Synthesis of enantio- and diastereo-isomerically pure β- and γ-substituted glutamic acids via glycine condensation with activated olefins

Abstract

The glycine fragment in the nickel(II) complex formed from the Schiff base of glycine and (S)-o[(N-benzylprolyl)amino]benzophenone undergoes base-catalysed Michael addition in methanol in the presence of MeONa to the activated olefins methyl acrylate, acrylonitrile, methyl methacrylate, acrolein, and methyl trans-cinnamate. Complexes of substituted (S)-glutamic acid or its derivatives were formed in good chemical yields with almost complete diastereoselection at the α-carbon atom of the amino acid moiety. Diastereoselection at the β- and γ-atoms was not significant, but the isomeric complexes could be easily separated chromatographically. Cleavage of the pure diastereo-isomers with aqueous HCl gave, in good yields, optically pure glutamic acids and regenerated the original chiral reagent. The configurations of the amino acid β- and γ-carbon atoms were determined by ¹H n.m.r. spectroscopy and crystal structure X-ray analysis of the corresponding original complexes. The addition to acrolein, catalysed by triethylamine in methanol, leads to the 1,4-adduct exclusively. The amino acid thus obtained could be converted into (S)-proline by reduction with NaBH₄.