5 Aliphatic Compounds Part (ii) Other Aliphatic Compounds By P. F. GORDON ICI Organics Division Blackley Manchester M9 3DA 1 Introduction The following discussion highlights only a small proportion of the enormous number of eligible publications and so some areas are unfortunately neglected whilst others can be covered only scantily. Nevertheless the major theme of stereocontrol in the synthesis of 'other aliphatic compounds' is reflected by the number of references included in the sections which follow. 2 Alcohols and Ethers The preparation of stereodefined alcohols and ethers has engaged the interest of synthetic organic chemists for many years and particularly those involved in natural product synthesis. This year has proved to be no exception with several useful additions to the literature.The reduction of P-hydroxyketones to provide diols has received considerable attention no doubt because of the ready availability of the starting materials. Several papers have revealed new methods and new reagents to effect this useful step as shown by the reduction of (chiral) hydroxyketone (1) by lithium triethylborohydride.'" The diastereoselectivity is high regardless of the nature of the substituents and the configuration at C-3 of the starting material. By com-parison other reducing agents e.g. DIBAL give lower selectivities and are much more affected by the stereochemistry at C-3. Interestingly omission of the silyl groups leads to a complete reversal in the stereochemistry of the reduction reaction.' The diols derived from (1) have been eventually elaborated to avenaciolide and isoavenaciolide.A related reducing reagent the triacetoxyborohydride [Me4NHB(OAc),] also reduces hydroxyketones in high yield to give the anti-1,3-diol with diastereoselectivities approaching 99%.*Simple substituents at the 2-position of the hydroxyketone appear to have little effect on the stereochemical outcome of the reaction. The same stereochemistry is observed when the less common reducing agent diisopropylchlorosilane is used.3 Once again the diastereoselectivity is very high (95% ) with intermediate formation of (2) followed by intramolecular transfer of hydrogen suggested by the high selectivity. ' (a) K. Suzuki M. Shimazaki and G.4. Tsuchihashi Tetrahedron Lett. 1986,27 6233;(b) K.Suzuki M.Miyazawa M. Shimazaki and G.4. Tsuchihashi ibid. p. 6237. D.A. Evans and K. T. Chapman Tetrahedron Lett. 1986,27 5939. S.Anwar and A. P. Davis J. Chem. Soc. Chem. Commun. 1986 831. 99 100 P. E Gordon Of course the interest in chiral reductions is not just limited to P-hydroxyketones since there is still much interest in reducing isolated ketones to chiral alcohols. The efficient asymmetric reduction of unsymmetrical ketones (R'COR2) in which R' and R2 have similar steric requirements is difficult to attain as testified by the paucity of reagents capable of effecting the reaction. However it now appears that borolane (3) is such a reagent and will reduce various ketones such as 2-propanone 2-methyl-4- octanone etc.in good chemical and asymmetric yield."" A rationale for the very high asymmetric induction observed is also pre~ented.~' H. C. Brown and co-workers have continued their studies in this area and have developed a convenient route to (3) (4) the new chiral borohydride reagent (4) which is generally effective in the asymmetric reduction of alkylphenylketones and hindered aliphatic ketones as well as ket~esters.'",~(-)-Diisopinocampheylchloroborane which is known to reduce (hetero)aralkyl ketones. will also reduce a-tertiary aliphatic ketones to the alcohol with enantiomeric excesses frequently exceeding 90%." Significantly many of the ketones studied resist reduction by many other reagents described previously. Boron reagents are not restricted merely to reductions but have wider application as demonstrated in the synthesis of all four possible stereoisomers of &methyl-homoallylalcohols e.g.(5).6 The key step in the synthesis is the addition of crotyl-diisopinocampheylboron to aldehydes (RCHO) whereby any of the four stereoisomers can be specifically prepared by choosing the appropriate geometrical isomer of the crotyl group (2 or E) and the enantiomer of the isopinane. Enan- tioselectivities are in the region of 95% and diastereoselectivities greater than 99%. A rather similar approach to the synthesis of chiral homoallylalcohols (6) involves (a) T. Imai T. Tamura A. Yamamuro T. Sato T. A. Wollmann R. M. Kennedy and S. Masamune J. Am. Chem. Soc. 1986 108 1402; (b)S. Masamune R. M. Kennedy and J.S. Petersen ibid. p. 1404. (a) H. C. Brown W. S. Park and B. T. Cho J. Org. Chem. 1986 51 1934; (b) ibid. p. 3396; (c) H. C. Brown J. Chandrasekharan and P. V. Ramachandran ibid. p. 3394. H. C. Brown and K. S. Bhat 1.Am. Chem. SOC.,1986 108 293. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 101 the addition of chiral allylic tin( 1v)-diethyltartrate complexes to aldehydes.' Enan- tiomeric excesses are at best reasonable however the route is simple and various substituents a to the alcohol group are tolerated. Tartrates have also been used as chiral auxiliaries in modified E-crotylboronates which add to chiral aldehydes (7) and (8) to produce alcohols (9) and (lo) respectively.8 ?3 OHC/I/O R HO HO OH Many of the alcohols just mentioned are intermediates in synthetic sequences and so apart from having defined stereochemistry at the alcohol centre they must also contain other functional groups capable of further synthetic manipulation.Hence homoalkynylalcohols (11) fall in this general category since they can be prepared by reaction of allenylboronic acid with chiral p-hydroxyketones and can then be converted into chiral lactones by manipulation of the alk~ne.~ Complete 1,3-asymmetric induction is observed in this reaction and as might be expected chemical yields are good. Addition of organometallic reagents to aldehydes either or both of which contain a chiral centre has proved popular in the enantioselective synthesis of alcohols and the next few examples further illustrate the point.Mulzer and his group have investigated the stereochemical course of reactions between organometallic reagents and glyceraldehyde derivatives and have shown that chromium(I1) salts of crotyl bromide will add with high enantiofacial and low diastereofacial selectivity whereas dilithium propionate shows quite the opposite behaviour.'O"Tb Furthermore condi- tions have been worked out leading to the elaboration of all four stereoisomers of brevicomin with enantiomeric excesses approaching 100°/~ ; a corrected value for the optical rotation of (+)-exo-brevicomin is also given in the same paper. 2-Methylfuran adds to glyceraldehyde acetonide to give after ring-opening of the furan and reduction 'carbohydrate'-like multifunctionalized chains such as alcohols (12) and (13)." A high yielding route to various related alditols such as D-lyXitOl ' G.P. Boldrini E. Tagliavini C. Trombini and A. Umani-Ronchi J. Chem. Soc. Chem. Cornrnun. 1986 685. W. R. Roush and R. L. Halterman J. Am. Chem. SOC.,1986 108 294. N. Ikeda K. Omori and H. Yamamoto Tetrahedron Lett. 1986 27 1175 lo (a) J. Mulzer P. de Lasalle and A. Freissler Liebigs Ann. Chem. 1986 1152; (b) J. Mulzer A. Angermann and W. Munch ibid. p. 825. 'I J. Jurczak S. Pikul and K. Ankner Tetrahedron Lett. 1986 27 1711. 102 I? E Gordon ribitol and xylitol also relies upon a highly stereospecific addition to glyceraldehyde acetonide.12 Thus vinyl copper reagents derived from Grignard reagents (14) add to give the syn-diols (15) whereas vinyl cuprates provide anti-diols.The alditols are then produced by epoxidation of the double bond and ring-opening of the epoxide. Likewise optically active a-hydroxy and a$-dihydroxy aldehydes useful intermediates for the synthesis of arachidonic acid metabolites can be synthesized starting from glyceraldehyde a~etonide.'~ Interestingly by the use of the appropriate organometallic reagent and epoxidation conditions all four possible isomers of the epoxide (16) can be obtained. Nucleophilic attack at the epoxide then leads to diols (17) which cleave to either a-hydroxyaldehyde (18) and the starting glyceraldehyde acetonide if (17 R' = H) or a,P-dihydroxyaldehyde (19) from (17 R = H). OSiBu' Phz OBDM OHC&Nu OR' OHC OR' Titanium reagents appear particularly effective at promoting asymmetric induc- tions when chiral auxiliaries are present.For instance chiral benzylic alcohols can be made in very high enantiomeric excess from benzaldehydes and norephedrine- modified tetramethyltitani~rn.'~~ Unfortunately unacceptably low levels of asym- metric induction occur with aliphatic aldehydes. The same authors have explored the chemistry of titanium reagents further and have found that by careful selection of the titanium reagent Le. RTi(OPri) extremely high non-chelation controlled addition to chiral a-siloxyketones occurs.'4b Thus starting from a-siloxyketone (20) a very high ratio (99:l) of alcohols (21) to (22) is obtained; in complete contrast Grignard reagents and alkyl lithium reagents complexed with titanium tetrachloride provide the opposite stereochemistry.Most of the organometallics discussed thus I' M. Kusakabe and F. Sato J. Chem. SOC.,Chem. Commun. 1986 989. S. Okamoto T. Shimazaki Y. Kitano Y. Kobayashi and F. Sato J. Chem. SOC.,Chem. Commun. 1986 1352. (a) M. T. Reetz T. Kukenhohner and P. Weinig Tetrahedron Lett. 1986 27 5711; (b) M. T. Reetz and M. Hullmann J. Chem. SOC..Chem. Commun. 1986 1600. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds far are used in stoicheiometric amounts. However in the addition of dialkylzinc reagents to aldehydes catalytic quantities of the chiral auxiliary (23) suffice to give high asymmetric ind~ction.'~ R'SiO R'SiO R'SiO The chemistry of 2,3-epoxy alcohols is particularly interesting in view of their ready access by Sharpless oxidation of the corresponding alkene.Scheme 1 illustrates some of the useful transformations carried out this year characterized by high yields and high stereocontro1.'6 RIA ~2 R1& R3 CHO JI OH X'" i II OH R2 OH OH OH Reagents i Ref. 16a; ii Ref. 166; Ref. 16c; iv Ref. 16d Scheme 1 Organoyttrium and organolanthanoid reagents are observed to alkylate epoxides with regioselectivities complementary to organocuprate reagents currently the stan- dard reagent for epoxide alkylation." For example epoxide (24) is alkylated to give alcohol (25) by the above reagents whereas alcohols (26) result from alkylation by organocuprate reagents.Is M Kitamura S. Suga K. Kawai and R. Noyori J. Am. Chem. Soc. 1986 108 6071. (a) Y. Takeda T. Matsumoto and F. Sato J. Org. Chem. 1986,51,4728; (b)Y. Kitano T. Matsumoto and F. Sato J. Chem. SOC., Chem. Commun. 1986 1323; (c) J. M. Palazbn B. Ahorbe and V. S. Martin Tetrahedron Lett. 1986 27 4987; (d) L.-x. Dai B.-L. Lou Y.-z. Zhang and G.-z. Guo ibid. p. 4343. 1. Mukerji A. Wayda G. Dabbagh and S. H. Bertz. Angew. Chem. lnt. Ed. Engl.. 1986. 25 760. 104 P. E Gordon Recently several different groups have investigated the selective cleavage of chiral acetals as a route into chiral alcohols. In this way optically pure propargylic alcohols (27) can be obtained in excellent yield and selectivity by reductive cleavage of the ketal(28) with organoaluminium reagents.18 A more facile ring-opening is observed when dioxolanes (29) are opened with nucleophiles e.g.by organocopper reagents or silylated organometallics to yield chiral secondary alcohols (30).'9"7bThe ready availability of the chiral auxiliary from polyhydroxybutyrate used in the dioxolane makes this an attractive route to such chiral alcohols. Chiral tetrahydrofurans (31) can also be cleaved by Me2BBr to produce syn-1,3-diols (32).20This route therefore represents an easy method for generating one extra chiral alcohol centre since the tetrahydrofurans are themselves obtained from 4-alken- 1,2-diols containing a chiral centre at the 2 position. A Scheme 2 illustrates a novel and efficient entry into cyclic ether C-glycosides and relies on a polarity inversion at the anomeric carbon.2' Yet another reference to cyclic ethers involves their preparation by rhodium carbenoid cyclization.22 Thus rhodium(1r) acetate catalyses the cyclization of diazo compounds (33) to seven and eight membered cyclic ethers (34) in good yield.An interesting study of metal exchange reactions in chiral alkenylcarbamates (35) reveals that deprotonation occurs with retention of configuration whereas lithium- titanium exchange occurs with inversion. This reaction presents the intriguing possibility of a hitherto unobserved inversion at an sp3 carbon during electrophilic substitution although this remains to be proven c~nclusively.~~ l8 K. Ishihara A. Mori I. Arai and H. Yamamoto Tetrahedron Lett. 1986 27 983.19 (a) D. Seebach R. Imwinkelrkd and G. Stucky Angew. Chem. Int. Ed. Engl. 1986 25 178; (b)S. L. Schreiher and J Reapn. Tetrahedron Lett. 1986 27. 2945. 20 Y. Guindon Y. St. Denis S. Daignealt and H. E. Morton Tetrahedron Lett. 1986 27 1237. 2' S. Hanessian M. Martin and R. C. Desai J. Chem. SOC.,Chem. Commun. 1986 926. 22 J. C. Heslin C. J. Moody A. M. 2.Slavin and D. J. Williams Tetrahedron Lett. 1986 27 1403. 23 D. Hoppe and T. Kramer Angew. Chrm. Int. Ed. Engl. 1986 25 160. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 105 RO’. a Y OR OR OCH2Ph I P h CH 20**v.*0 H OCH2Ph Reagents i BuOK BuLi Bu,SnCI; ii Bu,NF PhCH,Br; iii BuLi MeI; iv BH,Me2S NaOH H202 Scheme 2 Although several references to stereocontrolled carbonyl reductions have been included chemoselective carbonyl reductions still remain of interest to the synthetic chemist.In this context lithium borohydride in mixed solvents containing methanol (1 equivalent) is reported to be effective in reducing esters lactones and epoxides to the corresponding alcohol whereas carboxylic acids chloro nitro and carbamoyl groups remain unaff e~ted.~~ If larger quantities of methanol are used (4 equivalents) then nitro nitrile as well as primary and tertiary amide groups can be reduced. However secondary amides and metal carboxylates still remain unscathed and so a useful differentiation between functional groups especially in the amide series is available. A ‘universal’ high yielding route to vicinal diols appears to be the reductive coupling of aldehydes and ketones using magnesium on graphite at ambient tem- perat~re.~~ This reagent seems to emulate other commonly used reagents and has a wider scope.Quite often monoprotection of a.symmetrica1 diol is desired in a synthetic sequence and this has now been achieved using a combination of sodium hydride and t-butyldimethylsilylchloride.26 Finally in this section the preparation and n.m.r. analysis of o-methylmandelate esters is cited as an excellent method for establishing the absolute configuration of a secondary alcoh01;~’ full details are provided in the reference. 24 K. Soai and A. Ookawa J. Org. Chem. 1986 51 4000. 25 R. Csuk A. Fiirstner and H. Weidmann J. Chem. Soc.Chern. Cornmun. 1986 1802. 26 P. G. McDougal J. G. Rico Y.-I. Oh and B. D. Condon J. Org. Chem. 1986 51 3388. 27 B. M. Trost J. L. Belletire S. Godleski P. G. McDougal and J. M. Balkovec J. Org. Chern. 1986 51 2310. 106 I? E Gordon 3 Alkyl Halides New and improved syntheses of alkyl halides are always worth noting especially because of their role in so many synthetic sequences. The synthesis of asymmetric alkyl halides may be considered a bonus and is illustrated by the synthesis of chiral a-bromoacetals and hence ketones from the corresponding chiral acetal (36).28 A particularly noteworthy aspect is the high selectivity observed at room temperature. A different sort of selectivity i.e. chemoselectivity is observed in the monochlorina- tion of ketones uia the intermediacy of monoorganothallium derivative^.^^ The monothallium compound is produced from the ketone using an aqueous solution of thallium trichloride and thence gives specifically the product derived from thallation of the methyl group in a methyl ketone.Replacement of the thallium then gives specifically the chloromethylketone. An important route to organofluorine compounds is by displacement of other halogens with KF-sulpholane. It now seems that simple addition of calcium fluoride to potassium fluoride considerably enhances the yield in this displacement rea~tion.~’ Me0 0 R2 2cxco2Me II / I\ OX0 R R’ (36) (37; Z =C02R3;CN) One of the classic reactions of alkyl halides is their hydrolysis to the alcohol.Electrolysis has now been applied to this reaction in the form of a single cell with sacrificial magnesium electrode^.^^ Good yields of alcohols are possible in common solvents such as DMF and acetonitrile. Alkyl halides (R’X)also provide access to the ketones (37) via a palladium-catalysed carbonylative cross-coupling with active methylene compounds.32 Unfortunately the reaction is restricted to aryl and vinyl halides. 4 Aldehydes and Ketones The synthesis of hydroxyketones has again been the focus of intense activity reflecting their importance in natural product synthesis. In this context ketones (38) are derived from !-lactic acid uia an acylation-reduction sequence employing lithium bis-p-tolylthiomethanide; ketones (38) can then be enantioselectively reduced and deprotected to yield chiral aldehydes (39).33 On the other hand chiral epoxy silyl ethers (40) rearrange to chiral p-hydroxyketones (41) stereo~pecifically.~~ In this case titanium tetrachloride proves to be the most effective Lewis acid catalyst for the rearrangement and migratory aptitudes prove to be fairly typical of pinacolone- type rearrangements.28 G. Castaldi S. Cavicchioli C. Giordano and F. Uggeri Angew. Chem. Inf. Ed. Engl. 1986 25 259. 29 J. Glaser and I. Toth J. Chem. Soc. Chem. Commun. 1986 1336. 30 J. H. Clark A. J. Hyde and D. K. Smith J. Chem. SOC. Chem. Commun. 1986 791. 31 S. Sibille E. d’Incan L. Leport and J. Perichon Tetrahedron Leff. 1986 27 3129. 32 T. Kobayashi and M. Tanaka Tetrahedron Lett.1986 27 4745. 33 G. Quanti L. Banfi and E. Narisano J. Chem. Soc. Chem. Commun. 1986 136. 34 K. Maruoka M. Hasegawa and H. Yamamoto J. Am. Chem. SOC.,1986 108. 3827. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds The aldol reaction is probably the method of choice for producing P-hydroxy- ketones and certainly work continues apace in this important area of research. For instance the Lewis acid (42)proves to be an effective catalyst for enantioselective additions of enolsilanes (and trimethylsilylcyanide) to aldehydes.35 The rhodium complex [(CO)Rh(DPPB)+X-] and IUI(CO)~will also catalyse aldol reactions between silyl enol ethers and aldehydes; surprisingly this is the first example of the use of rhodium catalysis in such reactions.36 A more unusual type of aldol reaction has been reported to give unsaturated ketones (43).37In this case 1,4 addition of iodide ions to an a,P-acetylenic ketone yields an allenolate which will then add to aldehydes (R'CHO) to give (43).A high 2-stereoselectivity is achieved if the reaction is maintained at -78 "Cwhereas at 0 "C the E-isomer predominates.Ph G-Ph I Cl (42) SiMe3 (43) RMew Me %Me3 In turn unsaturated acetylenic ketones are readily prepared by treatment of aldehydes with vanadium acetylides via an oxidative nucleophilic addition.38 The synthesis is a versatile one since alkyl and aryl acetylides as well as aryl alkyl and vinyl aldehydes will undergoe the reaction in good chemical yield. In contrast the synthesis of chiral acetylenic ketones such as (44) depends on the facile aluminium- catalysed pinacol rearrangement of alcohols (45).39 The rearrangement occurs with very high selectivity with the acetylenic group acting as the non-migrating one.The same paper also describes the stereospecific reduction of the acetylenic ketones (44) to chiral alcohols with high threo selectivity. A useful route to a$-unsaturated ketones has been detailed and involves the palladium-catalysed decarboxylative cross-condensation of aryl halides.40 The yield 35 M. T. Reetz F. Kunisch and P. Heitmann Tetrahedron Lett. 1986 27,4721. 36 S. Sato I. Matsuda and Y. Izumi Tetrahedron Lett. 1986 27,5517. 37 M. Taniguchi and T. Hino Tetrahedron Lett. 1986 27,4767. 38 T. Hirao D. Misu and T. Agawa Tetrahedron Lett.1986 27,933. 39 K. Suzuki T. Ohkuma M. Miyazama and G.4. Tsuchihashi Tetrahedron Lett. 1986 27,373. 40 M.Kadokura T.-a. Mit and Y. Watanabe J. Chem. SOC.,Chem. Commun. 1986 252. 108 I? E Gordon of products are high in the examples quoted but so far examples appear limited to arylketones. Michael addition of ketones to unsaturated esters occur with high enantioselectivity (e.e. > 92% ) and antidiastereoselectivity (d.e. > 90% ) if they are converted first into the SAMP or RAMP hydra zone^.^' After formation of the lithium salt the addition to the unsaturated esters provides the ketoester (46) with either the S or R configuration depending upon the configuration of the starting hydrazone. Copper-catalysed conjugate additions of Grignard reagents to a,@-unsaturated ketones in the presence of trimethylchlorosilane-HMPA occur in higher yield and with enhanced regio stereo and chemoselecti~ity.~~~*~ It appears that the silyl chloride is more than a simple enolate trap and genuinely accelerates the addition reaction.Paquette and his group have reported on n-facially controlled nucleophilic additions of chiral vinyl organometallic reagents to chiral @ y-unsaturated ketones.43 Although limited in scope so far the paper demonstrates the feasibility of attaining n-facially controlled nucleophilic addition of chiral vinyl organometallics to chiral unsaturated ketones. The reaction is illustrated in Scheme 3 and is one of seven examples. MeO-OMe OMe + Scheme 3 Several other examples of selective nucleophilic additions of Grignard reagents have been reported.In what is claimed to be the first example of a highly stereoselec- tive addition of Grignard reagents to chiral open-chain a-ketoacetals (47) chiral a-hydroxyacetals (48) have been obtained both in high chemical yield and with high diastereo~electivity.~~~*~ This particular route has been used to prepare various chiral a-hydroxyketones after unmasking (48) and thence (R)and (S)-mevalolac- tone.44aIn the case of the a,@-unsaturated acetal (49) nucleophilic attack by phenyl copper reagent takes place exclusively at the &position to give chiral @-substituted 41 D. Enders K. Papadopoulos and B. E. M. Rendenbach Tetrahedron Lett. 1986,27 3491. 42 (a)E.Nakamura S. Matsuzawa Y. Horiguchi and 1. Kuwajima Tetrahedron Lert. 1986 27 4029; (b) Y. Horiguchi S. Matsuzawa E. Nakamura and I. Kuwajuma ibid. p. 4025. L. A. Paquette and K. S. Learn J. Am. Chem. SOC.,1986 108 7873. 43 44 (a) Y. Tamura T. KO H. Kondo H. Annoura M. Fuji R. Takeuchi and H. Fujioka Tetrahedron Lert. 1986 27 2117; (h)M. P. Heitz F. Gellibert and C. Mioskowski ibid. p. 3859. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 109 aldehyde (50) after deprotection and recovery of the chiral auxiliary.45The reaction therefore provides an alternative to a Michael addition reaction and avoids the problem of the competing 1,2-addition; unfortunately the reaction is of rather limited scope as it stands. A quite different use of chiral acetals can be seen in the specific and aluminium-catalysed cleavage of 2-and 4-substituted cyclohexanone acetals to give chiral2-and 4-substituted cyclohe~anones.~~ Since the cyclohexanone acetals are obtained from the cyclohexanone the overall procedure represents an effective method for converting achiral cyclohexanones into chiral ones.Me02C Me02C 77 '2C02Me 0 R' 0 RqR1 0 HU K' (47) (48) X I N,-C-COR YCHO I Y 'Ph R Apart from the above there have been a host of references to the synthesis and reactions of aldehydes and ketones. For instance a synthesis of a new class of chiral ketone derivative (51) has been published in which the a-carbon contains four different labile groups chosen from halogens (X) oxygen and sulphur groups (Y) and nitrogen functions such as azide amino and nitro group (Nf).47These com-pounds should be particularly useful as intermediates.Scheme 4 illustrates some further transformations in which higher yields or better selectivities are attainable with the reagents des~ribed.~~-~' Finally in this section there have been a number of reports dealing with enan-tioselective deprotonation. In the first chiral lithium bases (52) give chiral enol ethers upon deprotonation and trapping of the enolate derived from 4-alkylcyc-lo hex an one^.^^ Thus enantiomeric excesses in the region 80-97O/0 have been achieved with the base (52; R' = Ph X = 4-methylpiperidyl). A similar approach uses the chiral base (53) with symmetrical ketones so far limited to cyclohexanones; after trapping of the enolate enantiometric excesses approaching 74% have been obtained.54 4s P.Mangeney A. Alexakis and J. F. Normant Tetrahedron Lett. 1986,27 3143. 46 Y. Naruse and H. Yamamoto Tetrahedron Lett. 1986,27 1363. 47 Y. Takeuchi M. Asahina A. Murayama K. Hori and T. Koizium J. Org. Chern. 1986,51 955. 48 J. A. Soderquist and E. L. Miranda Tetrahedron Lett. 1986,27 6305. 49 T.Hirao D.Misu K. Yao and T. Agawa Tetrahedron Lett. 1986,27 929. so G. A. Molander and G. Hahn J. Org. Chern. 1986,51 1135. " T. Sato H. Matsuoka T. Igerashi and E. Murayama Tetrahedron Lett. 1986,27 4339. 52 T. Satoh S. Motoheshi and K. Yamakawa Tetrahedron Lett. 1986,27 2889. 53 R. Shirai M.Tanaka and K. Koga J.Am. Chern. SOC.,1986,108,543. N. S.Simpkins J. Chern. SOC.,Chern. Cornmun. 1986.88. 54 110 P. F. Gordon RMgBr + RCOCl c):-(-xi R 2.0 Ri v R' = R' = -CH=CH-R 0 iv R'= Me I II RCCHR' I RC02R' R~*OH X 0 %Me2 ; ii VCI,; iii SmI,; iv R3SnCH2; v Ph.!!CHR2 MCPBA Reagents i CI (-> I Scheme 4 A completely different approach to chiral ketones relies upon the asymmetric oxidation of 1,3-dithiolanes to the S-oxide followed by separation of the diastereoisomers and thence deprotection to the resolved ketone.55 This therefore provides a convenient method for resolving carbonyl compounds. 5 Carboxylic Acids and their Derivatives The formation of a and P-hydroxyacids with defined stereochemistries has been an important synthetic target for some years now because of their importance as subunits in natural products.p-Hydroxyacids can be prepared by exploiting the aldol reaction and useful references to this methodology can still be found. For example chiral ferrocenyl-gold (I) complexes catalyse the asymmetric aldol reaction of isocyanates with aldehydes producing optically active 5-alkyloxazoline carboxy- late^.'^ The oxazolines can then be hydrolysed to the corresponding a-amino-p- hydroxy carboxylic acid esters in high yield. An alternative route into chiral hydroxy acids much used in recent years requires the presence of a chiral auxiliary. Usually the auxiliary is treated with the acid prior to the aldol reaction. This route has again proved a popular oiie as exemplified in the reactions of the new thiones (54).The latter react viu their tin enolates with a$-unsaturated aldehydes and 4-acetoxyazetidinones to give a-hydroxy-y,6-unsaturated acids and 4-substituted-P- '' 0. Bortolini F. Di Furia G. Licini G. Modena and M.Rossi Tetrahedron Lett. 1986 27 6257. Y. Ito M. Sawarnura and T. Hayashi J. Am. Chem. Soc. 1986. 108 6405. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds lactams respectively with enantioselectivities approaching 100°/o.57a1b Further studies with the known chiral auxiliary (55) have yielded rather interesting results. For example the acid derivatives (55 R = -COCH2R) can be converted readily into the triisopropoxy tin enolate which then reacts with aldehydes to give aldol products (56) possessing the opposite diastereoselectivity than that obtained with boron enolate~.~'~ Thus use of either titanium or boron permits convenient access to both stereoisomers starting from the same chiral auxiliary.The same chiral auxiliary can be used in crotonate imides [56 R = C(O)C=CR] which then react with aldehydes to give vinyl compounds (57) with high diastereoselectivity. If the chiral auxiliary (58) is used products with the opposite diastereochemistry are obtained.58bA variation on the use of titanium enolates utilizes triphenyl phosphine as complexing agent whereupon a dramatic enhancement of the anti-syn ratio is observed.59 Chiral iron complex e.g. (59) is a more unusual chiral auxiliary that has excited much interest in the last two or three years.In the presence of Lewis acids these enolates (59) undergo highly stereoselective aldol reactions with ketones and imines to give the corresponding hydroxycarboxylic acids and P-aminoacids respectively after removal of the iron.60 In the same (full) paper the latter have been converted into p-lactams thus providing a useful extension to this area of chemistry. P-Silylenolates (60) will also participate in diastereoselective aldol reac- tions and depending upon the stereochemistry of the enolate erythro products from (60;X = Me Y = Li) or threo products from (60;X = Li Y = Me) are obtained.6' xcJJRl (59) a-Hydroxycarboxylic acids can also be synthesized conveniently by hydroxylation of the enolate of the carboxylic acid.The chiral auxiliaries used in the enantiospecific aldol reactions described above function equally well in this hydroxylation reaction. 57 (a) Y. Nagao Y. Hagiwara T. Kurnagai M. Ochiai T. Inoue K. Hashirnoto and E. Fujita J. Org. Chem. 1986 51 2391; (b)Y. Nagao T. Kurnagai S. Tarnai T. Abe Y. Kurarnoto T. Taga S. Aoyagi Y. Nagase M. Ochiai Y. Inoue and E. Fujita J. Am. Chem. SOC.,1986 108 4673. 58 (a) M. Nerz-Stormes and E. R. Thornton Tetrahedron Lett. 1986 27 897; (b) D. A. Evans E. B. Sjogren J. Bartroli and R. L. Dow ibid. 1986 27 4957. 59 C. Palazzi L.Colombo and C Gennari Tetrahedron Lett.. 1986 27 1735. 60 L. S. Liebeskind M. E. Walker and R. W. Fengl J. Am. Chem. SOC.,1986 108 6328. 61 I. Fleming and J. D. Kilburn 1.Chem.SOC.,Chem. Commun. 1986 305. 112 €? E Gordon Thus the protected hydroxylated acid derivatives (61) are synthesized from the corresponding acid derivative upon treatment with dibenzyl peroxydicarbonate.62" Specificity can be as high as 99% and the method can be considered a viable alternative to several of the existing procedures. In a related reaction DBAD (Boc-N=N-Boc) gives the chiral hydrazines (62) in equally high yield which can be used further or cleaved to the amine constituting a very useful route to chiral a-amino acids.62b An alternative to using an achiral oxidizing agent and chiral substrate as described above is to generate a chiral oxidizing agent capable of a-hydroxylating the enolate. This has been done with the chiral oxaziridine (63).63The chemical yields are very good but enantiomeric excesses are somewhat variable.Chiral a-substituted-a- hydroxycarboxylic acids can also be synthesized by first taking an achiral hydroxyacid and then enantiospecifically alkylating it. This has been demonstrated via the intermediacy of chiral dioxolanones (64) which can be alkylated in excellent yield and with good ~pecificity.~~ Hydrolysis then yields the chiral substituted a-hydroxyacid and starting chiral auxiliary. In contrast to these routes to chiral a-hydroxyacids are others proceeding by way of a rearrangement reaction. Thus chiral ester (65) undergoes an auxiliary directed diastereoselective Claisen rearrange- ment to hydroxyacid (66) following a hydrogenation step.65 Similarly the chiral esters (67) rearrange to a-hydroxyesters (68) in good yields and with high diastereoselectivities.66a9Particularly noteworthy here is that zirconium enhances considerably the enantioselectivity observed in the rearrangement.Theene reaction of chiral glyoxylates with alkenes also leads to chiral a-hydroxy esters (69) in which the enantiospecificity is controlled during the rearrangement step.67 In particular 62 (a) M. P. Gore and J. C. Vederas J. Org. Chem. 1986 51 3700; (6) D. A. Evans T. C. Britton R. L. Dorow and J. F. Dellaria J. Am. Chem. Soc. 1986 108 6395. 63 F. A. Davis M. S. Haque T. G. Ulatowski and J. C. Towson J. Org. Chem. 1986 51 2402. 64 W. H. Pearson and M.-C. Cheng J. Org. Chem. 1986 51 3746. 65 J. Kallmerten and T.J. Gould J. Org. Chem. 1986 51 1152. 66 (a) M. Uchikawa T. Hanamoto T. Katsuki and M. Yamaguchi Tetrahedron Lett. 1986 27,4577; (6) M. Uchikawa T. Katsuki and M. Yamaguchi hid. p. 4581. 67 J. K. Whitesell R. M. Lawrence and H. H. Chen J. Org. Chem. 1986. 51 4779. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds OMOM R' /I1 0 R2 R3 OMOM ,OMOM LPh R' OH (68) (69) (70) the nature of the chiral auxiliary used for the reaction has been carefully examined and of the thirteen auxiliaries tried the cyclohexane (70) appears the best with induction levels claimed to be better than 99.9 to 0.1. In their turn chiral P-hydroxyesters derived from tartaric acid have been converted into chiral epoxyesters (71) uia bromination and ring-closure.68 By suitable manipu- lation of reaction conditions and substrate all four possible stereoisomers are attainable in both a diastereoisomeric and enantiomeric pure state.Likewise esters derived from the chiral isobornyl alcohol (72) can be chlorinated and brominated highly enantiospecifically to give chiral a-halogenoesters which furnish azidoesters upon treatment with sodium azide.6' A simple hydrogenation step then leads to chiral a-aminoacids (73) in what constitutes a simple high-yield route to these important materials. Another synthesis of chiral a-aminoacids proceeds by a different strategy and starts from the benzophenone imine of the methyl ester of glycine." The asymmetric induction occurs during the allylation reaction catalysed by pal- ladium co-ordinated to a chiral ligand.Although the phosphorus ligand (+DlOP) appears the best of the ligands tried optical yields are still only of the order of 60%. V (so, t(l>) (71) (72) (73) In the highly diastereoselective a-alkylation of a,@-unsaturated esters (74) to P,y-ester (75) no new asymmetric centres are induced instead an almost complete (>95%) 1,3-transfer of chirality is observed upon treatment with an organocopper- 68 S. Saito Y. Nagao M. Miyazaki M. Inaba and T. Moriwake Tetrahedron Lett. 1986 27 5249. 69 W. Oppolzer R. Pedrosa and R. Moretti Tetrahedron Lett. 1986 27 831. 'O J. P. Genet D. Ferroudl S. Juge and J. R. Montes Tetrahedron Lett. 1986 27 4573. 114 P. F.Gordon Lewis acid complex.71 In contrast iron complexes such as (76) are usually synthe- sized with the purpose of inducing new or additional chiral centres into a suitable substrate. A series of papers has been published dealing with various aspects of asymmetric inductions involving such chiral iron ligands. In particular conditions have been worked out for improved stereochemical control in the alkylation of enolates derived from (76) resulting in an amelioration in the observed selectivities to greater than 200 1.72a In this case it seems that addition of an aluminium reagent followed immediately by the alkylating agent is beneficial. A most unusual synthesis of a pentanoic acid also uses the same type of iron complex and proceeds by an iterative homologation process involving alternate carbonylation and reduction steps.72bThus all the carbon atoms in the pentanoic acid are derived from carbon monoxide and this paper therefore represents an interesting model study of building carbon chains from simple precursors i.e.synthesis gas. Because of their good electron-accepting ability the carboxylic acid group and certain of its derivatives are efficient promoters of the Michael reaction. In several areas of carboxylic acid chemistry the accent has been on asymmetric induction reactions and this is certainly the case for the Michael reaction. In conjugate additions to alkylidene malonates the chiral enamines (77) add to give chiral triesters with excellent enantiomeric exce~s.~~~.~ As might be expected the level of asymmetric induction depends critically on reaction temperature and solvent and in this case toluene-HMPA at -95°C gives best results.An alternative method for promoting asymmetric inductions in Michael reactions is to convert the unsaturated carboxylic acid group into a chiral amide with a chiral amine. This method works well with amine (78) since Grignard reagents add to the resulting chiral a,p-unsaturated amide with enantiomeric excesses in the range 80-90% .74 Simple hydrolysis then releases the chiral auxiliary for further use. Several references to chiral iron com- plexes have already been noted and the following two demonstrate further their versatility in asymmetric synthesis. a-Alkyl-a,p-unsaturated acyl groups attached directly to the chiral iron centre c$ (76) undergo asymmetric Michael additions to yield E-enolates which can then be trapped to yield quaternary carbon centres highly ~tereo~electively.~~~~~ If amines are used as nucleophiles then chiral p-aminoacids are formed which can be cyclized to give stereodefined 2,3-disubstituted- p-lactams in good yield.75b 71 T.Ibuka T. Nakao S. Nishii and Y. Yamamoto J. Am. Chem. SOC., 1986 108 7420. 72 (a) S. L. Brown S. G. Davies D. F. Foster J. 1. Seeman and P. Warker Terrahedron Lett. 1986 27 623; (b) S. L. Brown and S. G. Davies J. Chem. SOC.,Chem. Commun. 1986 84. 73 (a) K. Tomioka K. Ando K. Yasuda and K. Koga Tetrahedron Lett. 1986,27,715; (6) K. Tomioka K. Yasuda and K. Koga ibid. p. 4611. K. Tomioka T.Suenaga and K. Koga Tetrahedron Lett. 1986 27 369. (a) S. G. Davies and J. C. Walker J. Chem. SOC., 74 75 Chem. Commun. 1986,495; (b) S. G. Davies I. M. Dordor-Hedgecock. K. H. Sutton and J. C. Walker Tetrahedron Lett. 1986. 27 3787. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds Finally in this section two reports have been published referring to efficient methods for transesterification. In the first distannoxane is found to be an efficient catalyst for transesterification of methyl esters with various alcohols,76a whereas in the second butyl lithium in tetrahydrofuran catalyses the In this latter case the process works for aromatic and @-unsaturated methyl esters with primary secondary and (particularly) tertiary alcohols.6 Lactones Just as in previous sections an important theme running through many lactone syntheses is one of asymmetric induction. For instance acid-catalysed ring-opening of epoxide (79) takes place at C-1 with complete retention of configuration at C-2 to form ethers (80). However in base nucleophiles attack at C-2 with inversion to give lactols (81). Both lactols (80) and (81) may be oxidized to the corresponding y-lactones and so the overall route represents a useful synthesis of highly substituted stereodefined y-lactone~.~~ Ziegler and his group have studied the synthesis and use of y- butyrolactones as templates in the preparation of invictolide (+)-methyl-Prelog- Djerassi lactone and other homochiral tripropionate Thus the 3-methyl-y- butyrolactone (82) can be converted into enolethers (83) which then rearrange to lactones (84).Lactones (84) can then be transformed to lactones (85) by a Baeyer- 76 (a) J. Otera T. Yano A. Kawabata and H. Nozaki Tetrahedron Lett. 1986,27,2383;(6)0.Meth-Cohn J. Chem. SOC.,Chem. Commun. 1986 695. 77 L. Lussmann D. Hoppe P. G. Jones C. Fittschem and G. M. Sheldrick Tetrahedron Lett. 1986,27,3595. 78 (a) F. E. Ziegler E. P. Stirchak and R. T. Wester Tetrahedron Lett. 1986 27 1229; (b) F. E. Ziegler A. Kneisley and R. T. Wester ibid.,p. 1221; (c) F. E. Ziegler and R. T. Wester ibid. p. 1225. 116 P. F. Gordon Villiger reaction. An iterative process is then used to access (+)-methyl-Prelog- Djerassi lactone.Similarly the S-isomer of (82) has been used to generate (+)-invictolide and no doubt various related systems such as (86) can be obtained by a similar sequence.78b Achiral monosubstituted lactones can be kinetically resolved by an enantioselec- tive partial neutralization with (1S)-(+)-10-camphorsulphonic acid following an initial alkaline hydrolysis of the lactone ri11g.7~ In this way (R) or (S) isomers can be obtained in good enantiomeric excess. Chiral lactones have also been obtained by acid-catalysed cyclization of ketone dithioacetals (87) leading to protected lac- tones (88) with the stereochemistry known at ~-2.~' (87) It is by no means true that all the interesting work carried out in the lactone area is concerned with stereocontrolled reactions since there is considerable scope for useful lactone ring synthesis.a-Methylene- y-lactones (89) are of great topical interest and can be prepared from tin reagents (90) via a Lewis acid-catalysed reaction with aldehydes (R'CHO) followed by acid-catalysed cyclization.81 Alterna- tively la2tones (89) are formed when cyclopropanes (91) are added to iminium salts (CH2=NMe2C1-) followed by ring-closure.82 Both routes are characterized by good yields of desired product. Radical reactions have been the subject of renewed interest ' to synthetic chemists and several applications to lactone synthesis can be found this year. For example alkenoyloxymethyl iodides or selenides are readily cleaved with tributylstannane to radicals such as (92) concomitant with ring-closure to the corresponding 5-or 6-membered lac tone^.^^ Ketyl radicals (93) also undergo facile ring-closure onto alkynes giving rise to a-methylene- y-butyrolactones (94) in excel- lent yield.84 The possible intermediacy of radicals in the samarium iodide-induced l9 K.Fuji M. Node and M. Murata Tetrahedron Lett. 1986 21 5381. 8o K. Suzuki T. Masuda Y. Fukazawa and G.4. Tsuchihashi Tetrahedron Lett. 1986 27 3661. J. E. Baldwin R. M. Adlington and J. B. Sweeney Tetrahedron Lett. 1986,27 5423. 82 H.-A. Reissig and H. Lorey J. Chern. SOC.,Chem Comrnun. 1986 269. 83 A. L. J. Beckwith and P. E. Pigou J. Chern. SOC.,Chern. Cornrnun. 1986 85. 84 M. D. Bachi and E. Bosch Tetrahedron Lett. 1986 21 641. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds reductive coupling of ketones or aldehydes (R3COR4) to a,P-unsaturated esters (R'CHCHR2COEt) must also be con~idered.'~" In this case good yields of the y-lactone (95) result and the coupling reaction may also be extended to other electron-deficient alkenes.Similarly samarium iodide promotes the cyclization of bromoaldehyde (96) to medium and large ring lactones (97) and would therefore appear to be a versatile reagent for lactone synthesis.85b Bu3Sn E .7&t3 RHNOC R' R' Ac Y. Most of the preceding discussion has dealt with building lactone rings; however one paper discusses the chiral functionalization of lactone rings. Thus lactone enolates will react with chiral enamines (98) via an addition-elimination reaction yielding chiral lactones (99) in reasonable enantiomeric excess.86 This is therefore claimed to be the first example of a chiral induction through a one-pot addition- elimination sequence in an aliphatic system.7 Phosphorus and Sulphur Chiral sulphur groups have proved extremely useful in asymmetric inductions and so new or improved routes to preparing chiral sulphur groups are always to be welcomed. This is the case for the oxidation of sulphide to chiral sulphoxides via 85 (a)S.4. Fukuzawa A. Nakanishi T. Fujinami and S. Sakai J. Chem Soc. Chem. Commun. 1986,624; (b)T. Tabuchi K. Kawamura J. Inanaga and M. Yamaguchi Tetrahedron Lett. 1986 27 3889. 86 K. Fuji M. Node H. Nagasawa Y. Naniwa and S. Terada J. Am. Chem. SOC.,1986 108 3855. 118 P.F. Gordon the chiral iodine oxidizing agent (loo).*’ Fair levels of asymmetric induction are observed and good chemical yields can be expected. Chiral sulphoxides have been the most exploited of the chiral sulphur groups and several references demonstrating their versatility are again to be found. Thus the sulphoxide (101) rearranges to provide the (R)-hydroxyenoates (102) with fairly good optical purity (70%) and in acceptable yields (>68’/0 ).88 In a completely different reaction chiral P-ketosul- phoxides have been enantiospecifically reduced to the corresponding P-hydroxysul-phoxides followed by conversion into butenolides (103) via oxidation to the sulphin- ate and treatment with the sodium salt of iodoacetic acid.*9 Because the nature of the reducing agent ultimately determines the stereochemistry of the hydroxysul- phoxide both enantiomers of (103) are accessible upon demand merely by altering the reducing agent.In the synthesis of (+)-pentalene a chiral vinyl sulphoxide is used in a highly enantiospecific Michael reaction to give the 5,5 ring system (104 X = O).90Interestingly reduction of the sulphoxide gives the sulphide (104 X = :) which is then ring-closed hydrolytically in good yield by a mixture of formic and trifluoroacetic acids. This reagent combination seems to circumvent the problems previously experienced in hydrolysing vinyl sulphides with an a carbon-hydrogen bond. 02+);*.. RCO; R1-’C02Me 0 (101) (102) Although used less frequently chiral sulphones will also function as useful chiral auxiliaries and have been prepared in high enantiomeric excess from achiral sulphin- ates by a palladium-catalysed rearrangement in the presence of chiral phosphorus ligands.” Chiral sulphur groups have also been applied to asymmetric inductions in the Michael reaction because of their strong electron acceptor properties.Thus in conjugate additions of organometallic reagents to vinyl sulphoximines (105) high asymmetric induction is observed (>90Y0).~~ The Michael adducts can then be transformed to various interesting compounds by simple manipulation of the sul- phoximine group; for instance sulphoximine (105 R = C02R) can be readily cleaved to give chiral 2-alkylalkanoic acids. ” T. Imamoto and H. Koto Chem. Letr. 1986 967.88 H. Kosugi M. Kitaoka A. Takahashi and H. Uda J. Chem. SOC.,Chem. Commun. 1986 1268. 89 G. Solladie C. Frechou G. Demailly and C. Greck J. Org. Chem. 1986 51 1912. 90 D. H. Hua J. Am. Chern. SOC.,1986 108 3835. 91 K. Hnroi and K. Makino Chem. Lett. 1986 617. 92 S. G. Pyne J. Org. Chem. 1986 51 81. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 119 Several efficient routes to thiolesters have again been published. Nucleophilic attack by sulphur in thiolacids upon alcohols is catalysed by zinc iodide and yields the corresponding thiolesters in high yield.93" The reaction appears quite general with primary secondary tertiary allylic and benzylic alcohols all reacting well. An alternative route to thiolesters also yields satisfactory results and involves the reaction of anhydrides or acid chlorides with thiols catalysed by cobalt(I1) chloride.93b Once again the reaction appears quite general.In their turn thiols have been prepared under the mildest conditions presently available by desilylation of the appropriate a-trimethylsiloxy sulphides which can be made by standard literature meth0ds.9~ Warren and his group have continued their studies of the synthetic utility of the Homer-Wittig reaction and have now devised a route to Horner-Wittig intermediates (106) stereoselectively; the latter can then be used to generate 2-a,P-unsaturated acids in high yield.95" Similarly Horner-Wittig adducts (107) are prepared by reduction of the corresponding ketone with cerium trichloride catalysis and the resultingdcohols converted into the E-isomer of the unsaturated hydroxya~ids.~'~ R' Ph2P+ I HO-PRI C0,Bu' H (106) (107) (108) Several new chiral phosphines such as (108) have been developed and found to be highly effective ligands in the catalytic asymmetric synthesis of (R)-(-) -pantolac-tone.96 The phosphines find application in the hydrogenation step and will presum- ably have wider application.Finally in this section it has been shown that triethyl- phosphine advantageously replaces triphenylphosphine tributylphosphine and other such phosphorus( 111) reagents in phosphazene reactions (amide and phthalimide formation) and disulphide cleavage-based reactions such as found in reduction of disulphides thioester formation and some hydroly~es.~' 8 Amines and Related Functional Groups As in many of the other sections asymmetric inductions in amine chemistry is of topical interest though perhaps not a dominating theme.An elegant route to chiral amines in high asymmetric yield has been developed by Brown and co-workers using organoboron reagents. Thus borinanes (R*B0,Me3) of essentially 100% optical purity prepared by asymmetric hydroboration of readily available prochiral olefins followed by removal of the chiral auxiliary can be converted into borinic ester derivatives (R*MeBOMe30Ac).98 Elaboration of these esters to the primary amine is then easily accomplished by treatment with hydroxylamine o-sulphonic 93 (a) J. G. Ganthier F. Bourdon and R. N. Young Tetrahedron Lett.1986 27 15; (b) S. Ahmad and J. Iqbal ibid. p. 3791. 94 D. N. Harpp and M. Kobayashi Tetrahedron Lett. 1986 27 3975. 9s (a)D. Levin and S. Warren Tetrahedron Lett. 1986,27,2265; (b)N. Greeves and S. Warren ibid.,p. 259. 96 H. Takahashi M. Hattori M. Chiba T. Morimoto and K. Achira Tetrahedron Lett. 1986 27 4477. 97 F. Urpi and J. Vilarrasa Tetrahedron Lett. 1986 27 4623. 98 H. C. Brown K.-W. Kim T. E. Cole and B. Singaram. J. Am. Chem. SOC.,1986 108 6761. 120 P. I? Gordon acid. An alternative approach starts from a chiral imine which provides the amine (109) after treatment with an allylic boron compound. The high 1,2 asymmetric induction is rationalized via a six-membered chair-like transition state.99 A totally different approach to chiral amines is demonstrated in Scheme 5.'O0 Noteworthy aspects of this route are the hindered nature of the amines in which two tertiary carbons can be constructed (Y to the nitrogen.Since chiral hindered amines are frequently used in chiral induction reactions this then constitutes a valuable route to some potentially novel and synthetically useful systems. R3 R R3 i R / 3-NH2+0=( -)rN=C, R' RZ R4 R' R2 R4 Reagents i TiCl,; ii H2-Pt/C; iii PbO,; iv Na Scheme 5 Scheme 6 outlines a new general high yield synthesis of primary amines."' Although one group (Y to the amino function must be aryl the second group (R') can be varied depending only upon the accessibility of the organometallic reagent. ArCHO + NHzSOzNH2 -(ArCH=N)#02 \ii iii R I ArCHNHz Reagents i RM; ii H202-Py; iii NaOH Scheme 6 Protection and deprotection of amines is a vitally important process in organic synthesis.In this context 4-trimethylsilylethanesulphonylchloride is reported to be a new reagent for the protection of amines as the corresponding sulphonamide.lo2 99 Y. Yamamoto S. Nishii K. Maruyama T. Komatsu and W. Ito J. Am. Chem. SOC.,1986 108 7778. 100 E. J. Corey and A. W. Gross J. Org. Chem. 1985,51 5391. 101 F. A. Davis M. A. Giangiordano and W. E. Starner Tetrahedron Lett. 1986 27 3957. 102 S. M. Weinreb D. M. Demko T. A. Lessen and J. P. Demars Tetrahedron Lett. 1986 27 2099. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 121 Although amines have previously been protected as sulphonamides a major problem has often been the vigorous conditions required for deprotection.In this case deprotection can be carried out simply by treatment with fluoride ions. The t- butyldiphenylsilyl group is another good amine protecting group notably stable to chromatography basic and hydrolytic reagents as well as alkylating and acylating reagents yet it is cleaved readily by mild acid and pyridine-HF.lo3 Regarding the cleavage of protecting groups tellurolates have been proposed as efficient reagents for the removal of the trichloro-t-butyloxycarbonyl moiety and complements the alternative methods of deprotection.lw One of the most important reactions involving the amine group is the acylation reaction as used in peptide synthesis.In this context fluorenylmethoxycarbonylamine acid derivatives of 3-hydroxy-4-oxodihydroben-zotriazene are particularly effective acylating agents in solid-phase peptide syn- thesis.''' An important advantage with these reagents is their self-indicating ability since upon completion of the coupling reaction the transient yellow colour fades. One of the conventional routes to primary amines particularly aromatic amines is via reduction of the corresponding nitro group; occasionally however the reverse reaction is desired. Dimethyldioxirane appears to be an excellent reagent if not the reagent of choice for converting amines of all types into the corresponding nitrocom- pound with yields typically better than 80%.'O6 A more conventional synthesis of nitroaliphatics proceeds by nitrotrifluoroacetoxylation of 1,3 dienes.'07 Elimination of the acetoxy group is induced easily to yield 1 -nitro- 1,3-dienes in fair to good yields.Finally mesyl azide appears to be a superior reagent for the diazo transfer reaction."* It is relatively cheap and facilitates easy work-up of the reaction products. 9 Reviews The Table below lists some of the reviews relevant to this chapter. Title Reference (1) Asymmetric epoxidation of allylic alcohols the Sharpless 109 epoxidation (2) The application of elemental fluorine in organic synthesis 110 (3) R-and S-(2,3)-o-lsopropylideneglyceraldehydesin stereo- 11 1 selective organic synthesis (4) The chiroptical properties of carbonyl compounds 112 (5) a-Oxoketene dithioacetals and related compounds 113 103 L.E. Overman M. E. Okazaki and P. Mishra Tetrahedron Lett. 1986 27 4391. 104 M. V. Lakshmikantham Y. A. Jackson R. J. Jones G. J. O'Mallay K. Ravichandran and M. P. Cava Tetrahedron Lett. 1986 27 4687. 105 E. Atherton L. Cameron M. Meldal and R. C. Sheppard J. Chem. Soc. Chem. Commun. 1986 1763. 106 R. W. Murray R. Jeyaraman and L. Mohan Tetrahedron Lett. 1986 27 2335. 107 A. J. Bloom and J. M. Mellor Tetrahedron Lett. 1986 27 873. D. F. Taber R. E. Ruckle jun. and M. J. Hennesey J. Org. Chem. 1986 51 4077. 109 A. Pfenninger Synthesis IY86 89. 'lo S. T. Purrington B. S. Kagen and T. B. Patrick Chem. Rev. 1986 86 997. J. Jurezak S. Pikul and T. Bauer Tetrahedron 1986 42 447.112 D. N. Kirk Tetrahedron 1986 42 777. 113 R. K. Dieter Tetrahedron 1986 42 3029. 122 P. E Gordon Title Reference Oxazoles in carboxylate protection and activation 114 The synthesis of mevinic acids 115 N-Hydroxy-a-amino acids in organic chemistry 116 Advances in the synthesis of a-methylene lactones 117 Multiple convergent syntheses via conjugate-addition 118 reactions to cycloalkenyl sulphones Recent advances in the chemistry of chlorosuiphonyl 119 isocyanate Organic synthesis with a-chlorosulphides 120 Synthesis of sulphoxides by oxidation of thioethers 121 Conjugated nitroalkenes versatile intermediates in organic 122 synthesis Reductive cleavage of aliphatic nitro-groups in organic 123 synthesis Silyl-substituted cyclopropanes as versatile synthetic reagents 124 II4 H.H. Wasserman K. E. McCarthy and K. S. Prowse Chern. Reu. 1986 86 845. 115 T. Rosen and C. H. Heathcock Tetrahedron 1986 42 4909. 116 H. C. J. Ottenheiim and J. D. M. Herscheid. Chem. Reu. 1986 697. 117 N. Petragnani H. M. C. Ferrdz and G. V. J. Silva Synthesis 1986 157. I in P. L. Fuchs and T. F. Braish Chem. Rev. 1986 86 903. 119 D. N. Daher and K. S. K. Murthy Synthesis 1986 437. 120 B. D. Dilworth and M. A. McKerven Tetrahedron 1986 42 3731. 12’ M. Madesclaire Tetrahedron 1986 42 5459. 122 A. G. M. Barrett and G. G. Graboski Chern. Reu. 1986 86 751. 123 N. Ono and A. Kaii Synthesis 1986 693. 124 L.A. Paquette Chem. Rev. 1986 86 733.