Engineered P450-based biocatalysts for C(sp3)−H amination reactions

Catalytic methods for the direct amination of C(sp³)–H bonds are of outstanding synthetic relevance owing to the ubiquitous occurrence of amine functionalities in organic molecules, from natural products to fine chemicals and drugs. While important progress has been made in the development of transition metal-based catalysts for this transformation, natural enzymes capable of supporting C—H amination chemistry via direct C—H bond functionalization are not available. In this lecture, we will present recent advances made in our laboratory toward the development of P450-based catalysts for promoting C—H amination reactions via a nitrene transfer process. Presentation of these results will be complemented with a discussion on our current understanding of the mechanism of these reactions and of key structural features that influence the reactivity and selectivity of these biocatalysts. Finally, we illustrate how mechanistic insights could be leveraged to guide the rational design and protein engineering of P450-based biocatalysts with significantly enhanced C−H amination reactivity. These results constitute a first step toward the development of sustainable and atom-economical biocatalytic strategies for the construction of carbon-nitrogen bonds in the synthesis and manufacturing of drugs, advanced synthetic intermediates, and other high added value compounds.