Pure and Applied Chemistry

Abstract: The zoanthamine alkaloids, a type of heptacyclic marine alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive biological and pharmacological properties as well as their unique chemical structures with stereochemical complexity. Namely, norzoanthamine can suppress the loss of bone weight and strength in ovariectomized mice and has been considered a promising candidate for an antiosteoporotic drug, whereas zoanthamine has exhibited potent inhibitory activity toward phorbol myristate-induced inflammation in addition to powerful analgesic effects. Recently, norzoanthamine derivatives were demonstrated to inhibit strongly the growth of P-388 murine leukemia cell lines, in addition to their potent antiplatelet activities on human platelet aggregation. These distinctive biological properties, combined with novel chemical structures, make this family of alkaloids extremely attractive targets for chemical synthesis. However, the chemical synthesis of the zoanthamine alkaloids has been impeded owing to their densely fuctionalized complex stereostructures. We report here the first and highly stereoselective total syntheses of norzoanthamine and zoanthamine, which involves stereoselective synthesis of the requisite triene for intramolecular Diels-Alder reaction via three-component coupling reactions, a key intramolecular Diels-Alder reaction, and subsequent crucial bis-aminoacetalization as the key steps.