Ligand-Enabled Pd-Catalyzed Enantioselective Synthesis of Quaternary Amino Acids and Glycolic Acids Derivatives

Abstract

Abstract Quaternary amino acids and glycolic acids, in which the all-substituted carbon stereocenters are adjacent to the carbonyl groups, are widespread in many biologically relevant compounds and pharmaceuticals. One specific case, α-quaternary amino acid, plays a crucial role as modifiers of peptide conformation, compared with natural amino acids. There are numerous methods on enantioselective alkylation at the α-carbon of these compounds. However, the asymmetric arylation at the α-carbon is synthetically challenging. This report describes two individual protocols for the rapid synthesis of optically active α-aryl quaternary amino acids and glycolic acids derivatives, respectively, by Pd catalysis and two unique Sadphos ligands. The methods employ two common heterocycles, azalactones and 5H-oxazol-4-ones, as amino acids and glycolic acids precursors and show a broad scope, high yields and excellent enantioselectivity. Analyses of the transition-state structures via Noncovalent interaction, Energy decomposition analyses (EDA) and natural bond orbital (NBO) reveals that CH···O interactions between the ligand and carbonyl group in the substrate play a critical role in the efficient stereocontrol.