Homochiral lithium amides for the asymmetric synthesis of β-amino acids

Abstract

Secondary homochiral lithium amides derived from α-methylbenzylamine undergo highly diastereoselective conjugate additions to a range of α,β-unsaturated esters. The corresponding β-amino acids are readily liberated by successive N-debenzylation and ester hydrolysis, furnishing ( R)-β-amino butyric acid, ( R)-β-amino pentanoic acid, ( S)-β-leucine, ( R)-β-amino octanoic acid, ( S)-β-phenylalanine, ( S)-β-tyrosine methyl ether, ( S)-β-tyrosine hydrochloride and ( S)-β-(2-methoxyphenyl)-β-amino propanoic acid in high yields and high ee. The application of this procedure to the synthesis of the natural products ( R)-β-DOPA and ( R)-β-lysine is demonstrated. The development of a simplified one-pot reaction protocol applicable to the multi-gram scale synthesis of homochiral β-amino esters is also delineated.