Single-Electron Oxidation-Initiated Enantioselective Hydrosulfonylation of Olefins Enabled by Photoenzymatic Catalysis

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2748 - 2756

Published: Jan. 12, 2024

Controlling the enantioselectivity of hydrogen atom transfer (HAT) reactions has been a long-standing synthetic challenge. While recent advances on photoenzymatic catalysis have demonstrated great potential non-natural photoenzymes, all transformations are initiated by single-electron reduction substrate, with only one notable exception. Herein, we report an oxidation-initiated enantioselective hydrosulfonylation olefins using novel mutant gluconobacter ene-reductase (GluER-W100F-W342F). Compared to known systems, our approach does not rely formation electron donor–acceptor complex between substrates and enzyme cofactor simplifies reaction system obviating addition regeneration mixture. More importantly, GluER variant exhibits high reactivity broad substrate scope. Mechanistic studies support proposed mechanism reveal that tyrosine-mediated HAT process is involved.

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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Directed Evolution and Unusual Protonation Mechanism of Pyridoxal Radical C–C Coupling Enzymes for the Enantiodivergent Photobiocatalytic Synthesis of Noncanonical Amino Acids

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 23, 2025

Visible light-driven pyridoxal radical biocatalysis has emerged as a new strategy for the stereoselective synthesis of valuable noncanonical amino acids in protecting-group-free fashion. In our previously developed dehydroxylative C–C coupling using engineered PLP-dependent tryptophan synthases, an enzyme-controlled unusual α-stereochemistry reversal and pH-controlled enantiopreference were observed. Herein, through high-throughput photobiocatalysis, we evolved set stereochemically complementary PLP enzymes, allowing both l- d-amino with enhanced enantiocontrol across broad pH window. These newly acid synthases permitted use range organoboron substrates, including boronates, trifluoroborates, boronic acids, excellent efficiency. Mechanistic studies unveiled unexpected racemase activity earlier enzyme variants. This promiscuous was abolished shedding light on origin enantiocontrol. Further mechanistic investigations suggest switch proton donor to account stereoinvertive formation highlighting stereoinversion mechanism that is rare conventional two-electron enzymology.

Language: Английский

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Asymmetric Synthesis of α-Chloroamides via Photoenzymatic Hydroalkylation of Olefins

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(11), P. 7191 - 7197

Published: March 5, 2024

Photoenzymatic intermolecular hydroalkylations of olefins are highly enantioselective for chiral centers formed during radical termination but poorly selective set in the C–C bond-forming event. Here, we report evolution a flavin-dependent "ene"-reductase to catalyze coupling α,α-dichloroamides with alkenes afford α-chloroamides good yield excellent chemo- and stereoselectivity. These products can serve as linchpins synthesis pharmaceutically valuable motifs. Mechanistic studies indicate that formation occurs by exciting charge-transfer complex templated protein. Precise control over orientation molecules within potentially accounts observed The work expands types motifs be prepared using photoenzymatic catalysis.

Language: Английский

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Asymmetric photoenzymatic incorporation of fluorinated motifs into olefins

Science, Journal Year: 2024, Volume and Issue: 385(6707), P. 416 - 421

Published: July 25, 2024

Enzymes capable of assimilating fluorinated feedstocks are scarce. This situation poses a challenge for the biosynthesis compounds used in pharmaceuticals, agrochemicals, and materials. We developed photoenzymatic hydrofluoroalkylation that integrates motifs into olefins. The photoinduced promiscuity flavin-dependent ene-reductases enables generation carbon-centered radicals from iodinated fluoroalkanes, which directed by photoenzyme to engage enantioselectively with approach facilitates stereocontrol through interaction between singular unit enzyme, securing high enantioselectivity at β, γ, or δ positions groups enzymatic hydrogen atom transfer-a process is notably challenging conventional chemocatalysis. work advances strategies integrating chemical opens avenues asymmetric synthesis compounds.

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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A New Age of Biocatalysis Enabled by Generic Activation Modes

JACS Au, Journal Year: 2024, Volume and Issue: 4(6), P. 2068 - 2080

Published: May 31, 2024

Biocatalysis is currently undergoing a profound transformation. The field moves from relying on nature's chemical logic to discipline that exploits generic activation modes, allowing for novel biocatalytic reactions and, in many instances, entirely new chemistry. Generic modes enable wide range of reaction types and played pivotal role advancing the fields organo- photocatalysis. This perspective aims summarize principal harnessed enzymes develop biocatalysts. Although extensively researched past, highlighted when applied within enzyme active sites, facilitate transformations have largely eluded efficient selective catalysis. advance attributed multiple tunable interactions substrate binding pocket precisely control competing pathways transition states. We will highlight cases synthetic methodologies achieved by engineered provide insights into potential future developments this rapidly evolving field.

Language: Английский

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A chiral hydrogen atom abstraction catalyst for the enantioselective epimerization of meso -diols

Science, Journal Year: 2024, Volume and Issue: 386(6717), P. 42 - 49

Published: Oct. 3, 2024

Hydrogen atom abstraction is an important elementary chemical process but very difficult to carry out enantioselectively. We have developed catalysts, readily derived from the Cinchona alkaloid family of natural products, which can achieve this by virtue their chiral amine structure. The catalyst, following single-electron oxidation, desymmetrizes

Language: Английский

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Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 31, 2025

Language: Английский

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Modular Access to Chiral Amines via Imine Reductase-Based Photoenzymatic Catalysis

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(20), P. 14278 - 14286

Published: May 10, 2024

The development of catalysts serves as the cornerstone innovation in synthesis, exemplified by recent discovery photoenzymes. However, repertoire naturally occurring enzymes repurposed direct light excitation to catalyze new-to-nature photobiotransformations is currently limited flavoproteins and keto-reductases. Herein, we shed on imine reductases (IREDs) that remote C(sp3)–C(sp3) bond formation, providing a previously elusive radical hydroalkylation enamides for accessing chiral amines (45 examples with up 99% enantiomeric excess). Beyond their natural function catalyzing two-electron reductive amination reactions, upon visible-light or synergy synthetic photoredox catalyst, IREDs are tune non-natural photoinduced single-electron processes. By conducting wet mechanistic experiments computational simulations, unravel how engineered intermediates toward productive enantioselective pathway. This work represents promising paradigm harnessing nature's asymmetric transformations remain challenging through traditional chemocatalytic methods.

Language: Английский

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