Harnessing Photoenzymatic Systems for Intermolecular C–H Fluorination

Organofluorine compounds are vital in pharmaceuticals, and enzymes, nature's most efficient catalysts, offer tremendous potential for precise fluorination. However, no enzymatic strategies for intermolecular C-H fluorination have been realized-until now. We present the first radical photoenzymatic system enabling intermolecular C-H fluorination using an unnatural amino acid within a robust de novo protein scaffold. This system achieves chemoselective benzylic monofluorination in aqueous solutions with Selectfluor, driven by hydrogen atom transfer from the photoexcited amino acid. It successfully fluorinated various aromatic compounds and enabled biosynthesis of fluorinated polyketides and chiral fluorinated alcohols. These results establish radical photoenzymatic systems as a powerful new approach for efficient, selective biocatalytic fluorination, with direct relevance to pharmaceuticals.