5 Aliphatic Compounds Part (ii) Other Aliphatic Compounds By P. F. GORDON Process Technology Department ICI Fine Chemicals Manufacturing Organisation Huddersfield HD2 1 FF 1 Introduction The following discussion covers only a small proportion of the total number of publications which fall within the scope of this chapter. Nevertheless some of the major themes dominating work in this area particularly stereocontrolled reactions and the upsurge of interest in carbonylations are reflected in the sections that follow. 2 Alcohols and Ethers An important route to stereodefined chiral alcohols involves the reduction of the corresponding ketones. In a major study Brown and co-workers have taken ten ketones each representing a particular class of ketone and reacted them with six different reducing agents.On the basis of the results obtained a recommendation of the most efficient asymmetric reducing agent for each individual class of ketone has been made.’ More specifically in the P-ketoesters (l) the ester group has been designed so as to block the approach to one face of the ketonic carbonyl group. Hydride reduction then proceeds either uia the transition state in which the ester and ketone carbonyls are syn ZnC12-Zn(BH,)2 or alternatively uia the transition state in which the carbonyls are anti (Dibal BHT) thus allowing both configurations of the final alcohol to be selected.2 The Heathcock Group has explored diastereo- facial selectivity in reductions of a-disubstituted ketones and aldehydes in terms of trajectory analysis and not surprisingly can rationalize the results in terms of the direction of approach of the hydride ion.3 R2wR’ OH I But Me ’ H.C. Brown W. S. Park B. T. Cho and P. V. Ramachandran J. Org. Chem. 1987 52 5406. ’ D. F. Taber P. B. Deker and M. D. Gaul J. Am. Chem. Soc. 1987 109 7488. E. P. Lodge and C. H. Heathcock J. Am. Chem. SOC.,1987 109 2819. 113 114 P. E Gordon Li R3 An alternative route to chiral alcohols proceeds by selective attack of an organometallic reagent at an aldehyde group. Organozinc reagents in conjunction with various chiral catalysts have been studied extensively this year and give predictable and high levels of stereocontrol. For example Corey and Hannon have converted various chiral aminoalcohols e.g.ephedrine and prolinol into the corre- sponding tertiary aminophenolic alcohols (2) and then used the latter as very effective catalysts for the addition of dialkylzincs to aromatic aldehyde^.^",' Similarly methyl- substituted prolinol derivatives (3) have been used with good results,' as have chiral piperazines (4),6certain cinchona alkaloid^,^ and (polymeric) immobilized amino- alcohols (5).8 Interestingly the amino alcohols (6) catalyse asymmetric additions to both alkyl and aromatic aldehydes.' E and 2-y-Alkoxy siloxyallyltin reagents add to aldehydes stereoselectively to give the threo alcohols (7) thus complementing earlier reports of erythro selective additions of y-alkylallyltin reagents;" these results can be rationalized in terms of chelation control.In contrast erythro and threo alcohols can both be obtained from a-disubstituted aldehydes using tetrabutyl ammonium bromide and either an alkyl- lithium (threo) or a cuprate reagent (erythro)." Titanium reagents are preferred in the catalytic addition of optically active carbamates (8) to aldehydes.I2 In particular titanium(IV) isopropoxide promotes additions which go with retention of configur-ation whereas titanium( IV) trisdiethylamino chloride promotes additions going with inversion. Various organometallics can be added to the aldehyde group in a,@-epoxyaldehydes without interfering with the epoxide group. In this way the R' I I. NPr (a) E. J. Corey and F. J. Hannon Tetrahedron Lett. 1987 28 5237; (b) ibid.p. 5233. K. Soai S. Niwa Y. Yamada and H. Inoue Tefrahedron Lett. 1987 28 4841. ' K. Soai A. Ookawa K. Ogawa and T. Kaba J. Chern. SOC.,Chern. Cornrnun. 1987 467. ' A. A. Smaardijk and H. Wynberg J. Org. Chern. 1987 52 135. S. Itsuno and J. M. J. Frechet J. Org. Chern. 1987 52 4140. K. Soai S. Yokoyama K. Ebihara and T. Hayasaki J. Chern. SOC.,Chern. Cornrnun. 1987 1690. (a) M. Koreeda and Y. Tanaka Tefrahedron Lett. 1987 28 143; (b) G. E. Keck D. E. Abbott and M. R. Wiley ibid. p. 139; (c) G. E. Keck and S. Castellino ibid. p. 281; (d) S. D. Kahn G. E. Keck and W. J. Hehre ibid. p. 279. " Y. Yamamoto and K. Matsuoka J. Chern. SOC.,Chem. Cornrnun. 1987 923. '*T. Kramer and D. Hoffe Tetrahedron Lett. 1987 28 5149. Aliphatic Compounds -Part ( ii) Other Aliphatic Compounds corresponding epoxy alcohols can be obtained with moderate to high stereoselectivity with best results appearing to result from the use of tin reagents catalysed by boron-based Lewis acids in dichloroniethane.’3 The epoxy group itself can be induced to ring-open to yield the corresponding alcohol.Thus threo and erythro 2,3-epoxyalcohols are attacked by a range of nucleophiles to provide the corresponding diols in high yield. In this case the threo epoxyalcohols are found to react faster and with higher selectivity at the C-3 position than the corresponding erythro compound^.'^ In complete contrast organocuprates attack preferentially at the C-2 position to yield the corresponding diol in good yield.’’ Vinyloxiranes (9) are readily formed from the corresponding epoxyalcohol after oxidation to the aldehyde followed by a Wittig reaction.Organocuprates (LiMe,Cu) can then be used to open the epoxide in a predominantly anti SN2’ fashion to yield (E)-allylic alcohols ( E-and 2-2,3-epoxysilanes containing an isopropyl group on silicon provide a convenient access to threo and erythro 1,2-diols respectively. Once again the epoxide is attacked by a nucleophile to yield a silyl alcohol follow.ed by oxidation of the carbon silicon bond to give the corre- sponding stereodefined 1,2-di01.~’ This particular sequence has been .used in the synthesis of exobrevicomin. Silyl reagents have also been used in the conversion of 3-hydroxybutenolides (11) into P,y-epoxyesters (12) using trimethylsilyliodide fol- lowed by cyclization with silver oxide.’‘ In the same paper the esters (12) have been converted into the corresponding chiral p-hydroxyesters in high enantiomeric purity using organocuprate reagents.Alternatively P-hydroxyesters can be prepared from a&-epoxyesters using the currently in vogue reagent samarium iodide to reduce the epoxide function.” A somewhat less direct approach to stereodefined alcohols can be seen in the palladium-catalysed reaction between vinyl oxiranes ( 13) and tosylisocyanate to give oxazolidinones (14) which can then be hydrolysed to the corresponding amino- alcohol.20 The route is effectively a cis hydroxyamination procedure and has been applied to the synthesis of (-)-acosamine.Whereas the last reaction relied upon palladium to promote the epoxide ring-opening the epoxide ring in epoxyalcohol (15) is cleaved during the rearrangement step to hydroxy ketone (16).2’The overall rearrangement constitutes a new method for the construction of quaternary carbon centres in high yield. l3 G. P. Howe S. Wang and G. Proctzr Tetrahedron Lett. 1987 28 2629. I4 K. S. Kirshenbaum and K. B. Sharpless Chem. Lett. 1987 11. l5 J. M. Chong D. R. Cyr and E. K. Mar Tetrahedron Lerr. 1937 28 5009. J. A. Marshall and J. D. Trorneter Tetrahedron Letr. 1987 28 4985. ” K.Tamao E. Nakajo and Y. Ito J. Org. Chem. 1987 52 4412. ’‘ M. Larchevcque and S. Henrot Terrahedron Letr. 1987 28 1781. I’ K. Otsubo J. Inanaga and M. Yamaguchi 7etrahedron Left. 1987 28 4437.20 B. M. Trost and A. R. Sudhakar .I. Am. Chem. Soc. 1987 109 3792. *I M. Shimazaki H. Hara K. Suzuki and G.-i. Tsuchihashi Tetrahedron Lett. 1987 28 5891 116 P. F. Gordon References to the construction of diols have already been noted. However several papers have appeared detailing some elegant routes to polyols. For example diepoxides figure as intermediates in the syntheses of symmetrical and enantiotopi- cally differentiated polyols with the key step being a stereospecific ring-opening of the epoxide. Scheme 1 illustrates one approach**" whereas a quite different method starts from diepoxide (17) and relies upon a meso selective base-catalysed Payne rearrangement to generate the chiral polyol (18) a useful precursor for Teurilene.22b I OH OH OH OH fi Scheme 1 HO 0 OH (a)S.L. Schreiber M. T. Goulet and G. Schulte J. Am. Chem. SOC.,1987 109 4718; (b)T. R. Hoye and S. A. Jenkins ibid. p. 6196. Aliphatic Compounds -Part ( ii) Other Aliphatic Compounds A very powerful iterative strategy to polypropionates has been used in a rapid synthesis of the C( 19)-C(29) sector of Rifamycin S.23Two Lewis acid-catalysed cyclocondensation reactions form the key steps in the synthesis in which the successor aldehyde is fashioned from the anomeric carbon of its pyranoid pre- decessor (see Scheme 2). Both processes occur under essentially perfect diastereofacial (Cram-Felkin) selectivity. The first process is catalysed by titanium tetrachloride and exhibits cis selectivity whereas the second process relies on a boron Lewis acid catalyst and shows trans selectivity.Me Me Me I OMe TMs:<e OMe Me Me Me Me Scheme 2 Several catalysts have already been mentioned in the context of asymmetric additions to aldehyde. The nucleophile is frequently a metal carbanion though this is not always the case as demonstrated by the asymmetric allylation of aldehydes with allyltrimethyl~ilane.~~ The catalyst in this case is diphenylboryl triflate which promotes excellent yields and high enantiomeric excesses of the corresponding ethers (19). Another ether synthesis involving silyl derivatives is achieved using either trimethylsilyl triflate or trimethylsilyl iodide as catalyst and involves the reductive coupling of aldehydes with trialkyl~ilanes.~~ Symmetrical ethers are obtained with both catalysts in good yield.However if alkoxylsilanes are used with trimethylsilyl iodide catalyst then unsymmetrical ethers can be readily prepared. The cleavage of ethers has been studied extensively in the last decade with silyl compounds the most popular class of reagent for effecting the transformation. In 23 S. J. Danishefsky D. C. Myles and D. F. Harvey J. Am. Chern. Soc. 1987 109 862. 24 T. Mukaiyama M. Ohshima and N. Miyoshi Chem. Lett. 1987 1121. 25 M. B. Sassaman K. D. Kotian G. K. S. Prakash and G. A. Olah J. Org. Chem. 1987 52 4314. 118 P. F. Gordon this context diiodosilane (DIS) has been shown to be particularly effective in the cleavage and deoxygenation of ethers (and alcohols) and demonstrates a high selectivity for secondary alkoxy functions.2h In this respect it exhibits a complernen- tary reactivity to that found with trimethylsilyl iodide (TMSJ).For example primary alcohols are converted into the corresponding iodides almost two orders of magni- tudes faster with TMSJ than DIS whereas quite the opposite situation is observed for secondary alcohols. A related and useful reaction can be seen in the silyl promoted cleavage of spiroketals. This particular transformation has been used in the enan- tioselective functionalization of 2-substituted- 1,3-diols. The overall sequence is fairly simple and starts by reacting the diol with 1-menthone to give the ketal diastereoisomer in which the iarge substituent predictably occupies the equatorial position.After reaction with the trimethylsilyl enol of acetophenone the monoprotec- ted neomenthyl derivative is formed and then converted into monoprotected diol (20) with recovery of the chiral 'This method has been extended by the same authors to encompass the resolution of variously substituted 1,3-diol~.~",~ RI OR^ 2% X = OTHP OCPh, SPh R' R2 R2 OR^ The protection of alcohols is illustrated by the reported use of p-methoxybenzyl- oxymethyl chloride which protects alcohols under mild conditions and can be removed easily with DDQ.28 The diphenylmethylsilylether (DPMS) group also appears to be a useful addition to the range of available protecting groups.29 It is stable to Grignard and Wittig reagents and silicon gel chromatography yet can be removed under very mild basic conditions -far milder than those used for the removal of the t-butyldimethylsilyl protecting group.Finally in this section chiral acetals (21) are claimed to be convenient reagents for determining the enantiomeric purity of alcohols by NMR spectro~copy.~" 3 Alkyl Halides The conversion of alcohols into alkyl halides is one of the classic functional group transformations. However despite the great deal of attention this reaction has received there are still a few areas that demand attention such as in the preparation of sterically hindered alkyl chlorides from the corresponding alcohols a notoriously inefficient reaction. Scheme 3 provides an elegant solution to the problem and works for a range of sterically very hindered alcohol^.^' Asymmetric a-bromination of carboxylic acids is possible uia the chiral amides (22 X = H).32The amides are converted into the boron enolate in the first step and then treated with NBS to provide the bromo derivatives (22 X = Br) with very high 26 E.Keinan and D. Perez J. Org. Chem. 1987 52 4846. 27 (a) T. Harada T. Hayashi I. Wada N. lwa-ake and A. Oku J. Am. Chern. SOC. 1987 109 527; (b) T. Harada I. Wada and A. Oku Terrahedron Len. 1987 28 4181; (c) T. Harada H. Kurokawa and A. Oku ibid. p. 4843; (d) ibid. p. 4847. 28 A. P. Kozikowski and J.-P. Wu Telrahedron Lerr. 1987 28 5125. 29 S. E. Denmark R. P. Hammer E. J. Weber and K. L. Habermas J. Org. Chem. 1987 52 165. 30 T.H. Chan 0.-J. Peng D. Wang and .I.A. Guo J. Chern. SOC.Chem. Cornrnun. 1987 325. 31 D. Crich and S. M. Fortt S,ynthesis 1987 35. 32 D. A Evans J. A. Ellman and R. L. Dorow Tetrahedron Left. 1987 28 1123. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds A 0 Scheme 3 enantio~electivity.~~ The same paper describes a method for converting the chiral halogeno acids derived from (22) by hydrolysis into chiral amino acids using the simple two-step sequence of azide displacement and reduction. New ways to incor- porate a fluorine into a molecule are always to be welcomed especially in view of the ever increasing use of fluorine-containing molecules in the plant protection and pharmaceutical industries. In this context iodine 'fluoride converts hydrazones into the corresponding difluoro compounds in high yield.33 Bn (22) A number of variations upon the halogen exchange reaction have been published.For instance alkyl chlorides even sterically hindered ones can be converted into the bromide with hydrogen bromide catalysed by iron( 111) bromide,34 whereas aryl chlorides and bromides are readily converted into the iodide using alumina and charcoal-supported copper( I) iodide.35 Dehalogenation of alkyl and aryl halides can be accomplished with a sodium borohydride suspension in toluene using tributyltin chloride and polyether phase-transfer catalysts.36 Samarium iodide also effects the same transformation in quantitative yields.37 Finally in this section alkyl halides can be readily homologated in three steps via the sequence conversion into the Grignard reagent followed by treatment with an aminomethylether (R'OCH,NR:) and then ethylchl~roformate.~~ 4 Aldehydes and Ketones A convenient route to aldehydes and ketones is by direct conversion from carboxylic acids and their derivatives.The fact that the methods in current use are not entirely satisfactory is emphasized by the large number of new reagents and methods to accomplish the transformation. Some of these are highlighted in Scheme 4.39a-h 33 S. Rozen M. Brand D. Zamir and D. Hebel J. Am. Chem. Soc. 1987 109 896. 34 K. B. Yoon and J. K. Kochi J. Chem. Soc. Chem. Commun. 1987 1013. 3s J H. Clark and C. W. Jones J. Chem. Soc. Chem. Commun. 1987 1409. 36 D.E. Bergbreiter and J. R. Blanton J. Org. Chem. 1987 52 472. 37 J. Inanaga M. Ishikama and M. Yamaguchin Chem. Lett. 1987 1485. 38 E. Yankep and G. Charles Tetrahedron Lett. 1987 28 427. 39 (a) R. J. P. Corriu G. F. Lannean and M. Perrot Tetrahedron Lett. 1987 28 3941; (b) J. S. Cha J. E. Kim S. Y. Oh J. C. Lee and K. W. Lee Tetrahedron Lett. 1987,28 2389; (c) J. S. Cha J. E. Kim M. S. Yoon and Y. S. Kim ibid. p.6231; (d) J. S. Cha J. E. Kim S. Y. Oh and J. D. Kim ibid. p.4575; (e) J. S. Cha and S. S. Kwon J. Org. Chem. 1987 52 5486; cf) S. Collins and Y. Hong Tetrahedron Lett. 1987 28 4391; (g) C. Cardellicchio V. Fiandenese C. Marchese and L. Ronzini Tetrahedron Left. 1987 28 2053; (h) Y. Tominaga S. Kohra and A. -Hoxomi Tetrahedron Lett.1987 28 1529. 120 P. F. Gordon R' = li R' = alkyl R = aliphatic aromatic R' = alkyl R' = H ___. RCOCl RC0,R Several of the methods in Scheme 4 refer to the reduction of acids to aldehydes. An alternative approach is by oxidation of primary and secondary alcohols and this has now been successfully carried out using tetrabutylammonium per-ruthenate with morpholine-N-oxide as a mild catalytic oxidant; yields are typically in the range 80-90% .40 Homologation of ketones and aldehydes is also a sought after process and a particularly efficient route is shown in Scheme 5 and relies upon a new synthetic application of benzodithiolium cations.41 Scheme 5 40 W. P. Griffith S. V. Ley G. P. Whitcombe and A. D. White J.Chern. SOC.,Chem. Commun. 1987 1625. 41 M. Cerciti I. Degano and R. Fochi S-vnthesis 1987 79. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 121 In the past few years the upsurge of interest in carbonylation reactions has been quite marked. This year has seen several different approaches to the synthesis of aldehydes and ketones. For instance one paper describes the palladium-catalysed reductive carbonylation of esters to give aldehydes at low pressure using synthesis gas.42 In contrast organomanganese carbonyls are the source of the carbonyl group in two recently published papers. Methyl magnesium pentacarbonyl which is more reactive than the corresponding benzyl complex with regard to migratory aptitude inserts a carbonyl group into various activated and strained double and triple bonds to give organomanganese compounds (23).In the case of activated alkenes the selectivity of addition as might be expected is very high with the manganese (CO) moiety substituting alpha to the activating substituent. The manganese is readily removed by photodemetallation to yield the corresponding ketone.43a Alternatively for manganacycles derived from alkynes acid treatment gives a mixture of enones and furanone whereas reduction with DIBAL yields the butenolide via a further carbonyl insertion reaction.43b R3 H I Pr' &-mie OLi OR Pr' Li Over the past decade significant advances have been made in the art of controlling selectivity in the aldol reaction. This trend continues as exemplified by the diastereoselective reaction between simple aldehydes and the lithium enolate of N-propionylpyrrolidine to yield the anti-aldol product with catalytic quantities of a titanium reagent (Cp,TiC12).44The enantioselective aldol reaction of t-butylketone with benzaldehyde in the presence of the carefully selected chiral ligand (24) proceeds in excellent yield and with good enantiomeric excess.45 During studies into the total synthesis of macrolides an investigation into the diastereofacial selectivities of enolates (25) was ~ndertaken.~~ Several interesting points emerged from the study which centre around the nature of the 0x0-substituent (-OR).If the substituent is a hydroxy group i.e. R = H then si-facial selectivities are observed in the aldol reaction whereas the selectivity is totally reversed i.e.re-facial upon protection of the hydroxy group R # H. Thus without altering the nature of the backbone functionality especially at the chiral centres the diastereofacial selectivity can be predictably controlled. Allo-threonine and threonine have both been prepared in high enantiomeric excess (in a 1.7 1 ratio) by the aldol condensation between acetaldehyde and the zinc chelate of a Schiff base.47 Interestingly the Schiff base is prepared from glycine and 42 J. L. Graff and M. G. Romanelli J. Chem. SOC.,Chem. Commun. 1987 337. 43 (a) P. DeShoong G.A. Slough and A. L. Rheingold Tetrahedron Lett. 1987,28,2229; (b) P. DeShoong D. R. Sidler and G. A. Slough Tetrahedron Lett.1987 28 2233. 44 P. J. Murphy G. Procter and A. T. Russell Terrahedron Lett. 1987 28 2037. 45 A. Andro and T. Shioiri J. Chem. Soc. Chem. Commun. 1987 1620. 46 P. A. McCarthy and M. Kageyama J. Org. Chem. 1987 52 4681. 47 H. Kuzuhara N. Watanabe and M. Ando J. Chem. SOC.,Chem. Commun. 1987 95. 122 P. E Gordon a chiral pyridoxal like pyridinophene. The reaction therefore represents a "bio- mimetic" aldol reaction in which the zinc complex of the pyridine base is acting as an enzyme mimic. The aldol reaction can also be applied to a wide variety of different ketones and aldehydes; however cross-enolate additions with sterically hindered ketones are frequently troublesome. One approach which circumvents the problems is detailed in Scheme 6 and uses methylallylmagnesium chloride as a ~ynthon.~' Di-t-butylketone is used to illustrate the sequence.Bu' Bu'+ Bu' Me B u' OH Me . .. ... I II 1111 Bu' Reagents i 0,; ii Me2$ iii oxalic acid A Scheme 6 0 R' OR2 (26) (27) A more unusual route to aldol-type products (26) and (27) starts from acetals R3CH(OR2)2,and enolsilylethers or bistrimethylsiloxyalkenes respectively and is catalysed by electrogenerated acid derived from perchlorate Salka9 The yields of products (26) and (27) are generally excellent. Palumbo and co-workers have developed a new high yielding and general ketalization procedure which involves the use of a polystyryl diphenylphosphine- iodine complex.50 Yields are typically greater than reaction times are usually less than one hour and as might be expected with a polymerically immobilized reagent work-up is simple.An improved route to 1,3-dioxolan-4-ones (28) from carbonyl compounds has also been claimed. The silyl reagent (29) effects the transformation in excellent yield and works where many other reagents fail com- ~letely.~' The peroxysulphur compound formed from 2-nitrobenzenesulphonyl 48 W. H. Bunnelle M. A. Rafferty and S. L. Hodges J. Org. Chem. 1987 52 1603. 49 S. Torii T. Inokuchi S. Takagishi H. Horike H. Kuroda and K. Uneyana Bull. Gem. Soc. Jpn. 1987 60,2173. 50 R. Caputo C. Ferreri and G. Palumbo Synthesis 1987 386. 51 W. H. Pearson and M.-C. Cheng J. Org Chem.. 1987 52 1353. Aliphatic Compounds -Part ( ii) Other Aliphatic Compounds OSiMe3 Me3siorv 0 chloride and potassium peroxide converts tosylhydrazones into the corresponding ketones in almost quantitative yields at -30 0C.52 5 Carboxylic Acids and their Derivatives In common with ketones carboxylic acid esters form enolates readily and so many of the methods used for achieving stereospecificity in ketone enolate reactions are equally valid for ester enolates.Over the last few years an increasingly popular strategy for controlling the stereochemistry in aldol-type additions has been to employ “chelating” metals. A good illustration of what can be achieved can be seen in the synthesis of a,P-dihydroxy esters by reaction of the enolates of chiral glycolates (30) and (31) with aldehydes.53 By the appropriate choice of metal and chiral glycolate precursor any of the four possible stereoisomers of the resulting a$-dihydroxy esters (32) can be obtained in optically pure form.Zirconium is found to promote syn additions whereas the lithium ion favours the anti product. Little is known about the alkylation of P-amino acid esters. However a recent study has helped to highlight the very high 1,k-1,2-inductions possible in the a-alkylation of N-acylamino butanoates with lithium as c~unterion.~~ The same paper also contains several routes to the chiral starting material. The influence of the metal ion is critical in the reactions of dienolates (33) as determined in a recent Although the reactions of (33) are frequently lacking in both regio- and diastereo- selectivity it has been found that the y-tin derivative easily formed from (33) can give either the syn or anti forms of ester (34) with high diastereoselectivity by judicious choice of reaction conditions n .O OH 0 OH (33) (34) 52 Y.H. Kim H. K. Lee and H. J. Cheng Tetrahedron Left. 1987 28 4285. 53 W. H. Pearson and M.-C. Cheng J. Org. Chem. 1987 52 3176. 54 D. Seebach and H. Estermann Tetrahedron Leu. 1987 28 3103. 55 Y. Yamarnoto S. Hatsuya and J.4. Yarnada J. Chem. SOC.,Chem. Commun. 1987 561. 124 P. F. Gordon The upsurge of interest in carbonylation reactions has already been noted. This is further illustrated by the following references several of which have the distinct advantage of proceeding at atmospheric pressure.A novel method for the carbonyla- tion of aromatic halides has been developed which involves a photostimulated cobalt-catalysed carbonylatiori reactior under very mild conditions i.e. atmospheric pressure and ambient temperature to yield the corresponding carboxylic acids in high yield.56 Similary a cobalt salt is used in a facile carbonylation of benzyl halides giving the arylacetic acids in high yield.57 Once again mild conditions are employed although the catalytic system (CoC1,-NaBH,-CO-NaOH) is different. a-Hydroxy-carboxylic acids can also be formed very efficiently by carbonylation of both alkyl and aryl halides.58 In this case a palladium-phosphine complex is used as catalyst and the reaction conditions are rather more severe than in the previous two examples.The same catalyst combination i.e. palladium-phosphine is reported in another carbonylation; however the substrates phenols and aliphatic alcohols are quite different." Nevertheless yields of the corresponding carboxylic acids are still high and the reaction occurs at atmospheric pressure. In contrast carbonylation of alcohols with the catalyst combination copper chloride-di-t-butylperoxide results not in replacement of the hydroxy group by the carboxylic acid group as in the previous reference but rather leads to the formation of dialkyl carbonates.60 The preparation of synthetic a-amino acids is currently an area of topical interest. Evans and co-workers have generated chiral-a- halogeno-P-hydroxy carboxylic acids (35) by aldol additions ofthe chiral acid derivatives (36)(X = Cl) with aldehydes.61" The amino acid is then easily accessible by azidation and reduction (see also reference 32).A more general amino acid synthesis occurs via direct azide transfer to a chiral acid derivative (36 X = aryl alkyl) followed by reduction.61h A common feature in the last two syntheses is the formation of a chiral oxazolidinium azide in which the chiral auxiliary the oxazolidine ring has to be removed to generate the desired chiral azido carboxylic acid prior to reduction. The same authors have now shown that lithium peroxide is a far superior reagent for this exocyclic cleavage of the oxazolidine ring thus allowing the recovery of the chiral auxiliary.61' Furthermore the reagent works for all classes of oxazolidinone-derived carboximides encountered thus far Vederas has also developed an efficient entry into chiral a-amino acids which is effectively the functionalization of an existing amino acid serine.62 In the ,-, CI I, Ph Me Ph Me H2N COiH (35) (36) (37) 56 K.Kudo T. Shibata T. Kashimura S. Mori and N. Sugita Chem. Lett. 1987 577. 57 N. Satyanarayana and M. Periasamy Tetrahedron Lett. 1987 28 2633. 58 T.-a. Kobayashi T. Sakakura and M. Tanaka Tetrahedron Lett. 1987 28 2721. 59 R. E. Dolle S. J. Schmidt and L. I. Kruse J. Chem. Soc. Chem. Cornmun. 1987 59. 60 G. E. Morris D. Oakley D. A. Pippard and D. J. H. Smith J. Chem. Soc. Chem. Commun. 1987,410. 61 (a) D. A. Evans E. B. Sjogren A. E. Weber and R.E. Conn Tetrahedron Lett. 1987,28,39; (h) D. A. Evans and T. C. Britton .I. Am. Chem. Soc. 1987 109 6881; (c) D. A. Evans T. C. Britton and J. A. Ellman Tetrahedron Lett. 1987 28 6141. 62 L. D. Arnold J. C. G. Drover and J. C Vederas J. Am. Chem. Soc. 1987. 109 4649. Aliphatic Compounds -Part ( ii) Other Aliphatic Compounds first step serine is cyclized to its lactone which can then be attacked by Grignard reagents (RMgCI) to give amino acids (37) with complete retention of optical purity (>9996 ) after deprotection.62 The conjugate addition of phenyldimethylsilyl cuprate reagents to cinnamate and crotonate esters and amides of known chiral auxiliaries is highly diastereoselective and provides P-silylesters which are useful synthetic intermediates in their own right.43 Interestingly the sense of diastereoselection in the silyl cuprate addition is opposite to that normally observed.Chlorotrimethylsilane has been used in the asymmetric Michael addition of chiral enamines of a -alkyl-P-ketoesters to activated alkenes." In this particular instance the silane acts as an efficient catalyst for the addition reaction rather than as a co-reactant. A study of the diastereoselectivity of conjugate additions to y-substituted a$-unsaturated esters has demonstrated the importance of the double bond geometry and type of reagent in controlling the selectivity. Thus Lewis acid-mediated addition of organocuprate reagents to trans esters (38) gives the saturated anti isomer (39) whereas the cis ester provides access to the syn is~mer.~~',~ On the other hand organocopper reagents add in anti fashion regardless of the starting geometry.In the reaction between alkyl halides lithium amides and a,@-unsaturated carboxylic esters the unsaturation is retained with alkylation occurring at the a-position to give a-alkyl-a$-unsaturated carboxylic esters in good yield.64 In this example the lithium amide functions as a nucleophile rather than its more usual role as a strong base and adds to the unsaturated ester to give the anion at the a -position which can then be alkylated. In the final step the amine is eliminated to regenerate the unsaturated ester. Nu Y-co2R' R +co2R R (38) (39) A new solution to the formation of P-ketoamides (from P-ketoesters) has been published.This particular transformation is frequently plagued by problems such as competitive formation of the enamine poor yields and severe reaction conditions. A practical solution involves the prior formation of the thioester followed by silver trifluoroacetate-catalysed amidation under very mild reaction condition^.^' Yields are typically in the region of 6O-8O% and the method works even for non-basic amines. An alternative amidation though this time for simple esters only requires very mild thermal conditions and utilizes electrochemistry.68 The amidation reaction occurs in the cathodic compartment and works equally well for aliphatic and aromatic amines. 63 I. Fleming and N. D. Kindon J. Chem. SOC., Chem. Commun. 1987 1177. 64 K.Tomiska W. Seo K. Ando and K. Koga Tetrahedron Lett. 1987 28 6637. 65 (a) Y. Yamamoto S. Nistui and T. Ibuka J. Chem. SOC., Chem. Commun. 1987,464; (6) ibid. p. 1572. 66 T. Uyehara N. .4sao and Y. Yarnamoto J. Chem. SOC.,Chem. Commun. 1987 1410. 67 S. V. Ley and P. R. Woodward Tetrahedron Lett. 1987 28 3019. 68 K. Arai C.-h. Shaw K. Nozawa K.4. Kawai and S. Nakajima Tetrahedron Lett. 1987 28 441. 126 l? E Gordon A convenient route to nitriles proceeds by nucleophilic displacement of a halide with cyanide ion. For instance lithium cyanide in THF is very effective in converting alkyl halides and tosylates into the corresponding itri rile.^^ Significantly the corre- sponding sodium and potassium salts are almost totally ineftective.Malic acid figures in at least two reports this year. A convenient synthesis of (R)-malic acid is reported as starting from R,R-dimethyltartrate and proceeds uia the intermediacy of the thione (40) which yields the maleate upon treatment with tributyltin h~dride.~’ In the second malic acid is used to prepare a new chiral synthon (41) which has been used for the preparation of the chiral side-chain fragment of 24,25-dihydroxycalciferol.”Phenyl malonic acid can be asymmetrically decarboxylated to the monacid (42) in good yield using copper iodide-cinchona alkaloids as catalyst.’* Me0 CyC O2M e s (40) 0 (43) 6 Lactones and Lactams Samarium iodide is enjoying some topicality as a reagent and its application in the lactone area can be seen in the synthesis of chiral lactones (43).73 The role of the samarium iodide is twofold it promotes the efficient intramolecular Reformatsky reaction in (44) and controls the stereochemistry of ring-closure by co-ordination between the samarium cation and the oxygens from the ester enolate and the ketone.The yields are high and with the ready accessibility of the precursor (44) the method represents a useful and general synthesis of various polysubstituted lactones. More specifically optically active N-trityl homoserine lactone has been synthesized in just three steps from a cheap and readily available precursor (-)-aspartic acid as depicted in Scheme 7.74 The versatility of the asymmetric Michael reaction has already been demonstrated at several points in earlier sections and has now been applied to the synthesis of chiral 4-substituted lactones.The route is fairly simple and relies upon very familiar 69 S. Harusawa R. Yoneda Y. Ornori and T. Kurihara Terrahedron Lett. 1987 28 4189. 70 M. Alpegiani and S. Hanessian J. Org. Chem. 1987 52 278. ‘I J. Sterling E. Slovin and D. Rarasch Tetrahedron Lett. 1987 28 1685. 72 0. Toussaint P. Capdevielle and M. Maurny Tetrahedron Left. 1987 28 539. 73 G. A. Molander and J. B. Etter J. Am. Chern. Sac. 1987 109 6556. 74 J. E. Baldwin M. North and A. Flinn Terrahedron Left.. 1987 28 3167. Aliphatic Compounds -Part ( ii) Other Aliphatic Compounds FOIH (Co2Bn (Co2Bn Reagents i DIBAH; ii CF',CO,H Scheme 7 chiral auxiliaries.Thus Michael addition of metallated acetaldehyde RAMP and SAMP hydrazones to a,P-unsaturated esters yield 8-oxopentanoates. The latter can be reduced and cyclized to chiral lactones (45)in high enantiomeric excess typically >95% and in high chemical yield.75 The use of cheap chiral precursors is always an attractive option to take in producing more complex materials and often avoids the complications associated with using chiral auxiliaries. In the straightforward synthesis of (-)-lactones (46) glucose is the starting material. The particularly noteworthy aspects of this synthesis are the very mild oxidizing conditions which permit the use of relatively labile protecting groups the high yields and the high levels of chirality retained.76 R' The lactones prepared thus far are formed by conventional lactonization pro- cedures; however in one paper this year the ring-closure is effected by photolysis.This method is particularly useful in promoting the anti-Markovnikov intramolecular addition of a carboxylic acid to a double bond to give the five-membered ring lactone -a lactonization procedure which is difficult to achieve by standard synthetic method^.'^ The attention devoted to the lactone area is not confined merely to their construc- tion but also encompasses their use as chiral templates. Work in this latter respect has been extended to the construction of polypropionate chains by an iterative procedure involving the preparation of butenolide rings. Scheme 8 illustrates a 75 D. Enders and B.E. M. Rendenbach Chem. Ber. 1987 120 1223. 76 S. Valverde S. Garcia-Ochoa and M. Martin-Lomas 1. Chem. SOC. Chem. Commun. 1987 1714. P. G. Gassman and K. J. Bottorff J. Am. Chem. SOC.,1987 108 7547. '7 128 P. F. Gordon OH ~ WCOZH 0 .OH OH Reagents i LiC(SPh),; ii MeOPh; iii Ra-Ni; iv DEAD PPh, PhC02H; v K2C03 Scheme 8 typical sequence starting from a readily accessible butenolide and has been used by one group in the synthesis of the C(7)-C(13) fragment of erythronolide and shows the versatility of the approa~h.~~",~ The lactol ring system has also been used as a 'template' for chiral inductions in open-chain systems. Thus chiral y-and 6-lactols (47) are reduced to diols (48) by methyl titanium chloride representing highly selective 1,4 and 1,5 asymmetric inductions re~pectively.~~" If a Lewis acid catalyst is used with an organometallic reagent especially a zinc reagent then 2,5-disubstituted ethers are obtained instead.79h OH Finally in this section optically pure p-lactams have been produced via the intermediacy of hydroxylamines as outlined in Scheme 9." R* "a -o'r'y C02Me -3 R* 0 + * RNHOH Reagents i H2-Pd/C; ii Bu;NHSO4 MsCI; Na-NH Scheme 9 78 (a) G.Stork and S. D. Rychnovsky J. Am. Chem. Soc. 1987 109 1564; (b) S. Hanessian and P. J. Murray J. Org. Chem. 1987 52 1170. 79 (a) K. Tomooka T. Okinaga K. Suzuki and G.-i. Tsuchihashi Tetrahedron Lett. 1987 28,6335; (b) K. Tomooka K. Matsuzawa K. Suzuki and (3.4. Tsuchihashi ibid.p. 6339. S. W. Baldwin and J. Aubi Tetrahedron Left. 1987 28 179. no Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 7 Amines Imines and Other Nitrogen Compounds The general theme of asymmetric synthesis has been a recurrent one throughout each of the previous sections and it comes as no surprise to find several good examples in this section. For example in the synthesis of chiral amines (49) organocerium reagents are added to the familiar SAMP hydrazones (50) followed by reduction of the intermediate hydrazine to the amine.81 In this example organocerium reagents prove to be far superior to other organometallic reagents in the addition reaction to provide the hydrazine in high diastereoisomeric excess. There have been a host of references to the synthesis of amines and the following provides selected highlights; several of the references cover the use of azides in amine synthesis.t-Alkylchlorides can be converted into the corresponding t-alkyl- amines in two steps by azide transfer with trimethylsilyl azide catalysed by tin tetrachloride followed by reduction with triethylphosphite.82 Amines can be pre- pared from the alcohol directly in a convenient one-pot synthesis using hydrazoic acid di-isopropyl azodicarboxylate and triphenylpho~phine.~~ The azide group is also part of a sequence for converting amides (51) into amides (52) whilst avoiding drastic hydrolysis conditions as shown Dibutyltinhydride and the tin salt (PhS)3Sn-Et3N+H are two useful reagents for the reduction of azides to amines.The thiotin reagent is claimed to be the best reducing agent for azides reported thus far whereas dibutyltin hydride is not as powerful but can be used in common solvents even water and allows for a convenient mild w~rk-up.~~ RNHCOR + R-NCOR’ -+ R-N + RNHCOR’ I (51) NO (52) Protection of amines is an important reaction and every year seems to produce various new protecting reagents. The norbornene reagent (53) has been shown to be an excellent stable reagent for the introduction of the alkoxycarbonyl protecting group.86 ” S. E. Denmark T. Weber and D. W. Piotrowski J. Am. Chem. Soc. 1987 109 2224. 82 A. Koziara K. Osowska-Pacewicka S. Zawadzki and A. Zwierzak Synthesis 1987 487. 83 E. Fabiano B.T. Golding and M. M. Sadeghi Synthesis 1987 190. 84 J. Garcia and J. Villarasa Tetrahedron Lett. 1987 28 341. 85 M. Barta F. Urpi and J. Villarasa Tetrahedron Lett. 1987 28 5941. 86 P. Henklein H.-U. Heyne W.-R. Halatsch and H. Niedrich Svnthesis 1987 166. 130 P. F. Gordon Nitro groups are useful synthetic intermediates and so new methods to incorporate and remove nitro groups are always to be welcomed. Ranganathan and co-workers have reported a safe and practical route to the nitroethylene transfer reagent 2-nitroethylphenylsulphoxidewhich avoids the use of 2-nitroethanol as shown in Scheme -P HOCH,CH,OH PhSCH,CH,OH -* PhSCH,CH,Br 0 I I PhSCH2CH2N0 +-PhSCH,CH,NO Scheme 10 Nitronium tetrafluoroborate in sulpholane is an effective desilylative-nitrating reagent and the method is claimed to be the first effective nitrodesilylation at a saturated carbon.88 Finally triethylsilane proves to be an effective reagent for the reductive removal of the nitro group in a-or P-nitro~ulphides.~~ 8 Sulphur and Phosphorus Since the sulphur and phosphorus area is covered to some extent in other chapters in this volume this section will be kept brief.Optically active sulphur groups have proved very popular in asymmetric induction reactions over the last few years. Solladie and his group have now published improved procedures for preparing large scale quantities of optically pure methyl-p-tolyl sulphoxide which should greatly improve the use of these reagents." Chiral 1-alkynyl-p-tolylsulphoxidescan also be prepared in high yields from the corresponding alkynyl magnesium bromide and chiral menthyl~ulphinate.~~ As a further step the alkynic bond can be reduced to either the E or 2 alkenyl sulphoxides -useful intermediates in their own right.92 Several examples of the use of chiral sulphoxides are again evident this year as illustrated by the total synthesis of Talaromycins A and B which have been accom- plished by successive asymmetric inductions of all the chiral centres using a chiral sulphinyl group as outlined in Scheme ll.92"-' The trifluoromethyl compound (54) can be synthesized from ethyl trifluoroacetate and the corresponding methylsulphoxide in high yield and in good optical The sulphoxide (54) then provides easy access to various chiral trifluoromethyl- substituted compounds which will no doubt be of interest for the pharmaceutical and agrochemical industries.A convenient synthesis of menthyl sulphinate esters has been published and starts from the sulphonyl chloride and corresponding menthyl alcohol.94 High yields of material are assured if trimethyl phosphite is used as the co-reactant. 87 S. Ranganathan D. Ranganathan and S. K. Singh Tetrahedron Lett. 1987 28 2893. 88 G. A. Olah and C. Rochin J. Org. Chem. 1987 52 701. 89 N. Ono T. Hashimoto T. X. Jun and A. Kaji Tetrahedron Lett. 1987 28 2277. 90 G. Solladie J. Hutt and A. Girardin Synthesis 1987 173. 91 H. Kosugi M. Kitaoka K. Tagami A. Takaheshi and H. Uda J. Org. Chem. 1987 52 1078. 92 (a) C.Iwata M. Fujita Y. Moritani K. Hattori and T. Imanishi Tetrahedron Lett. 1987 28 3135; (b) C. Iwata Y. Moritani K. Sugiyama M. Fujita and I. Imanishi ibid. p. 2255; (c) C. Iwata M. Fujita Y. Moritani K. Sugiyama K. Hattori and T. Imanishi ibid. p. 3131. Y3 T. Yamazaki N. Ishikawa H. Iwatsubo and T. Kitazume J. Chem. SOC.,Chem. Commun. 1987 1340. 94 J. M. Klunder and K. B. Sharpless J. Org. Chem. 1987 52 2598. Aliphatic Compounds -Part ( ii) Other Aliphatic Conipounds 131 + \ OR 1 iv v 6 , RO 0 VIII. :34' foH,o -.no<*-c-IX OH ICHl <Ix J Reagents. i LiNEt? [O]; ii. K2C0, 18-crown-6; iii HCI; iv ZnCI,; v TFA benzyl bromide; vi Bu,NF; vii KH; viii TsCI Py;ix P(OMe)3; x Me,CuLi Scheme 11 Thioethers have been produced in excellent yields using a new methodology which involves the fluoride or cyanide ion destannylation of the sulphur-transfer reagents R,SnSSnR, or R3SnSR' in the presence of various alkyl and activated halide^.'^ The conditions are mild neutral and anhydrous and both symmetrical and unsymmetrical thioethers have been prepared.Phosphono-P -ketoesters (55 X = OEt) are valuable synthetic intermediates in the synthesis of (E)-4-alkenyl-3-oxoesters and oxomacrolides.96 The thioester start- 95 D. N. Harpp and M. Gingras Terrahedrori Letr. 1987 28 4373. 96 S. V. Ley and P. R. Woodward Tetrahedron Lett.. 1937 28 345. 132 P. F. Gordon ing material (55,X= SEt) for these reactions is readily obtained from diketene after bromination thiolation and an Arbuzov reaction.Finally in this section a general procedure for the near quantitative preparation of alkyldibenzyl phosphates has been developed and starts by treating alcohols with phosphoramide and methyl tetrazole.97 9 Reviews The following table lists some of the more relevant reviews published in 1987. Title Reference Cross-coupling reactions based on acetals 98 Stereoselective synthesis of building blocks with three consecu- 99 tive stereogenic centres. Important precursors of polyketide natural products Stereoselective aldol reactions with cu,P-unsubstituted chiral 100 enolates Direct homogeneous hydrogenation 101 Formylating reagents 102 Sultone chemistry 103 Camphor derivatives as chiral auxiliaries in asymmetric 104 synthesis Twenty-five years of dimethylsulphoxonium methylide 105 (Corey's reagent) Advances in the preparation of biologically active organo- 106 fluorine compounds Synthetic routes to tetrahydrofuran tetrahydropyran and 107 spiroketal units of polyether antibiotics and a survey of spiroketals of other natural products Asymmetric synthesis of carbon-carbon bonds using sulphinyl 108 cycloalkenones alkenolides and pyrones 97 J.W. Perich and R. B. Johns Tetrahedron Left.,1987 28 101. 98 T. Mukaiyama and M. Murakami Synthesis 1987 1043. 99 R. W. Hoffman Angew. Chem. In[. Ed. Engl. 1987 26 489. loo M. Braun Angew. Chem. Int. Ed. Engl, 1987 26 24. lo' J. M. Brown Angew. Chem. Int Ed. Engl. 1987 26 190. G. A. Olah L.Ohannesian and M. Arvanaghi Chem. Rev. 1987 87 671. D. W. Roberts and D. L. Williams Tetrahedron 1987 43 1027. lo4 W. Oppolzer Tetrahedron 1987 43 1969. 105 Y. G. Gololobov A. N. Nesmeyanov V. P. Lysenko and I. E. Boldeskul Tetrahedron 1987 43 2609. 1Oh J. T. Welch Tetrahedron 1987 43 3123. 107 T. L. B. Boivin Tetrahedron 1987 43 3309. lo* G. H. Posner Acc. Chem. Rex 1987 20 72.