Total Syntheses of Natural Polycyclic Sesterterpenoids With Anticancer Bioactivities

Cancer remains a leading cause of death worldwide, reinforcing the need for new therapeutics. Natural products-particularly terpenoids-continue to yield potent anticancer agents and inspire novel biological targets. Within this space, sesterterpenoids (C25) form a smaller yet influential class whose intricate polycyclic architectures have hindered systematic SAR exploration. Advances in modern synthesis now enable efficient access to these molecules and their analogs, accelerating biological studies and design. This review article surveys representative total syntheses of polycyclic sesterterpenoids (≥3 rings), focusing on phorbaketals, ophiobolins, salmahyrtisol A, and scalaranes. Their reported bioactivities span from nano- to micromolar cytotoxicity against various cancer cell lines. Synthetic strategies toward phorbaketals feature gold-catalyzed spiroketalization and late-stage diversification. Ophiobolin routes assemble 5-8-5 frameworks using Nozaki-Hiyama-Kishi coupling, radical cascades, and atom-transfer/radical polyene cyclizations. A biomimetic synthesis of salmahyrtisol A leverages Friedel-Crafts construction of a pentacycle from sclareol-derived precursors. Scalarane syntheses employ reductive Heck cyclization, titanocene(III)-mediated polycyclizations, and intramolecular Diels-Alder reactions to forge dense stereochemical arrays and furan-annulated cores. Collectively, these advances deliver scalable access, clarify steric and conformational controls governing reactivity, and create opportunities for SAR-driven optimization of anticancer sesterterpenoids.