The selective oxyfunctionalization of isolated sp3 C?H bonds in complex molecules represents a formidable challenge in organic chemistry. Here, 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 artemisinin 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 three efficient biocatalysts for the selective hydroxylation of primary and secondary C?H sites in a relevant yet previously inaccessible region of this complex natural product. 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 this molecule.

Controlled oxidation of isolated sp3 C?H bonds in complex molecules via P450 catalysts with fine-tuned regio- and stereoselectivity

245th National Meeting (2013)

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