Synthetic methodology study demonstrates a concise nine-step route to the withaferin A A/B ring motif from stigmasterol, suggesting improved access for future pharmacological evaluation.
Withanolides are C28 steroidal lactone plant-based natural products with diverse pharmacological activities, yet their synthesis remains challenging owing to the highly oxidized A/B ring system. Herein, we report a concise, protecting group-free route to the 1‑oxo‑2‑ene‑4β‑hydroxy‑5β,6β‑epoxy A/B ring motif, a key pharmacophore feature of many withanolides. Starting from commercially available stigmasterol, the target framework is assembled in nine steps, featuring a Wharton rearrangement and diastereoselective epoxidation directed by an axial hydroxyl group. This strategy offers an orthogonal approach to existing routes and provides efficient access to this synthetically challenging core, thereby facilitating structure–activity relationship studies and biological evaluations of withanolide natural products.
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Che et al. (2026) studied this question.
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