Catalyst-controlled site-selective dehydrogenation, a stepping stone for C–H oxidations in complex terpenes synthesis

Olefins are a privileged motif present in natural products and pharmaceuticals and serve as reliable entry points for oxygen installation in total synthesis. While dehydrogenation is an efficient strategy to forge olefins in complex organic molecules, limitations of current methods restrict its broader use as a stepping stone toward net site-selective oxidation. Here, we show that catalyst-controlled, site-selective dehydrogenation of multiple β,γ- and γ,δ-C–H bonds, enabled by distinct palladium and copper catalysts, allows oxidation at multiple sites. This approach enables stereo- and/or regioselective oxidation of C–H and C–C double bonds, including oxidation of sterically hindered C–H bonds over more accessible ones in diterpenes. These transformations are not readily achieved using existing chemical or enzymatic methods. The utility of this strategy is demonstrated through the synthesis of ten natural products. Olefins are key motifs in natural products, but current dehydrogenation methods are limited for site-selective oxidations. Here, the authors report palladium- and copper-catalyzed, site- and stereoselective dehydrogenations followed by oxidations, including sterically hindered C–H bonds, enabling the synthesis of ten natural products.