Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C–H Functionalization Strategy

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(2), P. 1580 - 1587

Published: Jan. 2, 2024

Lactones are cyclic esters with extensive applications in materials science, medicinal chemistry, and the food perfume industries. Nature's strategy for synthesis of many lactones found natural products always relies on a single type retrosynthetic strategy, C–O bond disconnection. Here, we describe set laboratory-engineered enzymes that use new-to-nature C–C bond-forming to assemble diverse lactone structures. These engineered "carbene transferases" catalyze intramolecular carbene insertions into benzylic or allylic C–H bonds, which allow different ring sizes scaffolds from simple starting materials. Starting serine-ligated cytochrome P450 variant previously other carbene-transfer activities, directed evolution generated P411-LAS-5247, exhibits high activity constructing five-membered ε-lactone, lactam, ketone (up 5600 total turnovers (TTN) >99% enantiomeric excess (ee)). Further engineering led variants P411-LAS-5249 P411-LAS-5264, deliver six-membered δ-lactones seven-membered ε-lactones, respectively, overcoming thermodynamically unfavorable strain associated these compared γ-lactones. This new was further extended complex based fused, bridged, spiro rings. The enzymatic platform developed here complements biosynthetic strategies assembly expands structural diversity accessible through functionalization.

Language: Английский

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Enzyme engineering for biocatalysis

Molecular Catalysis, Journal Year: 2024, Volume and Issue: 555, P. 113874 - 113874

Published: Jan. 31, 2024

Contemporary Biocatalysis heavily relies on enzyme engineering as natural enzymes frequently lack the requisite attributes for effective organic synthesis. The inherent limitations in stability, catalytic activity, and selectivity of wild-type often hinder their suitability chemical Over past 25 years, there has been an unprecedented advancement protein tools, empowering enzymologists to customise precisely meet demands In this discussion, we delineate some most crucial techniques significance facilitating

Language: Английский

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Flow Electroreductive Nickel‐Catalyzed Cyclopropanation of Alkenes Using gem‐Dichloroalkanes

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Cyclopropanes are valuable motifs in organic synthesis, widely featured pharmaceuticals and functional materials. Herein, we report an efficient electrochemical methodology for the cyclopropanation of alkenes, leveraging a nickel‐catalyzed process continuous‐flow. The developed protocol demonstrates broad substrate scope, accommodating both electron‐rich electron‐poor alkenes with high group tolerance. Beyond dichloromethane as feedstock methylene source, enables synthesis methylated, deuterated, chloro‐substituted cyclopropanes. Mechanistic investigations suggest electro‐generation nickel carbene key intermediate. Notably, reaction operates under ambient conditions, tolerates air moisture, achieves scalability through continuous‐flow technology, offering straightforward route to multi‐gram quantities enhanced throughput.

Language: Английский

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Biocatalytic Enantioselective Reduction of Cyclopropenyl Esters and Ketones Using Ene-Reductases

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(8), P. 6188 - 6193

Published: April 8, 2024

Enantioselective reduction of cyclopropenyl esters and ketones to optically active cyclopropanes has been achieved by using whole-cell-overexpressing ene-reductases (EREDs). By these enzymes, trans-cyclopropanes were isolated in good yield high enantiomeric excess. A wide range cyclopropane obtained, a variety substituent patterns on the cyclopropenes tolerated.

Language: Английский

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Biocatalytic Strategy for the Highly Stereoselective Synthesis of Fluorinated Cyclopropanes

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(33)

Published: May 16, 2024

Abstract Fluorinated cyclopropanes are highly desired pharmacophores in drug discovery owing to the rigid nature of cyclopropane ring and beneficial effects C−F bonds on pharmacokinetic properties, cell permeability, metabolic stability molecules. Herein a biocatalytic strategy for stereoselective synthesis mono‐fluorinated gem‐difluoro is reported though use engineered myoglobin‐based catalysts. In particular, this system allows broad range alkenes be cyclopropanated presence diazoacetonitrile with excellent diastereo enantiocontrol (up 99 : 1 d.r. % e.e.), thereby enabling transformation not currently accessible chemocatalytic methods. The synthetic utility present approach further exemplified through gram‐scale key gem‐difluorinated intermediate useful preparation fluorinated bioactive

Language: Английский

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Unlocking the reactivity of diazo compounds in red light with the use of photochemical tools

Chemical Communications, Journal Year: 2023, Volume and Issue: 59(99), P. 14649 - 14652

Published: Jan. 1, 2023

The red light-irradiation of structurally diversified diazoalkanes gives access to reactive intermediates via direct photolysis and photosensitization or photoredox approaches.

Language: Английский

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Designing Ruthenium Phthalocyanine with Chiral Pockets Formed by (1R,2S,5R)-Menthoxy Groups for Enantioselective Catalysis

ACS Catalysis, Journal Year: 2025, Volume and Issue: unknown, P. 4984 - 5001

Published: March 10, 2025

Unprecedented chiral ruthenium(II) complexes with phthalocyanines having motifs near the catalytic metal site have been prepared by cross condensation of 3,6-bis-aryloxy-phthalonitrile (α-Ar*O)2Pn bearing two (1R,2S,5R)-menthoxy groups orthogonal to aromatic plane and (15-crown-5)phthalonitrile. Four containing menthyl (M) 15-crown-5 units (C), notably RuPc[MC3](CO), RuPc[opp-M2C2](CO), RuPc[adj-M2C2](CO), RuPc[M3C](CO), were isolated in pure form fully characterized UV–vis, circular dichroism, HRMS, various 1H NMR 13C techniques. Their evaluation benchmark asymmetric cyclopropanation reaction styrene derivatives ethyl diazoacetate indicated that RuPc[opp-M2C2](CO) complex was most efficient terms diastereo- enantioselectivity. Further study revealed strong dependence stereoselectivity on solvent nature salt additives, which caused conformational rearrangement flexible surrounding, as evidenced multinuclear CD spectra. For instance, upon moving from commonly used CH2Cl2 EtOH addition NaPF6, a significant enhancement enantioselectivity (from 35 84% p-methylstyrene) obtained. Of particular importance is very high diastereoselectivity many substrates promoted incorporation sodium cations into crown ether cavities phthalocyanine attain trans/cis ratio up 499:1. Such regulating effect catalysis involving tetrapyrrolic has not previously observed, rendering this prominent example tunable catalyst. The developed synthetic strategy paves way environment around receptors tune properties.

Language: Английский

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Engineering metalloenzymes for new-to-nature carbene and nitrene transfer biocatalysis

CHINESE JOURNAL OF CATALYSIS (CHINESE VERSION), Journal Year: 2025, Volume and Issue: 72, P. 4 - 23

Published: May 1, 2025

Language: Английский

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Biocatalytic, stereoconvergent alkylation of (Z/E)-trisubstituted silyl enol ethers

Nature Synthesis, Journal Year: 2023, Volume and Issue: 3(2), P. 256 - 264

Published: Nov. 2, 2023

Language: Английский

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Recent Synthetic Advances on the Use of Diazo Compounds Catalyzed by Metalloporphyrins

Molecules, Journal Year: 2023, Volume and Issue: 28(18), P. 6683 - 6683

Published: Sept. 18, 2023

Diazo compounds are organic substances that often used as precursors in synthesis like cyclization reactions, olefinations, cyclopropanations, cyclopropenations, rearrangements, and carbene or metallocarbene insertions into C−H, N−H, O−H, S−H, Si−H bonds. Typically, reactions from diazo catalyzed by transition metals with various ligands modulate the capacity selectivity of catalyst. These can modify enhance chemoselectivity substrate, regioselectivity enantioselectivity reflecting these preferences products. Porphyrins have been catalysts several important for also medicinal applications. In chemistry compounds, porphyrins very efficient when complexed low-cost (e.g., Fe Co) and, therefore, recent years, this has subject significant research. This review will summarize advances studies involving field metalloporphyrins (M−Porph, M = Fe, Ru, Os, Co, Rh, Ir) last five years to provide a clear overview possible opportunities future Also, at end review, properties artificial metalloenzymes hemoproteins biocatalysts broad range applications, namely those concerning carbene-transfer be considered.

Language: Английский

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