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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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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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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Photoenzymatic Redox-Neutral Radical Hydrosulfonylation Initiated by FMN

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(9), P. 6710 - 6716

Published: April 16, 2024

The photoinduced unnatural reactions catalyzed by flavin-dependent enzymes usually proceed through reduction pathways, which required the use of electron-sacrificial reagents. Herein, we developed a photoenzymatic redox-neutral radical hydrosulfonylation induced oxidated flavin (FMN) with sulfinates or sulfonyl hydrazines as precursors. reaction involved excited FMN acquiring an electron from substrate, and resulting sulfuryl was captured alkene. It is then stereoselectively quenched semiquinone (FMNsq) hydrogen atom transfer. This study circumvents need for NADPH recycling systems expands potential patterns in photobiocatalysis.

Language: Английский

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Light-promoted photocatalyst-free and redox-neutral hydrosulfonylation of unactivated alkenes using sulfinic acid

Green Chemistry, Journal Year: 2024, Volume and Issue: 26(11), P. 6578 - 6583

Published: Jan. 1, 2024

Using sulfinic acid as a sulfonyl source, we have developed light-promoted photocatalyst-free alkene hydrosulfonylation reaction without any additives.

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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Photocatalytic Enantioselective Hydrosulfonylation of α,β‐Unsaturated Carbonyls with Sulfonyl Chlorides

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(46)

Published: Oct. 2, 2023

This research explores the enantioselective hydrosulfonylation of various α,β-unsaturated carbonyl compounds via use visible light and redox-active chiral Ni-catalysis, facilitating synthesis enantioenriched α-chiral sulfones with remarkable enantioselectivity (exceeding 99 % ee). A significant challenge entails enhancing reactivity between metal-coordinated moderate electrophilic sulfonyl radicals, aiming to minimize background reactions. The success our approach stems from two distinctive attributes: 1) Cl-atom abstraction employed for radical generation chlorides, 2) single-electron reduction produce a key enolate Ni-complex. latter process appears enhance feasibility radical's addition electron-rich radical. An in-depth investigation into reaction mechanism, supported by both experimental observations theoretical analysis, offers insight intricate process. Moreover, versatility methodology is highlighted through its successful application in late-stage functionalization complex bioactive molecules, demonstrating practicality as strategy producing sulfones.

Language: Английский

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Asymmetric Carbohydroxylation of Alkenes Using Photoenzymatic Catalysis

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(31), P. 17018 - 17022

Published: July 27, 2023

Alkene difunctionalizations enable the synthesis of structurally elaborated products from simple and ubiquitous starting materials in a single chemical step. Carbohydroxylations olefins represent family reactivity that furnish complex alcohols. While examples this type three-component coupling have been reported, catalytic asymmetric remain elusive. Here, we report an enzyme-catalyzed carbohydroxylation alkenes catalyzed by flavin-dependent "ene"-reductases to produce enantioenriched tertiary Seven rounds protein engineering reshape enzyme's active site increase activity enantioselectivity. Mechanistic studies suggest C–O bond formation occurs via 5-endo-trig cyclization with pendant ketone afford α-oxy radical which is oxidized hydrolyzed form product. This work demonstrates photoenzymatic reactions involving can terminate radicals mechanisms other than hydrogen atom transfer, expanding their utility synthesis.

Language: Английский

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