Enzymatic Synthesis of Saturated Bioisosteres of Ortho‐Substituted Benzenes by Artificial Photoenzyme DOI Open Access
Yuting Bai, Yi-yun Sheng, Yi Fu

et al.

Chemistry - A European Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Saturated bioisosteres of ortho-substituted benzenes are significant interest due to their enhanced pharmacokinetic properties, such as improved metabolic stability and reduced toxicity, making them valuable in drug design development. However, efficient synthesis remains a challenge organic chemistry. Herein, we report the biocatalytic saturated using engineered artificial photoenzymes. The photoenzyme, incorporating genetically encoded unnatural amino acids with benzophenone photosensitizer residue, facilitate formation chiral moderate enantiomeric excess via energy transfer process. Our results demonstrate versatility photoenzymes mediating new-to-nature reactions that difficult achieve conventional chemical or enzymatic methods.

Language: Английский

Radical Reactions with N-Heterocyclic Carbene (NHC)-Derived Acyl Azoliums for Access to Multifunctionalized Ketones DOI

Hui Cai,

Xiaoqun Yang,

Shi‐Chao Ren

et al.

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(11), P. 8270 - 8293

Published: May 13, 2024

As one of the most important key intermediates, NHC-bound acylazolium-based ionic transformations have been intensively explored in past two decades. With expeditious development NHC-catalyzed radical recent years, acylazolium chemistry has reached another level, with number relevant publications increasing significantly. However, a summary focused on acylations NHC-derived acyl azoliums classified according to mechanistic difference not reported. Such detailed classification and deep analysis provide opportunities for better understanding history trend this field. In review, reactions N-heterocyclic carbene (NHC)-derived are systematically introduced. The achievements challenges within area also summarized discussed at end.

Language: Английский

Citations

23
From Ground-State to Excited-State Activation Modes: Flavin-Dependent “Ene”-Reductases Catalyzed Non-natural Radical Reactions DOI
Haigen Fu, Todd K. Hyster

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

Citations

20
Carbene-catalyzed chirality-controlled site-selective acylation of saccharides DOI Creative Commons
Yingguo Liu, Zhixiong Zhong, Yuyang Tang

et al.

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

Published: Jan. 2, 2025

Acylation stands as a fundamental process in both biological pathways and synthetic chemical reactions, with acylated saccharides their derivatives holding diverse applications ranging from bioactive agents to building blocks. A longstanding objective organic synthesis has been the site-selective acylation of without extensive pre-protection alcohol units. In this study, we demonstrate that by simply altering chirality N-heterocyclic carbene (NHC) catalysts, site-selectivity saccharide reactions can be effectively modulated. Our investigation reveals intriguing selectivity shift stems combination factors, including match/mismatch inter- / intramolecular hydrogen bonding between NHC catalyst substrates. These findings provide valuable insights into design reaction engineering, highlighting potential glycoside analysis, such fluorescent labelling, α/β identification, orthogonal selective late-stage modifications. The units synthesis. Here, authors

Language: Английский

Citations

2
Directed Evolution and Unusual Protonation Mechanism of Pyridoxal Radical C–C Coupling Enzymes for the Enantiodivergent Photobiocatalytic Synthesis of Noncanonical Amino Acids DOI
Lei Cheng,

Zhiyu Bo,

Benjamin Krohn-Hansen

et al.

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

Citations

2
Asymmetric photoenzymatic incorporation of fluorinated motifs into olefins DOI
Mao‐Lin Li, Yaru Yuan, Wesley Harrison

et al.

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

Citations

15
Molecular Editing of Ketones through N-Heterocyclic Carbene and Photo Dual Catalysis DOI
Qing‐Zhu Li,

Mei-Hao He,

Rong Zeng

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(32), P. 22829 - 22839

Published: Aug. 1, 2024

The molecular editing of ketones represents an appealing strategy due to its ability maximize the structural diversity ketone compounds in a straightforward manner. However, developing efficient methods for arbitrary modification ketonic molecules, particularly those integrated within complex skeletons, remains significant challenge. Herein, we present unique recasting that involves radical acylation

Language: Английский

Citations

15
Catalyzing the future: recent advances in chemical synthesis using enzymes DOI
Julia C. Reisenbauer, Kathleen M. Sicinski, Frances H. Arnold

et al.

Current Opinion in Chemical Biology, Journal Year: 2024, Volume and Issue: 83, P. 102536 - 102536

Published: Oct. 5, 2024

Language: Английский

Citations

11
Photoenzymatic Redox-Neutral Radical Hydrosulfonylation Initiated by FMN DOI

Linye Jiang,

Dannan Zheng,

Xiaoyang Chen

et al.

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

Citations

9
Unnatural Thiamine Radical Enzymes for Photobiocatalytic Asymmetric Alkylation of Benzaldehydes and α-Ketoacids DOI
Xin Liu,

Sheng Xu,

Heyu Chen

et al.

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

Citations

8
A New Age of Biocatalysis Enabled by Generic Activation Modes DOI Creative Commons
Shubhanshu Jain, Felipe Ospina, Stephan C. Hammer

et al.

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

Citations

8