Synthesis of Polycylic Compounds Possessing Biological Activities by Novel Intramolecular Cascade Reactions

通过一步反应以立体和区域选择性的方式形成多个键的级联反应是有机合成中最理想的过程之一。级联反应又称多米诺骨牌反应和串联反应。我们已经开发了两种类型的级联反应，这两种反应对天然产物的合成很有用。因此，具有两种类型的不饱和羰基的化合物的分子内双Michael反应提供了融合到具有五个立体生成中心的六元环的多环化合物。另一方面，酮不饱和酯的分子内Michael-Aldol反应构建了一个融合成具有四个立体生成中心的四元环的多环环体系。这些级联反应可以在五个不同的条件下进行，使用六甲基二硅氮化锂或Lewis酸和Lewis胺的组合。它们既有分子内反应的优点，又有级联反应的优点。在这个项目中，我们实现了以下具有重要生物学意义的天然产物的全合成：(1)吲哚生物碱的合成，Tacamonine的合成，在三乙胺存在下，在三乙胺的存在下，用TBSOTf处理C-2位具有α，β-不饱和酯功能的吲哚衍生物和C-3位的不饱和酰胺基。(2)倍半萜类化合物、雪松二醇和雪松二醇的合成5-取代环戊烯酮的分子内双Michael反应得到三环[5.2.1‘.0^&lt；1.5&gt；]正十一烷，再转化为雪松二醇和雪松二醇。(3)倍半萜类化合物库莫林的合成以4-取代环戊酮的分子内双迈克尔反应为关键步骤完成了氯莫林的有效全合成。

Cascade reactions forming multiple bonds in a stereo- and regio-selective manner by one procedure is one of the most ideal process in organic synthesis. The cascade reaction is also called as domino and tandem reaction. We have already developed two types of cascade reactions, which are useful for natural products synthesis. Thus, the intramolecular double Michael reaction of a compound having two types of unsaturated carbonyl groups provides a ploycyclic compound fused to six membered ring possessing five stereogenic centers. On the other hand, the intramolecular Michael-aldol reaction of the keto unsaturated ester constructs a polycyclic ring system fused to four membered ring having four stereogenic centers. These cascade reactions could be carried out under five different conditions using lithium hexamethyldisilazide or combinations of Lewis acids and Lewis amines. They have various advantages due to both merits of intramolecular reaction and cascade reaction. In this project, we achieved following total syntheses of natural products possessing important biological(1) Synthesis of Indole Alkaloid, TacamonineTreatment of an indole derivative having an alpha, beta-unsaturated ester function at the C-2 position and an unsaturated amide group at the C-3 position with TBSOTf in the presence of triethylamine provided the indoloquinolizidine derivative. Synthesis of tacamonine was carried out in a facile manner from the product.(2) Synthesis of Sesquiterpenoids, Cedranediol and CedranoxideIntramolecular double Michael reaction of 5-substituted cyclopentenone gave tricyclo[5.2.1 .0^<1.5>]decane, which was converted into cedranediol and cedranoxide.(3) Synthesis of Sesquiterpenoid, CulmorineAn effective total synthesis of culmorine was accomplished via the intramolecular double Michael reaction of 4-substituted cyclopentenone as key step.