Enantiodivergent Radical Alkylation by Synergistic Lewis‐Acid‐Enzyme and Photoredox Catalysis
Jiawei Zhang, Qiaoyu Zhang, Ran Ge, Aokun Liu, Bin Chen, Zihan Zhang, Beibei Zhao, Jinhai Yu, Yue Zhao, Lu Yu, Mingfeng Cao, Binju Wang, Xiaoqiang Huang
Abstract
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.