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.

项目总结/摘要 手性三氟乙胺（α-CF 3胺）是临床候选药物中使用的一种重要官能团， 调节构象、pKa、效力、渗透性、代谢和药代动力学， 成为药物的前景。不幸的是，合成α-CF 3胺的已知化学催化策略 使用定制的前体、贵金属或设计配体，限制了它们在药物发现中的广泛应用 努力通过利用工程酶已知的催化非生物反应的能力， 化学选择性、区域选择性和对映体选择性，本文提出α-CF 3胺可以通过酶促反应合成 胺是一种在结构单元和复杂分子中具有高发生率的通用官能团。 具体而言，铁血红素酶将使用定向进化技术进行工程改造，以将CF 3- 含有类卡宾转化为胺，得到叶立德铵。定向进化将被用来转移这些 铵叶立德分为三个不同的反应途径：类卡宾N-H插入，[2，3]-σ迁移 重排和[1，2]-史蒂文斯环扩张，这将提供获得多种、适应性强的手性形式的途径 α-CF 3胺可用于早期和后期合成阶段。这些研究将改变范式， 人造底物和有毒金属到丰富的胺和环境友好的酶，民主化 这个令人垂涎的功能组，因为他们在药物发现中的轻松部署。这些努力也将解锁活动 这是酶所不知道的，进一步扩大了可以用自然界的 催化剂的这一提议的成功将提供高价值的化学基序，可能导致发现新的 药物和创新战略，以合成人类健康的必然结果的基本分子。