Enantiomerically Enriched α-Methyl Amino Acids. Use of an Acyclic, Chiral Alanine-Derived Dianion with a High Diastereofacial Bias

Article abstract of DOI:10.1021/jo00110a029

Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)-trans-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol.Sequential treatment of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv) at -78 deg 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 upon its derivative dianion.In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides.If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6.Of particular note, the alkylation with 3,4-bis((tert-butyldimethylsilyl)oxy)benzyl bromide (18) (94:6 diastereomeric ratio, 72percent yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched form.In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10percent HMPA to the reaction milieu.The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation.Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation.This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion.