Asymmetric Semisynthesis of Ovatodiolide

From both structural and functional perspectives, the large family of α-methylene-γ-lactone-type cembranolides represents a remarkable class of natural products. As potent lead compounds for anti-inflammatory, antiviral, and antifibrotic applications, their therapeutic potential continues to attract extensive investigation. Nevertheless, synthetic routes to such cembranolides remain scarce. Herein, we report a distinctive skeletal integration strategy to access this class of complex diterpenes from the naturally abundant precursor (+)-costunolide. This approach leverages a highly regioselective ring-opening metathesis (ROM), an enantioselective Rh-catalyzed asymmetric allylic substitution, and a tandem ring-opening metathesis/ring-closing metathesis (ROM/RCM) reaction. Notably, the strategy enables a concise 5-step semisynthesis of the flagship cembranolide, ovatodiolide, for the first time. This modular route offers a general means to access ovatodiolide-type cembranolides, thereby facilitating structure-activity relationship studies within this biologically significant family.