The Natural Redox Cofactor Pyrroloquinoline Quinone (PQQ) Enables Photocatalytic Radical Cyclizations

Photoenzymatic catalysis facilitates stereoselective new‐to‐nature chemistry under mild conditions. In addition to the rational design of artificial photoenzymes, naturally occurring redox enzymes can be repurposed to promote photoredox catalysis in the chiral protein environment. Here, we show that enzymes utilizing the pyrroloquinoline quinone (PQQ) cofactor expand the toolbox of photobiocatalysis. PQQ absorbs visible light and is capable of single‐electron transfer. It thus exhibits mechanistic similarities to flavin cofactors, which are widely used for photoenzymatic approaches. First, we established the trimethyl ester PQQMe 3 as a stand‐alone photoredox catalyst in pure organic solvent. Upon excitation, PQQMe 3 enables the redox‐neutral radical cyclization of an N ‐(bromoalkyl)‐substituted indole. We then tested a panel of PQQ‐dependent sugar and alcohol dehydrogenases for photoenzymatic catalysis in aqueous buffer, focusing on a redox‐neutral radical reaction to form oxindoles. Under optimized reaction conditions, we obtained a 69% yield and an 82:18 enantiomeric ratio. Our work thus demonstrates that PQQ enzymes are capable of stereoselective photoredox catalysis. Future enzyme engineering efforts based on computational modeling and directed evolution will fully unlock their synthetic potential.