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, β2,2,3‐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 β2,2,3‐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 β2,2,3‐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.