Photobiocatalytic Enantioselective C(sp3)–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 alike to functionalize otherwise inert C(sp3)–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(sp3)–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(sp3)–H sites in a broad range of substrates to furnish valuable enantioenriched ketone motifs with good to high enantioselectivity (up to 96% e.e.). Mechanistic and reactivity studies support the involvement of radical species derived from the Breslow intermediate and C–H substrate, along with the critical role of the photocatalyst and hydrogen atom abstraction reagent for productive catalysis. This study illustrates the productive integration of ThDP-mediated biocatalysis with chemical HAT, expanding the range of asymmetric C(sp3)–H functionalization transformations accessible through biocatalysis.