8 Aliphatic Compounds Part (ii) Other Aliphatic Compounds By A. R. TATCHELL School of Chemistry Thames Polytechnic Wellington Street London SE 18 6PF 1 Alcohols and Ethers Chiral alcohols oxirans and oxaziridines of known absolute configuration give rise to liquid-crystal-induced circular dichroism (LCICD) when added to the achiral nematic liquid crystal N-p-methoxybenzylidene-p'- butylaniline (MBBA). It has been proposed that the axes of adjacent MBBA molecules are induced to lie in a helical arrangement by virtue of the presence of the interposed chiral dopant and the direction of helicity is correlated with the molecular interactions between the substituents of the chiral dopant and the adjacent MBBA molecules.' The formation of mono-esters from symmetric 1,2- and 1,3-diols in good yields has been made feasible by their conversion into the corresponding known stann- oxanes by treatment with dibutyltin oxide and subsequent reaction with one molar equivalent of an acylating agent followed by hydrolysis.The sequential addition of two acylating agents to the stannoxane gives a mixed diester.2 Selective oxidation of a limited range of 2,2-disubstituted butane-1,4-diols using either a benzoyl peroxide-nickel(I1) bromide reagent mixture or triphenylmethyl tetrafluoroborate provides a route to the corresponding pp-disubstituted- y -butyrola~tones.~ With these reagents very little of the aa-disubstituted isomeric lactone is formed. Although (S)-1,2-O-isopropylideneglycerolis readily available from 1,2:5,6-di- 0-isopropylidene-D-mannitol uia (R)-1,2-0-isopropylideneglyceraldehyde the enantiomeric glycerol derivative (2) which could serve as the starting material for the synthesis of important drugs is less easily accessible.Ascorbic acid (1)has now been used as an inexpensive chiral source for this compound (Scheme 1); as an i-iii CH,OH (2) HO-'OH HO OK (1) Reagents i Me,CO MeCOCl; ii NaBH,; iii NaOH H'; iv Pb(OAc), EtOH; v NaBH, NaOH Scheme 1 W. H. Pirkle and P. L. Rinaldi J. Org. Chem. 1980 45 1379. * A. Shanzer Tetrahedron Lett. 1980 21 221. M. P. Doyle R. L. Dow V. Bagheri and W. J. Patrie Tetrahedron Lett. 1980 21 2795. 123 124 A. R. Tatchell HZCOMS -H CH,CN CH,CN CH,CN CH ,CO ,- (3) Reagents i TsCI Et,N; ii KCN NaI NaHCO, DMSO; iii HCI MeOH at 0 "C; iv MsCI Et,N; v KN, MeCN 18-crown-6; vi H2 Pd/C; vii H,SO Scheme 2 example of its utility its conversion into (R)-4-amino-3-hydroxybutanoicacid (3) a useful anti-epilectic and hypotensive drug has been described (Scheme 2).4 The synthesis of chiral oxirans has been the subject of several publications.Thus some monosubstituted (S)-oxirans have been formed in high optical purity from the toluene-p-sulphonate of (S)-1,2-O-isopropylideneglycerol[the enantiomer of (2)] by conversion into (S)-2,2-dimethyl-4-alkyl- 1,3 -dioxolan with lithium dialkyl- cuprates ring-opening to the acetyl derivative of the corresponding bromohydrin followed by base-catalysed cy~lization.~ The previously published synthesis of (2S,3S)-2,3-epoxybutane from (2R,3R)-tartaric acid has been shown to proceed in better than 99.9% diastereoisomeric and enantiomeric purity by employing com- plexation chromatography on nickel(I1) bis-[( 1R)-3-(heptafluorobutyryl)camphor-ate].6 In this synthesis the formation of the oxiran system also arises from a base-catalysed cyclization of an ester of a bromohydrin.The asymmetric cyclization of prochiral 1,3-dichloropropan-2-ol and racemic 2,3-dichloropropan- 1-01 using active cobalt(sa1en)-type complexes [e.g. N,N'-disalicylidene-( 1R,2R)- 1,2-cyclo- hexanediaminato-coba1t(11)],has also been de~cribed.~ t-Butyl hydroperoxide in the presence of the chiral catalyst quininium benzyl chloride converts cycohex-2-en-1-one into (2S,3S)-2,3-epoxycyclohexanonein 20% enantiomeric excess (e.e.).* The same hydroperoxide with titanium(1v) isopropoxide in the presence of optically active diethyl tartrate has been found to epoxidize a wide range of allylic alcohols with high asymmetric induction (>90% e.e.).The configurations of the epoxy-alcohols that are obtained coupled with the observation that the enantiomeric tartrates give rise to opposite configurations in the products has allowed a preliminary view to be proposed for the direction of attack of the peroxide.' Intramolecular epoxidation (noted in last year's Report) has also been the subject of further study." A convenient and highly stereospecific method for the conversion of oxirans into thiirans using potassium thiocyanate in the presence of silica gel or else supported upon it has been reported." The yields are very acceptable since the work-up procedures are simple and the thiirans are readily purified from unreacted starting material by column chromatography.M. E. Jung and T. J. Shaw J. Am. Chem. SOC.,1980,102,6304. U. Schmidt J. Talbiersky F. Bartkowiak and J. Wild Angew. Chem. In?.Ed. Engl. 1980 19 198. V. Schurig B. Koppenhoefer and W. Buerkle J. Org. Chem. 1980 45 538. 'T. Takfichi M. Arihara M. Ishimori and T. Tsuruta Tetrahedron 1980 36 3391. H. Wynberg and B. Marsman J. Org. Chem. 1980,45,158. T. Katsuki and K. B. Sharpless J. Am. Chem. SOC.,1980,102,5974. lo J. Rebek Jr. and R. McCready J. Am. Chem. SOC.,1980,102 5602. M. 0.Brimeyer A. Mehrota S. Quici A. Nigam and S. L. Regen J.Org. Chern. 1980,45,4254. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 2 Aldehydes and Ketones Although high enantiomeric purity is being achieved in the synthesis of oxirans as described above the formation of chiral cup-epoxy-aldehydes whose configurations can be mechanistically established has been little studied. A procedure that has now been reported12 arises from the development of a synthetic method for chiral CY -hydroxy-carboxylic acids which uses a stereoselective bromohctonization of for example (S)-tigloylproline; this method was noted in last year's Report. The acyl derivative (4) on bromination gives the bromo-lactone (5)contaminated with less than 8% of the diastereoisomer (6);ring-opening of the lactone with methoxide ion followed by reduction yields the ap-epoxy-aldehyde (7) (Scheme 3).The configur- ational assignment follows from mechanistic considerations and high chemical and optical yields are obtained for a representative range of unsaturated acids. -0JqBr R+ H R' R2 R2 R2 (4) Reagents i (S)-ethyl prolinate (EtO),PO(CN) Et I;ii KOH EtOH H20;iii NBS Bu'OK; iv NaO at -78 "C; v NaAIH,(OCH,CH,OMe), at 0 "C Scheme 3 (S)-2-Methoxymethylpyrrolidinecontinues to be used as an efficient chiral induc- ing reagent. On reaction with l-bromo-3-phenylprop-2-eneit forms the chiral allylamine (8) which on deprotonation forms the chiral homo-enolate equivalent (9).13 Alkylation then proceeds with very acceptable stereoselectivity (4845% e.e.) to yield the enamine (lo) which on hydrolysis gives the chiral P-alkyl-aldehyde (11)(Scheme 4).Five different alkyl halides were employed and the configurations of the products were assigned by standard procedures and from a consideration of the favoured direction of approach of the alkylating reagent. A polymer-supported reagent that is prepared by treating poly(2-vinylpyridine) with a borane-dimethyl sulphide complex when heated in benzene solution in the presence of boron trifluoride etherate reduces aldehydes and ketones in good yield.14 Swelling of the polymer-borane complex by preheating in benzene or " S. Terashima M. Hayashi and K. Koga Tetrahedron Lett. 1980 21,2733. l3 H. Ahlbrecht G. Bonnet D. Enders and G. Zimmermann Tetrahedron Left. 1980 21 3175. l4 F.M Menger H. Shinozaki and H.-C. Lee J. Org. Chem. 1980 45 2724. 126 A. R. Tatchell d P h OHC iii -H-eoMe (8) (9) (10) Reagents i Bu'Li Bu'OK light petroleum at -78 "C;ii RX at -78 "C; iii 4M-HCl Et,O Scheme 4 alternatively prior partial alkylation of the polymer leads to reagents which effect faster reductions because a less compact configuration exposes the reactive sites to the carbonyl reactant. The reduction of saturated alkyl aryl ethylenic and acetylenic ketones with a range of chiral reducing reagents continues to be explored. Two publications report the use of protected glucofuranose derivatives with sodium borohydride in the presence of a carboxylic acid.15 B-(3-Pinanyl)-9-borabicyclononanemade from either (+)-or (-)-pinene which has been used so successfully for the reduction of aldehydes to chiral 1-deuteriated primary alcohols has been found to reduce cup-acetylenic ketones to the corresponding secondary alcohols in reasonable to excellent enantiomeric excess.16 Also noted this year is the use of lithium aluminium hydride that is complexed with amino-diols derived from tartaric acid (12),17 with a mixture of (-)-N-methylephedrine and N-ethylaniline,'8 and with analogues of Darvons alcohol (13).19 In the latter instance the new chiral ligands offer some promise for elucidating the relative importance of structural features in determining the degree of selectivity and the predominant configuration that is obtained.The chiral acetylenic alcohols prepared by procedures similar to that discussed above or by the reaction of aldehydes with lithium trimkthylsilylacetylide in the presence of a chiral amino-alcohol followed by alkaline hydrolysis," have been elaborated into optically active 4-alkyl-butyrolactones (14)21 and into optically active 4-alkyl-butenolides (15) (Scheme 5).20*22The butenolide (15; R = C8HI7) on epoxidation ring-opening of the lactone with ammonia followed by oxidation Is J.D. Morrison E. R. Grandbois and S. I. Howard J. Org. Chem. 1980 45 4229; A. Hirao S. Nakaharna H. Mochizuki S. Itsuno and N. Yamazaki ibid. p. 4231. l6 M. M. Midland D. C. McDowell R. L. Hatch and A. Tramontano J. Am. Chem. SOC.,1980,102,867. l7 M. Schmidt R. Amstutz G. Grass and D. Seebach Chem. Ber. 1980,113 1691. S. Terashima N.Tanno and K. Koga Chem. Lett. 1980 981; J. Chem. Sac. Chem. Commun. 1980 1026. l9 N. Cohen R. J. Lopresti C. Neukom and G. Saucy J. Org. Chem. 1980 45,582. 2o T. Mukaiyama and K. Suzuki Chem. Lett. 1980,255. 21 J. P. Vigneron and V. Bloy Tetrahedron Lett. 1980 21 1735; M. M. Midland and A. Tramontano ibid. p. 3549. 22 J. P. Vigneron and J. M. Blanchard Tetrahedron Lett. 1980 21 1739. 127 Aliphatic Compounds -Part (ii) Other Aliphatic Compounds RCH(0H)C-CH -% RCH(OH)CrCCO,H -+ H (14) 0 RCH(OH)CH=CHCO,H __+ H C,Hl,CO CONH2 (15) (16) Reagents i BuLi at -78 "C;ii CO,;iii H,,Pd/BaSO, quinoline; iv H'; v H2, Pt Scheme 5 of the product gave (+)-tetrahydrocerulenin ( 16).22 This compound had previously been synthesized from carbohydrate precursors.High asymmetric induction has been achieved in the reaction of organometallic reagents with chiral a -alkoxy-ketones and with p-alkoxy-aldehydes that have an a-chiral For example 3-hydroxydecan-2-one as its benzyl ether (17; R' = C7H15,R2 = CH2Ph) reacts with butylmagnesium bromide in THF to give a threo (18):erythro (19) ratio of 200 1(Scheme 6 illustrates the reaction with one enan- R' R' Me R' Bu + H=H*-Me R20 0 R20 OH R20 OH (18) (19) threo erythro Scheme 6 tiomer). The erythro-isomer (19)was formed in high selectivity (100 1)by allowing the protected compound 6-hydroxytridecan-5-one to react with methylmagnesium chloride in THF. It was noted that the nature of the solvent and of the protecting group were crucial to the successful stereoselectivity that was achieved.The reagents of choice for the reactions using p-alkoxy-aldehydes (which do not show such high asymmetric inductions when they react with Grignard reagents) are the lithium dialkylcuprates when the threo-isomer predominates. The results may be rational- ized on the basis of the Cram cyclic chelate model (20) where the favourable transition state develops from attack of the nucleophile from the side that is remote from the alkyl group. Interestingly however the reaction of lithium enolates with a-alkoxy-aldehydes e.g. 2-(benzyloxy)propanal gives the predominant stereoisomer in which the Felkin model (21) for asymmetric induction appears to R' :$oR2 R' *! 9 0 I \ ,I (21) /m (20) 23 W.C. Still and J. H. McDonald 111 Tetrahedron Lett. 1980 21,1031; W.C.Still and J. A. Schneider ibid.,p. 1035. 128 A. R. Tatchell be followed.24" Here the favourable transition state develops from attack of the nucleophile in an anti-periplanar direction from the large group which in this case is regarded as being the alkoxy substituent; a theoretical justification for this criterion has been p~blished.~~' It is argued that competition between the two alternative transition states is feasible and that variations in the degree of selectivity will thus be a function of the basicity of the alkoxy-oxygen and hence of the degree of electron-donating character of R2. Electron-withdrawing groups in R2 would decrease chelation effects and promote the reaction uia the Felkin model.3 Carboxylic Acids Each of the enantiomeric forms of fluorosuccinic acid has been synthesized from (2R)- and (2S)-malate esters by the reaction with diethylaminosulphur trifluoride followed by hydroly~is.~~ The configurations were unambiguously assigned on the basis of a similar conversion of dimethyl (2S,3R)-[3-2Hl]malate (22) obtained from monosodium fumarate by fumarase-catalysed hydration with deuterium oxide into 2-fluor0-[3-~H~]succinicacid (23) and examination of the proton-fluorine coupling constants of the derived deuteriated i.e. (24) and non-deuteriated anhydrides. In this way the fluorination reaction was shown to proceed with inversion of configur-ation and (-)-(2s)-malic acid therefore gives (-)-(2R)-fluorosuccinic acid.The latter exhibited a negative c.d. curve and is therefore anomalous when compared with the bromo- and chloro-acids; this has allowed the previously assigned configur- ation of (+)-fluorosuccinic acid which is a metabolite of p-fluorophenylacetic acid that is produced by Pseudomonas species to be corrected. A new metabolite from an aqueous culture medium of Paecilomyces uariotii has been assigned the structure (25) on the basis of chemical degradation and spectroscopic studies.26 Y0,Me 70,Me D\ ,? (22) (23) (24) Reagents i Et,NSF,; ii H,O'; iii MeCOCl Scheme 7 (S)-2-(Hydroxymethyl)pyrrolidinehas been used as a chiral auxiliary agent for the synthesis of chiral 2-alkyl-carboxylic acids in high enantiomeric excess (54-95'/0).~'This reagent was first converted into the chiral amide by acylation followed by stereoselective enolization [(Z)geometry preferred] by reaction with lithium di-isopropylamide and addition of an alkyl halide followed by hydrolysis.Chiral 2-hydroxy-acids have been prepared either from cy -keto-esters by alkylation using a modified LiAlBu4 reagent,28 or by the reaction of organometallic reagents with 24 (a)C. H. Heathcock S. D. Young J. P. Hagen M. C. Pirrung C. T. White and D. VanDerveer J. Urg. Chem. 1980 45 3846; M. Chtrest H. Felkin and N. Prudent Tetrahedron Lett. 1968 2199; (6) N. T. Anh and 0.Eisenstein Nouu. J. Chim. 1977 1 61. 25 G. Lowe and B. V. L. Potter J. Chem. SOC.,Perkin Trans. 1 1980 2029. D. C. Aldridge R. M. Carman and R. B.Moore J. Chem. SOC.,Perkin Trans. 1 1980,2134. " D. A. Evans and J. M. Takacs Tetrahedron Lett. 1980 21,4233. 28 D. Abenhafm G. Boireau and B. Sabourault Tetrahedron Lett. 1980,21,3043. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 129 chiral a-keto-oxa~olines;~~ in both cases modest enantiomeric excesses were obtained. threo-2-Alkyl-3-hydroxy-carboxylic acids were formed in a highly stereoselective reaction between aldehydes and a new group of bulky propionate esters namely 2,6-dimethylphenyl and 2,6-di-t-butyl-4-methoxyphenyl propion-ate^.^' This work complements other extensive studies on stereoselective aldol-type condensation reactions which were reported last year31 and which have been further extended this year.32 The diastereoisomeric derivatives prepared from partially active methyl 2-and 3-hydroxy-carboxylates and (+)-(R)-2-me thoxy-2 -(trifluorome thy1)phenylacetic acid with [Eu(fod),] show a lanthanide-induced shift of the protons in the methoxy- carbonyl group and the methine group that may be correlated with the enantiomeric purity and absolute configuration of the parent It had previously been noted that complexes of chiral lanthanide shift reagents with the parent acids do not establish enantiomeric purity.Spme interesting amino-acids have been reported. Thus the boron analogue H3N-BH2C02Hof glycine has now been ~ynthesized~~" by a simple exchange of an amino-group between ammonia and the N-trimethyl analogue which was described This amino-acid appears to have significant anti-tumour and antihyperlipidaemic activity.An amino-acid with iron-chelating qualities avenic acid A (26) has been isolated from the root washings of plants of Avena sativa which had first been grown in an iron-containing nutrient solution and then in one which was iron-free until the plants exhibited pronounced iron-induced chloro~is.~~~ The plant washings were submitted to ion-exchange chromatography and (26)was isolated by elution with an ammonia-formic acid buffer solution. Avenic acid B (27) HO N N OH HO N H2 was also isolated and its synthesis has been The synthesis of (&)-cleonine (28) which is an amino-acid component of the family of bleomycin- phleomycin antibiotics has been accomplished from cy~lopentanone.~~ The route involves conversion into the cyanhydrin protection of the hydroxyl function by formation of an acetal reduction of the cyano-group to the corresponding aldehyde followed by a Strecker reaction of the protected amino-nitrile; finally hydrolysis and deprotection give (28).The toxic amino-acid a-methylene-P-alanine (29) isolated from a Red Sea sponge Fasciospongia cavernosa has been synthesized from 3-bromo-2-(bromomethyl)propanoicacid by sequential esterification elimination 29 A. I. Meyers and J. Slade J. Org. Chem. 1980 45 2785. 30 C. H. Heathcock and M. C. Pirrung J. Org. Chem. 1980,45 1727. 31 R. Brettle Annu. Rep. Prog. Chem. Sect. B. 1979 76 330. 32 C. H. Heathcock C. T. Buse W. A. Kleschick M. C. Pirrung J. E. Sohn and J. Lampe J.Org. Chem. 1980 45 1066; D. A. Evans and L. R. McGee Tetrahedron Lett. 1980,21 3975 and references cited therein. 33 F. Yasuhara and S. Yamaguchi Tetrahedron Lett. 1980 21,2827. 34 (a) B. F. Spielvogel M. K. Das A. T. McPhail K. D. Onan and I. H. Hall J. Am. Chem. Soc. 1980 102 6343; (b)B. F. Spielvogel L. Wojnowich M. K. Das A. T. McPhail and K. D. Hargrave ibid. 1976,98,5703. 35 (a) S. Fushiya Y. Sato and S. Nozoe Tetrahedron Lett. 1980 21 3071; (b) Chem. Lett. 1980 1215. 36 K. Kato Tetrahedron Lett. 1980 21 4925. 130 A. R. Tatchell FH2 H,NCH,CCO,H of one molecule of hydrogen bromide and nucleophilic replacement of the second bromine with an arnino-gro~p.~' Underivatized amino-acid enantiomers may be separated by h.p.l.c.using a reversed-phase column packing and a chiral eluant consisting of (S)-proline in aqueous copper(I1) acetate solution; resolution of basic neutral and acidic amino- acids was achieved.38 N-Acetyl-0-t-butyl esters of amino-acids have been separ- ated by h.p.1.c. by using a column packing of a chiral phase bonded to silica gel with an eluant of diethyl ether or methylene dichloride or chlor~form.~~ 4 Lactones and Macrolides The reactions of /3 -propiolactone may be classified as those involving substitution in the ring and those involving ring-opening. In the former category the conversion of the lactone (30) into its anion (31) and the subsequent reaction of (31) with a variety of electrophilic reagents leads to substitution products (32) that are not readily obtained by other means.4o The considerable stability of the anion in THF at -78 "C[although it undergoes p-elimination to give the alkene (33) on warming to room temperature] has been attributed to the orthogonal arrangement [shown in (34)] of the orbital at C-3 and the cT-orbital between C-4 and oxygen which -0,C H (33) Reagents i LiNPri2 at -78 "C; ii R3X;iii heat Scheme 8 precludes either anti-or syn-elimination sequences.The range of electrophilic reagents used to 'trap' the intermediate (31) was considerable and in all cases the stereoselectivity of the reaction leading to (32) was very high (usually > 98%).In the case of an analogous anion (35) the reaction with phenyl isothiocyanate afforded entry into the rare class of thietanimines (36),41as shown in Scheme 9.37 A. Holm and P. J. Scheuer Tetrahedron Lett. 1980 21 1125. 38 E. Gil-Av A. Tishbee and P. E. Hare J. Am. Chem. Soc. 1980 102,5115. 39 A. Dobashi K. Oka and S. Hara J. Am. Chem. Soc. 1980,102,7122. 40 J. Mulzer and T. Kerkmann J. Am. Chem. SOC., 1980 102 3620. 41 J. Mulzer and T. Kerkmann Angew. Chem. Int. Ed. Engl. 1980 19,466. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds PhNCS heat H,O ___, r-co21 Scheme 9 Ring-opening reactions of P-propiolactone and its analogues have been effected by lithium dialkyl~uprates~~ or by Grignard reagents in the presence of copper(I1) to give homologous acids in which the chain has been extended by three carbon atoms. The enantiomeric forms of 2-substituted y-butyro- and 8 -valero-lactones have been synthesized from the readily available 2-methyloxazoline (38).44 Scheme 10 illustrates a typical sequence for the butyrolactones; the valerolactones were pre- pared similarly but using 3-(trimethylsily1oxy)propyl bromide or iodide in place of ethylene oxide in the reaction of (38) and in place of 2-(trimethylsily1oxy)ethyl iodide in the reaction of (39).The configurations of the products (41) and (42) were deduced from their c.d.spectra and from their 'H n.m.r. spectra in the presence of chiral solvents and the enantiomeric excesses were determined by h.p.1.c. of for example the intermediate diastereoisomeric mixture derived from (40) or (43) after removal of the trimethylsilyl group.OMe (38) OMe (39) OMe 1 iv (42) Me,SiO Me0 (40) OMe (43) Reagents i BuLi 03 ;ii Me3SiC1;iii LiNPr', RX; iv LiNPr', ICH2CH20SiMe3; v H' Scheme 10 The a -methylene-y-butyrolactones (44) and (45) have been synthesized from methyl 3,5-O-isopropylidene-a -D-xylof~ranoside~~ and from 1,2-O-isopropyl-idene-a -D-xylofurano~e,~~ respectively. Previously published methods for the pre- paration of a -alkylidene-y-butyrolactones yield the (E)-isomer as the predominant product. However it has now been reported that the (E)-and (2)-isomers of 42 T. Fujisawa T. Sato T. Kawara M. Kawashirna H. Shimizu and Y. Ito Tetrahedron Left. 1980 21 2181; T. Fujisawa T. Sato T. Kawara A. Noda and T. Obinata ibid.,p. 2553; T. Fujisawa T. Sato T. Kawara and K.Naruse Chem. Lett. 1980 1123. 43 J. F. Normant A. Alexakis and G. Cahiez Tetrahedron Lett. 1980 21 935. 44 A. I. Meyers Y. Yarnamoto E. D. Mihelich and R. A. Bell J. Org. Chem. 1980,45 2792. V. Nair and A. K. Sinhababu J. Org. Chem. 1980 45 1893. "T. F. Tam and B. Fraser-Reid J. Chem. Soc. Chem. Commun. 1980 556. 132 A. R. Tatchell a-ethylidene-y-butyrolactone may be formed from the intermediate (47) (Scheme 11) according to the catalyst used in the subsequent elimination reaction. The stereoisomeric nature of the intermediate (47) formed by a titanium(1v)-chloride- catalysed aldol condensation was presumed from a consideration of the likely transition state (46)of the reaction. Subsequently the (2)-isomer (48)resulted from a boron-trifluoride-catalysed anti-elimination process and the (E)-isomer (49)from a base-catalysed syn-elimination that was induced with lithium bis(trimethy1- ~ily1)amide;~~" the stereochemical aspects of these eliminations had been established earlier.47b 0 C"" = oA '-0 3SiMe3 + .ii LMe,Si (46) (48) (49) Reagents i Me,SiOSO,CF, Et,N Et,O; ii MeCHO TIC],; iii BF,.OEt,; iv LiN(SiMe,) Scheme 11 Full details are now available of macrolide syntheses which use a palladium-catalysed intramolecular cyclization of the stabilized anions of allylic acetates and the total synthesis of several naturally occurring macrolides has been achieved by this method.48 This general method is an important alternative to methods which result from cyclization of w -functionalized carboxylic acids or their derivatives under conditions of high dilution.Recent catalysts which have found use for this lactonization reaction are cyanuric chloride4' and dibutyltin oxide;" the latter is also useful for lactam formation. The p -keto-lactone (&)-diplodialide A (50) had been synthesized previously by a lactonization pro~edure,~'" and indeed a variant of this method has been reported this year which involves the silver-perchlorate-catalysed cyclization of the S-(2-pyridyl) hydroxythioester (5l)'lbfollowed by removal of the protecting group (R') 47 (a)K. Yamamoto Y. Tomo and S. Suzuki Tetrahedron Lett. 1980,21,2861. (6) P. F. Hudrlik and D. Peterson J. Am. Chem. Soc. 1975,97 1464; P. F. Hudrlik D. Peterson and R. J.Rona J. Org. Chem. 1975,40,2263. 48 B. M. Trost and T. R. Verhoeven J. Am. Chem. SOC. 1980,102,4743. 49 K. Venkataraman and D. R. Wagle Tetrahedron Lett. 1980 21 1893. 50 K. Steliou A. Szczygielska-Nowosielska A. Favre M. A. Paupart and S. Hanessian J. Am. Chem. SOC. 1980,102,7578. 51 (a)T. Ishida and K. Wada J. Chem. SOC.,Perkin Trans. 1 1979,323; (b)A. B. Shenvi and H. Gerlach. Helv. Chim. Acta 1980 63 2426. 133 Aliphatic Compounds -Part (ii) Other Aliphatic Compounds and oxidation by manganese dioxide. However an alternative synthesis involving an intramolecular Eschenmoser sulphide-contraction reaction (see Scheme 12) has been developed employing the intermediate (52) followed by elimination of the acetoxy-residue.52 (52) Scheme 12 5 Amides and Lactams In the formation of the dilithiated derivative of an a@ -unsaturated secondary amide [e.g.(53) and (55; R = H or alkyl)] the second metallation process appears to take place at the @'-position rather than at the anticipated y-or @-positions.Subsequent reaction with a range of electrophiles E' then leads to the @'-substitution products i.e. (54) or (56)respectively (Scheme 13). Although the acyclic examples show lesser regioselectivity the reaction offers a means for substitution at a site that has not previously been regarded as being readily acce~sible.~~ CONHMe CONHMe CONHMe CONHMe 0 j,ij +R~E + (JE ~f i,ii R R (53) (54) (55) (56) Reagents i 2 molar equivalents of Bu'Li TMEDA THF at -78 "C;ii E' Scheme 13 A remarkably simple method for the cyclodehydration of y- 8- and &-amino- acids to the corresponding lactams involves heating the amino-acid in toluene in the presence of neutral alumina or silica Attention is being increasingly directed towards the asymmetric synthesis of @ -1actams.Utilizing an earlier developed cycloaddition method involving dimethyl- keten methyl trimethylsilyl acetal(57) with an imine in the presence of titanium(1v) chloride asymmetric induction has been realized at C-4 to the extent of 44-78% by employing a chiral imine. For example (S)-butylidene-(1 -phenylethyl)amine (58;R' = Pr" R2= Ph) gives (59);the configuration at C-4 was assigned as (S)on the basis of chemical degradation procedures and this was related to the probable 52 R.E.Ireland and F. R. Brown Jr. J. Org. Chem. 1980,45,1868. 53 P.Beak and D. J. Kempf J. Am. Chem. Soc. 1980,102,4550. s4 A.Blade-Font Tetrahedron Lett. 1980 21 2443. 134 A. R. Tatchell transition states of the reaction. A variant used Schiff bases that had been generated from a chiral ester of an a-amino-a~id.~~ Somewhat more modest asymmetric inductions have been found with p-lactam formation using an aryl aldimine with the lithium enolate of for example a (-)-menthy1 ester.56 Best results were obtained by using the menthyl ester from 2-phenylpropanoic acid with N-benzylideneaniline. R1CH=NCHMeR2 Ph (58) H AMe + TIC] R'C-NCHMeR2 -pr"ho OMe Me-/ Me2C=C' Me \ (59) OSiMe (57) N-Hydroxy-2-azetidinones (the elegant synthesis of which was mentioned last year and which has now been described in detail57") have been cleanly reduced with titanium(II1) chloride in buffered solution to the corresponding p -1actam; acid- sensitive protecting groups and base-sensitive chiral centres at C-3 were unaffected by these condition^.^^ 6' Amines and Imines (S)-1-Dimethoxymethyl-2-methoxymethylpyrrolidine, which was used as a reagent in the reported asymmetric synthesis of CY -alkyl-a -amino-acids last year has now been employed in the asymmetric synthesis of amine~.'~ The sequence involved the reaction of the reagent with propargylamine to give the amidine (60),which was then converted first into the 3-silylated derivative and then into the lithiated complex (61).Reaction with an appropriate alkyl halide followed by hydrolysis gave the CY -alkylated propargylamine (62);the sequence could be repeated to give dialkylated products (63). The configurations and enantiomeric excesses of mono- and di-alkyl- propargylamines were deduced by their conversion into the corresponding amino- acids. From these configurations it appeared that the alkylation takes place from a direction opposite to that observed in the asymmetric synthesis of amino-acids [cf. also (9) + (ll)].The reason for this opposite stereoselectivity in two apparently similar reactions is not at present clear. (60) (61) 55 I. Ojima and S. Inaba Tetrahedron Lett. 1980 21 2077,2081. 56 C. Gluchowski L. Cooper D. E. Bergbreiter and M. Newcomb J. Org.Chem. 1980,45 3413. 57 (a)M. J. Miller P.G. Mattingly M. A. Morrison and J. F. Kerwin Jr. J. Am. Chem. Soc. 1980,102 7026; (6) P. G. Mattingly and M. J. Miller J. Org. Chem. 1980,45 410. M. Kolb and J. Barth Angew. Chem. Int. Ed. EngI. 1980,19 725. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 135 A very convenient method for preparation of the synthetically important Mannich salt i.e. dimethyl(methy1ene)ammonium iodide has been developed. NNN’N’-Tetramethylmethylenediaminewas added to an anhydrous solution of trimethylsilyl iodide in ether when the product was rapidly precipitated in 96% yield.59 The conversion of primary aliphatic amines into azides,60 fluorides,61 and nitrate esters6’ via the appropriate pyridinium salts are further examples of this very versatile reaction methodology.7 Other Nitrogen-containing Compounds The (2)-formamidines (64) that are formed by the addition of a secondary amine to an aryl isocyanide at low temperature in the presence of silver chloride are thermodynamically unstable and they isomerize to the (E)-isomers (65) on heating or on treatment with acid. The n.m.r. spectrum of the (E)-isomer (65; Ar = rn -ClC,H,) revealed equivalent methyl signals at 34 “C but non-equivalence at -30 “C; restricted rotation about the C-N bond at the lower temperature is thus inferred. In contrast the (2)-isomer (64; Ar = m-ClC6H4) shows no such tem- perature effect over the range +34 to -80 “C and both methyl groups maintain their equivalence. The explanation offered is that the N-aryl and dimethylamino-groups are orthogonal to the N-C=N plane (66); when an ortho-substituent is present in the aryl residue two methyl signals are observed and it is suggested that in this case there is also conformational restriction about the N-aryl bond.63 H\@ H Ar H \/ \@ /C=N ,C=N C=N Me-N \Ar Me-N B \ Me Me Mi’’ \ N/Q Me (64) (65) (66) Aliphatic aldoximes may be smoothly dehydrated to nitriles by treatment with sulphuryl chloride fluoride (ClS0,F) ;64 the reductive cleavage of ketoximes with vanadium(I1) chloride offers a means of regenerating the parent ketones in good yield.65 The conversion of aliphatic and alicyclic (but not apparently aromatic) aldehydes and ketones into nitriles having one additional carbon atom has been effected by way of their corresponding 2,4,6-tri-isopropylbenzenesulphonyl-hydrazones by heating with a three-fold excess of potassium cyanide (Scheme 14).The method is particularly applicable to parent ketones or aldehydes having additionally an olefinic function; an example is given using a keto-steroid as a substrate.66 ’’ T. A. Bryson G. H. Bonitz C. J. Reichel and R. E. Dardis J. Org. Chem. 1980,45 524. 6o A. R. Katritzky G. Liso E. Lunt R. C. Patel S.S.Thind and A. Zia J. Chem. Soc. Perkin Trans. 1 1980,849. A. R. Katritzky A. Chermprapai and R. C. Patel J. Chem. Soc. Perkin Trans. 1 1980 2901. 62 A. R. Katritzky and J. Marzorati J. Org. Chem. 1980,45 2515. 63 A. F. Hegarty and A. Chandler J. Chem. Soc. Chem. Commun. 1980 130.64 G. A. Olah S.C. Narang and A. Garcia-Luna Synthesis 1980,659. 65 G. A. Olah M. Arvanaghi and G. K. Surya Synthesis 1980 220. 66 J. Jiricny D. M. Orere and C. B. Reese J. Chem. Soc. Perkin Trans. 1 1980 1487. 136 A. R. Tatchell R' R'\ KCN R'\ C-NHNHS0,Ar -[R>Cr$=N{ -R2,CHCN C=NNHSO,Ar + \ R2/ ~2' \CN Ar = 2,4,6-Pr1&H2 Scheme 14 Reductive cleavage of the cyano-group to yield the corresponding alkane may be effected by using a catalyst of potassium dispersed over neutral alumina prepared at 150 "Cunder an atmosphere of argon. Subsequently the catalyst (14%K/A120,) was used at room temperature as a hexane slurry to which the nitrile was added. The reaction is compatible with the presence of THP and other acetal-protecting groups and with the presence of an olefinic system although here migration of the double-bond may be observed in some instances.The usefulness of the method is shown by a synthesis of (Z)-dodec-9-en-l-y1 acetate the sex pheromone of Para-lobesia vitaeana (Scheme 15).67 . .. HOCH2(CH2)4CH2Br<THPOCH2(CH2)4CH2CN I THPOCH2(CH2)4CH(CH2)2CH&HEt %AcOCH,(CH&CH&HEt Reagents i NaCN phase-transfer catalyst n-C,oH22; ii 3,4-dihydro-2H-pyran Amberlyst H-15; iii LiNPr', EtCHkHCH,CH,I; iv K/Al,O,; v MeCO,H MeCOCl Scheme 15 y-Nitro-alkanoic acids which are readily prepared by a Michael addition reaction between a nitro-alkane and an acrylic ester followed by hydrolysis have been converted into cyclopentenones by treatment with a polyphosphoric acid-methanesulphonic acid system.68 Scheme 16 illustrates one mechanistic sequence that has been suggested for a reaction which ultimately yields dihydrojasmone the first intermediate being the y-nitro-acylium ion.Me PnCH,bc ___*pn3 +pnCH2Yo [-HNO,] [-H'l -z6 o+o It O//NYo 0 0 Pn = pentyl Scheme 16 8 Phosphorus Compounds A mild and selective procedure for monodemethylation of phosphate and phosphon- ate esters involving stirring with t-butylamine at room temperature has been described in two publication^.^^ Total dealkylation may be effected by employing trimethylsilyl iodide followed by hydrolysis of the intermediate trimethylsilyl ester." 67 D. Savoia E. Tagliavini C. Trombini and A. Umani-Ronchi J. Org. Chem. 1980,45 3227.68 T.-L. Ho J. Chem. SOC.,Chem. Commun. 1980 1149. 69 M. D. M. Gray and D. J. €1. Smith Tetrahedron Lett. 1980 21 859; D. J. H. Smith K. K. Ogilvie and M. J. Gillen ibid. p. 861. 70 G. M. Blackburn and D. Ingleson J. Clitw. Soc. Ptvkin Tmtts. 1 1980 1150. 137 Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 4-Acetoxyazetidin-2-one (67) (Scheme 17) when treated with a range of phosphite or phosphonite esters provides a route to 4-oxoazetidin-2-yl-phosphon-ates (68)and -phosphinates (69) whence acid hydrolysis gives a -aminophosphonic (70)and a-aminophosphinic (7 1)analoguesof aspartic acid.71 Such compounds have been incorporated into dipeptides for pharmaceutical evaluation. 0 II P-OR' - 0 II+-R-H HOZC NH2 0 (67) (68) R2= OR' (69) R2 = Me (70) R2 = OH (71) R2= Me Scheme 17 Chiral tertiary phosphines of high enantiomeric purity are required for incorpor- ation into catalysts for asymmetric synthesis.Improved optical purities have been achieved by utilizing the synthetic route illustrated in Scheme 18.72 OMen OMen OMen ... *I* I I RI--P R'--P+ cF3so3-A R'--p I 5 R'--P 4 "s 4 \SMe 4 \ 4 'RZ Ph Ph Ph Ph R' = Me or Et; Men = (-)-menthy1 Reagents i CF,SO,Me; ii Bu'SLi; iii R2Li at -50 "C Scheme 18 9 Alkyl Halides Several methods have been described for the conversion of alcohols into alkyl halides. A general reagent for bromide formation from primary secondary tertiary allylic and benzylic alcohols is lithium bromide plus trimethylsilyl chloride in acetonitrile.A useful alternative which shows regioselectivity is pyridinium bromide perbromide plus hexamet hyldisilane ;for example 2 -me th ylpentane -2,4 -diol gives 2-bromo-2-methylpentan-4-01. With (-)-octan-2-01 this latter reagent results in an 88% inversion of configuration in the alkyl Retention of configuration (>92%)in the conversion of alcohol into alkyl bromide results from a double inversion process involving first the formation of the alkyl phenyl selenide (from the alkyl methanesulphonate and sodium phenyl selenide) followed by reac- tion with a bromine-triethylamine reagent. Conformationally preferred cyclic sys- tems wherein the leaving group in either of these reactions is axial give poorer yields owing to competing elimination processes.74 The effectiveness of a range of reducing agents and the influence of solvents on the reaction course have been studied for the hydrogenolysis of alkyl halides and alkyl toluene-p-sulphonates.Lithium triethylborohydride appears to be more effective than lithium aluminium hydride for the reduction of acyclic alkyl halides and alicyclic iodides and both these reagents are superior to other complex metal 7' M. M. Campbell and N. Carruthers J. Chem. SOC.,Chem. Commun. 1980 730. 72 J. Omelahczuk W. Perlikowska and M. Mikolajczyk J. Chem. Sac. Chem. Commun. 1980 24. 73 G. A. Olah B. G. B.Gupta R. Malhotra and S. C. Narang J. Org. Chem. 1980,45 1638. 74 M. Sevrin and A. Krief J. Chem. SOC., Chem. Commun. 1980,656. 138 A. R. Tatchell hydride~.~~ However the selectivity exhibited by LiAlH4 towards hydrogenolysis of halides and tosylates is crucially solvent-dependent.Thus in diethyl ether LiA1H4 effects hydrogenolysis of alkyl tosylates but not alkyl iodides while the opposite selectivity is observed in diglyme. This selectivity is dramatically illustrated in the case of 1 1 -bromoundecyl toluene-p-sulphonate where either functionality may be reduced according to the solvent employed. The solvent effect has been attributed to poor solvation of the lithium cation in diethyl ether resulting in diminished nucleophilicity of the tetrahydroaluminate anion towards displacement of iodide. In this solvent the lithium cation could well complex specifically with the tosylate group thereby enhancing its leaving qualities; the lithium cation would be strongly solvated in diglyme solution and this could result in the reverse functional rea~tivity.~~ 10 Reviews The structural features and the symmetry properties resulting in optical activity are reviewed in an historical account which points out some of the many misconceptions (some fifty or so) that have arisen since the time of van't Hoff and Le Bel.77 A review on the resolution of racemates by chromatography is timely,78 and a discussion of resolution by direct crystallization of racemic conglomerates intere~ting.~~ A survey of the methods of stereo-control in synthetic procedures for acyclic systems80 complements a review published at the end of last year on recent advances in asymmetric synthesis.81 There is also a review on the stereochemistry of phosphorus compounds.82 Reviews have also appeared on the hydrogenolysis of organic halides,83 the use of the fluoride ion as a base in organic reaction^,^^ the thermal and photochemical decomposition of azoalkane~,~~ the conversion of the primary amino-group into other functionalities,86 and the reactions of squaric acid and its derivatives.87 75 S.Krishnamurthy and H. C. Brown J. Org. Chem. 1980 45 849. 76 S. Krishnamurthy,J. Org. Chem. 1980 45 2550. 77 J. K. O'Loane Chem. Rev. 1980,80,41. 78 G. Blaschke Angew. Chem. Int. Ed. Engl. 1980 19 13. 79 A. Collet M.-J. Brienne and J. Jacques Chem. Rev. 1980,80 215. P. A. Bartlett Tetrahedron 1980 36 3. " J. W. ApSimon and R. P. Seguin Tetrahedron 1979 35 2797.82 C. R. Hall and T. D. Inch Tetrahedron 1980,36,2059. 83 A. R. Pinder Synthesis 1980 425. 84 J. A. Clark Chem. Rev. 1980 80,429. 85 P. S. Engel Chem. Rev. 1980 80 99. 86 A. R. Katritzky Tetrahedron 1980 36 679. 87 A. H. Schmidt Synthesis 1980,961.