Photobiocatalytic Enantioselective Benzylic C(sp 3 )–H Acylation Enabled by Thiamine-Dependent Enzymes via Intermolecular Hydrogen Atom Transfer

Hydrogen atom transfer (HAT) constitutes a powerful mechanism exploited in biology and chemistry to functionalize ubiquitous C(sp 3 )–H bonds in organic molecules. Despite its synthetic potential, achieving stereocontrol in chemical HAT-mediated C–H functionalization transformations remains challenging. By merging the radical reactivity of thiamine (ThDP)-dependent enzymes with chemical hydrogen atom transfer, we report here a photobiocatalytic strategy for the enantioselective C(sp 3 )–H acylation of an organic substrate, a transformation not found in nature nor currently attainable by chemical means. This method enables the direct functionalization of benzylic C(sp 3 )–H sites in a broad range of substrates to furnish valuable enantioenriched ketone motifs with good to high enantioselectivity (up to 96% ee). Mechanistic and spectroscopic studies support the involvement of radical species derived from the Breslow intermediate and C–H substrate, highlight the critical role of the photocatalyst and hydrogen atom abstraction reagents for productive catalysis, and reveal a specific enzyme/photocatalyst interaction favoring single electron transfer during catalysis. Further insights into how the enantioselectivity of the C–C bond-forming reaction is controlled by the enzyme and influenced by active site mutations were gained via molecular modeling. This study illustrates the productive integration of ThDP-mediated biocatalysis with chemical HAT, expanding the range of asymmetric C(sp 3 )–H functionalization transformations that can be accessed through biocatalysis.