Practical synthesis of anti-β-hydroxy-α-amino acids by Pd(II) -catalyzed sequential C(sp(3) )-H functionalization.

Abstract

An improved and practical procedure for the stereoselective synthesis of anti-β-hydroxy-α-amino acids (anti-βhAAs), by palladium-catalyzed sequential C(sp(3) )-H functionalization directed by 8-aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β-methyl C(sp(3) )-H of alanine derivative, β-acetoxylation of both alkylic and benzylic methylene C(sp(3) )-H bonds affords various anti-β-hydroxy-α-amino acid derivatives. As an example, the synthesis of β-mercapto-α-amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β-branched α-amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side-chain AAs, which could be explained by the competition of intramolecular C-OAc bond reductive elimination from Pd(IV) intermediates vs. intermolecular attack by an external nucleophile (AcO(-) ) in an SN 2-type process.