The discovery of small-molecule agents for therapeutic applications depends on the ability for chemists to access new biologically relevant regions of the chemical space. To this end, late-stage modification has emerged as an attractive strategy to selectively derivatize natural products with inherent biological activity. While late-stage C—H functionalization methods to add complexity to the periphery of the molecular skeleton are numerous, methods to edit the skeleton itself remain comparatively less explored. Here we report the integration of enzymatic late-stage functionalization and chemical synthesis as a novel approach for the skeletal editing of natural product scaffolds. Using engineered cytochrome P450 catalysts in combination with carbonyl rearrangement chemistries, a diverse panel of natural products were skeletally edited through a net one-atom ring expansion. These results demonstrate the value of the present chemoenzymatic late-stage C—H functionalization approach for the generation and exploration of natural product derived scaffolds.

Skeletal editing of natural products enabled by cytochrome P450-catalyzed C—H functionalization

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