Direct Enantioselective Allylic Alkylation of α-Amino Esters to Quaternary Glutamates via Strategic Pyridoxal Catalyst Design

Abstract

The difficulty for N-unprotected α-substituted glycinates as α-C nucleophiles originates from both competing N nucleophilic interference and steric hindrance of the α substituent, which makes direct asymmetric α-C alkylation of N-unprotected α-substituted glycinates with Morita–Baylis–Hillman (MBH) adducts especially challenging. Given the wide utilization of α-quaternary chiral glutamic acid derivatives in therapeutic studies, we took advantage of biomimetic carbonyl catalysis to achieve their efficient synthesis. A bifunctional centrally chiral pyridoxal, featured with an expanded catalytic cavity and reduced steric hindrance around the aldehyde group, was designed and synthesized. In this work, we describe the novel centrally chiral pyridoxal enabled direct asymmetric α-C alkylation of N-unprotected α-substituted glycinates with MBH acetates. A broad range of α-quaternary chiral glutamic acid derivatives with multiple modifications were produced with high reactivity and excellent stereocontrol.