Journal
ACS CATALYSIS
Volume 5, Issue 3, Pages 1685-1691Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cs5018612
Keywords
C-H amination; cytochrome P450; biocatalysis; carbonazidate; oxazolidinones
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Funding
- U.S. National Institute of Health [GM098628]
- U.S. NSF [CHE-0946653]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM098628] Funding Source: NIH RePORTER
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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.
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