Enantiodivergent Radical Alkylation by Synergistic Lewis‐Acid‐Enzyme and Photoredox Catalysis

Artificial metalloenzymes (ArMs) and photoenzymatic catalysis represent two cutting-edge approaches to creating new enzyme reactivity. However, the potential of merging these two strategies remains underdeveloped for enantiocontrolled biotransformations. Herein, we develop a synergistic metalloenzymatic and photoredox catalysis platform to enable enantiodivergent radical alkylation of 2-acyl imidazoles. Specifically, cupin proteins are redesigned to function as copper(II)-based Lewis-acid-enzymes (LAses), which, in synergy with tripyridinyl-ruthenium-based photoredox catalysis, precisely control the generation, reactivity, and selectivity of abiological radicals, thereby unlocking non-natural enzyme reactivity. Powered by protein engineering, repurposed photo-LAses facilitate the green and efficient synthesis of diverse enantioenriched α-chiral ketones in high enantioselectivity (both enantiomers accessible, up to 97% yield and 98.5:1.5 enantiomeric ratio [er]). Detailed mechanistic studies suggest a radical addition to the metalloenzymatic enolate pathway and explain the switched selectivity from dark to photoconditions.