ArticleJournal of the American Chemical Society2023
Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes.
Article in Journal of the American Chemical Society, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Designing and Engineering Enzymes for New-to-Nature Photobiocatalysis.Methods in molecular biology (Clifton, N.J.) · 2026Review
- Aromatic Coupling Reactions Catalyzed by "ene"-Reductase under Visible Light Irradiation.ACS omega · 2025Article
- Introduction of flavin anions into photoredox catalysis: acid-base equilibria of lumichrome allow photoreductions with an anion of an elusive 10-unsubstituted isoalloxazine.Chemical science · 2025Article
- An efficient lysate-based approach for biosynthesis of the pyrrolobenzodiazepine natural product tilimycin.Journal of biotechnology · 2025Article
- Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation.Nature communications · 2025Article
- Engineering the Reaction Pathway of a Non-heme Iron Oxygenase Using Ancestral Sequence Reconstruction.Journal of the American Chemical Society · 2024Article
- A metalloenzyme platform for catalytic asymmetric radical dearomatization.Nature chemistry · 2024Article
- Threonine Aldolase-Catalyzed Enantioselective α-Alkylation of Amino Acids through Unconventional Photoinduced Radical Initiation.Journal of the American Chemical Society · 2024Article
- Stereodivergent photobiocatalytic radical cyclization through the repurposing and directed evolution of fatty acid photodecarboxylases.Nature chemistry · 2024Article
- From Ground-State to Excited-State Activation Modes: Flavin-Dependent "Ene"-Reductases Catalyzed Non-natural Radical Reactions.Accounts of chemical research · 2024Review
- Asymmetric Synthesis of α-Chloroamides via Photoenzymatic Hydroalkylation of Olefins.Journal of the American Chemical Society · 2024Article
- Regiodivergent Radical Termination for Intermolecular Biocatalytic C-C Bond Formation.Journal of the American Chemical Society · 2024Article
- Novel applications of photobiocatalysts in chemical transformations.RSC advances · 2024Review
- Non-Native Site-Selective Enzyme Catalysis.Chemical reviews · 2023Review
- P450-catalyzed atom transfer radical cyclization.Methods in enzymology · 2023Article
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9 authors.
Funding
Abstract
Substituted arenes are ubiquitous in molecules with medicinal functions, making their synthesis a critical consideration when designing synthetic routes. Regioselective C-H functionalization reactions are attractive for preparing alkylated arenes; however, the selectivity of existing methods is modest and primarily governed by the substrate's electronic properties. Here, we demonstrate a biocatalyst-controlled method for the regioselective alkylation of electron-rich and electron-deficient heteroarenes. Starting from an unselective "ene"-reductase (ERED) (GluER-T36A), we evolved a variant that selectively alkylates the C4 position of indole, an elusive position using prior technologies. Mechanistic studies across the evolutionary series indicate that changes to the protein active site alter the electronic character of the charge transfer (CT) complex responsible for radical formation. This resulted in a variant with a significant degree of ground-state CT in the CT complex. Mechanistic studies on a C2-selective ERED suggest that the evolution of GluER-T36A helps disfavor a competing mechanistic pathway. Additional protein engineering campaigns were carried out for a C8-selective quinoline alkylation. This study highlights the opportunity to use enzymes for regioselective radical reactions, where small molecule catalysts struggle to alter selectivity.
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