title: Synthetic studies of the zoanthamine alkaloids: the total syntheses of norzoanthamine and zoanthamine.
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 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.
authors.affiliation: Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yoshimura
authors.forename: Minoru
authors.initials: M
authors.lastname: Sasaki
authors.forename: Izumi
authors.initials: I
authors.lastname: Hattori
authors.forename: Kei
authors.initials: K
authors.lastname: Komatsu
authors.forename: Mio
authors.initials: M
authors.lastname: Sakai
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanino
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyashita
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012615:Sea Anemones / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D001381:Azepines; D006576:Heterocyclic Compounds, 4 or More Rings; D011804:Quinolines; C542309:zoanthamine; C400280:norzoanthamine