Photoenzymatic C(sp ³ )–H Functionalization of 1,3-Dicarbonyls Enables Enantioselective Hydroalkylation of Styrenes

Photoenzymatic catalysis has evolved into a powerful strategy for achieving challenging asymmetric radical transformations over the past decade. While considerable progress has been made, prefunctionalized radical precursors are generally required. Therefore, leveraging ubiquitous C–H bonds as radical precursors for photoenzymatic catalysis is highly desirable. Here we report that engineered flavin-dependent ene-reductases enable photoenzymatic hydroalkylation of styrenes via direct oxidation of abundant 1,3-dicarbonyls at neutral pH, generating electrophilic carbon-centered radicals from C(sp 3 )–H bonds. This strategy achieves 100% atom economy and overcomes common competing pathways such as Aldol condensation and the de Mayo reaction, affording a broad array of enantioenriched 1,3-dicarbonyl products in good yield with excellent enantioselectivity. Computational studies revealed that radical generation proceeds via a proton-coupled electron transfer process and elucidated the origin of enantioselectivity.