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

Accounts of Chemical Research, Год журнала: 2024, Номер 57(9), С. 1446 - 1457

Опубликована: Апрель 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.

Язык: Английский

---

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, Год журнала: 2025, Номер unknown

Опубликована: Янв. 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.

Язык: Английский

---

Asymmetric photoenzymatic incorporation of fluorinated motifs into olefins

Science, Год журнала: 2024, Номер 385(6707), С. 416 - 421

Опубликована: Июль 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.

Язык: Английский

---

Photoenzymatic Redox-Neutral Radical Hydrosulfonylation Initiated by FMN

ACS Catalysis, Год журнала: 2024, Номер 14(9), С. 6710 - 6716

Опубликована: Апрель 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.

Язык: Английский

---

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

Green Chemistry, Год журнала: 2024, Номер 26(11), С. 6578 - 6583

Опубликована: Янв. 1, 2024

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

Язык: Английский

---

Enantioselective alkene hydroalkylation overcoming heteroatom constraints via cobalt catalysis

Nature Synthesis, Год журнала: 2024, Номер 3(9), С. 1134 - 1144

Опубликована: Июль 10, 2024

Язык: Английский

---

Research Progress and Perspectives on Anti‐Poisoning Hydrogen Oxidation Reaction Electrocatalysts for Hydrogen Fuel Cells

Small, Год журнала: 2025, Номер unknown

Опубликована: Янв. 5, 2025

Abstract As global demand for clean and sustainable energy continues to rise, fuel cell technology has seen rapid advancement. However, the presence of trace impurities like carbon monoxide (CO) hydrogen sulfide (H₂S) in can significantly deactivate anode by blocking its active sites, leading reduced performance. Developing electrocatalysts that are resistant CO H₂S poisoning therefore become a critical priority. This paper provides comprehensive analysis mechanisms reviews key strategies developed over past few decades enhance impurity tolerance electrocatalysts. It begins examining differences oxidation reaction (HOR) acidic alkaline environments, focusing on roles binding (HBE) hydroxide (OHBE). Next, it outlines three main approaches mitigate poisoning: (I) bifunctional mechanisms, (II) direct (III) constructing protective layers. The review then shifts countering poisoning, emphasizing both electrocatalyst design structural improvements cells. Finally, highlights recent advances anti‐poisoning electrocatalysts, discusses their applications limitations, identifies challenges future opportunities further research this field.

Язык: Английский

---

Ground-state flavin-dependent enzymes catalyzed enantioselective radical trifluoromethylation

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 31, 2025

Язык: Английский

---

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

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(20), С. 14278 - 14286

Опубликована: Май 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.

Язык: Английский

---

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

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(32), С. 22476 - 22484

Опубликована: Июль 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.

Язык: Английский

---