Photoenzymatic Hydrogenation of Heteroaromatic Olefins Using ‘Ene’‐Reductases with Photoredox Catalysts

Flavin‐dependent ‘ene’‐reductases (EREDs) are highly selective catalysts for the asymmetric reduction of activated alkenes. This function is, however, limited to enones, enoates, and nitroalkenes using the native hydride transfer mechanism. Here we demonstrate that EREDs can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. Experimental evidence suggests the reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to the corresponding neutral benzylic radical in solution. DFT calculations reveal this radical to be “dynamically stable”, suggesting it is sufficiently long‐lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer. This reduction mechanism is distinct from the native one, highlighting the opportunity to expand the synthetic capabilities of existing enzyme platforms by exploiting new mechanistic models. HAT‐trick: Flavin‐dependent ‘ene'‐reductases can reduce vinyl pyridines when irradiated with visible light in the presence of a photoredox catalyst. The reaction proceeds via a radical mechanism where the vinyl pyridine is reduced to a neutral benzylic radical in solution. Calculations reveal this radical to be “dynamically stable” and therefore sufficiently long‐lived to diffuse into the enzyme active site for stereoselective hydrogen atom transfer (HAT).