Enantiodivergent α‑Amino C–H Fluoroalkylation Catalyzed by Engineered Cytochrome P450s

• Published in: Journal of the American Chemical Society Vol. 141; no. 25; pp. 9798 - 9802
• Main Authors: Zhang, Juner, Huang, Xiongyi, Zhang, Ruijie K, Arnold, Frances H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-06-2019
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.9b04344

The introduction of fluoroalkyl groups into organic compounds can significantly alter pharmacological characteristics. One enabling but underexplored approach for the installation of fluoroalkyl groups is selective C­(sp 3)–H functionalization due to the ubiquity of C–H bonds in organic molecules. We have engineered heme enzymes that can insert fluoroalkyl carbene intermediates into α-amino C­(sp 3)–H bonds and enable enantiodivergent synthesis of fluoroalkyl-containing molecules. Using directed evolution, we engineered cytochrome P450 enzymes to catalyze this abiological reaction under mild conditions with total turnovers (TTN) up to 4070 and enantiomeric excess (ee) up to 99%. The iron-heme catalyst is fully genetically encoded and configurable by directed evolution so that just a few mutations to the enzyme completely inverted product enantioselectivity. These catalysts provide a powerful method for synthesis of chiral organofluorine molecules that is currently not possible with small-molecule catalysts.