Photobiocatalytic Strategies for Organic Synthesis

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(9), P. 5459 - 5520

Published: April 28, 2023

Biocatalysis has revolutionized chemical synthesis, providing sustainable methods for preparing various organic molecules. In enzyme-mediated most reactions involve molecules operating from their ground states. Over the past 25 years, there been an increased interest in enzymatic processes that utilize electronically excited states accessed through photoexcitation. These photobiocatalytic a diverse array of reaction mechanisms are complementary to one another. This comprehensive review will describe state-of-the-art strategies photobiocatalysis synthesis until December 2022. Apart reviewing relevant literature, central goal this is delineate mechanistic differences between general employed field. We organize based on relationship photochemical step and transformations. The include studies, substrate scopes, protein optimization strategies. By clearly defining mechanistically-distinct chemistry, we hope illuminate future synthetic opportunities area.

Language: Английский

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From Ground-State to Excited-State Activation Modes: Flavin-Dependent “Ene”-Reductases Catalyzed Non-natural Radical Reactions

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: 57(9), P. 1446 - 1457

Published: April 11, 2024

ConspectusEnzymes are desired catalysts for chemical synthesis, because they can be engineered to provide unparalleled levels of efficiency and selectivity. Yet, despite the astonishing array reactions catalyzed by natural enzymes, many reactivity patterns found in small molecule have no counterpart living world. With a detailed understanding mechanisms utilized catalysts, we identify existing enzymes with potential catalyze that currently unknown nature. Over past eight years, our group has demonstrated flavin-dependent "ene"-reductases (EREDs) various radical-mediated selectivity, solving long-standing challenges asymmetric synthesis.This Account presents development EREDs as general radical reactions. While developed multiple generating radicals within protein active sites, this account will focus on examples where flavin mononucleotide hydroquinone (FMNhq) serves an electron transfer initiator. initial mechanistic hypotheses were rooted electron-transfer-based initiation commonly used synthetic organic chemists, ultimately uncovered emergent unique site. We begin covering intramolecular discussing how activates substrate reduction altering redox-potential alkyl halides templating charge complex between flavin-cofactor. Protein engineering been modify fundamental photophysics these reactions, highlighting opportunity tune systems further using directed evolution. This section highlights range coupling partners termination available reactions.The next intermolecular role enzyme-templated ternary complexes among cofactor, halide, partner gating ensure it only occurs when both substrates bound highlight applications activation mode, including olefin hydroalkylation, carbohydroxylation, arene functionalization, nitronate alkylation. also discusses favor steps elusive solution reductive nitroalkanes. aware several recent EREDs-catalyzed photoenzymatic transformations from other groups. discuss results papers context nuances substrates.These biocatalytic often complement state-of-the-art small-molecule-catalyzed making valuable addition chemist's toolbox. Moreover, underlying principles studied potentially operative cofactor-dependent proteins, opening door different types enzyme-catalyzed anticipate serve guide inspire broad interest repurposing access new transformations.

Language: Английский

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Asymmetric C-Alkylation of Nitroalkanes via Enzymatic Photoredox Catalysis

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(2), P. 787 - 793

Published: Jan. 6, 2023

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules natural products. The C-alkylation of secondary with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling stereoselectivity this type reaction remains challenging. Here, we report highly chemo- stereoselective alkyl halides catalyzed by an engineered flavin-dependent "ene"-reductase (ERED). Directed evolution old yellow enzyme from Geobacillus kaustophilus provided triple mutant, GkOYE-G7, capable synthesizing high yield enantioselectivity. Mechanistic studies indicate that excitation enzyme-templated charge-transfer complex formed between substrates cofactor responsible radical initiation. Moreover, single-enzyme two-mechanism cascade was developed to prepare simple nitroalkenes, highlighting potential use one two mechanistically distinct reactions.

Language: Английский

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Using Data Science for Mechanistic Insights and Selectivity Predictions in a Non-Natural Biocatalytic Reaction

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(32), P. 17656 - 17664

Published: Aug. 2, 2023

The study of non-natural biocatalytic transformations relies heavily on empirical methods, such as directed evolution, for identifying improved variants. Although exceptionally effective, this approach provides limited insight into the molecular mechanisms behind and necessitates multiple protein engineering campaigns new reactants. To address limitation, we disclose a strategy to explore reaction space garner driving enzymatic transformations. Specifically, explored selectivity an "ene"-reductase, GluER-T36A, create data-driven toolset that explores rationalizes observed predicted selectivities substrate/mutant combinations. resultant statistical models related structural features enzyme substrate were used effectively predict in reactions with out-of-sample substrates mutants. Our provided deeper understanding enantioinduction by GluER-T36A holds potential enhance virtual screening

Language: Английский

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Unnatural Thiamine Radical Enzymes for Photobiocatalytic Asymmetric Alkylation of Benzaldehydes and α-Ketoacids

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(12), P. 9144 - 9150

Published: May 30, 2024

Despite substantial progress made toward elucidating the natural radical enzymology with thiamine pyrophosphate (TPP)-dependent pyruvate:ferredoxin oxidoreductases (PFORs) and pyruvate oxidases (POXs), repurposing naturally occurring two-electron TPP-dependent enzymes to catalyze single-electron transformations significant synthetic value remains a daunting task. Enabled by synergistic use of visible-light photocatalyst fluorescein set engineered derived from benzoylformate decarboxylase (BFD) benzaldehyde lyase (BAL), we developed an asymmetric photobiocatalytic decarboxylative alkylation benzaldehydes α-keto acids produce highly enantioenriched α-branched ketones. Mechanistically, propose that this dual catalytic involves oxidation enzyme-bound Breslow intermediate subsequent interception photoredox-generated transient alkyl radical. In conjunction visible light photoredox catalysis, biocatalysis represents emerging platform discover optimize are unknown biological systems not amenable small-molecule catalysis.

Language: Английский

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Photoenzymatic Enantioselective Synthesis of Oxygen‐Containing Benzo‐Fused Heterocycles

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(50)

Published: Oct. 30, 2023

New-to-nature biocatalysis in organic synthesis has recently emerged as a green and powerful strategy for the preparation of valuable chiral products, among which oxygen-containing benzo-fused heterocycles are important structural motifs pharmaceutical industry. However, asymmetric these compounds through radical-mediated methods is challenging. Herein, novel photoenzymatic developed to realize efficient enantioselective structure-guided engineering flavin-dependent 'ene'-reductase GluER. It shows that variant GluER-W100H could efficiently produce various benzoxepinones, chromanone indanone with different rings high yields great stereoselectivities under visible light. Moreover, results well supported by mechanistic experiments, revealing this process involves electron donor-acceptor complex formation, single transfer hydrogen atom transfer. Therefore, we provide an alternative approach chemoenzymatic skeletons bioactive pharmaceuticals.

Language: Английский

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Threonine Aldolase-Catalyzed Enantioselective α-Alkylation of Amino Acids through Unconventional Photoinduced Radical Initiation

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(32), P. 22476 - 22484

Published: July 4, 2024

Visible light-driven pyridoxal radical biocatalysis has emerged as a promising strategy for the stereoselective synthesis of valuable noncanonical amino acids (ncAAs). Previously, use well-tailored photoredox catalysts represented key to enable efficient phosphate (PLP) enzyme-catalyzed reactions. Here, we report PLP-dependent threonine aldolase-catalyzed asymmetric α-C–H alkylation abundant using Katritzky pyridinium salts alkylating agents. The engineered aldolases allowed this redox-neutral proceed efficiently, giving rise challenging α-trisubstituted and -tetrasubstituted ncAA products in protecting-group-free fashion with excellent enantiocontrol. Mechanistically, enantioselective α-alkylation capitalizes on unique reactivity persistent enzymatic quinonoid intermediate derived from PLP cofactor acid substrate allow novel C–C coupling. Surprisingly, photobiocatalytic process does not require well-established operates through an unconventional photoinduced generation involving PLP-derived aldimine. ability develop reactions without relying classic photocatalysts or photoenzymes opens up new avenues advancing intermolecular that are known either organic chemistry enzymology.

Language: Английский

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Engineering a Photoenzyme to Use Red Light

Published: March 18, 2024

Photoenzymatic catalysis is an emerging platform for asymmetric synthesis. In most of these reactions, the protein templates a charge transfer complex between cofactor and substrate, which absorbs in blue region electromagnetic spectrum. Here, we report engineering photoenzymatic ‘ene’-reductase to utilize red light (620 nm) radical cyclization reaction. Mechanistic studies indicate that ac-tivity achieved by introducing broadly absorbing shoulder off previously identified cyan absorption feature. Molecular dynamics simulations, docking, excited-state calculations suggest 𝜋→ 𝜋* transition from flavin while feature red-shift transition, occurs upon substrate binding. Differences excitation event help disfavor alkylation cofactor, pathway catalyst decomposition observed with but not red.

Language: Английский

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Catalysis by Nature's photoenzymes

Current Opinion in Structural Biology, Journal Year: 2022, Volume and Issue: 77, P. 102491 - 102491

Published: Oct. 30, 2022

Language: Английский

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Mechanistic investigation of repurposed photoenzymes with new-to-nature reactivity

Current Opinion in Green and Sustainable Chemistry, Journal Year: 2025, Volume and Issue: 52, P. 101009 - 101009

Published: Feb. 27, 2025

Language: Английский

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