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: 10313399
• 负责人: Edwin Alfonzo
• 金额: $ 6.6万
• 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 2024-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10313399
• 关键词: Address; Adoption; Amines; Ammonium; Benign; Biological Availability; Biomedical Research; Brain; Carbon; Chemicals; Clinical Medicine; Complex; Directed Molecular Evolution; Drug Kinetics; Engineering; Enzymes; Fluorine; Goals; Health; Heme Iron; High Prevalence; Human; Hydrogen Bonding; Incidence; Knowledge; Lead; 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.

项目摘要/摘要 手性三氟乙胺（α-CF3胺）是用于临床候选者的必不可少的功能组 调节物质，PKA，效能，渗透性，代谢和药代动力学，改善其 成为药物的前景。不幸的是，合成α-CF3胺的已知化学催化策略 使用量身定制的前体，贵金属或设计师配体，限制了它们在药物发现中的广泛部署 努力。通过利用工程酶的已知能力来催化物质反应的独家反应 化学，区域和对映选择性，在这里提出α-CF3胺可以合成酶促合成 来自Amines，这是一个通用官能团，在构建块和复杂分子中入射高。 具体而言，铁血红素酶将使用定向的进化技术进行设计，以转移CF3- 含胺的类carbenoids可负担得起铵。定向进化将用于转移这些 铵将铵变成三种不同的反应途径：carbenoid n – h插入，[2,3] - 含量 重排和[1,2] - stevens环的扩展，它将提供对潜水员的手性的访问权限 α-CF3胺可用于早期和晚期合成阶段。这些研究将使范式从 人为的底物和有毒金属对丰富的胺和环境良性酶，使民主化 这个令人垂涎的功能组在药物发现方面便利地部署。这些努力也将解锁活动 酶未知，进一步扩大了可以使用自然的化学反应的曲目 催化剂。该提议的成功将负担得起高价值的化学图案，这可能会导致发现新的 药物和创新策略综合人类健康的必需分子。