Stereoselective Photoenzymatic Hydroarylation for the Construction of Quaternary Stereocenters

Quaternary carbon stereocenters are a crucial component of many bioactive molecules, but they can be challenging to prepare stereoselectively. Olefin hydroarylations are an attractive means for preparing this motif; however, existing methods struggle to set stereocenters on substrates lacking traditional catalyst binding handles. Here, we report a stereoselective photoenzymatic olefin hydroarylation using a repurposed Baeyer–Villiger monooxygenase. Three rounds of iterative site-saturation mutagenesis yielded a photoenzyme capable of preparing valuable tetrahydroquinolines in high yields with excellent enantioselectivity. The engineered variant accepts various arene substituents, highlighting the synthetic utility of this methodology. DFT calculations and control experiments suggest that the protein templates a through-space interaction between the tertiary radical and aromatic group, which attenuates the oxidation potential of the radical, enabling C–C bond formation.