UC Berkeley

Methyl groups are ubiquitous in natural products and biologically active compounds, but methods for their selective transformation in such structures are limited. For example, terpenoids contain many methyl groups, due to their biosynthetic pathways, but few reactions of these groups in such structures have been reported. We demonstrate that the combination of methyl C-H silylation and oxidation proximal to native hydroxyl or carbonyl groups occurs in a range of terpenoids and show that the installed hydroxyl group serves as a toehold to enable substitution, elimination, or integration of the methyl carbon into the terpenoid skeleton by the cleavage of C-C bonds. In one case, substitution of the entire methyl group occurs by further oxidation and decarboxylative coupling. In a second, substitution of the methyl group with hydrogen occurs by photochemical hydrodecarboxylation or epimerization by retro-Claisen condensation. In a third, photocatalytic decarboxyolefination formally eliminates methane from the starting structure to generate a terminal olefin for further transformations. Finally, a Dowd-Beckwith-type rearrangement cleaves a nearby C-C bond and integrates the methyl group into a ring, forming derivatives with unusual and difficult-to-access expanded rings. This strategy to transform a methyl group into a synthon marks a distinct approach to restructuring the skeletons of complex architectures and adding functional groups relevant to medicinal chemistry.