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Synthetic Studies on Endistonins, Which Potent Anti-virel Activity.

具有有效抗病毒活性的内皮调节素的合成研究。

基本信息

批准号：
13672208
负责人：
TOKUYAMA Hidetoshi
金额：
$ 2.24万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

The aim of this research is to establish an efficient and practical synthetic route to eudistomins, which have proved to possess potent anti-viral and anti-tumor activity. After fundamental explorations of the synthetic route, we thoroughly investigated a strategy utilizing our indole synthesis by radical cyclization of o-alkenylthioanilides. The stereoselective formation of the 7-membered oxathioazepin ring was successfully achieved via β-lactam fused system. Although the desired indole formation precursor could be obtained, the expected indole formation reaction did not take place at all in spite of extensive investigation on the reaction conditions. In the course of investigation, however, we have developed a novel transformation of primary amines to N-alkylhydroxylamines.We then turned our attention to develop a novel formation of oxathiazepin by intramolecular alleviation of thiol. Finally, we achieved a total synthesis of (-)-eudistomin C featuring highly diastereoselective Picte … More d-Spenglar reaction catalyzed by dichloroacetic acid, and a novel protocol for the formation of oxathiazepin. The requisite indole segment was prepared by Macor's procedure exploiting intramolecular Heck reaction. After conversion to hydroxylamine derivative protectin with methyl thiomethyl (MTM) group by Mitsunobu reaction, the compound was subjected to Picted-Spengler reaction conditions with the Garner's aldehyde. In the presence of dichloroacetic acid, the desired diastereomer was obtained in high selectivity. The crucial oxathiazepin formation was started by conversion of MTM protected compound to thioacetate by treatment with sulfuly1 chloride and thioacetice acid in the presence of base After functional group manipulation, the obtained cyclization precursor bearing mesylate and thioacete functionalities was treated with potassium carbonate in methanol to furnish the oxathiazepin ring in high yield. Finally, total synthesis of (-)-eudistomin C was completed by deprotection of Boc and methoxu group with BBr_3. Less

本研究的目的是建立一种高效实用的eudistomin合成路线，该路线已被证明具有有效的抗病毒和抗肿瘤活性。在对合成路线进行了基本探索之后，我们深入研究了利用邻链烯基硫代苯胺自由基环化合成吲哚的策略。通过β-内酰胺稠合系统成功实现了7元硫杂氮卓环的立体选择性形成。尽管可以获得所需的吲哚形成前体，但尽管对反应条件进行了广泛的研究，但预期的吲哚形成反应根本没有发生。然而，在研究过程中，我们开发了一种将伯胺转化为 N-烷基羟胺的新方法。然后，我们将注意力转向通过硫醇的分子内减轻来开发新的氧硫氮平形成方法。最后，我们实现了 (-)-eudistomin C 的全合成，其特点是二氯乙酸催化的高度非对映选择性 Picte … 更多 d-Spenglar 反应，以及形成 oxathizepin 的新方案。必需的吲哚片段是通过Macor's 程序利用分子内Heck 反应制备的。通过 Mitsunobu 反应将其转化为具有甲硫甲基 (MTM) 基团的羟胺衍生物保护素后，将该化合物与 Garner 醛进行 Picted-Spengler 反应条件。在二氯乙酸存在下，以高选择性获得所需的非对映异构体。关键的氧硫氮杂卓形成是通过在碱存在下用磺酰氯和硫代乙酸处理将MTM保护的化合物转化为硫代乙酸酯开始的。在官能团操作后，将获得的带有甲磺酸酯和硫代乙酸酯官能团的环化前体用碳酸钾在甲醇中处理，以高产率提供氧硫氮杂环。最后通过BBr_3脱去Boc和甲氧基团，完成(-)-eudistomin C的全合成。较少的