Total Synthesis of the Euphorbia Diterpenoid Pepluacetal

The first total synthesis of the Euphorbia diterpenoid pepluacetal is disclosed in both racemic and chiral fashions. The synthesis strategically relies on a photo‐induced Wolff rearrangement/lactonization cascade (WRLC) reaction to access the cyclobutane moiety, a ring‐closing metathesis/cyclopropanation sequence to rapidly forge the 7–3 bicyclic system, and a late‐stage Rh‐catalyzed transannular carbenoid insertion to C(sp 3 )−H bond followed by a Baeyer–Villiger oxidation and ring‐opening manipulations to install the side chain. The synthetic route demonstrates excellent stereochemical control on the non‐classical concave‐face bond formation, remote traceless stereochemical relay and high scalability to provide 20 mg of (+)‐pepluacetal.