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.

项目概要/摘要 手性三氟乙胺（α-CF3 胺）是一种重要的官能团，用于临床候选药物 调节构象、pKa、效力、渗透性、代谢和药代动力学，改善其 不幸的是，已知的化学催化策略合成α-CF3胺。 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 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、区域选择性和对映选择性，这里提出α-CF3胺可以通过酶法合成 来自胺，一种通用官能团，在结构单元和复杂分子中出现率很高。 具体来说，铁血红素酶将使用定向进化技术进行工程设计，以转移 CF3- 含有类胡萝卜素到胺以提供铵叶立德的定向演化将用于转移这些物质。 铵叶立德进入三个不同的反应途径：类胡萝卜素 N-H 插入、[2,3]-sigmatropic 重排和 [1,2]-史蒂文斯环扩展，这将提供多种、适应性强的手性形式 可用于早期和后期合成阶段的 α-CF3 胺这些研究将改变范式。 将底物和有毒金属设计成丰富的胺和环境友好的酶，民主化 这个令人垂涎的职能小组在药物发现方面的轻松部署也将开启活动。 酶未知，进一步扩展了可以使用 Nature's 催化的化学反应 该提案的成功将提供高价值的化学基序，从而可能导致新的发现。 合成对人类健康至关重要的基本分子的药物和创新策略。

项目成果

Enzymatic Nitrogen Insertion into Unactivated C-H Bonds.

酶促氮插入未活化的 C-H 键。

• DOI: 10.1021/jacs.2c08285
• 发表时间: 2022-10-04
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: S. Athavale;Shi;Anuvab Das;S. C. Mallojjala;Edwin Alfonzo;Yueming Long;Jennifer S. Hirschi;F. Arnold
• 通讯作者: F. Arnold

Enzymatic Nitrogen Incorporation Using Hydroxylamine.

使用羟胺进行酶促氮掺入。

• DOI: 10.1021/jacs.3c08053
• 发表时间: 2023-09-06
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Shi;Anuvab Das;Edwin Alfonzo;Kathleen M. Sicinski;Dominic Rieger;Frances H. Arnold
• 通讯作者: Frances H. Arnold