Asymmetric Radical Alkylation Enabled by Synergistic Photoredox Enamine Biocatalysis

Abstract Class I aldolases, a unique link among biochemistry, organic chemistry, and computational chemistry are powerful C─C bond‐forming enzymes in synthetic chemistry and industry because of their unparalleled selectivity, extensive substrate scope and scalability. However, the types of reactions catalyzed by class I aldolases are restricted and radical reactions have yet to be accomplished. Here, we demonstrate a proof‐of‐concept study in which a synergistic photoredox biocatalysis strategy can be applied to realize new catalytic functions of enamine‐dependent aldolases. This new reactivity enables asymmetric alkylation of a prochiral radical under exclusive stereocontrol, a challenging task for amine catalysts. Both enantiomeric products were obtained in a stereoconvergent fashion from wild‐type and engineered aldolases. This synergistic photoredox biocatalysis strategy has resulted in a new‐to‐nature enzymatic reaction and led to an asymmetric transformation that is not feasible for organocatalysis. We envision that this discovery will motivate the development of enzymatic enamine and iminium catalysis for valuable asymmetric radical transformations, complementing the prevailing organocatalysts.