Synergistic Photoenzymatic Anti-Markovnikov Hydroaryla-tion of Olefins via Heteroaryl Radical Intermediates

Heteroaromatic alkylations are indispensable reactions for synthesizing biologically active molecules. The anti-Markovnikov hydroarylation of olefins using heteroaryl hal-ides furnishes the product as a single regioisomer, however, catalytic variants are ineffective in controlling the stereochem-ical outcome of these reactions. Here, we report a synergistic photoenzymatic hydroarylation of olefins using flavin-dependent ‘ene’-reductases with ruthenium photoredox cata-lysts. Enzyme homologs were identified, which provide access to both product enantiomers in greater than 80% yield with up to 99:1 er. This method is effective for styrenyl and unactivat-ed alkenes, highlighting the generality of this approach. Bind-ing assay study revealed strong binding of the photocatalyst with the enzyme for superior catalytic activity. Mechanistic studies suggest efficient intermolecular coupling is possible because alkene binding accelerates the consumption of the aryl halide.