Flavin‐dependent ene‐reductases (EREDs) are known to stereoselectively reduce activated alkenes, but are inactive toward carbonyls. Demonstrated here is that in the presence of photoredox catalysts, these enzymes will reduce aromatic ketones. Mechanistic experiments suggest this reaction proceeds through ketyl radical formation, a reaction pathway that is distinct from the native hydride‐transfer mechanism. Furthermore, this reactivity is accessible without modification of either the enzyme or cofactors, allowing both native and non‐natural mechanisms to occur simultaneously. Based on control experiments, we hypothesize that binding to the enzyme active site attenuates the reduction potential of the substrate, enabling single‐electron reduction. This reactivity highlights opportunities to access new catalytic manifolds by merging photoredox catalysis with biocatalysis.
Photoenzymes are biological catalysts that use light to convert starting materials into products. These catalysts require photon absorption for each turnover, making quantum efficiency an important optimization parameter. Flavin-dependent "ene"-reductases (EREDs) display latent photoenzymatic activity for synthetically valuable hydroalkylations; however, protein engineering has not been used to optimize this nonnatural function. We describe a protein engineering platform for the high throughput optimization of photoenzymes. A single round of engineering results in improved catalytic function toward the synthesis of g, d, e-lactams, and acyclic amides. Mechanistic studies show that key mutations can alter the enzymes excited state dynamics, enhance its photon efficiency, and ultimately increase catalyst performance. Transient absorption spectroscopy reveals that engineered variants display dramatically decreased radical lifetimes, indicating an evolution toward a concerted mechanism.
Herein, we describe a regioselective Rh-catalyzed decarboxylative cross-coupling of β–keto acids and alkynes to access branched γ,δ–unsaturated ketones. Rh-hydride catalysis enables the isomerization of an alkyne to generate a metal-allyl species that can undergo carbon-carbon bond formation. Ketones are generated under mild conditions, without the need for base or activated electrophiles.
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