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Dydio P, Key HM, Hayashi H, et al. Chemoselective, Enzymatic C-H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor. J Am Chem Soc. 2017;139(5):1750-1753doi: 10.1021/jacs.6b11410.
Dydio, P., Key, H. M., Hayashi, H., Clark, D. S., & Hartwig, J. F. (2017). Chemoselective, Enzymatic C-H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor. Journal of the American Chemical Society, 139(5), 1750-1753. https://doi.org/10.1021/jacs.6b11410
Dydio, Paweł, et al. "Chemoselective, Enzymatic C-H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor." Journal of the American Chemical Society vol. 139,5 (2017): 1750-1753. doi: https://doi.org/10.1021/jacs.6b11410
Dydio P, Key HM, Hayashi H, Clark DS, Hartwig JF. Chemoselective, Enzymatic C-H Bond Amination Catalyzed by a Cytochrome P450 Containing an Ir(Me)-PIX Cofactor. J Am Chem Soc. 2017 Feb 08;139(5):1750-1753. doi: 10.1021/jacs.6b11410. Epub 2017 Jan 26. PMID: 28080030.
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J Am Chem Soc. 2017 Feb 08;139(5):1750-1753. doi: 10.1021/jacs.6b11410. Epub 2017 Jan 26.

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

Journal of the American Chemical Society

Paweł Dydio, Hanna M Key, Hiroki Hayashi, Douglas S Clark, John F Hartwig

Affiliations

  1. Department of Chemistry, University of California , Berkeley, California 94720, United States.
  2. Chemical Sciences Division, Lawrence Berkeley National Laboratory , 1 Cyclotron Road, Berkeley, California 94720, United States.
  3. Department of Chemical and Biomolecular Engineering, University of California , Berkeley, California 94720, United States.
  4. Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory , 1 Cyclotron Road, Berkeley, California 94720, United States.

PMID: 28080030 DOI: 10.1021/jacs.6b11410

Abstract

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.

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