Asymmetric Radical Coupling to Form β2,2,3-Amino Acid Esters by Synergistic Chiral Phosphoric Acid and Photocatalysis

Abstract

β-Amino acids are essential building blocks in bioactive molecules, offering unique properties and potential in peptide and drug synthesis. Among them, β^2,2,3-amino acids—characterized by a contiguous quaternary and tertiary stereocenter—represent a structurally unique subclass with promising biological potential. However, their broader application has been hampered by the scarcity of general and efficient synthetic methods. To address these challenges, we have developed a visible-light-driven radical-radical coupling strategy enabled by chiral phosphoric acid (CPA) catalysis. In this synergistic dual catalytic system, β-keto esters are activated by CPA and undergo single-electron oxidation to generate tertiary carbon radicals, while redox-active NHPI esters derived from α-amino acids are reduced via SET to form α-amino alkyl radicals. Under the chiral environment provided by CPA, these radicals engage in highly selective cross-coupling to afford β^2,2,3-amino esters in good yields with excellent diastereo- and enantioselectivity. This strategy provides a mild, modular approach for the stereo-controlled assembly of structurally complex β^2,2,3-amino esters, overcoming long-standing limitations in substrate scope and reaction efficiency. Beyond its synthetic utility, this method offers new opportunities for expanding the chemical space of β-amino acid derivatives and holds promise for advancing medicinal chemistry and peptide-based drug discovery.