Synthesis of Antitumor Manzamine Alkaloid Isolated from Sponge and Development of Highly Bioactive Molecule

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A marine alkaloid, manazamine A has been attracted considerable attentions since it showed strong anti-malarial activity in vivo as well as cytotoxicity. We studied on the asymmetric total synthesis of manzamine A and related alkaloids. Key features of the synthesis were development of Diels-Alder reactions to construct hydroisoquinoline ring (AB ring system in the manzamine A structure) and application olefin metathesis reaction to synthesize azacycloalkenes, which are found in manzamine A structure. The results obtained from this research are summarized as follows.1) Synthetic route for ABC tricyclic intermediate for manzamine A in large scale has been established based on Diets-Alder reaction of chiral dienophile and siloxydiene followed by intramolecular Michael reaction. The ABC tricyclic intermediate was further converted to ABCD tetracyclic core system by construction of an azocine ring using olefin metathesis reaction. Suitable substituents for E ring elaboration were introduced on ring B.Total synthesis of manzamine A by our approach is now in a final stage to complete.2)The Diels-Alder reaction of 5-(1-siloxyvinyl)-1, 2, 3, 6-tetrahydropyridine derivative and methyl propiolate afforded hydroisoquinoline derivative in good yield. The Diels-Alder adduct was reacted with methyl acrylate in the presence of MS4A and tetrabutylammonium floride to give desired cis-perhydroisoquinoline derivative selectively. Total synthesis of manzamine B from this product was investigated.3) The central tetracyclic ring system of nakadomarine A was synthesized by two new synthetic routes.