（-）-Notoamide B的全合成

Marine fungus-derived prenylated indole alkaloid (-)-notoamide B has been recently isolated and characterized, which is featured by the novel bicyclo[2.2.2]diazaoctane ring skeleton as well as the excellent antitumor activity. This project is focused on the total synthesis of (-)-notoamide B, by applying an Ag-catalyzed asymmetric Friedel-Crafts alkylation developed by our group to the synthesis of C3-isoprenylated diketopiperazine derivatives with high efficiency; Moreover, such derivatives further undergo an Ag-catalyzed one-pot 4-step cascade reactions of ring-opening, intramolecular Diels-Alder reaction, hydrolysis and oxidation, to furnish (-)-notoamide B and finally prove the biosynthetic pathway of isoprenylated indole alkaloid family that remaines obscure for decades. This project is targeting at the key scientific problem that is still a blank in our country, and worthy of intensive strudies.

(-)-Notoamide B为近年来从海洋真菌中分离得到的一种含有bicyclo[2.2.2]diazaoctane骨架、具有显著抗癌活性的含异戊烯基吲哚生物碱。本项目拟以（-）-notoamide B为研究对象，通过本课题组发展的银催化的不对称傅克反应一步高效实现吡咯并吲哚啉骨架C3-位不对称异戊烯基化；以3-位取代异戊烯二酮哌嗪衍生物为反应前体，通过探索银离子催化的串联"四步一锅"的开环、分子内Diels-Alder反应、水解、氧化反应，实现光学异构体(-)-notoamide B的不对称仿生全合成，并最终验证该类异戊烯基吲哚生物碱生源合成途径。该项目瞄准目前热点科学问题，在国内尚属空白，具有显著的科学意义和研究价值。

在该项目资助下，我们针对异戊烯基类吲哚生物碱家族代表性成员开展了仿生合成，关键探索以C3a位异戊烯基取代的手性吲哚二酮哌嗪衍生物为关键中间体的不对称仿生IMDA反应，构建此类生物碱结构中特征性的氮杂双环[2.2.2]环辛烷骨架。我们以本课题组发展的银促进的傅克反应在吲哚C3a位实现不对称异戊烯基化制备吡咯并吲哚三环中间体；以该中间体为原料，我们通过发展一种TiCl4/NaBH4条件下还原开吡咯环的方法，经后续官能团转化成功制备C3a位异戊烯基取代的手性吲哚二酮哌嗪中间体；在20% KOH甲醇溶液条件下，该中间体立体选择性发生不对称IMDA反应生成单一endo加成产物并成功构建氮杂双环[2.2.2]环辛烷骨架；经几步的官能团转化，最终我们以16步，约3%的总收率实现了(–)-depyranoversicolamide B的不对称全合成，具有重要的科学意义。