While biocatalysis and electrochemistry each offer unique advantages, such as enzyme selectivity and traceless electron use, their integration for unlocking new enzyme function remains limited. Here, we report a new-to-nature electroenzymatic desymmetrization strategy that enables the enantiodivergent synthesis of biaryls bearing axial chirality. By synergistically combining protein engineering and mediated electrolysis, we repurpose thiamine-dependent enzymes for the highly efficient biocatalytic desymmetrization of biaryl dialdehydes, achieving high enantioselectivity (up to >99% e.e., with enantiodivergence accessible in some cases), excellent yield (up to 99%), and low enzyme loading (down to 0.1 mol %, up to 930 TON). Mechanistic investigations confirm that electrochemically generated enzyme-bound radicals are key to this unnatural reactivity, and the engineered protein scaffolds provide precise enantiodiscrimination while preventing detrimental overoxidation. This work showcases the potential of synergistic electroenzymatic synthesis as a powerful platform for unlocking new enzyme reactivity, offering a compelling alternative to established methods such as photobiocatalysis and artificial enzymes.
Shi et al. (Sun,) studied this question.