Chemoselective, Enzymatic C–H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor

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• 作者：Paweł DydioHanna M. Key ; Hiroki Hayashi ; Douglas S. ClarkJohn F. Hartwig
• 刊名：Journal of the American Chemical Society
• 出版年：2017
• 出版时间：February 8, 2017
• 年：2017
• 卷：139
• 期：5
• 页码：1750-1753
• 全文大小：321K
• ISSN：1520-5126

文摘

Cytochrome P450 enzymes have been engineered to catalyze abiological C–H bond amination reactions, but the yields of these reactions have been limited by low chemoselectivity for the amination of C–H bonds over competing reduction of the azide substrate to a sulfonamide. Here we report that P450s derived from a thermophilic organism and containing an iridium porphyrin cofactor (Ir(Me)-PIX) in place of the heme catalyze enantioselective intramolecular C−H bond amination reactions of sulfonyl azides. These reactions occur with chemoselectivity for insertion of the nitrene units into C−H bonds over reduction of the azides to the sulfonamides that is higher and with substrate scope that is broader than those of enzymes containing iron porphyrins. The products from C−H amination are formed in up to 98% yield and ∼300 TON. In one case, the enantiomeric excess reaches 95:5 er, and the reactions can occur with divergent site selectivity. The chemoselectivity for C–H bond amination is greater than 20:1 in all cases. Variants of the Ir(Me)-PIX CYP119 displaying these properties were identified rapidly by evaluating CYP119 mutants containing Ir(Me)-PIX in cell lysates, rather than as purified enzymes. This study sets the stage to discover suitable enzymes to catalyze challenging C–H amination reactions.