The natural redox cofactor 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 have been repurposed for this approach. Most prominently, flavin-containing cofactors can promote photoredox catalysis in the chiral protein environment, with several examples of enantioselective C–C bond forming reactions reported in recent years. Here, we add another class of natural enzymes, which utilize the pyrroloquinoline quinone (PQQ) cofactor, to the toolbox of photobiocatalysis. Although structurally distinct from flavin, PQQ exhibits mechanistic similarities, as it also absorbs visible light and is capable of single-electron transfer. First, we established the trimethyl ester PQQMe3 as a stand-alone photoredox catalyst in pure organic solvent. Upon excitation, PQQMe3 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 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 modelling and directed evolution will fully unlock their synthetic potential.