Electricity-driven enzymatic dynamic kinetic oxidation

Electrochemistry is undergoing a resurgence in synthetic chemistry and has compelling advantages¹. Repurposing natural enzymes through synthetic chemical strategies holds promise for exploring new chemical space^2-6. Elegant strategies, including directed evolution^7-10, artificial enzymes¹¹ and photoenzymatic catalysis^12,13, have demonstrated their capacities for expanding the applications of enzymes in both academia and industry. However, the integration of electrochemistry with enzymes has primarily been limited to replicating previously established enzyme functions^14-16. Key challenges in achieving new enzyme reactivity with electricity include compatibility issues and difficulties in heterogeneous electron transfer. Here we report the reshaping of thiamine-dependent enzymes with ferrocene-mediated electrocatalysis to unlock an unnatural dynamic kinetic oxidation of α-branched aldehydes. This robust electroenzymatic approach yields various bioactive (S)-profens with up to 99% enantiomeric excess; it is applicable with whole cells overexpressing the enzyme and using down to 0.05 mol% enzyme loadings. Mechanistic investigations show multiple functions of the electroenzyme in precise substrate discrimination, accelerating racemization and facilitating kinetically matched electron transfer events.