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

作为一种海洋生物碱，manazamine A因其在体内具有很强的抗疟疾活性和细胞毒性而受到广泛关注。研究了曼扎胺A及其相关生物碱的不对称全合成。该合成的主要特点是利用diols - alder反应构建了氢异喹啉环（manzamine A结构中的AB环体系），并应用烯烃复分解反应合成了manzamine A结构中的氮杂环烯烃。本研究的结果总结如下：1)以手性亲二烯与硅氧二烯的Diets-Alder反应和分子内Michael反应为基础，建立了ABC三环甲酰胺A中间体的大规模合成路线。通过烯烃复合反应，构建偶氮环，ABC三环中间体进一步转化为ABCD四环核心体系。在b环上引入了合适的取代基来进行E环的精化。2) 5-（1-硅氧乙烯基）- 1,2,3,6 -四氢吡啶衍生物与丙酸甲酯的Diels-Alder反应得到了收率较高的氢异喹啉衍生物。在MS4A和四丁基氟化铵存在下，Diels-Alder加合物与丙烯酸甲酯选择性反应，得到所需的顺式过氢异喹啉衍生物。以该产物为原料，研究了曼扎胺B的全合成。3)通过两条新的合成路线合成了中腺苷A的中心四环环体系。

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.