Biocatalyzed Synthesis of Chiral Trifluoroethylamines via Disparate Mechanisms of Ammonium Ylides

通过不同的铵叶立德机理生物催化合成手性三氟乙胺

• 批准号: 10670882
• 负责人: Edwin Alfonzo
• 金额: $ 0.87万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2023-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670882
• 关键词: Adoption; Amines; Ammonium; Benign; Biological Availability; Biomedical Research; Brain; Carbon; Chemicals; Clinical Medicine; Complex; Directed Molecular Evolution; Disparate; Drug Kinetics; Engineering; Environment; Enzymes; Fluorine; Goals; Health; Heme Iron; High Prevalence; Human; Hydrogen Bonding; Incidence; Knowledge; Libraries; Ligands; Medicine; Metabolic Pathway; Metabolism; Metals; Methods; Molecular Conformation; Mutation; Nature; Outcome; Pathway interactions; Penetrance; Performance; Periodicity; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Prevalence; Process; Property; Reaction; Reagent; Societies; Stereoisomer; Techniques; Testing; Variant; Veins; Work; catalyst; chemical reaction; clinical candidate; cost; cyclic amine; drug discovery; functional group; improved; innovation; success; toxic metal; ylide

Project Summary/Abstract Chiral trifluoroethylamine (α-CF3 amines) is an essential functional group used in clinical candidates to modulate conformation, pKa, potency, permeability, metabolism, and pharmacokinetics, improving their prospects of becoming medicines. Unfortunately, known chemocatalytic strategies to synthesize α-CF3 amines use tailor-made precursors, precious metals, or designer ligands, limiting their wide deployment in drug discovery efforts. By leveraging engineered enzymes’ known ability to catalyze abiological reactions with exquisite chemo-, regio-, and enantioselectivity, here it is proposed that α-CF3 amines can be synthesized enzymatically from amines, a universal functional group with high incidence in building blocks and complex molecules. Specifically, iron-heme enzymes will be engineered using directed evolution techniques to transfer CF3- containing carbenoids to amines to afford ammonium ylides. Directed evolution will be used to divert these ammonium ylides into three disparate reaction pathways: carbenoid N–H insertion, [2,3]-sigmatropic rearrangement, and [1,2]-Stevens ring expansion, which will provide access to diverse, adaptable forms of chiral α-CF3 amines that can be used in early and late synthesis stages. These studies will shift the paradigm from contrived substrates and toxic metals to abundant amines and environmentally benign enzymes, democratizing this coveted functional group for their facile deployment in drug discovery. These efforts will also unlock activities unknown to enzymes, further expanding the repertoire of chemical reactions that can be catalyzed using Nature’s catalysts. This proposal’s success will afford high-value chemical motifs that may lead to discovering new medicines and innovative strategies to synthesize essential molecules of corollary to human health.

项目总结/文摘

项目成果

Enzymatic Nitrogen Incorporation Using Hydroxylamine.

• DOI: 10.1021/jacs.3c08053
• 发表时间: 2023-09
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Shi-Chao Gao;Anuvab Das;Edwin Alfonzo;Kathleen M. Sicinski;Dominic Rieger;Frances H. Arnold