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

Hong Zhang, Yuxing Cai, Yuqi Fang, Yong Huang () and Jiean Chen ()
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Hong Zhang: Shenzhen Bay Laboratory
Yuxing Cai: Clear Water Bay
Yuqi Fang: Shenzhen Bay Laboratory
Yong Huang: Clear Water Bay
Jiean Chen: Shenzhen Bay Laboratory

Nature Communications, 2025, vol. 16, issue 1, 1-10

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.

Date: 2025
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DOI: 10.1038/s41467-025-64024-7

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