grahn W. 97 Graillot Y. 194 Grandcloudon P. 198 Grande C.66 Grandjean P. 240 Grant D.M. 173 Grasselli P. 294 Gravier C. 303 Gray B.D. 148 Gray D. 99 Gray G.R. 299 Gray T. 207 282 Greck C. 183 303 Green B.N. 16 Greenberg M.M. 12 192 Greeves N. 95 Gregorcic A. 100 276 Gregory P.S.,164 Grehn L. 278 Grev R.S. 33 Grieco P.A. 42 Grierson D.S. 200 Grierson L. 48 Griesbaum K. 107 Griesinger C. 6 Griffin R.G. 12 Griffith W.P. 120 224 267 Griffiths G. 65 Griffiths P.R. 23 Griffiths W.J. 24 Grigg R. 48 260 Grimme W. 55 Grob C.A. 62 Groninger K.S. 85 293 295 Groh B.L. 102 Gross G. 185 Grossman R.B. 178 Grote J. 46 Grotemeyer J. 18 Groundwater P. 55 206 Grove D.D. 144 Grundke C. 45 108 Gruseck U.44 195 Grzejszczak S. 201 Guder H.J. 291 Guenot P. 201 Guerrero A. 274 Guest M.F. 31 37 78 Guette J.-P. 165 194 Guido D.M. 22 Guilford W.J. 53 Guilhem J. 87 Guner O.F. 38 Gunther H. 10 11 Guo B.-S. 106 Guo J.A. 118 Gupta A.K. 161 Gupta G. 6 Gupta R.B. 202 Gupta S.C. 176 Gurjar M.K. 300 Gushurst A.J. 63 Guthrie J.P. 74 Guy A. 165 194 Ha D.-C. 188 Ha T.-K. 40 Haag-Zeino B. 258 Habermas K.L. 118 Haddad M. 135 Haddon R.C. 30 173 180 Hadrich J. 91 Haelters J.-P. 139 Hahl R.W. 155 Hahn J.H. 19 Hahn W.R. 165 Hijek M. 108 Halatsch W.-R. 129 Haley E. 188 Hall G.G. 29 Hall M.B. 28 Hallberg A. 221 Haller K.J. 234 Halley F.169 Hamada M. 245 Hamada Y. 199 Hambidge K.M. 16 Hambley T.W. 176 Hamel N. 221 Hamida N.B. 237 Hamlin R. 236 Hammer R.P. 118 Hammond A. 249 Hammond S.M. 295 Hampel K. 190 Han C.-C. 77 Hanack M. 161 Hanamoto T. 278 Hanazawa Y. 267 Handa Y. 255 Handy N.C. 25 Hanessian S. 87 126 128 155 303 Haney W.A. 163 Hannon F.J. 114 Hansen S.W. 55 Hanson R.M. 101 Happer D.A.R. 79 Hara H. 115 Hara S. 95 217 Harada T. 118 Harbison G.S. 12 Harcourt R.D. 29 Harirchian B. 46 Harlow R.L. 45 112 Harmony M.D. 179 Harpp D.N. 131 Harrelson J.A. 63 74 Harrington P.J. 44 Harrington R.E. 170 Harris F.M. 24 Harris J.M. 79 Harrod J.F. 236 Harstock F.W.222 Hart D.J. 188 Hart H. 174 Hartman H. 41 Harusawa S. 126 Harvey D.F. 117 Harvey R.G. 176 Harwood L.M. 54 Haseba K. 258 Hashimoto H. 222 Hashimoto S. 145 150 Hashimoto T. 69 130 164 272 Hasikawa T. 225 Hassner A. 49 Hatsuya S. 123 Hattori Y. 130 Hauser F.M. 188 298 Hay P.J. 32 Hayakawa H. 109 Hayakawa K. 46 106 192 Hayama T. 278 Hayami J.-i. 165 Hayasaka T. 114 251 Hayashi H. 241 270 Hayashi M. 246 248 Hayashi S. 145 Hayashi T. 93 118 215 216 226 236 Hayashi Y. 145 246 Haynes R.K. 147 Healy E.F. 33 35 Healy L.L. 205 Heath P. 50 Heathcock C.H. 38 113 Hebel D. 119 312 Heckendorn R. 171 Heckles K. 16 Hees U. 196 Hegarty A.F.36 39 40 68 76 Hegedus L.S. 211 228 Hehre W.J. 26 30 38 41 48 66 99 114 Heidt P.C. 135 Heigl V.W. 44 Heilbronner E. 179 Heiliger L. 235 Heimgartner H. 109 Heinen H. 44 Heinisch G. 202 Heinrich N. 34 Heinze P.L. 55 Helgaker T. 36 Heller R.A. 71 166 Helmchen G. 41 Helson H.E. 162 Henderson D.A. 276 Henegar K.E. 151 Henion J.D. 22 23 Henke W. 19 Henklein P. 129 Henn L. 112 Hennen W.J. 297 Henrot S. 11 5 Hentzschel A. 302 Herbert J.M. 205 Herdtweck E. 98 Hernandez R. 84 Herndon C.S. 283 Herndon J.W. 138 Hernot D. 139 Herrinton P.M. 134 Herrmann W.A. 98 Herron N. 93 Herther W.R. 236 Herzfeld J. 12 Hess B.A. 32 Heuschmann M.44 195 Heyne H.-U. 129 Hibbert F. 60 75 Hiberty P.C.,31 157 Hidai M. 175 300 Hildebrand T. 198 Hillenkamp F. 19 Hillery P. 143 Hillier I.H. 31 37 40 78 Hilton B.D. 175 Himbert G. 112 Hinton J.F. 11 Hirai H. 106 Hirama M. 298 Hirao A. 273 Hiraoka K. 189 Hiratsuka H. 272 Hirayama K. 205 Hiroe Y. 175 Hirokami S. 185 Hirooka S. 180 Hirota T. 179 Hirst G.C. 144 160 Hirthammer M. 162 Hitchcock P.B. 232 235 239 Hitomi T. 104 Hlavka J.J. 17 Ho H. 219 Ho S. 175 266 Ho T. 266 Hobbs S.J. 53 Hoberg H. 101 Hoch M. 9 Hodges P.J. 155 Hodges S.L. 122 246 Hoferichter R. 172 Hoffe D. 114 Hoffman R.W. 132 Hoffmann H.M.R. 45 108 Hoffmann R. 45 100 144 248 258 294 Hohenhorst M.190 Hojatti M. 67 76 Hojo M. 221 223 Hokama K. 208 Holak T.A. 7 Holdgrun X. 203 Holdup D.W. 93 Holker J.S.E. 8 Holland F.S. 240 277 Holland H.J. 192 Hollinshead S.P. 193 Holmes J.L. 24 34 Holmes R.R. 39 Hommeltoft S.I. 6 Hon Y.-S. 150 Honda T. 291 Hone S. 274 Hong Y. 119 252 Hop C.E.C.A. 24 34 Hopf H. 97 106 178 Hopkins M.H. 134 Hopkins P.B. 75 Hori H. 300 Hori K. 33 221 Hori M. 202 303 Horike H. 122 Horirchian B. 43 Horiuchi Y. 179 Horner J.H. 239 Horner M.G. 50 158 Horsley D.B. 163 Hoshi M. 104 106 Hoshino M. 44 246 301 Hosoda A. 104 Hosseini M.W. 181 Hosur R.V. 6 Hou Z. 255 Houk K.N. 27 35 37 38 41 52 55 260 Houwen-Claason A.A.M.42 Howard J.A. 232 185 Howe G.P. 115 248 Howell E.E. 283 Howes A.J. 52 Hoxomi A. 119 Author Index Hoye T.R. 116 Hrnjez B.J. 50 158 Hsuno S. 273 Hu N.X. 277 Hua D.H. 135 Huang H.-N. 165 275 Huang Y.-Z. 103 Hucker J. 178 Hudlicky T. 136 Hunig S. 195 Huff J.R. 143 Hughes A.N. 44 201 Hughes D.W. 234 Hughes S. 65 Huguerre E. 198 Hwang C.-K. 187 Hwu J.R. 277 Hyuga S. 95 217 Ibaceta-Lizana J.S.L. 193 Ibata T. 167 Ibuka T. 125 Ichihara A. 159 174 Ichinose Y. 89 Ide H. 279 Idle J. 48 Ido T. 296 Iffert R. 26 Igarashi S. 100 Igawa A. 35 Iglesias E. 70 73 Igner E. 93 Ihara M. 87 141 Ihle N.C. 50 lida H.272 Iimura Y. 301 Ikariya T. 268 Ikeda N. 103 Ikeda Y. 103 Ikegami S. 150 224 Ikekawa T. 300 Ikemoto Y. 247 lkenaga K. 170 Ikota N. 145 Ila H. 161 Iloughmane H. 237 Irnada K. 179 Imamoto T. 256 Imamura A. 36 Imanishi T. 130 149 Imaoka S. 202 Imashiro F. 205 Inamoto Y. 221 Inanaga J. 115 119 255 272 Ingham S. 55 Ingold K.U. 90 Inokuchi T. 122 Inomata K. 100 Inoue H. 114 Inoue S. 99 226 237 269 Inoue Y. 222 284 hie A. 258 Irinoda K. 300 Irngartinger H. 172 Author Index Isaacs N.S. 60 78 254 Isakasson R. 177 lsakova V.V. 295 Ishi D. 17 Ishibashi M. 108 Ishida T. 107 Ishii T. 104 Ishii Y. 268 Ishikama M. 119 Ishikawa J.222 Ishikawa M. 272 Ishikawa N. 130 Ishiyama T. 106 218 Islam N.B. 176 Isogami Y. 167 Ito K. 214 273 lto M. 267 lto S. 298 Ito T. 231 Ito Y. 17 115 215 216 226 Itoh M. 137 296 ltoh T. 270 Itsuno S. 114 lwa-ake N. 118 Iwaki S. 85 Iwamura H. 178 Iwasaki H. 200 Iwasawa N. 171 241 Iwata C. 130 149 Iwata T. 236 lwatsubo H. 130 Iyengar N.R. 70 Iyer P.S. 165 Iyer S. 162 Izatt R.M. 181 Izumi Y. 244 lzuoka A, 178 Jackson A.H. 193 Jackson P.S. 101 Jackson W.R. 101 111 Jacob P.W. 137 Jacobs J.N. 288 Jacobson A.E. 143 Jacoby D. 135 Jager K.F. 85 295 Jakel E. 107 James A.P. 226 269 Jameson C.J. 9 Janairo G. 300 Janda K.D. 287 Janiak C.232 Janoschek R. 33 157 Jans A.W.H. 171 Janssen C.L. 31 Jansson A.M. 295 Jarret R.M. 10 Jarvie A.W.P. 240 Jastrzebski J.T.B.H. 263 Jayasuria K. 29 Jaynes B.H. 150 Jean M. 136 Jebaratnam D.J.. 138 220 Jefford C.W. 203 Jencks W.P. 60 64 67 78 94 Jenkins P.R. 44 103 142 296 Jenkins S.A. 116 Jenkins T.W. 284 Jenneskens L.W. 29 Jenni K. 101 Jennings H. 274 299 Jennings W.B. 176 Jensen F. 37 52 Jensen H.J.Aa. 36 Jenson T.M. 146 Jerina D.M. 175 176 Jerzig J. 276 Jew S. 142 258 Jhingan A.K. 162 Jiang X. 16 Jie C. 35 53 Jintoku T. 168 Ji-Sheng L. 272 Jorgensen P. 36 Jogun K.H. 164 Johns A. 90 Johns R.B. 132 Johnson A. 109 Johnson C.R. 97 254 Johnson G.188 Johnson J.W. 158 Johnson K.A. 279 282 Johnson O. 185 Johnson P.D. 198 Johnson V.B. 34 Johnson W.S. 244 Johnston L.J. 166 Johnstone R.A.W. 16 Jones A.B. 153 Jones C.W. 119 Jones D.H. 281 Jones D.M. 285 Jones D.W. 41 45 202 Jones J.B. 275 Jones P.R. 234 Jones R. 190 204 Jones R.J. 198 Jones S. 159 Jones W.D. 168 Jonsaell G. 159 Jordan A.D. jun. 303 J~rgensen K.A. 100 Jorgenhen. W.L. 39.40,60,63,14 Jousseaume B. 240 Joyeau R. 169 Judice J.K. 239 Jug K. 26 29 Julia M. 82 Jun T.X. 130 272 Jung M.E. 144 153 190 Jungheim L.N. 188 Junjappa H. 161 Juntunen S.K. 107 Jurayj J. 53 Jurczyk S. 61 Just. G.. 81. 188 Jutzi P. 52 Kaba T.114 Kabalka G.W. 99 270 276 Kabuta C. 98 Kaczmarek L. 272 Kaftory M. 109 Kagamiyama H. 284 Kagan H.B. 243 Kagel J.R. 41 Kageyama M. 121 242 Kahn S.D. 27 30 38 41 48 66 114 Kahr B. 158 Kai Y. 177 Kaiuchi K. 177 Kaji A. 87 101 130 144 272 Kakihana M. 96 Kakodkar S. 195 Kakumoto T. 36 Kakusawa N. 207 Kalcher J. 33 Kalinoski H.T. 23 Kallfass D. 172 Kamal A. 182 Kambe N. 267 Kametani T. 87 141 187 291 Kamigata N. 87 Kamimura A, 87 101 144 Kamlet M.J. 79 Kanayama S. 225 Kaneda M. 8 Kaneda T. 177 Kanematsu K. 46 106 192 Kanemoto S. 104 218 Kanerva L.T. 79 Kaneyama M. 87 Kant J. 199 Kao J. 30 173 Kaplan J. 89 Karai M. 27 Karas M.19 Karpfen A, 30 Karplus M. 40 Karrick G.L. 171 Karsch H.H. 232 Kasahara I. 99 226 269 Kasai N. 177 Kashimura T. 124 Kasmai H.S. 205 Kasper D.L. 299 Kasztelan S. 93 Kataoka K. 255 Kataoka M. 157 Kataoka T. 202 Kati W.M. 286 Kato M. 96 235 236 Kato T. 180 Katogi M. 141 Katori T. 300 Katritzky A.R. 60 182 190 Katsifis A.G. 147 Katsuki T. 53 104 224 278 Katz J.-J. 94 Katz M. 175 Kaufman M.J.. 74 314 Author Index Kaufmann D. 195 King S.M. 277 Kojima N. 235 Kaupp G. 204 Kini G.D. 297 Kok G.B. 197 Kausch M. 159 Kinoshita H. 100 Kokx A.J.P.M. 304 Kaver W.J. 263 Kinsinger J.A. 23 Kolar C. 291 Kawagoe K. 267 Kirby A.J. 61 Kollman P. 6 40 Kawaguchi A.T. 41 Kirby G.W.44 Komeshima N. 145 Kawai K.-i. 125 Kirsch J.F. 283 284 Komiyama S. 269 Kawai T. 101 Kirschenheuter G.P. 29 Konings J.J.H.G. 304 Kawamura K. 291 Kirshenbaum K.S. 115 Konno M. 303 Kawamura N. 104 226 Kishi Y. 218 292 Koola J.D. 101 Kawano H. 268 Kishioka Y. 270 Kopelevich M. 4 10 Kawasaki K. 276 Kitagawa T. 276 276 Koreeda M. 114 Kawase T. 98 233 Kitamura M. 226 230 271 Kornberg A. 279 Kawazoe T. 217 Kitamura T. 250 Koroniak H. 55 Kay K.-Y. 178 Kitano Y. 225 Korth H.-G. 85 293 Kayama M. 100 Kitaoka M. 130 Koseki S. 33 Kazmi N.M. 299 Kitazume T. 130 Kosik M. 300 Kearns D.R. 6 Kitson F.G. 236 Kosiski K.A. 168 Keay B.A. 146 Kiwiet N.J. 38 Kostermans G.B.M. 133 178 Kebarle P. 19 Klabunde K.-U. 180 Kosugi H. 110 130 Keck G.E. 114 Klarner F.-G.55 189 195 Kosugi M. 217 Keeffe J.R. 76 Klaffke W. 295 Kotake H. 100 Keenan R.M. 151 Klaic B. 300 Kotian K.D. 117 Keinan E. 118 169 236 269 Klaubert D.H. 168 Kotnis A.S. 150 276 Klein A. 212 Kottenhahn M. 291 Keirs D. 267 Klemer A. 295 298 Kougo Y. 235 236 Kelley P.E. 21 Klingebiel U. 234 Kovac B. 179 Kelly B.J. 182 Klingler O. 185 Kowalski C.J. 105 Kelly D.J. 93 Klingstedt T. 218 Kowollik W. 300 Kelly R.C. 198 Klumpp G.W. 262 Koyasu Y. 175 Kennedy D.A. 176 Klunder A.J.H. 42 Koziara A. 129 Kenney P.M. 136 Klunder J.M. 101 130 Kozikowski A.P. 118 Kenny C. 137 256 Klym A. 74 Kozima S. 104 Kessler H. 291 Kneuper H.-J. 98 Kramer T. 114 Kevill D. 62 235 Knight D.W. 152 Kraemer W.P. 33 Keweloh N. 234 Knight J. 188 Krafft G.A. 44 201 Keyaniyan S.159 235 Knobler C.B. 181 Krafft M.E. 87 Khamsi J. 169 274 Knolker H.-J. 198 228 Kraft P. 195 Khan A.Q. 299 Knothe L. 179 Krato B. 52 Khan N. 55 Knowles J.R. 53 286 Kraus G.A. 150 174 Khanapure S.P. 174 Knudsen M.J. 119 Krause J.G. 268 Kibayashi C. 272 298 KO S.Y. 101 Kraut J. 283 Kice J.L. 65 Kobayashi H. 179 Krebs J. 228 Kiess R.U. 6 Kobayashi K. 137 141 175 Kreh R.P. 268 Kikukawa K. 170 229 Kreher R.P. 198 Kilic S. 236 Kobayashi M. 87 Kreiger M. 270 Kim B.H. 41 260 Kobayashi S. 33 245 Kreit C.L. 158 Kim C.-H. 207 Kobayashi T. 100 124 199 Kresge A.J. 62 67 74 76 Kim C.K. 39 27 1 Krief A. 134 135 139 Kim J.D. 119 Kobayashi Y. 104 225 267 Krieger C. 178 Kim J.E. 119 270 Koch P. 209 Krongauz V. 236 Kim K.-W. 101 276 Kochetkov N.K.300 Kropp M. 171 Kim M.-J. 275 Kochhar S. 284 Kriiger C. 101 Kim S. 161 278 Kochi J.K. 101 119 163 Kruk H. 175 Kim T.R. 64 65 Kodomari M. 164 Kruse C.G. 189 Kim Y.H. 123 Kocher M. 209 Kruse L.I. 124 170 Kim Y.S. 119 Koell P. 300 Ku Y.Y. 193 Kimbrough D.R. 53 Koft E.R. 150 Kuchta R.D. 279 Kimura M. 176 Koga K. 125 145 245 252 Kudo K. 124 Kimura T. 99 276 267 Kudo T. 33 Kindon N.D. 125 Kohra S. 119 Kunzer H. 79 King B.V. 18 Koike N. 108 Kuhn H.J. 159 King H.F. 32 Koizumi M. 31 Kulagowski J.J. 143 King J.L. 94 Koizumi T. 41. 145 Kulkarni S.U. 94 Author Index Kumamoto Y. 184 186 Kume T. 200 Kumobayashi H. 99 226 268 269 271 Kunesch N. 276 Kuniyoshi M. 179 Kunng F.-A. 170 Kunz H. 302 Kunze K.L. 28 Kuo E.111 Kuo M.-Y. 79 Kuramitsu S. 284 Kurihara T. 126 Kurita J. 207 Kuriyama K. 41 Kuroda H. 122 276 Kuroda S. 53 104 180 Kurokawa H. 118 Kurosawa K. 100 Kurotaki A. 303 Kurth M.J. 108 Kurusu Y. 106 Kuse M. 300 Kuwajima I. 253 Kuwajima S. 29 180 Kuzuhara H. 121 Kwok F.-C. 62 Kwon S.S. 119 270 Kyler K.S. 46 111 195 Kynast U. 231 Kyung S.-H. 253 Laali K. 165 Laborde E. 149 Laboureur J.L. 134 Lacher B. 87 Lachheim S. 98 Lacombe D. 167 Ladika M. 109 Laguzzi G. 189 Lai C.-Y. 174 Laidig K.E. 34 Laine R.M. 236 Lal G.S. 105 Lalande R. 82 Lallemand J.-Y. 93 Lamaire M. 165 LaMaire S.J. 101 277 La Mar G.N. 6 Lambert J.B. 235 Landergren M.11 Landor P.D. 109 Landor S.R. 109 Lane P. 29 Lane S. 159 Langhoff S.R. 31 Langridge R. 40 Langstrom B. 78 Lannean G.F. 119 Lansdown M.E. 205 Lanz J.W. 294 Lapitajs G. 212 Laporterie A. 237 Lapouyade R. 158 LarchevGque M. 115 Lardicci L. 108 111 Large L. 238 Larpent C. 98 Larson G.L. 233 Laszlo P. 165 Latajka Z. 27 Latif F. 296 Lattimer R.P. 20 Lau C.D.H. 28 Laude D.A. jun. 23 Laue E.D. 3 Laurent A. 191 Lauria M.R. 205 Lautens M. 215 Lavallee J.-F. 141 257 Lawler R.G. 6 Laws A.P. 69 177 180 Layh M. 159 Lazraq M. 237 Leatherbarrow R.J. 280 Lebioda L. 146 Leblanc Y. 298 Lebreton J. 53 146 265 Leckta T.C. 137 Le Corre M. 96 255 Lee B.C.39 Lee E.D. 23 Lee H.D. 94 Lee H.K. 123 Lee H.L. 304 Lee H.Y. 151 Lee I. 39 Lee J.C. 119 270 Lee K.W. 119 270 Lee M.C. 175 266 Lee M.L. 204 Lee S.-J. 44 Lee T.J. 29 177 Lee W.-C. 44 Leeper F.J. 190 Lee-Ruff E. 175 Lefort D. 87 Lefour J.-M. 31 157 Le Goff E. 209 Lehn J.-M. 181 Lehrich F. 106 Lein G.M. 181 Leis J.R. 70 73 77 Lelikvre J. 73 Lemaire M.,194 Le Merrer Y. 303 le Noble W.J. 112 Leon O. 282 Leong W. 110 251 Le Petit J. 109 Lerner R.A. 287 288 LeRoux J.-P. 158 Lerstrup K.A. 197 Leu L.-C. 277 Levin W. 176 Lewis E.S. 63 Lewis R.A. 44 Lewis T. 192 Lex J. 55 209 Ley S.V. 120 125 131 143 153 172 224 267 Lheureux M.237 Lhommet G. 135 Li C.S. 217 Li S. 27 Li W.S. 303 Li Z. 165 214 Liang C. 29 Liberato D.J. 23 Licandro E. 216 Lickiss P.D. 235 Lida H. 298 Liebeskind L.S. 162 228 Lii J.-H. 27 Liljefors T. 27 Lilly A.C. 30 Lim L.C. 44 Limbach H.-H. 209 Lin F.-T. 159 Lin H.-S., 54 155 Lin J. 149 Lin K.-C. 54 147 Lin S.H. 18 Lin Y.-I. 17 Lindh R. 33 Lindley P.F. 55 206 Lindsay D.A. 90 Lindsay Smith J.R. 70 Linstrumelle G. 107 249 Liou S.-Y. 44 Lipschutz B.H. 211 251 Lischka H. 30 Liu K.-T. 79 Lledos A. 38 40 Lloyd-Williams P. 145 Lluch J.M. 39 Lobo A.M. 78 Lodge E.P. 38 113 Loew G.H. 39 Lohray B.B. 273 Lomolder R. 88 Loncharich R.J.38 41 260 London R.E. 300 Lonn H. 274 Loo J.A. 21 Lorenz K.T. 43 Lorenz W. 196 Louris J.N. 21 Love B.E. 190 Lowe D.M. 280 Lu X. 170 223 272 Lubineau A. 301 Lucas E.A. 169 Luche J.L. 247 251 Luchetti L. 66 Luchinat C. 239 Ludrnan C.J. 185 Lugtenburg J. 175 Lukacs G. 296 Luke G.P. 11 1 Lum R.T. 169 Lundquist J.T. 268 Luo J. 174 Lusztyk J. 90 Luthman K. 292 Luthra A.K. 77 Lynch P.P. 193 Lysenko V.P. 132 Maas G. 112 184 196 Maccagnani G. 36 McCague R. 94 179 McCallum J.S. 170 McCann S.F. 200 McCarthy P.A. 121 242 McCloskey C.J. 101 McCloskey P.J. 142 McColl I.S. 172 McConnell J.A. 235 MacCorquodale F. 82 McCullogh R.D. 197 McCullough J.J.50 171 Macdonald D.I. 45 McDonald R.N. 64 McDonald S. 51 McDouall J.J.W. 26 3 1 34 36 38 48 McDowell M.A. 17 McDowell R.S. 29 McGarvey D.J. 137 McGhee W.D. 64 McGrath J.E. 236 McGuchan D.C. 164 Macielag M. 170 McIver J.W. 32 Mack H. 297 Mack J.P.G. 76 Mackay K.M. 11 McKean D.R. 98 170 McKee M.L. 36 McKeer L.C. 70 164 McKie J.A. 135 McLafferty F.W. 21 24 McLay N.R. 193 McLeod J.K. 34 296 300 McLure C.K. 48 McMahon R.J. 158 McMeekin P. 48 McMillan C.M. 148 McMillan W.D. 176 McMurry J.E. 133 McNab H. 197 207 Macor J.E. 203 McPhail A.T. 232 MacPherson D.T. 147 Maddaluno J. 39 Maddox J. 29 157 Madonik A.M. 239 Maeda H. 301 Maekawa E.88 Maeng J.H. 65 Maerker A. 10 11 Markl G. 204 Maetzke T. 270 Magdzinski L. 296 Magee. W.L. 195 Magnus P. 42 149 257 Magnusson G. 149 Mahapatro S.N. 98 Mahmud K.A.M. 70 Maier W.F. 11 1 162 Maigrot N. 187 193 Maillard B. 82 83 90 Main L. 168 Maiorana S. 216 Mais F.-J. 207 Majetich G. 145 Mak K.T. 94 Mak R.C.W. 238 Makashima T. 274 Makino K. 273 Makosza M. 71 166 167 Malcolm B.A. 283 284 Malhotra R. 110 Malik A. 296 298 299 Malinowski M. 272 Mallick I.M. 134 Mallion R.B. 173 Malone J.F. 176 Malone T.C. 200 Malrieu J.-P. 32 Malta M.S. 79 Manabe K. 230 Mancini G. 66 Mancini P.M.E. 72 Mandolini L. 59 68 164 Manfredi A. 212 Mangeney P.250 Mank A.W. 238 Mann J. 192 Mano T. 101 Maple S.R. 4 5 Mar E.K. 115 Marchese C. 119 Marcuzzi F. 112 Marczak A. 198 Marinas J.M. 254 Marinier A. 46 Marino J.P. 149 Marioni F. 66 99 Mark T.D. 18 Marquet J. 166 Marquez V.E. 207 Marrs. P.S. 136 Marsh B.K. 43 Marshall A.G. 20 Marshall J.A. 46 53 115 146 265 Marshall S.J. 240 Marson C.M. 190 Marterer W. 185 Marth C. 96 Martin D.G. 198 Martin H.-D. 207 Martin I. 61 Martin S.A. 21 22 Martin S.F. 155 201 Martinez G.R. 48 Martinez R.D. 72 Martin-Lomas M. 127 303 Author Index Maruoka K. 100 Maryanoff B.E. 303 Man D. 98 Masamune H. 101 Masamune S. 98 233 Mascarella S.W. 83 137 Mase M.66 Mash E.A. 135 263 Maskill H. 64 Mason R. 95 Mason S.C. 37 78 Massa W. 237 238 Masters A.P. 109 Masuda Y. 106 Masui Y. 268 Masumoto M. 180 Masuyama Y. 106 Mataka S. 179 Mathew J. 188 Mathews W.R. 22 Mathey F. 187 193 Matlin A.R. 137 Matsson O. 78 Matsubara S. 104 218 Matsuda H. 300 Matsuda I. 244 Matsuda T. 170 Matsui M. 149 Matsukawa M 255 272 Matsumoto H. 235 Matsumoto S. 166 Matsumoto T. 225 Matsunaga T. 108 Matsuoka K. 114 Matsuura T. 101 229 Matsuzaka H. 175 Matsuzawa K. 128 Matsuzawa T. 296 Matta M.S. 9 Mattay J. 171 Matthews C.R. 283 Matthews E.W. 236 Maumy M. 126 Maverick E.F. 181 Mawer I.M. 143 Maxka J. 236 Maycock C.D.267 Mayer H. 238 Mayer R.J. 283 Mayr H. 44,49 Mazzieri M.R. 94 Mbafor J.T. 109 Means C.M. 231 Mechoulam R. 164 Medani C. 300 Mederer K. 253 Medici A. 196 Medina J.C. 46 195 Meguro H. 300 303 Mehta G. 133 151 155 Mehta P.G. 170 Meijide F. 73 Meijs G.F. 135 Meinke P.T. 44 201 Author Index Meister M. 107 Melamede R.J. 279 Melchers H.-D. 109 Melendez J.L. 198 Melloni G. 112 170 275 Mellor J.M. 45 46 107 194 Melvin T. 82 Menegheli P. 165 Meou A. 109 Merbach A.E. 78 MerCnyi R. 106 Mergui S. 93 Merrill R.A. 12 192 Men K.M. 39 Mesheikh-Mohamadi M.E. 51 Messerle B.A. 7 Messmer R.P. 29 Mestdagh H. 162 Metivier P. 63 Metropoulos A.35 Metternich R. 294 Metzger J.O. 98 Metzler D.E. 284 Meul T. 180 Meyer B. 238 Meyer H. 237 Mhala M. 72 Micas-Langmuir D. 303 Michaelis R. 107 Michalska D. 32 Michelin R.A. 224 Michl J. 173 Middelhauve B. 207 Miekuz M. 222 Miet C. 276 Miginiac P. 241 Migita T. 217 Mikami K. 229 Mikhail G.K. 134 265 Miksztal A.R. 101 Mile B. 232 Miles H.T. 6 Miller D.D. 243 Miller J.A. 148 Miller L.L. 174 Miller L.V. 16 Miller R.S. 33 Millevolte A.J. 234 Milowsky AS. 106 188 Mimura T. 179 Minami I. 106 214 226 Minami T. 245 258 Minato A. 98 Minisci F. 89 90 268 Minowa N. 248 Mioshi N. 275 Misawa T. 300 Mishra P. 134 Mislow K. 158 Mison P.; 191 Missfeldt M.206 Mitani M. 300 Mitaoka M. 110 Mitchell J.C. 55 206 Miura M. 268 Miwa Y. 145 Miyake H. 144 Miyamoto H. 235 Miyashita M. 267 Miyata K. 272 Miyaura N. 106 218 Miyazawa M. 265 Miyoshi N. 117 267 Mizen M.B. 197 Mizoue K. 179 Mizrahi V. 279 Mizushima H. 176 Mlcoch J. 43 Mochida K. 237 Modak M.J. 279 Mohler H. 202 Moerlaein E.M. 238 Moerlein S.M. 168 Moffat J.B. 93 Moffatt J.R. 72 Mohr R. 172 Moise C. 254 Moison H. 96 Molander G.A. 126 135 137 142 146 256 260 262 264 Molino B.F. 296 Monahan L.C. 207 Monteiro H.J. 139 Moodie R.B. 69 Mooiweer H.M. 111 Mook R. 89 Moore C. 17 Moore H.W. 56 110 175 Moore M. 148 Moore T.172 Moore W.T. 18 Mooring A.M. 158 Mootoo D.R. 296 Mootz D. 207 Morales A, 19 Morand J.-P. 158 Moreno-Manas M. 166 More O’Ferrall R.A. 59 77 Mori S. 124 Moriarty R. 11 1 193 246 268 Morini G. 90 Morino Y. 284 Moritani Y. 130 Morley S.D. 231 Morokuma K. 36 Morosawa S. 176 Morris D.F.C. 72 Morris G.E. 124 222 Mortlock S.V. 248 Moskau D. 10 11 Mosquera M. 70 73 Mothenvell W.B. 169 Moursounidis J. 42 Mullen K. 180 Muller G. 232 233 Muench W. 302 Munzel N. 45 192 Mukaiyama T. 117 132 171 241 245 246 248 275 Muller B. 302 Mullholland R.L.,jun. 38 66 Mullican M.D. 159 Mulzer J. 302 Mun L.K. 238 Munowitz M.G. 12 Murahashi %-I. 225 268 Murai S.267 Murakami K. 159 Murakami M. 132 241 Muraoka T. 236 Murata I. 179 Murata S. 178 268 Murgia S.M. 163 Murphy C.J. 155 Murphy J.A. 90 Murphy J.T. 71 163 Murphy M.G. 77 Murphy P.J. 121 242 Murray B.A. 77 Murray P.J. 128 303 Murthy A.N. 155 Murthy K.S.K. 49 Musallam H.A. 268 Mustafa Ullah G. 148 Muzart J. 268 Myer L. 135 Myers A.G. 155 Myles D.C. 117 Nadler E.B. 75 Nag A. 269 Nagabhushan T.L. 170 Nagahara T. 187 Nagai Y. 100 234 235 236 Nagao Y. 85 Nagaoka H. 141 Nagase S. 33 Nagata M. 185 Nagata R. 101 Nagel U. 197 Nahm K. 50 Nair M. 195 Naito H. 44 105 Najim S.T. 235 Nakadaira Y. 98 205 Nakahama S. 273 Nakai T.229 Nakajima M. 252 267 Nakajima S. 125 Nakajima T. 157 Nakajo E. 115 Nakamura A. 112 Nakamura E. 253 Nakamura H. 303 Nakamura M. 180 Nakamuro A. 211 Nakanishi S. 214 Nakano M. 33 Nakano T. 100 Nakashima H. 245 Nakayama A. 177 318 Nakayama J. 44 246 Namen A.M. 145 Namura H. 268 Nantz M.H. 161 Napper A.D. 288 Natchus M. 136 Nativi C. 106 Naylor S. 16 19 Neary A.P. 69 177 Nedelec J.-Y. 87 Negishi E. 94 103 112 219 228 Negre M. 194 Nelsen S.F. 101 Nelson D.J. 102 Nelson K.A. 135 263 Neri D. ill Nesmeyanov A.N. 132 Neumann M. 203 291 Neusser H.J. 19 Newcomb M. 89 189 239 Nguyen M.T. 36 39 40 Nguyen N.V. 110 Ni Z. 223 Niazi U.38 48 Nibberling N.M.M. 64 Nicholas K.M. 165 214 Nicholson B.K. 168 Nicolaou G.A. 55 206 Nicolaou K.C. 187 303 Niedrich H. 129 Nieger M. 304 Nielsen R.B. 277 Niijima J. 44 Nikaido M.M. 149 Nikolic S. 173 Nilsen N.O. 109 Nisar M. 214 Nisato D. 286 Nishida S. 133 178 Nishida Y. 300 303 Nishikawa Y. 165 Nishimura J. 179 Nishimura S. 108 Nishinaga A. 229 Nishino H. 100 Nishiyama K. 236 Nistui S. 125 Niwa S. 114 199 271 Nkeng-fack A.E. 109 Nobes R.H. 33 Noltemeyer M. 234 Nomoto T. 44 105 Norden T.D. 179 Normant J.F. 250 North M. 126 Norton J.R. 211 Nouguier R. 300 Novi M. 167 Novoa J.J. 36 Noyori R. 99. 226 230 26Y 271 Nozaki H. 104 218 Nozaki K.89 Nozawa K. 125 Nozawa Y. 180 Nudelman A. 276 Nudelman N.S. 72 Nugent W.A. 45 112 169 Nunno L.D. 260 Nurmi T.T. 134 Nussbaumer P. 161 Nuwaysir L.M. 21 Nwokogu G.C. 174 Oakley D. 124 Oatley S.J. 283 Oba M. 236 Ochiai M. 85 O’Connor B.M. 26 Oda D. 96 Oda K. 140 Oda T. 268 Odaira Y. 177 Oei S.L. 6 Oelting M. 300 Ogasawara K. 303 Ogawa K. 114 Ogura F. 277 Ogura H. 276 Oh S.Y. 119 270 Ohanessian G.. 31 157 Ohannesian L. 132 Ohashi K. 217 Ohbayashi A, 179 Ohkata K. 66 Ohkawa M. 300 Ohki H. 247 Ohkuma T. 226 271 Ohrui H. 300 303 Ohshima M. 117 275 Ohta H. 270 Ohta T. 99 225 226 269 Ohtani T. 100 Ojima I. 188 Ojima J.180 Oka S. 229 Okada Y. 179 Okamoto S. 225 Okamoto T. 229 Okamura T. 141 O’Kane G.A. 176 Okawa T. 235 Okawara M. 86 189 Okazaki I. 31 Okazoe T. 97 255 Okinaga T. 128 Oku A. 118 179 Okukado N. 103 Okuno Y. 148 172 Olah G.A. 69 94 117 130 132 159 164 165 235 Olah J.A. 69 164 Oldfield E. 12 Olekszyk J. 77 Olesker A. 296 Oliva A. 39 Olivucci M. 34 48 Ollenhrite. R.M. 38 Author Index Olson E.S. 23 Olson R.E. 191 Olthoff J.K. 22 Omori Y. 126 O’NeilI P. 76 Ono M. 256 Ono N. 87 101 130 144 272 Onufper J.J. 283 Ookawa A, 114 272 Oplinger J.A. 54 150 Oppolzer W. 41 132 227 Orahovats A.S. 46 109 Orbe M. 292 Oref I. 158 Orsini F. 219 Ortega M.39 Orth R.G. 16 Osakada K. 223 O’Shea D.M. 83 167 Oshima K. 89 104 217 218 Oshino H. 253 Oshio H. 231 Osowska-Pacewicka K. 129 Osten H.J. 9 Ostercamp D.L. 60 Ostrowski S. 167 Otani S. 165 Otsubo K. 115 272 Otsubo T. 277 Otsuji Y. 214 Otting G. 7 Otto H.-H. 141 Overman L.E. 134 200 Overton K. 267 Ovodov Y.S. 295 Owczarczyk Z. 167 Oxford A.J. 54 Ozaki K. 270 Ozaki S. 300 Ozaki Y. 161 Pabon R.A. 43 Padma S. 133 Padwa A. 48 Pagani G.A. 198 Page M.I. 60 Page P.C.B. 201 Pagni R.M. 99 172 Paik Y. 32 Pak H. 82 Palabrica C.A. 203 Pale P. 112 Palit S.K. 269 Pals D.T. 286 Palumbo G. 122 Pan K. 146 Pancrazi A. 82 Panda M.67 Panek J. 82 Pannell L.K. 175 Papagni A. 216 Papahatjir D.P. 303 Paquette L.A. 51 54 133 150 152 155 220 Author Index Park J.H. 278 Park W.S. 113 271 Parker C.E. 22 Parker D.T. 42 Parker D.W. 51 Parker K.A. 168 Parrinello G. 98 170 223 Parrodi C. 97 Parsons P.J. 144 160 188 Parton B. 72 Pascal R.A.,jun. 176 178 Pataki J. 176 Patel B.P. 149 Patel M. 190 Patel V.F. 88 169 229 Paterson C.W. 90 Paterson I. 27 Pathak V.P. 151 Pathiaseril A. 27 Patin H. 98 Patricia J.J. 134 Pattenden G. 88 169 229 Patton A.T. 225 Patyk A. 187 Pau C.F. 38 66 Paul V. 90 Pauling L. 29 157 Paulsen H. 301 Pawar S.M. 300 Pawlak J.L. 143 Paynter O.I.93 Pazik J.C. 232 Pearl L.H. 286 Pearson A.J. 221 Pearson R.G. 59 63 Pearson W.H. 122 123 Peck D.R. 53 Pedersen S.F. 255 Pedrini R. 196 Peeran M. 61 179 Peirce P.L. 16 Pelizzoni F. 219 Pellerin B. 201 Pelletier J.C. 205 Pellissier N. 191 Pel'menshchikov A.G. 27 Pelter A. 97 Pefia M.E. 70 73 77 Penades S. 303 Peng 0.-J. 118 Pennetreau P. 165 Pentony S.L. jun. 23 Percy. J.M. 61 Perera S.A.R. 251 Pereyre M. 238 Perez C. 278 Perez D. 118 236 269 Periasamy M. 111 124 Pericas M.A. 38 110 Perich J.W. 132 Perkins M.J. 48 Perlmutter P. 101 111 Perri S.T. 56 175 Perrot. M. 119 Perry K.M. 283 Pete B. 44 201 Peters K. 206 Peterson G.A. 170 Peterson J.R.163 Peterson K.B. 41 Petrakis K.S. 170 Petrie C.R. 297 Petrignani J.-F. 222 Petrillo G. 167 Petterson l. 27 Pettersson L. 149 Pham T.N. 63 Phanstiel O. IV 108 Phee E.S. 71 Piccirilli J.A. 171 Pichardt J. 232 Pichon C. 169 Picken H.A. 137 Picotin G. 241 Pierre F. 51 Piers E. 136 Pies M. 145 Pigott M.A. 175 Pinder A.R. 164 Pinhey J.T. 169 Pinkerton A.A. 221 Pinna F. 224 Pinto D.J.P. 188 Piotrowski D.W. 129 252 Pippard D.A. 124 Piras P.P. 65 Pirrung M.C. 136 137 171 Piteau M. 69 164 Pitt C.G. 232 Pitt I.G. 159 Pitteloud R. 46 146 Piyasena H.P. 41 Plant A. 45 192 Plaquevent J.-C. 143 Pleasance S. 17 Pohl S. 184 234 235 Poisson J.276 Polgar L. 286 Politzer P. 29 33 Polizzi C. 108 Pollack R.M. 76 Pollack S.J. 288 Pollard K.O.B. 3 Pollart D.J. 174 195 Ponec R. 35 Ponomarenko V.A. 300 Pont J.L. 203 Popall M. 175 Pople J.A. 30 33 48 Popp F.D. 199 Poreti M. 20 Porter N.A. 209 Porter R.F. 24 Posner B.A. 94 Posner G. 132 142 200 258 Postma R. 34 Potthoff B. 106 182 Poulsen M.. 39 Poutasse C.A. 236 Power P.P. 204 Pozsgav V. 274 299 Prabhakar S. 78 Prakash G.K.S. 117 159 165 235 Prakash O. 246 268 Pramanik P. 10 Pramod K. 209 Pranata J. 30 Prasad C.V.C. 142 Prasitpan N. 193 Pratt D.E. 16 Pratt D.V. 75 Prestegaard J.H. 7 Preston S.C. 21 1 Principe L.M. 149 Pring B.G.295 Prinzbach H. 179 185 208 Prior L.M. 226 Procter G. 115 121 242 248 Profeta S. 27 Przystas T.J. 78 Pujasena H.P. 260 Pulay P. 25 33 Pullockaran J. 236 Purdy A.P. 232 Putinas J.M. 168 Pyun S.Y. 64 Qamhiyeh E. 27 Qiu W. 110 Qiu X. 188 Quabeck U. 263 Queneau Y. 301 Quinn D.M. 77 Quinn L.D. 44 201 Quintard J.-P. 238 Rabideau P.W. 171 Rabinovitz M. 174 178 Radner F. 68 163 Radom L. 24 26 33 37 Radom R. 34 Rae A.D. 231 Rafferty M.A. 122 246 Raganathan D. 130 Raganathan S. 130 Raguarsson U. 278 Rahm A. 238 Rai R.S. 111 Raimondi L. 49 260 Raimondi M. 26 29 31 Raines R.T. 286 RajanBabu T.V. 86 Rajca A. 29 109 Rajyaguru I. 36 37 Rakshit D.217 Ramachandran P.V. 113 Ramaiah M. 182 256 Ramer S.E. 8 Ramsey E.D. 17 Rance. M. 7 Randad. R.S.. 248 Author Index Randic M. 173 Rao A.V.R. 160 Rao C.B. 195 Rao C.S.K. 161 Rao M.N. 188 Rao M.S.C. 161 Rao S.A. 111 Rao S.N. 6 Rapin J. 20 Rapp J. 48 Rappoport Z. 68 75 76 Rassu G. 170 275 Raston C.L. 231 Ratovelomanana V. 107 249 Raucher S. 249 Rauk A. 33 Ravard A. 143 Rawal V.H. 198 Raychaudhuri S.R. 137 Raza Z. 300 Reddy D.R. 160 Reddy D.S.K. 155 Reddy R.T. 174 Reddy V.P. 52 Reed M.W. 56 Rees C.W. 204 Reetz M.T. 244 253 Regan A.C. 252 Regitz M. 172 184 196 Rehder D. 9 Reich H.J. 191 Reid J.G. 155 Reinhardt G. 174 Reisinger F.164 Reiter L.A. 195 Reitz A.B. 303 Rernington R.B. 29 177 Renaldo A.F. 98 170 219 Rendenbach B.E.M. 127 241 Renfrow R.A. 67 Reuben J. 9 Rey M. 112 Reynolds C.A. 39 40 Reynolds D.W. 43 Rezende M.C. 165 Rhee R.P. 188 298 Weingold A.L. 121 233 Ribbons D.W. 172 Ricard L. 187 Ricci A. 106 Rice J.E. 29 177 Rice K.C. 143 Richter F. 141 Richter H. 196 Sickborn B. 174 195 Ridd J.H. 69 71 163 Riede J. 232 Rieke R.D. 251 Rieth R. 161 Rigby J.H. 152 Riggs N.V. 26 Rigopoulos P. 68 Rihs G. 109 179 199 Ringsdorf H. 236 Ripmeester J.A. 12 Rise F. 112 138 257 Ritchie J.P. 28 Rizzo C.J. 140 Robb M.A. 26 31 34 36 38 48 Roberts B.P. 90 Roberts D.A.218 Roberts D.W. 101 132 Roberts J.E. 12 Roberts K. 61 110 268 Robertson R.E. 60 Robins R.K. 297 Robinson G.H. 231 Robinson J.A. 8 Robinson N.G. 183 Rochin C. 130 Rodger A. 35 Rodriguez J.H. 184 Rodriguez M. 110 254 Rodriguez M.S. 84 Roekens B. 161 Roelens S. 239 Roelofs N.H. 157 173 174 Rosch W. 196 Rogers B.D. 53 Roggo S. 270 Rohl J.A. 277 Rohlfing C.M. 32 Rokack J. 298 Rollins K. 22 Romanelli M.G. 121 Romine J.L. 54 155 Romney-Alexander T.M. 169 211 Ronzini L. 119 Roos B.O. 26 33 Rose E. 167 Rose M.E. 16 Rose-Munch F. 167 Roskamp E.J. 255 Ross R.J. 152 Rossi B. 107 Rossi R. 111 Rossier J.-C. 203 Rossiter J.T. 172 Rossky P.J.40 60 Roth K. 107 Roth R. 200 Rous A.J. 9 Roush W.R. 46 298 Roussel J. 165 Rowe J.E. 68 Rowecliffe D.J. 236 Rowley M. 247 Rozen S. 93 119 165 Ruckle R. 42 Ruddock K.S. 218 Rudolf K. 55 Rudzinski J.J. 65 Riichardt C. 91 Rueger H. 201 Ruelle P. 40 Ruhter G. 110 Ruiz J.M. 33 Runsink J. 171 Russell A.T. 121 242 Russell D.H. 21 Russell R.A. 159 Rutkowske R.D. 235 Ruttink P.J.A. 34 Ruzzuk A. 170 Rychnovsky S.D. 128 Rykowski A. 167 Rzepa H.S. 36 37 38 48 78 Saak W. 184 234 235 Sabbioni G. 275 Saburi M. 268 Sacripante G. 81 188 Sadeghi M.M. 129 273 Sadler I.H. 5 Saebo S. 33 34 Saegusa K. 96 Saegusa T. 107 Saferstein R. 61 Saika A.205 Saindane M.T. 150 Saito I. 101 Saito K. 36 Sakahura T. 168 Sakai K. 139 140 Sakai S. 36 244 261 Sakai T. 272 Sakakura T. 93 124 223 Sakamura S. 159 Sakata S. 150 Sakurai H. 98 205 Sakurai Y. 273 Salama P. 187 Salaun J. 277 Salazar G.E. 109 Salomon R.G. 137 Sammes P.G. 48 71 167 202 Samuelson A.G. 21 5 Sanchez R.M. 89 Sandall J.P.B. 69 163 Sander W. 187 Sanders D.C. 198 Sanders J.K.M. 3 Sanderson P.E.J. 273 Sandstroem A. 19 Sandstrom J. 177 Sangokoya S.A. 231 Sankararaman S. 163 Sankovic M. 300 Sannicolo F. 198 Sano H. 100 217 Sarkar A. 269 Sarkar S.K. 269 Sarma M.H. 6 Sarmah P. 270 Sarratosa F. 38 Sasaki H. 276 Sasaoka S.100 Sassaman M.B. 117 Sasson Y. 64 Satake K. 176 Author Index Satge J. 237 238 Sato F. 225 Sato R. 205 Sato S. 244 Sato T. 270 Sato Y. 237 Satoh N. 218 Satoh Y. 228 Sattur P.B. 182 Satyanarayana N. 124 Saul C.D. 101 Saunders M. 10 26 Sauvage J.-P. 209 Savariar S. 136 Saveant J.-M. 167 Savelli G. 59 72 Sawlewicz P. 62 Sawyer D.T. 166 Sawyer J.F. 12 234 Sax A.F. 33 Saxena A.K. 237 238 Saxton H.M. 46 Sayer J.M. 175 176 Sayers A. 169 Sayo N. 99 226 269 271 Saze K. 300 Scaiano J.C. 166 Scala A. 291 Schaad L.J. 32 Schaal R. 73 Schacht W. 195 Schade P. 180 Schafer A, 98 184 234 Schaefer H.F. 29 31 32 33 Schafer H.J. 88 107 Schaefer W.158 Schaeffer H.F. 111 177 Schaffner K. 159 Schanzenbach D. 302 Schauble J.H. 100 Schauer R. 299 Scheiner S. 27 Schepp N.P. 67 76 Scheutzow D. 33 Schickli C. 243 Schindler M. 30 33 159 Schipper P.E. 35 Schlag E.W. 18 20 Schlegel H.B. 25 36 38 48 Schleyer P. von R. 10 26 30 33 159 186 Schlichthoerl G. 302 Schmalstieg L. 179 Schmalz T.G. 173 Schmickler H. 180 209 Schmid G.H. 183 Schmidt J. 34 Schmidt M. 36 44 206 233 Schmidt R.R. 258 291 Schmidt S.J. 124 170 Schmidt S.P. 273 Schmidt T. 55 Schmitt R.J. 110 Schneider M.P. 107 Schneider W.P. 22 Schollkopf K. 164 Schoellkopf U. 304 Schonwalder K.H. 164 Schotz K. 30 Schore N.E. 149 Schotz K.159 Schreck M. 200 Schreiber S.L. 116 294 Schroer D. 55 189 Schulman L.H. 282 Schulte G. 116 Schultz A.G. 142 170 Schultz P.A. 29 Schultz P.G. 288 Schulz G. 161 299 Schulz J. 26 Schulz W.J. jun. 235 Schumann H. 232 Schuster G.B. 171 Schwartz C.E. 44 201 Schwartz K.B. 236 Schwartz T.R. 41 Schwarz H. 24 34 Schweig A. 45 186 192 Schwesinger R. 206 Scilimati A. 260 Scoble H.A. 22 Scorrano G. 59 Scott J.M.W. 60 Scott L.T. 157 173 174 Scott W.J. 170 Sebastiani G.V. 163 Sedelmeier G. 179 Sedgewick R.D. 15 Seebach D. 123 241 243 270 Segawa K. 106 Seigel M.M. 17 Seiler P. 34 Seitz G. 172 Sekiya K. 253 Self R. 16 Selim M.R. 44 103 Sellers H.33 Semmelhack M.F. 175. 212 266 Semra A. 167 Senanayake C. 152 Senn H. 7 Seo W. 125 Seoane P.R. 147 264 Serratosa F. 110 Serravalle M. 90 Servi S. 294 Sevlin A, 39 Seyferth D. 236 Sha C.-K. 194 Shabonowitz J.. 21 Shaik S.S. 31 35 59 63 157 Shamouilian S. 174 Shankaran K. 165 Shannon P.V.R. 193 Shariffudin R.S. 232 Sharma N.D. 176 Sharp J.T. 55 206 Sharp M.J. 168 Sharpless K.B. 101 115 130 Shaw C.-h. 125 Shaw G.S. 55 Shea K.J. 46 Shechter H. 195 198 Sheldrick G.M. 234 Shen Y. 110 Shepherd R.G. 163 Shepherd T. 185 Sheppard A.C. 267 Sheppard R.N. 78 Shevlin P.B. 36 Shi L. 103 Shibata F. 98 Shibata S. 271 Shibata T. 124 Shibutani M.180 Shigemori H. 148 172 Shigemoto T. 298 Shih J.G. 69 164 Shillady D.D. 38 Shima K. 142 Shimazaki M. 115 Shimazaki T. 225 Shimizu F. 300 Shimizu H. 202 Shimizu N. 98 Shimoda K. 100 Shimoyama H. 236 Shine H.J. 71 Shing T.K.M. 145 303 Shinozaki A. 241 Shioiri T. 121 Shiro M. 41 Shizuri Y. 148 172 Shomo R.E. 20 Shu C. 266 Shubert D.C. 142 146 260 264 Sibisi S. 3 Sicking W. 38 Sidler D.R. 121 Siebnik M. 276 Siegbahn P.E.M. 36 Sigmund S.K. 188 Silber J.J. 72 165 Silverman I.R. 244 Silverstein R.M. 171 Simandiras E.D. 25 Simmonds D.J. 93 Simon E.S. 275 Simova S.D. 46 Simoyi R.H. 72 Simpson G.R. 75 Simpson J.H. 102 249 Simpson T.J. 8 159 Sinai-Zingde G.136 Sinclair R. 236 Singaram B. 101 276 Singh B.P. 69 164 Singh J.O. 72 165 Singh. L.W.. 161 322 Singh S. 130 165 275 Singh U.C. 40 Singh V.K. 271 Singleton D.A. 42 Sinha A. 101 Sinigalia R. 224 Sinisterra J.V. 254 Siria J.C. 38 Siriwardane U. 188 Sironi M. 31 Sjogren E.B. 124 243 Skancke P.N. 36 Skattebd L. 109 Skilling. J. 3 Slater M.J. 149 Slawin A.M.Z. 172 Slebocka-Tilk H. 77 Slough G.A. 121 Slovin E. 126 Smaardijk A.A. 114 Smallridge A.J. 11 1 Smit C.N. 233 Smith A.B. 111 140 155 Smith C.M. 29 Smith C.T. 35 39 Smith D. 11 1 124 222 Smith D.L. 16 Smith J.D. 232 239 Smith J.R.L. 164 Smith R.D. 23 Smith R.W.22 Smith S. 37 78 Snapper M.L. 50 150 220 264 Snieckus V. 165 168 Snyder J.K. 203 so S.P. 34 Soai K. 114 199 241 251 27 1 272 Solcaniovi E. 108 Solladie G. 130 SolladiC-Cavallo A. 212 Solomon R. 159 Somei M. 193 Sonegawa M. 150 Song B.D. 60 Sonobe H. 44 Sonoda M. 267 Soos Z.G. 29 180 Sbrensen P.E. 78 Sorensen T.S. 33 109 Sorenson O.W. 6 Sosa C. 38 Spangler D. 39 Spears G.W. 27 Spellmeyer D.C. 27 55 Spencer J.D. 44 Spencer J.T. 201 Spengler B. 19 Speranza M. 189 Spitznagel G.W. 26 Spotzitz R.M. 268 Sprague J.T. 26 Springer J.P. 149 Spurr P.R. 179 Spyroudis S. 162 Squire R.H. 30 Srebenik M. 101 164 Srikrishna A. 191 Srivastava S.112 Staab H.A. 178 Stace A.J. 18 Stafford G.C.,jun. 21 Staley S.W. 179 Stalke D. 234 Stanczyk W.A. 233 235 Stanford J.E. 56 Stanforth S.P. 169 Stang P.J. 109 110 250 268 Stanger A. 62 235 Staunton J. 3 11 252 Stavber S. 100 Steckhan E. 43 Stedman G. 73 Steigel A. 207 Steigerwald M. 175 266 Stein S.E. 173 Steliou K. 187 StenstrBm Y. 109 Stephens R.J. 69 Stepnowski R.M. 20 Sterling J. 126 276 Sternfeld F. 143 172 Sternhell S. 176 Steuerle U. 133 StCvenart-De Mesrnaeker N. 81 106 Stevens K.C. 235 Stewart C.A. 197 Stewart J.D. 53 Stewart J.J.P. 26 Stewart L.J. 99 Stezowski J.J. 164 Still W.C. 27 Stille J.K. 98 101 102 170 220 223 249 Stirling C.J.M.65 Stohrer W.-D. 164 Stork G. 87 89 128 Stossel D. 161 Straub J.A. 298 Straus D.A. 233 Streith J. 199 Streitweiser A. jun. 29 74 Stroot M.K. 9 79 Strukelj M. 183 Strukul G. 224 Struthers-Semple C. 55 206 Studabaker W.B. 211 262 Stull P.D. 48 Sturgess M.A. 228 Sturm W. 228 Sturtz G. 139 Su W. 139 140 Suami T. 301 Suarez A.R. 94 Suarez E. 84 Subi M.P. 165 Author Index Subrahmanyam D. 155 Subramanian S. 3 Sudhakar A.R. 101 115 277 Suemune H. 139 140 Sugahara T. 268 Sugawara T. 178 Sugie Y. 246 Sugihara Y. 179 Sugimoto H. 166 Suginome H. 84 137 147 209 Sugita N. 124 Sugiura T. 226 Sugiyama K. 130 Sugiyama M. 296 Suguira T. 106 Suh G.-H.101 Suissa M.R. 177 Sulfat Y. 70 Sullivan A.C. 232 Sultana M. 193 Summers J.D. 236 Summersell R.J. 56 163 Sun J.-H. 272 Sunderbabu G. 191 Sundqvist B. 18 Sunner J. 19 Surber B.W. 110 268 Surendrakumar S. 48 260 Surjic V. 300 Susla M. 243 Suslick K.S. 98. 107 Sustmann R. 38 85 293 Sutherland J.K. 46 55 Sutkowski A.C. 3 11 Sutton K.H. 211 212 Suzuki A. 95 106 217 218 273 Suzuki H. 44 105 Suzuki K. 98 115 128 251 265 Suzuki T. 261 Swanson D.R. 112 228 Swenson R. 133 Swenton J.S. 172 Swindell C.S. 149 Switzer C. 200 Sworin M. 54 147 Sydnes L.K. 251 Syka J.E.P. 21 Szalay P.G. 30 Szelke M. 285 Tabei E. 234 Taber D.F. 113 Tabet J.C.20 Tabuchi T. 272 Tachdjian C. 87 Tachibana A. 31 33 Tada M. 296 Tadano K. 301 Taddei M. 106 Taft R.W. 59 79 Tagami K. 110 130 Author Index Taguchi T. 104 Tai J.C. 26 27 Taira K. 39 282 283 Tait B.D. 97 254 Takacs J.M. 137 226 Takagi K. 219 Takagishi S. 122 Takahashi A. 110 Takahashi I. 145 Takahashi K. 179 204 229 Takahashi M. 303 Takahashi S. 164 Takahashi T. 103 185 211 228 296 Takahasi T. 112 Takaheshi A. 130 Takai K. 97 255 Takaishi N. 221 Takaki K. 106 Takamine K. 255 Takamiya H. 108 Takano S. 303 Takaya H. 99 226 230 269 271 Takayama H. 41 44,105 145 Takayanagi H. 276 Takayoshi S. 208 Takeda A. 272 Takeda K.276 Takegoshi K. 205 Takei H. 142 Takemura H. 145 Takeuchi H. 165 Takeuchi I. 199 Takeuchi T. 17 Takewaki M. 106 Takimoto H. 189 Takuma K. 179 Tamao K. 98 11 5 Tamaru Y. 221 223 Tamura M. 185 Tamura R. 96 Tanaka C. 86 189 Tanaka H. 247 Tanaka M. 93 101 124 168 220 223 Tanaka Y. 100 114 Tanase S. 284 Tanase T. 300 Taneka S. 251 Taniguchi H. 33 168 255 Taniguchi M. 222 Taniguchi N. 87 Tanimoto S. 229 Tanoury G.J. 139 Tao X.-C. 272 Tao Y.-T. 44 Tarnchompoo B. 45 161 Tartakovsky E. 27 Tashiro K. 237 Tashiro M. 165 175 179 Tasturo M. 274 Tatemitsu H. 180 Tato J.V. 73 Taveras A.G. 170 Taylor E.C. 203 Taylor J.M. 70 164 Taylor P.R. 31 Taylor R.69 177 180 Taylor S. 143 172 Taylor T.G. 101 Taylor W.H. 179 Tee O.S. 70 Teichler I. 209 Teixeira-Dias J.J.C. 34 Teramae H. 31 33 Tereo T. 205 Terlouw J.K. 24 34 Tero-Kubota S. 231 Terpstra J.W. 98 Terrier F. 73 Tetler L.W. 17 Texier-Boullet F. 96 Thaisrivongs S. 286 Thakker D.T. 176 Thanabal V. 6 Thang T.T. 296 Thebtaranonth C. 45 161 Thebtaranonth Y. 45 161 Thetford D. 71 167 Thiebault A. 167 171 Thiem J. 291 Thies R.W. 147 Thom K.-L. 235 Thomas A.P. 106 Thomas E.J. 248 Thomas G. 111 Thomas P.J. 150 Thomas S.E. 216 217 Thompson A.M. 45 202 Thompson A.R. 12 Thompson D.P. 233 Thomson C. 39 40 54 Thorn D.L. 45 112 Thurkauf A, 143 Tidwell T.T.33 67 Tierney J. 99 Tietze L.F. 203 291 Tillement J.P. 23 Tilley T.D. 233 Tobe Y. 177 Todd J.F.J. 21 Todres Z.V. 102 Toelle R. 304 Tokai M. 107 Tokitoh N. 109 184 186 Tolbert L.M. 109 Tolman C.A. 93 Toma S. 108 Tomasi J. 27 40 Tominaga Y. 119 Tomioka K. 125 128 145 245 252 267 Tonachini G. 36 Topsom R.D. 59 Torii S. 122 247 Toro-Labbe A. 34 Torossian. G.. 164 Toru T. 88 Touchette N.A. 283 Toullec J. 67 Tour J.M. 139 257 Toussaint O. 126 Toyoda J. 167 Trabelsi M. 135 Tramontano A. 287 288 Tran P.M. 109 Tranchepain I. 183 Trevellick S. 69 163 Triantyphylides C. 109 Trichet F. 258 Trieu N.D. 222 Trifonov L.S. 46 109 Trimitsis G.159 Trimitsis M. 159 Trinadha Rao C. 134 Trinajstic N. 173 Trinquier G. 32 Trivedi N. 69 164 Trometer J.D. 115 Trost B.M. 38 101 108 110 112 115 134 138 139 147 169 215 220 257 264 265 277 Truchet F. 45 144 Trueblood K.N. 181 Truong P.N. 233 Tsai C.-Y. 44 194 Tsang R. 82 Tsang T.-H. 157 Tschamber T. 199 Tseng J. 36 Tso H.-H. 44 108 Tso J. 24 Tsong I.S.T. 18 TSOU,U.-P.E. 158 Tsuboyama K. 276 Tsuchihashi G. 115 128 265 270 Tsuchiya T. 207 Tsuda T. 107 Tsuge O. 208 Tsuji J. 106 211 214 226 Tsuji T. 133 178 Tsukamoto T. 267 Tsumuraya T. 238 Tsuno Y. 98 Tsuruta T. 244 Tsutsumi K. 202 Tsutsumi O. 269 Tu C.D. 282 Tuaristi E. 243 Tubtry F.200 Tufariello J.J. 106 188 Tughan G. 182 Tuncay A, 193 Tundo P. 254 Tunney S.E. 170 Turner D.L. 8 Turner R.W. 55 Turro N.J. 48 Tyler A.N. 15 324 Tyler J.W. 6 Tyrala A. 166 Ubeda D.C.N. 251 Uchida M. 258 Uchida Y. 175 268 Uda H. 110 130 Udseth H.R. 23 Ueda K.-i. 177 Uenishi J. 218 303 Ueno Y. 86 88 189 Ukai J. 103 Ukita T. 85 Ulan J.G. 11 1 Ullrich F.-W. 182 Ulrich S. 303 Umebayashi H. 241 Uneyana K. 122 Urano S. 39 Urpi F. 129 Ushirogouchi T. 36 Uskokovic M.R. 304 Usui Y. 153 Utaka M. 272 Utimoto K. 89 97 104 217 218 255 Uyehara T. 125 Uysal N. 73 Vacca J.P. 143 Vagberg J.O. 136 Vaid R.K. 11 1 268 Valenta Z.27 38 41 Valenti E. 38 110 Valverde S. 127 Van T.T. 161 van Berkel W.W. 64 van Dansik P. 133 178 van de Kuilen A. 189 van den Braken-van Leersum A.M. 175 van der Baan J.L. 262 van der Louw J. 262 van der Steen F.H. 263 Van Derveer D.G. 51 Vandevelde O. 161 van Duijneveldt F.B. 27 van Duijneveldt-van de Rijdt J.G.C.M. 27 Van Engel D. 176 178 van Hes R. 189 Van Horn D.E. 103 Vankar Y.D. 134 van Koten G. 263 van Lenthe J.H. 27 van Wet M.R.P. 263 Varma R.S. 270 276 Vasapollo G. 222 Vaultier M. 45 144 258 Vecchiani S. 66 Vedejs E. 44 48 95 96 201 Vederas J.C. 8 124 Vega S. 12 Vekemans J.A.J.M. 304 Ventura O.N. 38 40 Venturello P. 254 Verpeaux J.N.167 Vidal M. 99 Vidari G. 94 Viehe H.G. 106 Villar H.O. 29 Villarasa J. 129 Villefranca J.E. 283 Villeneuve P. 240 Vincens M. 99 Vincent M.A. 37 78 Vipond D. 48 Vismara E. 89 90 268 Vit Z. 108 Voelter W. 296 298 300 Vogel E. 179 180 209 Vogel P. 174 191 Vogler H. 180 Voityuk A.A. 27 Volatron F. 39 Vollhardt K.P.C. 162 198 228 Voltero L.R. 72 von Deyn W. 301 von Rosenberg J.L. 164 von Schnering H.G. 206 Vonwiller S.C. 147 Vorspohl K. 234 Voss H. 204 Vostrowsky O. 107 Vougioukas A.E. 243 244 Voyle M. 71 167 Vrieze K. 222 Vu C.T. 153 Wada I. 118 Wada M. 247 Wade K. 240 Wagland A.M. 46 194 Waglund T. 292 Wagner H.-U. 197 Wagner O.184 Wagner P.J. 50 Wagner W. 98 Wahl P. 178 Wakamatsu K. 89 Wakamatsu T. 303 Wakselman M. 169 Walchli R. 108 169 Waldmann H. 275 Walker J.C. 211 Wallace S.S. 279 Wallace T.W. 55 Wallasch M. 33 186 Walsh C.T. 284 Walter K. 20 Walter T.H. 12 Walton J.C. 82 Walton R. 82 Wang A.-J. 44 Wang B.H. 21 Wang D. 118 Wang K.K. 249 Author Index Wang S. 115 248 Wang W. 134 Wang Y. 292 Wang Z.-M. 267 Ward A.J. 7 Ward W.H.J. 281 Wariishi K. 246 Warmus J.S. 46 Warner J.C. 203 Warnock W.J. 48 260 Warren M.S. 283 Warren S. 95 Warrener R.N. 159 Wasylishen R.E. 9 Watanabe H. 234 235 236 Watanabe N. 121 Watanabe T. 189 Watanabe Y. 86 300 Watkins R.J.109 Watkinson P.J. 11 Watson B.T. 169 277 Watt C.I.F. 37 Watt I.F. 78 Waykole L. 133 Weaver O.G. 209 Webb K.S. 142 258 Weber A.E. 124 243 Weber E.J. 118 Weber G. 171 Weber T. 129 243 252 Webster F.X. 171 Webster N.J.G. 137 Weedon A.C. 52 76 149 Wege D. 195 Wehle D. 81 Wehrle B. 209 Wei C. 238 Wei Y. 236 Weidenbruch M. 184 234 235 Weidenhaupt H.-J. 109 220 Weidrnann H. 255 Weiler R. 71 166 Weinhold F. 34 Weinreb S.M. 182 Weisman G.R. 34 Weiss M.A. 7 Weiss R. 200 Weitekamp ~J.P.,5 Welch J.T. 132 Wells R.L. 232 Wells T.N.C. 280 Weltz M. 243 Wender P.A. 50 146 150 151 220 264 Weng L. 137 Wen-Ming T. 272 Wentrup C. 185 Wesdemiotis C.24 West P.R. 158 West R. 233 234 236 Westwood S.W. 83 167 Wetzel A. 180 Wetzel J.M. 277 Author Index Weyer H.-J. 179 Woods K.W. 139 Yano S. 300 Weyerstahl P. 68 Woodward P.R. 125 131 Yasuda H. 112 211 Whalen D.L. 176 Woolfitt A.R. 17 Yasuda K. 245 Whaley C. 46 Wooster N.F. 90 Yasukauchi T. 46 Wheeler R.A. 100 Wrek G.E. 236 Yates B.F. 24 34 37 Whitby R.J. 48 202 Wright P.E. 7 Yates J.R. 21 Whitcombe G.P. 120 224 Wright S.C. 31 Yazdi S.N. 164 267 WU H.-J. 146 Yefsah R. 277 White A.C. 163 WU J.-P. 118 Yeh H.J.C. 175 White A.D. 120 224 267 WU Y.-D. 37 38 Yeh M. 266 White A.H. 231 Wiirthwein E.-U. 33 186 Yellin N. 12 White J.D. 153 Whitesides G.M. 275 Wiithrich K. 7 Wulff W.D. 170 Yergey A.L. 23 Yianni P.172 Whiting M.C. 93 Wynalda M.A. 22 Yogi S. 208 Whittleton S.N. 37 78 Wynberg H. 114 Yohannes D. 170 Wiberg K.B. 28 34 Yokelson H.B. 234 Wicnienski N. 198 Xie Z.-F. 139 Yokoyarna S. 114 251 Widdowson D.A. 172 Yona I. 164 Widener R.K. 134 Yadav L.D.S. 169 Yoneda N. 273 Wilbers H. 298 Yadav-Bhatnagar N. 169 274 Yoneda R. 126 Wilen S.H. 61 Yagi H. 175 176 Yoneda T. 207 Wiley M.R. 114 Yamabe S. 189 Yonemura H. 100 Wilkins A.L. 11 Wilkins C.L. 21 23 Willby A.H. 16 Yamabe T. 31 33 Yamada F. 193 Yamada H. 46 Yoon J.C. 65 Yoon K.B. 119 Yoon M.S. 119 Williams A. 72 77 Yamada J. 123 240 252 Yoshida M. 273 Williams D.H. 16 19 Williams D.J. 61 172 204 Williams D.L. 73 77 132 Williams E.R. 21 Williams I.H. 27 Yamada K. 251 Yamada S. 44 84 105 147 Yamada Y.88 114 141 241 Yamagishi K. 273 209 303 Yoshida Z. 221 223 Yoshikawa S. 268 300 Yoshikoshi A. 267 Yoshitomi S. 164 Yousaf T.I. 60 63 Williams J.F. 300 Williams P.H. 201 Williams S.R. 172 Yamaguchi F. 165 Yamaguchi K. 296 Yamaguchi M. 53 104 115 Yuan C.W. 202 Yuh Y. 26 Yu C.-F. 44 Williamson S.A. 201 119 224 245 255 258 272 Yura T. 171 Williard P.G. 151 278 Wilson BE. 297 Yamaguchi Y. 46 192 Zamir D. 12 119 Wilson C.A. 63 Yamamoto A, 215 216 223 Zann D. 167 Wilson H. 59 236 Zard S.Z. 87 Wilson J.A.Z. 152 Yamamoto H. 100 103 145 Zare R.N. 19 Wilt J.W. 61 179 179 Zawadzki S. 129 Wilwerding J.J. 42 Yamamoto M. 145 251 Zax D.B. 12 Winchester W.R. 10 Yamamoto T. 223 Zbiral E. 299 Wingert H. 172 Yamamoto Y. 114 123 125 Zeller K.-P. 180 Winiarski J. 71 166 200 240 247 252 Zercher C.136 Winkler J.D. 151 Yamamura S. 148 172 Zettler M.W. 221 Winkler T. 171 Yamanaka S.-i. 179 Zhang H. 231 Winter G. 280 Winter T.J. 163 Yamashima N. 95 Yamashina N. 217 Zhang P. 161 Zhanpeisov N.U. 27 Wirth D.D. 43 Yamashita K. 36 Zhidomirov G.M. 27 Win J. 74 76 Yamashita M. 149 Zhou W.-S. 267 Wiseman G.H. 236 Yamashita S. 247 Zhu J. 170 Witz M. 165 275 Witzel T. 85 86 293 Wokaun A. 3 Wolfe S. 33 Yamato T. 69 165 175 Yamazaki N. 272 298 Yamazaki S. 229 Yamazaki T. 130 185 Ziegler F.E. 150 Ziegler T. 159 201 202 Ziller J.W. 232 Zhu N.-Z. 21 Wolfel G. 253 Yamoto T. 164 Zilm K.W. 12 192 Wolff A.R. 236 Yanez M. 69 164 Zimmerman H.E. 76 Wolleb H. 155 Yang J. 103 Zini R. 23 Wong H.N.C. 272 Yang N.C. 50 94 158 Zinke P.Y. 137 256 Wong M.E.33 Wong T. 272 Woo S.H. 174 Yang S.H. 217 Yang X. 50 Yang 2.-z. 179 Zipperer B. 208 Zuberi S.S. 165 275 Zubkov V.A. 295 Woodgate P.D. 205 Yankep E. 119 Zucca M.V. 11 2 325 326 Author Index Zucco C. 165 Zu-Kum T. 6 Zupan M. 100 216 Zwanenberg B. 42 Zweifel G. 110 251 Zwick B.D. 225 Zwierzak A. 129 Zybill C. 233

ISSN:0069-3030    

DOI:10.1039/OC9878400305

出版商:RSC    

年代:1987

数据来源: RSC