Chiral Synthesis of New Biologically Active Alkaloids Utilizing Hetero Diels-Alder Reaction

利用杂狄尔斯-阿尔德反应手性合成新型生物活性生物碱

基本信息

批准号：
08672450
负责人：
KIBAYASHI Chihiro
金额：
$ 1.6万
依托单位：
Tokyo University of Pharmacy & Life Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672450/
关键词：
lepadins A,B,C marine alkaloids tunicate decahydroquinoline cytotoxicity against human cancer cell lines chiral hydroxamic acid chiral acylnitroso compound intramolecular hetero Diels-Alder reaction 分子内ヘテロディールズ・アルダー反応矢毒蛙アルカロイドエピバチジン

项目摘要

Lepadins A,B,and C,isolated from tunicate Clavelina lepadiformis, are the first repoted example of marine natural products with a decahydroquinoline skeleton, and exhibit significant in vitro cytotoxixity against murine leukemia and human cancer cell lines. Although molecular structures and relative stereochemistry of these compounds have been assigned, their absolute stereochemistries still remain unknown. The present investigations were aimed at the first asymmetric total synthesis of lepadin alkaloids by utilizing intramolecular hetero Diels-Alder reaction as a basic strategy and also determining the absolute configuration of these alkaloids.According to our previous findings, we envisioned the use of aqueous conditions for enhancement of stereoselectivity in intramolecular acylnitroso hetero Diels-Alder reaction. Thus, the chiral hydroxamic acid derived from L-malic acid was oxidized by the periodate salt to generate the acylnitroso compound, which spontaneously underwent cycloaddition to afford the trans-adduct with high stereoselectivity. Asymmetric hydroxylation with Davis reagent followed by aldol reaction resulted in the stereoselective construction of the decahydroquinoline frame work, which incorporates all functionalities and right stereostructure required for the synthesis of Lepadins A,B,and C,and thus, can be utilized as a common key synthetic intermediate for the target compounds.

Lepadins A、B 和 C 是从被囊动物 Clavelina lepadiformis 中分离出来的，是具有十氢喹啉骨架的海洋天然产物的第一个报道实例，并且对小鼠白血病和人类癌细胞系表现出显着的体外细胞毒性。尽管这些化合物的分子结构和相对立体化学已经确定，但它们的绝对立体化学仍然未知。目前的研究旨在通过利用分子内杂 Diels-Alder 反应作为基本策略，首次不对称全合成 Lepadin 生物碱，并确定这些生物碱的绝对构型。根据我们之前的发现，我们设想使用水性条件来合成 Lepadin 生物碱。增强分子内酰基亚硝基杂狄尔斯-阿尔德反应的立体选择性。因此，由L-苹果酸衍生的手性异羟肟酸被高碘酸盐氧化生成酰基亚硝基化合物，该酰基亚硝基化合物自发地进行环加成，得到具有高立体选择性的反式加合物。使用 Davis 试剂进行不对称羟基化，然后进行羟醛反应，形成十氢喹啉框架的立体选择性结构，该框架包含合成 Lepadins A、B 和 C 所需的所有功能和正确的立体结构，因此可以用作通用密钥目标化合物的合成中间体。