The selective oxyfunctionalization of isolated sp3 C?H bonds in complex molecules represents a formidable challenge in organic chemistry. In this report, we describe a rational, systematic strategy to expedite the development of P450 oxidation catalysts with refined regio- and stereoselectivity for the hydroxylation of remote, unactivated C?H sites in a complex scaffold. Using bioactive terpenes as model substrate, we demonstrate how a three-tier strategy involving first-sphere active site mutagenesis, high-throughput P450 fingerprinting, and fingerprint-driven P450 reactivity predictions enabled the rapid evolution of efficient biocatalysts for the selective hydroxylation of unactivated C?H sites in relevant yet previously inaccessible regions of these complex natural products. The evolved P450 variants could be applied to provide direct access to the desired hydroxylated derivatives at preparative scales and in high isolated yields, enabling further elaboration of these molecules.

Controlled oxidation of remote sp3 C?H bonds in complex molecules using P450 catalysts with fine-tuned selectivity

246th National Meeting (2013)

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