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Photoexcitation is a common strategy for initiating radical reactions in chemical synthesis. We found that photoexcitation of flavin-dependent “ene”-reductases changes their catalytic function, enabling these enzymes to promote an asymmetric radical cyclization. This reactivity enables the construction of five-, six-, seven-, and eight-membered lactams with stereochemical preference conferred by the enzyme active site. After formation of a prochiral radical, the enzyme guides the delivery of a hydrogen atom from flavin—a challenging feat for small-molecule chemical reagents. The initial electron transfer occurs through direct excitation of an electron donor-acceptor complex that forms between the substrate and the reduced flavin cofactor within the enzyme active site. Photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. Although these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyse reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here, we demonstrate that these enzymes can catalyse redox-neutral radical cyclizations to produce enantioenriched oxindoles from α-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 α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

Strategies that provide enzymes with the ability to catalyse non-natural reactions are of considerable synthetic value. Photoredox catalysis has proved adept at expanding the synthetic repertoire of existing catalytic platforms, yet, in the realm of biocatalysis it has primarily been used for cofactor regeneration. Here we show that photoredox catalysts can be used to enable new catalytic function in nicotinamide-dependent enzymes. Under visible-light irradiation, xanthene-based photocatalysts enable a double-bond reductase to catalyse an enantioselective deacetoxylation. Mechanistic experiments support the intermediacy of an α-acyl radical, formed after the elimination of acetate. Isotopic labelling experiments support nicotinamide as the source of the hydrogen atom. Preliminary calculations and mechanistic experiments suggest that binding to the protein attenuates the reduction potential of the starting material, an important feature for localizing radical formation to the enzyme active site. The generality of this approach is highlighted with the radical dehalogenation of α-bromoamides catalysed by ketoreductases with Eosin Y as a photocatalyst.

Enzymes catalyse radical-mediated fluorine atom transfer reactions for enantioselective C(sp3)-F bond formation.

Flavin-dependent ‘ene’-reductases (EREDs) are exquisite catalysts for effecting stereoselective reductions. Although these reactions typically proceed through a hydride transfer mechanism, we recently found that EREDs can also catalyse reductive dehalogenations and cyclizations via single electron transfer mechanisms. Here, we demonstrate that these enzymes can catalyse redox-neutral radical cyclizations to produce enantioenriched oxindoles from α-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 suggest the reaction proceeds via the flavin semiquinone/quinone redox couple, where ground-state flavin semiquinone offers the electron for substrate reduction and flavin quinone oxidizes the vinylogous α-amido radical formed after cyclization. This mechanistic manifold was previously unknown for this enzyme family, highlighting the versatility of EREDs in asymmetric synthesis.

Photoexcitation is a common strategy for initiating radical reactions in chemical synthesis. We found that photoexcitation of flavin-dependent “ene”-reductases changes their catalytic function, enabling these enzymes to promote an asymmetric radical cyclization. This reactivity enables the construction of five-, six-, seven-, and eight-membered lactams with stereochemical preference conferred by the enzyme active site. After formation of a prochiral radical, the enzyme guides the delivery of a hydrogen atom from flavin—a challenging feat for small-molecule chemical reagents. The initial electron transfer occurs through direct excitation of an electron donor-acceptor complex that forms between the substrate and the reduced flavin cofactor within the enzyme active site. As a result, photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.

Vanadium-dependent haloperoxidases (VHPOs) are a uniquely robust class of enzymes capable of performing electrophilic halogenation of organic substrates. Despite their emerging biotechnological significance, the precise catalytic and halide-selection mechanisms of VHPOs under native conditions remains largely unexamined. Herein, we leverage single-particle cryogenic transmission electron microscopy (cryo-EM) to provide insight into the catalytic mechanism of the vanadium-dependent bromoperoxidase from Corallina pilulifera (CpVBPO) under catalytically relevant conditions. Specifically, we have collected the first set of high-resolution cryo-EM structures of CpVBPO in four catalytically relevant states including binding to phosphate, orthovanadate, orthovanadate and bromide, and orthovanadate and hydrogen peroxide. The collected structures, resolved at 2.2 to 3.2 Å, reveal deviations from previously reported X-ray diffraction (XRD) structures, particularly in the geometry of the vanadate cofactor and key residue interactions in the active site. Our findings suggest a trigonal planar, metavanadate-like geometry for the vanadate cofactor in the resting state, contradicting the commonly proposed orthovanadate geometry containing an apical hydroxo ligand. Furthermore, the dynamic roles of residues Asp335 and Leu337 in halide specificity in the catalytic cycle are proposed through observed conformational changes upon bromide binding. Using pKa calculations and structural analyses, a mechanism for generating hypobromous acid, mediated by His487, is presented. This study not only refines the structural and mechanistic understanding of CpVBPO, but also demonstrates the capabilities of cryo-EM to capture native-like enzyme structures under catalytically relevant conditions, offering a more informative approach for investigating the mechanistic features of VHPOs.

The enzymatic synthesis of heterocycles is an emerging biotechnology for the sustainable construction of societally important molecules. Herein, we describe an enzyme-mediated strategy for the oxidative dimerization of thioamides enabled by enzymatic halide recycling by vanadium-dependent haloperoxidase enzymes. This approach allows for intermolecular biocatalytic bond formation using a catalytic quantity of halide salt and hydrogen peroxide as the terminal oxidant. The established method is applied to a diverse range of thioamides to generate the corresponding 1,2,4-thiadiazoles in moderate to high yield and with excellent chemoselectivity. Mechanistic experiments suggest that the reaction proceeds through two distinct enzyme-mediated sulfur halogen- ation events that are critical for heterocycle formation. Molecular docking experiments provide insight into reactivity differences between biocatalysts used in the study. Finally, the developed biocatalytic oxidative dimerization is applied to a preparative scale chemoenzymatic synthesis of the anticancer agent penicilliumthiamine B. These studies demonstrate that enzymatic halide recycling is a promising platform for new-to-nature intermolecular bond formation.

Halogenated heteroarenes are key building blocks across numerous chemical industries. Here, we report that vanadium haloperoxidases are capable of producing 3-haloindoles through decarboxylative halogenation of 3-carboxyindoles. This biocatalytic method is applicable to decarboxylative chlorination, bromination, and iodination in moderate to high yields and with excellent chemoselectivity.