Chemoenzymatic Skeletal Editing of Natural Product Scaffolds via P450‐Controlled Site‐Selective Ring Expansion at Aliphatic C─H Sites

Abstract Methods for introducing subtle modifications at the level of single atoms/bonds (“skeletal editing”) are highly desirable in organic and medicinal chemistry, owing to their potential for fine‐tuning the structure and biological activity of organic molecules. Here, we report a chemoenzymatic strategy for enabling the skeletal editing of organic frameworks via ring expansion at the level of one or more aliphatic (methylene) C─H sites, as achieved through the synergistic combination of P450‐mediated site‐selective oxidation with subsequent Baeyer–Villiger rearrangement or ketone homologation. Combining this approach with engineered P450 catalysts exhibiting divergent regioselectivity enabled the expeditious synthesis of a panel of ring‐expanded analogs of various complex natural product substrates. Importantly, the skeletal modification was found to drastically altered the anticancer activity of some of these compounds. By the direct targeting of aliphatic C─H sites with tunable site‐selectivity, this strategy provides a powerful tool to rapidly access skeletally edited derivatives of natural products and other bioactive molecules for applications in drug discovery and chemical biology.