吲哚参与的不对称分子内串联环化反应及其在单萜吲哚生物碱全合成中的应用

4a,9a-Fused tetrahydrocarbazole is the key structural element in a variety of monoterpene indole alkaloids, which consists of a tetrahydrocarbazole unit and a five-membered heterocycle (oxygen- or nitrogen-heterocycle) with two adjacent quaternary stereogeneric centers at 4a and 9a positions and poses a synthetic challenge. Representative members in this alkaloid family are minfiensine, vincorine, and aspidophylline A. Although a number of synthetic routes have been reported for these natural products, only a few were able to establish the core structure in an efficient and highly enantioselective manner. The proposed research project will concentrate on the development of a novel indole-participating intramolecular cascade asymmetric cyclization reaction, which is designed on the basis of transition-metal (Pd/Ir) catalyzed asymmetric allylic alkylation reaction. The proposed asymmetric cascade cyclization reaction is expected to create the key skeleton of the above-mentioned alkaloids in one step efficiently and highly enantioselectively. The scope and limitation of this reaction are going to be studied in detail. Based on this reaction, studies on the total synthesis of representative natural products will be carried out to establish a new strategy for this alkaloid family.

4a,9a-并环四氢咔唑结构是许多单萜吲哚生物碱的核心结构骨架，由一个四氢咔唑单元和一个五员氮杂或氧杂环组成，四氢咔唑的4a和9a位具有两个相邻的四级碳立体中心，在合成上具有一定的挑战性。其中代表性的分子有minfiensine，vincorine，aspidophylline A等。目前文献中对这些活性生物碱的全合成已有报道，然而能够对4a,9a-并环四氢咔唑核心结构高效地进行不对称构建的方法仍然十分有限。本项目拟基于过渡金属（钯、铱等）催化的不对称烯丙基烷基化反应，设计和发展一类新型的吲哚参与的不对称分子内串联环化反应，用以高效地构建上述生物碱天然产物分子的核心结构骨架，并对这一新反应的特点与适用范围进行深入研究。本研究项目将以所发展的串联环化反应为基础，探索上述天然产物中代表性分子的新全合成策略。

并环四氢咔唑结构是许多单萜吲哚生物碱的核心结构骨架，代表性的天然产物分子有minfiensine，vincorine，aspidophylline A, strictamine等。目前文献中对这些活性生物碱的全合成已有报道，然而能够对并环四氢咔唑核心结构高效地进行不对称构建的方法仍然有限。本项目基于钯催化的烯丙基烷基化反应，设计和发展了两类吲哚参与的分子内环化反应，用以高效地构建上述生物碱天然产物分子的核心结构骨架。首先，我们实现了2位具有支链型和直链型烯丙基碳酸酯单元的色胺/色醇衍生物在钯和手性膦配体存在下的不对称分子内串联环化反应，成功构建了minfiensine，vincorine和aspidophylline A的4a,9a-并环四氢咔唑关键骨架，探索了这一新反应的普适性，并以这一反应为关键步骤完成了minfiensine的不对称全合成。其次，我们发展了以手性催化的Pictet-Spengler反应/吲哚参与的分子内烯丙基烷基化反应为关键步骤的新合成策略，用以构建天然产物strictamine所具有的1,4a-并环四氢咔唑关键骨架，并利用这一策略完成了strictamine的形式全合成。本研究项目以天然产物所具有的复杂骨架结构为目标，发展新型的反应和策略实现该类骨架的不对称构建，并实现了其中代表性分子的合成。