Chemoenzymatic Skeletal Editing: P450-Controlled Site-Selective Ring Expansion of Natural Product Scaffolds at Aliphatic C—H Sites

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. While contemporary methods for skeletal editing of organic molecules largely rely on modification of pre-existing functional groups, opportunities for executing these transformations at ubiquitous yet unreactive aliphatic C(sp3)—H sites are currently unavailable. Here, we report a chemoenzymatic strategy for enabling skeletal editing via ring expansion with high site-selectivity at the level of one or more aliphatic C—H sites in complex molecules. By combining cytochrome P450-catalyzed C—H oxidation with chemical oxidation and subsequent Baeyer-Villiger rearrangement or ketone homologation, a panel of structurally and functionally diverse natural products were edited by inserting a lactone or carbonylmethylene moiety into aliphatic regions of their carbocyclic skeletons. Using engineered P450 catalysts with divergent regioselectivity, a set of different ring-expanded products could be readily obtained from a single parent molecule, highlighting the potential of this approach for skeletal edit scanning and/or library generation. By enabling the 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 that would be hard to attain by purely chemical means. We envision this approach can also enable the device of non-traditional retrosynthetic disconnections for the synthesis of complex molecules.