Chemoselective, enzymatic C-H bond amination catalyzed by a cytochrome P450 containing an Ir(Me)-PIX cofactor

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

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1750-1753
Number of pages4
JournalJournal of the American Chemical Society
Volume139
Issue number5
DOIs
Publication statusPublished - Feb 8 2017

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Amination
Cytochrome P-450 Enzyme System
Azides
Enzymes
Sulfonamides
Porphyrins
Iridium
Substrates
Heme
Iron

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Chemoselective, enzymatic C-H bond amination catalyzed by a cytochrome P450 containing an Ir(Me)-PIX cofactor. / Dydio, Pawel; Key, Hanna M.; Hayashi, Hiroki; Clark, Douglas S.; Hartwig, John F.

In: Journal of the American Chemical Society, Vol. 139, No. 5, 08.02.2017, p. 1750-1753.

Research output: Contribution to journalArticle

Dydio, Pawel ; Key, Hanna M. ; Hayashi, Hiroki ; Clark, Douglas S. ; Hartwig, John F. / Chemoselective, enzymatic C-H bond amination catalyzed by a cytochrome P450 containing an Ir(Me)-PIX cofactor. In: Journal of the American Chemical Society. 2017 ; Vol. 139, No. 5. pp. 1750-1753.
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