The
zoanthamine alkaloids, a type of heptacyclic marine
alkaloid isolated from colonial zoanthids of the genus Zoanthus sp., have distinctive
biological and pharmacological properties in addition to their unique chemical structures with stereochemical complexity. Namely,
norzoanthamine (1) can suppress the loss of bone weight and strength in ovariectomized mice and has been expected as a promising candidate for a new type of antiosteoporotic
drug, while
zoanthamine (2) 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. Their 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 functionalized complex stereostructures. In this paper, we report the first and highly efficient total syntheses of
norzoanthamine (1) and
zoanthamine (2) in full detail, which involve stereoselective synthesis of the requisite triene (18) for an intramolecular Diels-Alder reaction via the sequential three-component coupling reactions, the key intramolecular Diels-Alder reaction, and subsequent crucial bis-aminoacetalization as the key steps. Ultimately, we achieved the total synthesis of
norzoanthamine (1) in 41 steps with an overall yield of 3.5 % (an average of 92 % yield each step) and that of
zoanthamine (2) in 43 steps with an overall yield of 2.2 % (an average of 91 % yield each step) starting from (R)-5-methylcyclohexenone (3), respectively.