Development of N-centered radical scavengers that enables photoredox-catalyzed transition-metal-free radical amination of alkyl pinacol boronates DOI Creative Commons
Changlei Zhu, Jiaxin Lin, Xiaoguang Bao

et al.

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

Published: April 4, 2025

In recent years, amination of alkylboronates through ionic copper catalysis or boron-ate complex 1,2-metalation has been well established, but complementary radical processes remain less studied before. Herein, based on rational design, we develop several imine-type N-centered scavengers and apply them to the alkylboronates. The reaction proceeds under mild photoredox-catalyzed transition-metal-free conditions features excellent functional group tolerance. It also enables preparation a range medicinally valuable amine derivatives from natural products. Further application this reagent in C-H amination, deoxygenative decarboxylative three component trifluoromethylative/sulfonylative aminations are realized. mechanistic studies DFT calculations conducted provide detailed evidence for mechanism.

Language: Английский

Active learning-assisted directed evolution DOI Creative Commons
Jason Yang, Ravi Lal,

James C. Bowden

et al.

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

Published: Jan. 16, 2025

Abstract Directed evolution (DE) is a powerful tool to optimize protein fitness for specific application. However, DE can be inefficient when mutations exhibit non-additive, or epistatic, behavior. Here, we present Active Learning-assisted Evolution (ALDE), an iterative machine learning-assisted workflow that leverages uncertainty quantification explore the search space of proteins more efficiently than current methods. We apply ALDE engineering landscape challenging DE: optimization five epistatic residues in active site enzyme. In three rounds wet-lab experimentation, improve yield desired product non-native cyclopropanation reaction from 12% 93%. also perform computational simulations on existing sequence-fitness datasets support our argument effective DE. Overall, practical and broadly applicable strategy unlock improved outcomes.

Language: Английский

Citations

9
Structural Insights into the N–N Bond-Formation Mechanism of the Heme-Dependent Piperazate Synthase KtzT DOI

Yunyun Yang,

Yanling Li, Licheng Yao

et al.

ACS Catalysis, Journal Year: 2025, Volume and Issue: 15(2), P. 1265 - 1273

Published: Jan. 7, 2025

N–N bond formation plays a critical role in the synthesis of organic compounds and has broad applications producing dyes, pharmaceuticals, functional materials. However, is challenging due to nucleophilicity nitrogen. Here, we determined crystal structures heme-dependent enzyme, KtzT, which catalyzes cyclization l-N5-hydroxyornithine (l-N5-OH-Orn) yield l-piperazate (l-piz) by linking two intramolecular nitrogen atoms. The complex structure KtzTC197A with l-N5-OH-Orn reveals substrate-interaction network, validated through mutagenesis experiments. Notably, N5 atom substrate directly coordinates heme iron, precluding oxygen binding. This supports prior knowledge that KtzT an oxygen-independent reaction. Intriguingly, exhibits distinct conformations our crystals. Based on distance between atoms product accommodation pose KtzTC197A/l-piz structure, conformation 2 likely productive pose, while more extended 1 may be transient state facilitating entry into catalytic tunnel. A potential pathway also proposed. These findings offer structural insights for developing bio- metal-catalyzed methods formation.

Language: Английский

Citations

3
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

14
Biocatalytic Synthesis of α-Amino Esters via Nitrene C–H Insertion DOI
Edwin Alfonzo,

Deirdre Hanley,

Zi‐Qi Li

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(40), P. 27267 - 27273

Published: Sept. 27, 2024

α-Amino esters are precursors to noncanonical amino acids used in developing small-molecule therapeutics, biologics, and tools chemical biology. α-C-H amination of abundant inexpensive carboxylic acid through nitrene transfer presents a direct approach α-amino esters. Methods for nitrene-mediated the protic bonds esters, however, underdeveloped. This gap arises because hydrogen atom abstraction (HAA) C-H by electrophilic metal-nitrenoids is slow: preferentially react with polarity-matched, hydridic bonds, even when weaker present. study describes discovery evolution highly stable protoglobin transferases that catalyze enantioselective intermolecular We developed high-throughput assay evaluate activity enantioselectivity mutant enzymes together their sequences using Every Variant Sequencing (evSeq) method. The enabled identification enantiodivergent function at ambient conditions

Language: Английский

Citations

5
Active Learning-Assisted Directed Evolution DOI Creative Commons
Jason Yang, Ravi Lal,

James C. Bowden

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 28, 2024

ABSTRACT Directed evolution (DE) is a powerful tool to optimize protein fitness for specific application. However, DE can be inefficient when mutations exhibit non-additive, or epistatic, behavior. Here, we present Active Learning-assisted Evolution (ALDE), an iterative machine learning-assisted workflow that leverages uncertainty quantification explore the search space of proteins more efficiently than current methods. We apply ALDE engineering landscape challenging DE: optimization five epistatic residues in active site enzyme. In three rounds wet-lab experimentation, improve yield desired product non-native cyclopropanation reaction from 12% 93%. also perform computational simulations on existing sequence-fitness datasets support our argument effective DE. Overall, practical and broadly applicable strategy unlock improved outcomes.

Language: Английский

Citations

4
One-Pot Decarbonylative Borylation of Aliphatic Aldehydes DOI

Chang Lian,

Jianning Zhang, Lei Zhang

et al.

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

We present a mild and direct method for the radical borylation of simple aliphatic aldehydes. By employing an enamine photocatalyst under light irradiation, aldehydes can be transformed effectively into alkyl boronic esters via formal decarbonylative process. This alternative route synthesis not only applied to transformation primary, secondary, tertiary but also adapted other conversion reactions through generated intermediate. Mechanistic studies indicate that 4-alkyl-1,4-dihydropyridines, formed in situ from aldehyde enamine, are key intermediate

Language: Английский

Citations

0
Development of N-centered radical scavengers that enables photoredox-catalyzed transition-metal-free radical amination of alkyl pinacol boronates DOI Creative Commons
Changlei Zhu, Jiaxin Lin, Xiaoguang Bao

et al.

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

Published: April 4, 2025

In recent years, amination of alkylboronates through ionic copper catalysis or boron-ate complex 1,2-metalation has been well established, but complementary radical processes remain less studied before. Herein, based on rational design, we develop several imine-type N-centered scavengers and apply them to the alkylboronates. The reaction proceeds under mild photoredox-catalyzed transition-metal-free conditions features excellent functional group tolerance. It also enables preparation a range medicinally valuable amine derivatives from natural products. Further application this reagent in C-H amination, deoxygenative decarboxylative three component trifluoromethylative/sulfonylative aminations are realized. mechanistic studies DFT calculations conducted provide detailed evidence for mechanism.

Language: Английский

Citations

0