Ten-Step Synthesis of Potent Anticancer Steroid Withanolide D

Withanolide D is a highly oxygenated steroid with a broad spectrum of biological activities (potent antitumor properties) and thus has stimulated considerable interest from synthetic chemists. Herein, we describe a concise 10-step synthesis of withanolide D, which features a Diels-Alder reaction with singlet oxygen, followed by a Kornblum-DeLaMare rearrangement to streamline functionalization of the critical A ring. A vinylogous aldol reaction was employed to forge the E ring with high regioselectivity and stereoselectivity. It should be noted that withanolide D could serve as the precursor for syntheses of six additional withanolide-type natural products, including withaferin A. This work establishes an efficient and modular route to withanolide D and related analogues, providing a robust platform for the synthesis of diverse withanolide derivatives as potential anticancer drug candidates.