Photobiocatalytic Enantioselective Benzylic C(sp)-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)-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)-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)-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)-H functionalization transformations that can be accessed through biocatalysis.