Products Cited in Publications Worldwide Photobiocatalytic Enantioselective Benzylic C (sp3)–H Acylation Enabled by Thiamine-Dependent Enzymes via Intermolecular Hydrogen Atom Transfer

Photobiocatalytic Enantioselective Benzylic C (sp3)–H Acylation Enabled by Thiamine-Dependent Enzymes via Intermolecular Hydrogen Atom Transfer

Lu, Yen-Chu; Adukure, Ronald D; Roy, Satyajit; Chien, Derek L; McGill, Matthew J; Polara, Sarthi; Cisneros, G Andrés; Scheidt, Karl A; Fasan, Rudi

DOI: PMID:

Abstract

Hydrogen atom transfer (HAT) constitutes a powerful mechanism exploited in biology and chemistry to functionalize ubiquitous 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% 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(sp3)−H functionalization transformations that can be accessed through biocatalysis.

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