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 paradigms

Asymmetric Redox-Neutral Radical Cyclization Catalyzed by Flavin-Dependent ‘Ene’-Reductases

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. While these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyze reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here we demonstrate that these enzymes can catalyze redox-neutral radical cyclizations to produce enantioenriched oxindoles from a-haloamides. This transformation is a C–C bond forming reaction currently unknown in nature and one for which there are no catalytic asymmetric examples. Mechanistic studies indicate the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground state flavin semiquinone provides the electron for substrate reduction and flavin quinone oxidizes the vinylogous a-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.</p

Static to inducibly dynamic stereocontrol: The convergent use of racemic β-substituted ketones.

The synthesis of stereochemically complex molecules in the pharmaceutical and agrochemical industries requires precise control over each distinct stereocenter, a feat that can be challenging and time consuming using traditional asymmetric synthesis. Although stereoconvergent processes have the potential to streamline and simplify synthetic routes, they are currently limited by a narrow scope of inducibly dynamic stereocenters that can be readily epimerized. Here, we report the use of photoredox catalysis to enable the racemization of traditionally static, unreactive stereocenters through the intermediacy of prochiral radical species. This technology was applied in conjunction with biocatalysts such as ketoreductases and aminotransferases to realize stereoconvergent syntheses of stereodefined γ-substituted alcohols and amines from β-substituted ketones