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

海绵抗肿瘤曼扎明生物碱的合成及高生物活性分子的开发

• 批准号: 11470467
• 负责人: NAKAGAWA Masako
• 金额: $ 9.15万
• 依托单位: CHIBA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470467/
• 关键词: Manzamine A; Manzamine B; Nakadomarin A; Marine Alkaloid; Anti-malarial agent; Diels-Alder reaction; Hydroisoguinoline; Olefin Metathesis Reaction; マンザミン; 抗マラリア作用; シロキシジエン

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.

Manazamine A 是一种海洋生物碱，因其在体内表现出强大的抗疟活性和细胞毒性而受到广泛关注。我们对曼扎明A及相关生物碱的不对称全合成进行了研究。该合成的主要特点是发展了Diels-Alder反应来构建氢异喹啉环（曼扎胺A结构中的AB环系），并应用烯烃复分解反应来合成氮杂环烯烃，该化合物存在于曼扎胺A结构中。本研究取得的主要成果如下：1)基于手性二烯体与硅氧基二烯的Diets-Alder反应及分子内Michael反应，建立了曼扎明A的ABC三环中间体的大规模合成路线。通过利用烯烃复分解反应构建氮辛环，将ABC三环中间体进一步转化为ABCD四环核心体系。 B环上引入了适合E环精制的取代基。通过我们的方法全合成曼扎胺A现已进入最后阶段。2)5-(1-硅氧基乙烯基)-1,2,3,6-四氢吡啶衍生物和丙炔酸甲酯的Diels-Alder反应以良好的产率提供了氢化异喹啉衍生物。在MS4A和四丁基氟化铵存在下，狄尔斯-阿尔德加合物与丙烯酸甲酯反应，选择性地得到所需的顺式全氢异喹啉衍生物。对该产物进行了曼扎明B的全合成研究。3)通过两条新的合成路线合成了nakadomarine A的中心四环体系。

项目成果

Masako Nakagawa, Yasuhiro Torisawa, Hideharu Uchida, Atsushi Nishida: "New Approaches to Total Synthesis of Manzamine A, Ircinal A and Related compounds."Jornal of Synthetic Organic Chemistry, Japan. 57. 1004-1015 (1999)

Masako Nakakawa、Yasuhiro Torisawa、Hideharu Uchida、Atsushi Nishida：“Manzamine A、Ircinal A 和相关化合物全合成的新方法。”合成有机化学杂志，日本。

Masako Nakagawa: "Total Synthesis of Marine Alkaloids, Manzamine A and Related Compounds."J.Heterocyclic Chem.. 37・. 567-581 (2000)

中川雅子：“海洋生物碱、曼扎明A和相关化合物的全合成”。杂环化学杂志.. 567-581 (2000)

Masako Nakagawa: "New Approach to Total Synthesis of Manzamine A, Ircinal A and Related Compounds"J.Synth.Org.Chem.,Jpn. 57・11. 1004-1015 (1999)

中川雅子：“Manzamine A、Ircinal A 及相关化合物的全合成新方法”J.Synth.Org.Chem.，Jpn 57・11（1999）。

Mitsuhiro Arisawa, Chiaki Kato, Hiroaki Kaneko, Atsushi, Nishida, Masako Nakagawa: "Concise Synthesis of Azacycloundecenes Using Ring-Closing Metathesis (RCM)."J.Chem.Soc.Perkin Trans. 1. 1873-1876 (2000)

Mitsuhiro Arisawa、Chiaki Kato、Hiroaki Kaneko、Atsushi、Nishida、Masako Nakakawa：“使用闭环复分解 (RCM) 简明合成氮杂环十一碳烯。”J.Chem.Soc.Perkin Trans。

Hideharu Uchida, Atsushi Nishida, Masako Nakagawa: "An Efficient Access to the Optically Active Manzamine Tetracyclic Ring System."Tetrahedron Letters. 40-1. 113-116 (1999)

Hideharu Uchida、Atsushi Nishida、Masako Nakakawa：“有效获取光学活性曼扎明四环系统。”四面体字母。