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(sp³)-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.