8 Aliphatic Compounds Part (ii) Other Aliphatic Compounds By A. R. TATCHELL School of Chemistry Thames Polytechnic Wellington Street London SE18 6PF An attempt has been made in this Report to provide some continuity with previous years though with a slightly different order of sections; a section on phosphorus compounds has been omitted since a complete chapter deals with this topic. Partic- ular interest over the past year has arisen from developments in chromatographic procedures for the resolution of racemic compounds the careful selection of chiral inducing agents in asymmetric synthesis simplification of multi-stage reaction sequences and selective epoxidation methodology. 1 Alcohols and Ethers The chiral2,2,2-trifluoro- 1-(9-anthryl)ethanol has previously been used as a solvat- ing agent for the determination of enantiomeric purity and absolute configurations by n.m.r.spectroscopy of the derived diastereoisomeric solvates. Consideration of the stability differences of these solvates has led to the design of a chiral stationary phase that has enabled enantiomers of a wide range of functionality to be separated by h.p.1.c.' The stationary phase (1)was prepared from Porasil by treatment first with (3-mercaptopropyl)trimethoxysilane and then with ( -)-(R)-2,2,2-trifluoro-l-[9-(10-a-bromomethyl)anthryl]ethanol. More than fifty resolutions have been effected and it has been possible to develop a simple concept of the interactions between the solute enantiomers and the stationary phase for assessment of the probability of a successful resolution and a prediction of elution order.W. H. Pirkle and D. W. House J. Org. Chem. 1979,44 1957. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds Full details have been reported of a general method that has been developed for the preparation of l-deuterio primary alcohols of high enantiomeric purity by using chiral trialkylboranes as reducing agents2 The most effective reagent was B-(3- pinanyl)-9-borabicyclo[3.3.1]nonane derived from (+)-a-pinene and 9-BBN which then rapidly reduced [1-2Hl]benzaldehyde to ( +)-(S)-[l-2Hl]benzyl alcohol; using optically pure ( +)-a-pinene none of the (R)-enantiomer could be detected by n.m.r. if one used a chiral shift reagent. With deuteriated /3 -([2-2H]-3-pinanyl)-9-BBN a range of saturated unsaturated and aromatic aldehydes were converted into the corresponding (R)-l-deuterio primary alcohols frequently in enantiomeric yields of greater than 90%.A critical study of the synthesis configurations and optical rotations of enantiomerically pure ( +)-(R)-[2-2H,]-2-phenylethanol,( +)-(R)-[1,1,2-2H3]-2-phenylethanol,and variously deuteriated phenylethanes has been rep~rted.~ Arsonated polystyrene resins have been employed as catalysts for the epoxidation of olefins with aqueous hydrogen per~xide;~ a useful expoxidizing reagent 0-ethylperoxycarbonic acid formed in situ from ethyl chloroformate and hydrogen peroxide under buffered conditions has also been de~cribed.~ Insertion of a methylene group into the carbonyl group of aldehydes and ketones to form oxirans using lithiated derivatives of N-(toluene-p-sulphony1)sulphimideshas much to commend it.6 Scheme 1illustrates a specific example.H MeC,&S02N Naf PhSCH3 4PhSCH2Li 5PhC-CH2 I I1 II c1 NTs NTs '0' Reagents i PhSCH3 CH,Cl, phase-transfer catalyst; ii BuLi DMSO; iii PhCHO Scheme 1 Epoxidation of polyunsaturated substrates (e.g. arachidonic acid eicosa-cis- 5,8,11,14-tetraenoic acid) with peroxy-acid reagents is largely non-selective; thus a methodology leading to specific epoxidation of the 5,6- and of the 14,15-double bonds has been de~eloped.~ The 5,6-epoxide was obtained by treatment of the acid (as its potassium salt) with potassium tri-iodide isolation of an unstable iodo-S -lactone followed by nucleophilic replacement of iodide with hydroxyl; the hydroxy S-lactone then collapses to give the 5,6-epoxide.The 14,15-epoxide was obtained by conversion of the carboxyl group into the corresponding peroxy-acid which on standing slowly underwent exclusive intramolecular oxygen transfer via a favourable fifteen-membered cyclic intermediate. The ring-opening of epoxides with the anion from trimethylsilylacetonitrile affords a route to y-trimethylsiloxy-nitriles which may then be readily converted into y -1actones.' Reductive ring-opening of epoxides with L~(OBU')~AIH in THF is usually very slow but may be remarkably facilitated by the addition of molar quantities of triethylborane .9 M. M. Midland S. Greer A. Tramontano and S. A. Zderic J.Amer. Chern. SOC.,1979 101,2352. R. L. Elsenbaumer and H. S. Mosher J. Org. Chern. 1979,44,600. S. E. Jacobson F. Mares and P. M. Zambri J. Amer. Chem. SOC.,1979,101,6946. R. D. Bach M. W. Klein R. A. Ryntz and J. W. Holubka J. Org. Chem. 1979,44 2569. C. R. Johnson K. Mori and A. Nakanishi J. Org. Chern. 1979,44,2065. 'E. J. Corey H. Niwa and J. R. Falck J. Amer. Chern. SOC.,1979,101 1586. I. Matsuda S. Murata and Y. Ishii J.C.S. Perkin I 1979,26. H. C. Brown and S. Krishnamurthy J. Org. Chern. 1979.44,3678. 148 A. R. Tatchell 2 Aldehydes and Ketones X-Ray photoelectron spectroscopy has been used to measure the OIs bonding energies of enolizable and non-enolizable dicarbonyl compounds." Essentially the aim was to determine whether the enol form exists in two asymmetric C forms rapidly interconverting via the symmetric C,,,or whether it exists entirely in the latter state.Since the method enables determinations to be made on a time scale of s some clear evidence on molecular symmetry was anticipated. Two dominant ionizations arising from the two non-equivalent oxygens of the C forms were found for malonaldehyde hexafluoroacetylacetone tropolone 9-hy- droxyphenalenone (2),and 6-hydroxy-2-formylfulvene (3). The last example is of particular interest since the oxygen-hydrogen-oxygen exchange process would be expected to be extremely rapid owing to the close proximity of the atoms concerned and their nearly linear relationship. /?-Thioxo-ketones exist exclusively in the (2)-en01 form (4) at 95 K but on irradiation (Aex 353 nm) are converted into the (2)-enethiol tautomer (5);on irradiation (Aex 288 nm) (5) reverts to (4)." The formation of (S)-2-methoxy-2-phenylpropionaldehyde(7)(see Scheme 2) in 97 f2% enantiomeric excess as judged after conversion into the corresponding methyl ester and subsequent n.m.r.spectroscopy with added chiral reagents,I2 and of (R)-2-methoxy-2-phenylacetaldehyde(10) (see Scheme 3) in greater than 70% enantiomeric excess13 illustrates the value of careful selection of the chiral inducing substrate [(6)or (8)] and the necessity of considering the probable transition state [e.g.(9)]of the reaction. It might be expected that both procedures will be exploited to prepare (in very high optical purity) a range of chiral a-hydroxy-aldehydes and their derived acids and alcohols.The asymmetric reduction of unsymmetrical ketones to chiral secondary alcohols has been an area of activity for over a decade. Chiral ligands that have been popular favourites for complexing with metal hydrides are derived from amines or alcohols lo R. S.Brown A. Tse T. Nakashima and R. C. Haddon J. Amer. Chem. SOC.,1979,101,3157. l1 L. Carlsen and F. Duus,J.C.S. Perkin ZZ,1979 1532. l2 E. L. Eliel and W. J. Frazee J. Org. Chem. 1979,44,3598. l3 L. Colombo C. Gennari C. Scolastico G. Guanti and E. Narisano J.C.S. Chem. Comm. 1979,591. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds \/ \/ Qo i-iii ( \-\ \ c\ \ c.\ Reagents i Bu'Li PhCHO; ii (COCI), DMSO Et,N; iii MeMgI; iv NaH MeI; v hydrolysis Scheme 2 p-tol-SOCHS-p-to1 CHO ... OH. -ii..0 + H+OH %H+OM~ ,&=... p-tol-SCH Lp:tol ph& Ph Ph -H \p-toI (10) (9) p-tol= p-tolyl Reagents i BuLi; ii PhCHO at -78 "C; iii Me,SO, H20 CH,Cl, Bu"0H; iv NaI I, Ph,P; v I, NaHCO, H20 dioxan Scheme 3 or from carbohydrates and the alkaloids. Currently the enantiomeric excesses in such reductions need to be high if they are to merit attention. For example the asymmetric reduction of a range of acetylenic ketones utilizing the complex [LiAIH(OR*)(OAr),] which arises from LiAI& and N-methylephedrine (R*OH) modified by the further addition of 3,5-dimethylphenol (ArOH) gives enantiomeric excesses in the range 75-90'/0.'~ Reduction of ketones with optically pure 6-hydroxysulphoximine-borane complexes has also been reported." Attention has now been turned to improving the enantiomeric excess arising from the addition of an alkyl group to the carbonyl group of aldehydes and ketones for the formation of chiral secondary and tertiary alcohols.In one method16 the lithium (or sodium) tetra-alkylaluminate was treated with either ( -)-N-methylephedrine ( -)-quinine or (+)-cinchonhe (R*OH) to give the chiral reagent [LiAI(R),(OR*)] which then reacted with carbonyl compounds to give chiral secondary and tertiary alcohols of useful optical purity. By employing chiral ligands derived from (S)-proline,17 reaction with alkyl-lithium (and also dialkylmagnesium) gave chiral reagents which then effected asymmetric addition to the carbonyl group of aldehydes to yield secondary alcohols in high optical yields (up to 95Y0).Although several methods for the selective reduction of aldehydes in the presence of ketones are available and indeed a further variant using lithium borohydride adsorbed on molecular-sieve zeolites has been shown to be effective,18 there are no efficient and simple methods for a selective reduction in the opposite sense. An attractive solution to the problem has utilized the lanthanoids as catalysts in the J.-P.Vigneron and V. Bloy Tetrahedron Letters 1979,2683. Is C. R. Johnson and C. J. Stark Jr. Tetrahedron Letters 1979,4713. l6 G.Boireau D. Abenhairn and E. Henry-Basch Tetrahedron 1979,35 1457. l7 T.Mukaiyarna K. Soai T. Sato H. Shirnizu and K.Suzuki J. Amer. Chem. SOC.,1979,101 1455. l8 P. A. Risbood and D. M. Ruthven J. Org. Chem. 1979,44,3969. 150 A. R. Tatchell reaction sequence~.'~ In the one-pot method the addition of cerium(II1) to an aqueous ethanolic solution of a mixture of an aldehyde and ketone or indeed to a compound containing both functional groups results in increased stability of the geminal diol from the aldehyde function and hence protection during the subsequent reduction with sodium borohydride. The synthesis of 2-hydroxy-3-methylcyclopent-2-enone (11) from methyl acryl- ate," of dihydrojasmone (12; R=C5H11) and cis-jasmone (12; R= CH,CHGCHEt) from undecane-2,5-dione and (Z)-undec-8-ene-2,5-dione respectively,2' and of squaric acid (13) and some new derivatives,22 utilizing a [2 + 21-cycloaddition reaction of tetra-alkoxy-ethylenes and oxy-ketens generated in situ have been effected in high yield and avoiding lengthy or multi-step pro- cedures and expensive chemicals.3 Carboxylic Acids A flexible method which (in principle) allows for the preparation of all the chiral methyl chiral lactic acids having all the possible permutations of the isotopes of hydrogen has been de~eloped.'~ The strategy for one such isomer is shown in Scheme 4. The conversion of (14) into (15) proceeds via a a-vinyl complex; the process by which this is formed is completely stereospecific as is the subsequent cleavage of the metal-vinyl bond. . H)=(CO,Et ii,iii H C02H CH,BrCOCO,Et 4 3D-H-D -kco2Et Br OCOMe T OCOMe T OH (14) (15) Reagents i (MeCO),O; ii [Pd(PPh,),]; iii CF,CO,T (CF,CO),O; iv Dz,[Rh{(R)-prophos}nbd]' ClO,-; v -OH HCI crystallize from Et,O-Pr',O Scheme 4 The stereospecific chain extension of an aldehyde to give a 5-substituted-2- methyl-(22,4B)-pentadienoicacid rather than the more stable (2E,4E)-isomer has been because of its relevance to the construction of the ansa bridge in the rifamycin~,~~' although the method clearly has more general applications (Scheme 5).l9 J. L. Luche and A L. Gemal J. Amer. Chem. SOC., 1979,101,5848; J. Org. Chem. 1979,44,4187. 2o R. C. Cookson and S. A. Smith J.C.S. Perkin I 1979,2447. 21 C. S. Subramaniam P. J. Thomas V. R. Mamdapur and M. S. Chadha J.C.S. Perkin I 1979,2346. 22 D. BelluS J. Org. Chem.1979,44 1208. 23 M. D. Fryzuk and B. Bosnich J. Amer. Chem. SOC., 1979,101 3043. 24 (a) E. J. Corey and G. Schmidt Tetrahedron Letters 1979,2317;(b)W. Oppolzer and V. Prelog Helo. Chim. Actu 1973,56 2287. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds Br Me ... MeS )+Me 5 Me>=( MeSMMe COzH Me C0,Et %H CO,Et MeS Me C02H Do C6H11d M e C6H11 C6Hll Reagents i EtI K2C03 DMF,ii NaSMe iii LiNPr',; iv C,H,,CHO; v Raney nickel; vi KOBu' Scheme 5 Full details are now available25 of the formation of chiral a-hydroxy-acids (89-98'/0 optical purity) by stereoselective bromolactonization of for example ( -)-(S)-N-tigloylproline followed by debromination and hydrolysis. An efficient one-pot procedure for the exclusive formation of either the erythro- or of the threo-2-amino-3-hydroxy-acids is an example of the application of the stereoselective reaction between lithiated derivatives and carbonyl compounds.26 For the ( f)-erythro -isomer (17) NN-bis(trimethylsily1)glycine trimethylsilyl ester (16) as its anion was treated appropriately with the carbonyl compound whereas for the threo-isomer (f)-threonine (18) the anion was derived from N-carbo- benzoxyglycine ethyl ester (19); in this latter case the initial product was an oxazolidone derivative which was then hydrolysed under acidic conditions.Scheme 6 illustrates both reactions using acetaldehyde. @le,Si),NCH ,CO,SiMe PhCH,OCONHCH,CO,Et (16) \ C0,H fl (19) H21'+4'+4H HO OH Me Me (17) (18) Reagents i LiNPr',; ii CH,CHO; iii HCl; iv conc.HCl Scheme 6 An asymmetric synthesis of a-alkyl-a -amino-acids using ( -)-(S)-1-dimethoxymethyl-2-methoxymethyl-pyrrolidine (20),which is readily prepared from (S)-proline as the chiral auxiliary reagent has been achieved with moderate enantiomeric excess.27 The racemic acid reacts with the reagent to form a mixture of the diastereoisomeric amidine esters (21). Deprotonation with lithium di-iso- propylamide gives a derivative (22) which then undergoes regiospecific and 25 S.-S. Jew S. Terashima and K. Koga Tetrahedron 1979,35 2337 2345. 26 A. Shanzer L. Somekh and D. Butina J. Org. Chem. 1979,44 3967. *' M. Kolb and J. Barth Tetrahedron Letters 1979 2999. 152 A. R. Tatchell OMe R2 R'CHC0,Me R '+CO,Me I I CH(OMe)* NY diastereoselective alkylation to form (23) on treatment with an alkyl halide; hydrolysis gives the a-alkyl-a-amino-acid.Novel approaches to the synthesis28 of (R)-6-methyltryptophan (a potential sweetening agent) and of ( f)-gabac~line~~ (5-amino-cyclohexa-l,3-dienoicacid) have been devised to enable these compounds to be prepared in more useful amounts. The resolution and order of elution of the enantiomers of racemic a- p- and y-amino-acids as their corresponding N-trifluoroacetyl isopropyl esters by g.l.c. using N-dodecanoyl-L-valine-t-butylamideas the stationary phase has provided a basis for a provisional hypothesis of selective intermolecular solute-solvent inter- actions. Coupled with a related study on the N-trifluoroacetyl-0-acyl derivatives of 2-amino-alkan-1 -oh a better appreciation of the influence of the function of the size of the 0-acyl substituent on retention values has been demon~trated.~' 4 Esters and Lactones Simple procedures whereby sterically hindered acids may be esterified in high yields with unactivated alkyl halides which involve the use of an anion-exchange resin in either a bi- or a tri-phase system have been described.31 Re-conversion into the hindered carboxylic acids has been found to take place smoothly when the ester reacts with propyl-lithi~m.~~ The alkylation of malonic ester is one of the oldest reactions in organic synthesis.However the formation of w -bromoalkyl malonic esters (for subsequent nucleo- philic replacement reactions of the halogen) presents obvious difficulties.This has been overcome by the use of trialkyl sodiomethanetricarboxylates which readily react with ao-dihalides; removal of the blocking alkoxycarbonyl group is effected by alkoxide ion lithium di-isopropylamide or boron trifl~oride.~~ /3-Keto-esters of the type R1COCH2C02R2 also occupy a position of central importance in the history of organic synthesis. New and convenient procedures for their preparation in high yield by the acylation of malonic acid derivative^,^^ or U. Hengartner D. Valentine K. J. Johnson M. E. Larscheid F. Piggott F. Scheidl J. W. Scott R. C. Sun J. M. Townsend and T. H. Williams J. Org. Chem. 1979 44 3741. 29 B. M. Trost and E. Keinan J. Org. Chem. 1979 44 3451; J.-P. Francois and M.W. Gittos Synth. Comm. 1979,9,741. 30 B. Feibush A. Balan B. Altman and E. Gil-Av J.C.S. Perkin 11 1979 1230. 31 G. M. Moore T. A. Foglia andT. J. McGahan J. Org. Chem. 1979 44 2425. 32 C. Lion J.-E. Dubois J. A. MacPhee and Y. Bonzougou Tetrahedron 1979,35,2077. 33 H. C. Padgett I. G. Csendes and H. Rapoport J. Org. Chem. 1979,443492,4173. 34 D. W. Brooks L. D.-L. Lu and S. Masamune Angew. Chem. Infernat. Edn. 1979,18,72;J. W. F. K. Barnick J. L. van der Baan and F. Bickelhaupt Synthesis 1979,787; W. Wierenga and H. I. Skulnick J. Org. Chem. 1979,44 310. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 153 from the conversion of a-diazo-P-hydroxy-esters catalysed by rhodium(I1) acetate,35 offer promise to supplement the methods already available.The absolute configurations of glycidic esters are required both for a study of the stereochemical consequences of their rearrangement with Lewis acids to the cor- responding formyl and for a study of the stereoselectivity of epoxidation of an &-unsaturated eFter having a chiral O-alkyl group.37 The specific example that has currently been selected for both these aspects is ethyl ( +)-(2S,3R)-3-methyl-3-phenylglycidate (24) ;the configuration at C-3 has been unambiguously determined by the sequence of conversions shown in Scheme 7. /OH Me Me J Ph )\OH PhAOH Me + Ph Reagents i LiAIH,; ii HIO, NaHSO,; iii TsC1; iv KMnO Scheme 7 The Diels-Alder reaction of dimethylfulvene with methyl acrylate provides an adduct (25) which when treated with lithium di-isopropylamide and an alkyl halide gives the product (26) in which the alkyl group occupies the exo-position.Pyrolysis effects the retro-reaction to yield methyl 2-alkyl-prop-2-en0ate.~~ A synthetic route to 2-alkyl-but-2-eno-lactones (27) has been developed from this procedure and its utility demonstrated by the synthesis of some relevant naturally occurring lac tone^.^^ The formation of a-methylene- y-butyrolactones from 1-phenyl-6-propane lactam offers a synthetic route that should be of wide appli~ability.~'" In essence the sequence involves the formation of 3-alkylideneazetidin-2-one (28) sequential isomerization and epoxidation of the double bond and finally an acid-catalysed 35 R. Pellicciari R. Fringuelli P.Ceccherelli and E. Sisani J.C.S. Chem. Comm. 1979 959. 36 J. M. Dornagala and R. D. Bach J. Org. Chem. 1979,44,2429 3168. 37 S. L. Abidi and J. L. Wolfhagen J. Org. Chem. 1979 44 433. '' R. Kimara A. Ichihara and S. Sakamura Synthesis 1979 516. 39 A. Ichihara N. Nio Y. Terayarna R. Kimura and S. Sakarnura Tetrahedron Letters 1979 3731. 40 (a)S. Kano T. Ebata K. Funaki and S. Shibuya J. Org. Chem. 1979,443946,(b)L. G.Mueller and R. G. Lawton ibid. p. 4741. 154 A. R. Tatchell rearrangement to the anilinomethyl-butenolide (29). Catalytic hydrogenation over Raney nickel followed by a Hofmann degradation of the derived quaternary methiodide gives the a-methylene-y-butyrolactone (30). When cyclic ketones are employed in the formation of the alkylidene derivative the ultimate product is the cis-fused ring system e.g.(31). The trans-a-methylene-y-lactone system(32) has been obtained by an acid-catalysed rearrangement of t-butyl 2-exo-(bicyclo- [4.1.O]hept-2-en-7-yl)pr0penoate.~'~ R' R2 R' R2 U CH2NHPh &o R2)50 a0 R' H H (31) The formation of large ring lactones by the tetrakis(tripheny1phos-phine)palladium-catalysed cyclization of allylic acetates having a sulphone function at a more remote position in the carbon chain which was noted in earlier Reports has now been applied to the formation of medium-sized ring lactones. The cycliza- tion process allows for the alternative formation of products of two ring-sizes; however a preference for the larger ring in the 8/6 9/7 and 10/8 possibilities is observed.This finding which is contrary to expectations on the basis that the formation of the smaller ring is kinetically more favoured means that these less accessible lactones may be prepared more readily (Scheme 8).41 HOWOAc PhS02y ,ow OAc 0 1 ii 0 S02Ph &S02Ph t- ;.t52ph (6%) " (94%) /\ Reagents i PhS02CH2C02H PPh3 EtO,CN=NCO,Et; ii NaH [(PPhJ4Pd] diphos Scheme 8 41 B. M. Trost and T. R. Verhoven J. Amer. Chem. SOC.,1979,101,1595. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds 155 5 Amides and Lactams N-Alkyl- and N-aryl-amides may be prepared in a one-pot reaction directly from aliphatic and aromatic acids; the species (33) has been proposed as the intermediate (Scheme 9).The reaction which proceeds to give almost quantitative yields of product has been adapted for the synthesis of five- six- and seven-membered ring lactams from o-amino-carboxylic acids4' o-NCsC6H4NO2 Bu3k6H4NO2 [R'C026Bu3] 5R'CONHR' (33) Reagents i Bu,P; ii R'C0,H; iii R2NHz Scheme 9 Liquid chromatographic separation of diastereoisomeric amides derived from either racemic carboxylic acids or lactones and optically pure amines followed by hydrolysis provides an efficient preparative method for optically pure acids and act ones.^^ Two /3 -1actam syntheses have been reported. The first involves cyclization of the 1,3-dianion from an a-phenyl-thioacetamide derivative with di-iodomethane (Scheme 10); subsequently oxidation at sulphur gave separable diastereoisomeric sulphoxides or alkylation at C-3 was effected after formation of an anion by reaction with b~tyl-lithium.~~ In the second synthesis the C-4-N bond was formed under milder conditions than those hitherto reported for the cyclization of /3 -halogeno-amides (34; X = Cl) and hence provided a reaction sequence that was compatible with the presence of substituents on C-3 which could result in facile racemization; the il Phs PhSCH PhSCH Reagents i NaH; ii CHz12 Scheme 10 ii 2 -* OR2 R' = COZBu' R2 = CH2Ph Reagents (X= Cl) i 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(WSC),DMF,NH,OCH,Ph; ii NaH DMF; iii H2 Pd/C (X = OH) i WSC DMF NH,OCH,Ph; ii Ph,P EtO,CN=NCO,Et; iii H2 Pd/C Scheme 11 42 P.A. Grieco D. S. Clark and G.P. Withers J. Org. Chem. 1979,44 2945. 43 H. Helmchen G. Nill D. Flockerzi W. Schuhle and M. S. K. Yousset Angew. Chem. Internat. Edn. 1979,18,62,63,65. 44 K. Hirai and Y. Iwano Tetrahedron Letters 1979 2031. 156 A. R. Tatchell sequence provided a route to substituted N-hydroxy-2-azetidinones(35).45 The success of the method depends on the selective ionization of the N-H bond in the hydroxamic acid derivative (34). Indeed the reaction was developed for direct use with the P-hydroxy-acid derivative (34; X = OH) as a convenient alternative to the P-halogeno-amide route (Scheme 11). Three novel fused p-lactam compounds (36) have been isolated from media after culture of Streptornyces cluvuligerus and they have been shown to be structurally related to the previously reported clavulanic acid (37).46 0LL3R 0nYH2OH C02H (36) R = CH20H CH20CH0 or COzH (37) 6 Amines and Imines The conversion of a primary amine into an aldehyde by amine oxidases may proceed via the removal of either the pro-R-hydrogen or the pro-S-hydrogen (Scheme 12).H H 02 HzOz H2O [RCHzNH] -LRCHO +NH3 RANH Scheme 12 Previous work had shown that the diamine oxidase from pea seedlings removes the pro-S-hydrogen from the methylene group of benzylamine. In an extension of this work to other amine oxidases (1R)- and (1S)-[l-3Hl]heptylamine have been synthesized and their configuration assigned on the basis of correlation with the known monodeuteriosuccinic The key intermediate for the synthesis of these labelled amines was (Z)-hept-3-enal (38) prepared from acrolein (Scheme 13).Deuterium and tritium labelling was introduced to give the corresponding alcohols (39) (see Scheme 14) by stereospecific transfer from labelled ethanol in a reaction that was mediated by liver alcohol dehydrogenase in the presence of the coenzyme Reagents i HC(OMe), HBr; ii PPh,; iii Pr'OH H' iv MeSOCH2Na DMSO C3H7CHO; V (C02W2,KO Me&O Scheme 13 " P.G. Mattingly J. F. Kerwin Jr. and M. J. Miller J. Amer. Chem. SOC.,1979,101 3983. 46 D.Brown and J. R. Evans J.C.S. Chem. Comm. 1979,282. 47 A. R. Battersby D. G. Buckley J. Staunton and P. J. Williams J.C.S. Perkin I 1979 2550. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds Scheme 14 NAD'. Standard conversions (toluene-p-sulphonate into nitrile; then into amide) gave the labelled amides (40) of inverted configuration.The deuteriated acid on ozonolysis gave 94 f5% optically pure ( +)-(2S)-[2-*H,]succinic acid; the tritiated amide by way of hydrogenation hydrolysis and Schmidt degradation gave (1s)-[ 1-3Hl]heptylamine. The enantiomeric amine was formed by a similar route but using the tritiated analogue of (38) ((2)-[ 1-3Hl]hept-3-enal} formed by the reaction of (38) with sodium borotriti-ide followed by oxidation with chromium trioxide in pyridine wherein the favourable 3H isotope effect was clearly beneficial. The configurationally authenticated amines when studied with the monoamine oxidase from rat liver mitochondria unequivocally demonstrated that the pro-R -hydrogen was stereospecifically removed during oxidative deamination.(R)-a-Phenylalkyl-amines have been formed in high optical purity (76-96%) by the stereoselective alkylation (Grignard reagent) of the hydrazone (41) derived from an aryl-aldehyde and ( -)-N-aminoephedrine (Scheme 15) .48 The stereoselectivity was considered to be due to the (E)-stereochemistry of the hydrazone and complex- ation of the hydrazone with the magnesium of the Grignard reagent before attack by the alkyl group. Ph H w Me H Ph I,HHH Me R&H,N<*Ar HO NNH,I HO NN=CHAr I H Me Me (41) Reagents i ArCHO; ii RMgX; iii Pd/C Scheme 15 The reductive alkylation of azoxy-compounds affords a route whereby a-alkyl- ation of a primary amine may be efficiently carried out (Scheme 16).49 The intermediate (42) was seen to arise from the homolysis of the di-iodo-amine (formed from iodination under oxidizing conditions) followed by trapping with nitrosoben- zene.The same intermediate could equally well arise from homolysis of the monoiodo-amine trapping and further iodination. Characteristically the examples selected for illustrating the value of the method were drawn from simple aliphatic amines steroidal amines and amino-glycosides. 48 H. Takahashi K. Tomita and H. Otomasu J.C.S. Chem. Comm. 1979,668. 49 D. H. R. Barton G. Lamotte W. B. Motherwell and S. C. Narang J.C.S. Perkin Z,1979,2030. 158 A. R. Tatchell R'CHzNHZ A -R1CH2N=NPh R1CHNH2 J. I 0 R2 (42) Reagents i I, Bu'OCl PhNO; ii R2Li; iii Zn H' Scheme 16 Full details are now available for the conversion of primary amines into iodides,50" bromides and chloride~,'~~ fl~orides,'~~ aldehyde^,^" and hydrocarbon^.^^' With each conversion a range of alkyl- arylalkyl aryl- and heteroaryl-amine systems were studied and the limitations of the method with respect to each of these systems noted.( +)-2-Amino-l-methoxymenth-8-ene reacts with (*)-aldehydes that are chiral at the a-position to give diastereoisomeric aldimines (43). The ratio of dia- stereoisomers and hence the optical purity of the aldehyde may be assessed with good accuracy from integration of the signals corresponding to the pair of doublets from the proton attached to C-1 of the aldimine.'l This methoxy-amine may also be used as a chiral inducing agent since the aldimine (43; R1= H R2= Hex or Me) after conversion into the lithiated derivative readily undergoes a stereoselective reaction at C-2 with a range of electrophiles; subsequent hydrolysis yields the chiral a -alkyl-aldeh~de.'~Similar alkylations of the aldimine derived from the tertiary amine (44) show somewhat lower stereoselectivity.In the case of aldjmines derived from (-)-(S)-phenylethylamine where the absence of a chelatable group might be expected to reduce the stereoselectivity of an alkylation reaction the yields and optical purities of the chiral aldehydes finally isolated are most en~ouraging.~~ In both these alkylation reactions interestir. conceptsof the transition states and of the conformation of the intermediates have been suggested to explain the stereoselec- tivity of the reactions.A A (43) (44) 7 Other Nitrogen Compounds A conventional synthetic sequence for conversion of an aldehyde (R'CHO) into the nitrile (R1R2CHCN)may proceed through as many as eight stages in overall yields (a) A. R. Katritzky N. F. Eweiss and P.-L. Nie J.C.S.Perkin I 1979,433; (6)A. R. Katritzky U. Gruntz A. A. Ikizler D. H. Kenny and B. P. Leddy ibid. p. 436; (c)A. R. Katritzky A. Chermprapai and R. C. Patel J.C.S. Chem. Comm. 1979,238; (d)A. R. Katritzky U. Gruntz,D. H. Kenny M. C. Rezende and H. Shiekh J.C.S.Perkin I 1979,430; (e)A. R. Katritzky M. J. Cook A. Ikizler and G. H. Millet ibid. p. 2500; (f)A. R. Katritzky J. Lewis and?.-L.Nie ibid. p. 442. A. I. Meyers and Z. Brich J.C.S. Chem. Comm. 1979,566. A. I. Meyers Z. Brich G. W. Erickson and S. G. Traynor J.C.S. Chem. Comm.. 1979,567. R. R. Fraser F. Akiyama and J. Banville Tetrahedron Letters 1979,3929; R. R. Fraser and J. Banville J.C.S. Chem. Comm. 1979,47. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds which rarely exceed 12%. An ingenious continuous process has been devised which allows for the quenching of the intermediate tertiary halide by allowing the reaction mixture to flow into a phase-transfer catalytic system to give finally the nitrile in > 90% yield.54 Alkyl and aryl isocyanates are formed in excellent yield by heating dry 2,4,6- triphenylpyridine N-acyl-imines (45) under reduced pressure.The acyl-imines are prepared either from l-amino-2,4,6-triphenylpyridinium perchlorate (46) or from 2,4,6-triphenylpyrylium perchlorate as shown in Scheme 17.55 Alkyl isocyanates (and also substituted ureas and urethanes) may also be synthesized in wide variety from the reagent (48),56 which incidentally has also been used for the preparation of N-t-butoxycarbonyl-amino-acidesters.57 Ph 3”2 (48) Reagents i RCOCl K,CO,; ii RCONHNH,; iii KOH; iv RNH Scheme 17 The coupling reaction between lithium acetylides and 2-chloro-2-nitropropane gives high yields of nitro-acetylenes which may then be elaborated to crp-unsaturated ketones (Scheme 18).58 RCrCLi & RCrCCMe2N02 [RCOCH2CMe2N02]-RCOCH=CMe2 Reagents i CICMe,NO,; ii Hg2+ H,SO Scheme 18 A nitro-group sited in an aliphatic or alicyclic system may be replaced with hydrogen by reaction with the sodium salt of methanethiol in HMPT or DMSOby a sequence which proceeds via a radical mechanism.With p -aryl-nitro-alkanes where the aryl residue is unsubstituted replacement with hydrogen occurs similarly in both HMPT and DMSO; when the aryl residue has electron-withdrawing 54 J. A. Foulkes and J. Hutton Synth. Comm. 1979,9,625. ’’ A.R. Katritzky L. Lewis and P-L. Nie J.C.S.Perkin I 1979.446. 56 H. Schmidt 0.Hollitzer A. Seewald and W. Steglich Chem. Ber. 1979 112,727. ” G.Schnorrenberg and W. Steglich Angew. Chem. Zntemat. Edn. 1979,18,307. 58 M. Jawdosiuk M. Makasza B. Mudryk and G. A. Russell J.C.S. Chem. Comm. 1979,488. 160 A.R. Tatchell substituents the reaction becomes solvent-dependent and replacement of the nitro-group with the thiomethyl group predominates in DMSO. With branched- chain nuclear-substituted @-aryl-nitro-alkanes rearrangment of the carbon skeleton side-chain during reaction provides a rationale of the mechanism of this interesting reaction.'' 8 Sulphur Compounds Application of flash vacuum pyrolysis and microwave spectroscopic techniques has enabled the structure of the lachrymatory factor of the onion to be finally identified as (2)-propanethial S-oxide (49).60 A new method for the formation of a range of episulphides in high yield from for example styrene and cyclic alkenes uses either succinimide N-sulphenyl chloride (50)or the corresponding phthalimide derivative.The adducts (51)were reduced to the episulphides by addition to LiAIa in THF at low temperaturea61 0 H \+ c=s Et/\ 0- 0 (49) (50) Alkyl phenyl sulphides may be oxidized to chiral sulphoxides having reasonable optical purity (up to 81%)by sodium metaperiodate or hydrogen peroxide in buffer solution with bovine serum albumin. Prolonged oxidation gave lower chemical yields of sulphoxide but usually of greater optical purity. This was seen to arise from a two-stage oxidation process the first stage being an oxidation to the chiral sulphoxide having excess of one enantiomer and the second a preferential oxidation of the less abundant enantiomer to the sulphone.62 Prediction of the configuration of the sulphoxides from a consideration of the nature of the substituents is at present premature.Racemic 2-alkyl-tetrahydrothiopyran-4-ones( f)-(53) readily formed from methyl acrylate (52) as shown in Scheme 19 give the optically pure cis-and trans-2-alkyl-tetrahydrothiopyran-4-01s (54) and (53 each having (S)configura-tion at C-4 when submitted to horse liver alcohol dehydrogenase (HLADH)-mediated reduction. These products which may be readily separated by chromatography were converted into the optically pure (3S)-alcohols (56) by desulphurization. The latter are not obtained in an optically pure state by the enzymic reduction of the corresponding acyclic s9 N. Kornblum S. C. Carlson and R. C. Smith J. Amer. Chem. Soc. 1979 101 647; N.Kornblum J. Widmer and S.C. Carlson ibid. p. 658. " E. Block R. E. Penn and L. K. Revelle J. Amer. Chem. SOC.,1979,101,2200. '' M.V. Bombala and S. V. Ley J.C.S. Perkin I 1979 3013. 62 T.Sugimoto T. Kokubo J. Miyazaki S. Tanimoto and M. Okano J.C.S. Chem. Comm. 1979,402 1052. ''J. Davies and J. B. Jones J. Amer. Chem. SOC.,1979,101,5405. Aliphatic Compounds -Part (ii) Other Aliphatic Compounds viil QR t viii OR + Q "R Reagents i H,S; ii NaH; iii H' A; iv (HOCH,), H'; v N-chlorosuccinimide; vi RMgX H'; vii HLADH NAD'; viii Ni Scheme 19 9 Alkyl Halides The nucleophilic substitution reactions of alkyl halides are the most widely used and the most effective monitor of the efficiency of bi- and tri-phase catalytic systems. Catalysts currently being further studied for value in this type of reaction are principally though not exclusively quaternary ammonium and phosphonium salts immobilized on a polystyrene matrix? or on silica gel.65 Polymer-bound acyclic poly(oxyethy1ene) monomethyl ethers have been used for generation of dichloro-carbene and for Michael addition and Wittig reactions.66 Apart from surveying the preparative value of these systems attention is being directed to correlating such factors as for example the distance between the anionic and cationic centres the length of the carbon chain linking the ionic site to the polymer matrix (which influences the degree of protrusion of the site into the reaction medium) and the porosity of the resin.Alumina has also been shown to catalyse nucleophilic substitutions and the oxidation of alcohols by pe~manganate.~' Polymer-immobilized quaternary ammonium fluorides have been effectively used for the introduction of fluorine (by replacement of sulphonyloxy-groups) into the steroid nucleus and into monosaccharide residues.68 The synthetic value of lithium organocuprates is likely to be enhanced by recent studies on polymer-bound iodo(triarylphosphine)copper(I) in contact with a solution of the alkyl- or aryl- lithium.69 64 S.L. Regen J. C. K. Heh and J. McLick J. Org. Chem. 1979,44,1961; S. L. Regen and J. J. Besse J. Amer. Chem. SOC.,1979,101,4059; H. Molinari F. Montanari S. Quici and P. Tundo ibid. p. 3920; M. S. Chiles and P. C. Reeves Tetrahedron Letters 1979 3367. 65 P. Tundo and P.Venturello J. Amer. Chem SOC.,1979,101,6606. 66 S. Yanagida K. Takahashi and M. Okahara J. Org. Chem. 1979,44 1099. " S.-J. Liaw S. Quici and S. L. Regen J. Org. Chem. 1979,44,2029; S. Quid and S. L. Regen ibid. p. 3436; S. L. Regen S. Quici and M. D. Ryan J. Amer. Chem. SOC.,1979,101,7629. " S. Colonna A. Re G. Gelbard and E. Cesarotti J.C.S. Perkin I 1979,2248. 69 R. H. Schwartz and J. S. Filippo Jr. J. Org. Chem. 1979,44,2705. 162 A. R. Tatchell 10 Reviews Reviews have appeared on esterification and alkylation reactions employing iso- thi~ureas;~' on the synthesis of carbonyl compounds by coupling reactions of lower homologue~;~' on the chemistry of formamide acetal~?~ on halogeno-la~tones;~~ he~arnethylenetetramine,~~ alkenediazonium salts," and nitroacetic and on organic synthesis using supported there has also been a survey of tri-phase catalysis.78 'O L.J. Mathias Synthesis 1979 561. '' S.F.Martin Synthesis 1979,633. 72 M.D. Dowle and D. I. Davies Chem. SOC.Rev. 1979,8 171. 73 R.F.Abdulla and R. S. Brinkmeyer Tetrahedron 1979,35 1675. 74 N.BlaieviE D. Kolbah B. Belin V. sunjik and F. Kadfei Synthesis 1979 161. 75 K. Bott Angew. Chem. Internat. Edn. 1979,18 259. 76 M.T.Shipchandler,Synthesis 1979,666. 77 A. McKillop and D. W. Young Synthesis 1979,422 481. 78 S.L.Regen Angew. Chem. Internat. Edn. 1979,18,421.