Biocatalyzed Synthesis of Chiral Trifluoroethylamines via Disparate Mechanisms of Ammonium Ylides

项目摘要/摘要 手性三氟乙胺(α-CF3胺)是临床候选药物中必不可少的官能团 调节构象、PKA、效力、通透性、代谢和药代动力学，改善其 成为药物的前景。不幸的是，已知的合成α-CF3胺的化学催化策略 使用定制的前体、贵金属或设计的配体，限制了它们在药物发现中的广泛部署 努力。通过利用已知的工程酶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，本文提出了α-CF3胺的酶促合成方法。 从胺出发，是一种普遍存在的官能团，在构筑块和复杂分子中的发生率很高。 具体地说，铁-血红素酶将使用定向进化技术来转移CF3- 含有卡宾到胺的，以提供叶立德铵。定向进化将被用来转移这些 叶立德铵进入三条不同的反应途径：类卡宾N-H插入，[2，3]-Sigmatrotic 重排和[1，2]-Stevens环扩张，这将提供获得多种可适应的手性形式的途径 可用于早期和晚期合成阶段的α-CF3胺。这些研究将把研究范式从 人造底物和有毒金属转化为丰富的胺和环境友好的酶，民主化 这种令人垂涎的官能团在药物发现中的部署非常方便。这些努力还将释放活动 对于酶来说是未知的，进一步扩大了可以使用自然的 催化剂。这个提议的成功将提供高价值的化学主题，这些主题可能会导致发现新的 药物和创新策略，以合成对人类健康必然产生的必要分子。

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.