Stereoselective diversification of α-amino acids enabled by N-heterocyclic carbene catalysis

Abstract

Abstract Chiral α-amino acids (AAs), essential to biological systems and drug design, drive demand for precise synthetic methods to access unnatural variants (UAAs) and stereochemically defined peptides. We report an N-heterocyclic carbene (NHC)-catalyzed strategy enabling enantioselective synthesis of α-(U)AA esters and peptides. Leveraging NHC-generated acyl azolium intermediates, this approach achieves dynamic kinetic resolution of racemic or chiral α-(U)AAs with broad substrate scope, including sterically hindered and unsaturated derivatives. Stereodivergent synthesis is accomplished via NHC-mediated proton shuttling, which usually furnishes enantio-complementary α-(U)AAs and peptides with >90% ee (de). Mechanistic studies establish that N,N’-diisopropylcarbodiimide activates α-(U)AAs to form oxazolone intermediates, which undergo NHC-mediated conversion to acyl azolium species. Divergent nucleophilic pathways are governed by chiral matching between catalyst and substrate, as evidenced by density functional theory (DFT) calculations revealing π-π interactions and steric effects as stereoselectivity determinants. The methodology’s utility is also demonstrated in solid-phase peptide synthesis, achieving direct chirality transfer from racemic precursors to peptides with minimal epimerization. This work provides a catalytic platform for stereocontrolled α-(U)AA and peptide synthesis, with implications for chemical biology and peptide therapeutic development.