Biocatalyzed Synthesis of Chiral Trifluoroethylamines via Disparate Mechanisms of Ammonium Ylides

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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.