ENANTIOMERICALLY ENRICHED ALPHA-METHYL AMINO-ACIDS - USE OF AN ACYCLIC, CHIRAL ALANINE-DERIVED DIANION WITH A HIGH DIASTEREOFACIAL BIAS

Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)-tran s-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol. Sequential treatm ent of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv ) at -78 degrees C in THF generates the corresponding chiral dianions. Alkylation of each of these with benzyl bromide reveals that only the (-)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upo n its derivative dianion. In fact, that dianion (6) consistently displ ays diastereomeric ratios in the range of 89:11 to 94:6 for alkylation s with a spectrum of nine alkyl halides. If one recrystallization step is included, a single diastereomeric product may be obtained, as is d emonstrated for the benzylation of 6. Of particular note,the alkylatio n with 3,4-bis((tert-butyldimethylsilyl)oxy)benzyl bromide (18) (94:6 diasteriomeric ratio, 72% yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-alpha-methyl-DOPA (Aldomet) , in enantiomerically enriched form. In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the additi on of 10% HMPA to the reaction milieu. The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-cro wn-6, following alkylation. Complete deprotection affords enantiomeric ally enriched (S)-alpha-methyl amino acids, in all cases examined, ind icating that dianion 6 displays a substantial bias in favor of si face alkylation. This sense of diastereoselection is consistent with a cha in-extended, internal chelate model for the reactive conformation of t he dianion.