title: Enzymatic C(sp3)-H Amination: P450-Catalyzed Conversion of Carbonazidates into Oxazolidinones.
abstract: Cytochrome P450 enzymes can effectively promote the activation and cyclization of carbonazidate substrates to yield oxazolidinones via an intramolecular nitrene C-H insertion reaction. Investigation of the substrate scope shows that while benzylic/allylic C-H bonds are most readily aminated by these biocatalysts, stronger, secondary C-H bonds are also accessible to functionalization. Leveraging this "non-native" reactivity and assisted by fingerprint-based predictions, improved active-site variants of the bacterial P450 CYP102A1 could be identified to mediate the aminofunctionalization of two terpene natural products with high regio- and stereoselectivity. Mechanistic studies and KIE experiments show that the C-H activation step in these reactions is rate-limiting and proceeds in a stepwise manner, namely, via hydrogen atom abstraction followed by radical recombination. This study expands the reactivity scope of P450-based catalysts in the context of nitrene transfer transformations and provides first-time insights into the mechanism of P450-catalyzed C-H amination reactions.
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14627, United States.
authors.forename: Ritesh
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14627, United States.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Kolev
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14627, United States.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Sutera
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14627, United States.
authors.forename: Rudi
authors.initials: R
authors.lastname: Fasan
keywords: C−H amination; biocatalysis; carbonazidate; cytochrome P450; oxazolidinones