nauclealise A的合成研究

Abstract

2016年由楊新全團隊從具有抗炎活性的藥物植物Nauclea officinalis分離並鑑定nauclealise A，結構為spiro[pyrrolidin-3,3'-oxindole]環的新型吲哚生物鹼，包含兩個尚未被鑑定的立體中心。經由實驗顯示抗腫瘤、抗菌和抗炎的生物活性，具有開發抗炎藥物的潛力。本論文以此結構作為有機合成的目標物，希望能夠以合成方法確認其結構，並訂定兩個立體中心的相對組態。 本研究以ethyl-2-methylpyrrole-3-carboxylate作為起始物，在氮上進行TIPS保護後，在4號位上以Vilsmeier-Haack反應引進甲醯基，再經由Wittig反應及水解後進行aldehyde homologation，同時，tryptamine在鹽酸中以DMSO作為氧化劑製備2-hydroxytryptamine氯化氫鹽，並與前述醛化合物進行分子內合環等一系列反應建構spiro[pyrrolidin-3,3'-oxindole]中的五環，也透過X-ray單晶繞射鑑定兩個非鏡像異構物的立體組態。接著對18號位 (pyrrole環) 上的碳進行甲醯基化反應，最後得到nauclealise A的結構，並與楊新全團隊的光譜數據進行分析。

In 2016, nauclealise A was isolated from Nauclea officinalis, a drug plant with anti-inflammatory activity, and chaterized by Xinquan Yang's group as a novel indole alkaloid with spiro[pyrrolidin-3,3'-oxindole] ring containing two stereogenic centers that have not yet been identified. Nauclealise A has been shown to possess anti-tumor, anti-bacterial and anti-inflammatory activities, and a potential lead compound for the development of anti-inflammatory drugs. In this thesis, we intended to synthesize nauclealise A to validate the structural assignments and to establish the relative configurations of two undetermined stereo configurations centers.In this study, ethyl-2-methylpyrrole-3-carboxylate was used as the starting material. After TIPS protection on nitrogen, the formyl group was introduced by Vilsmeier-Haack reaction at the position 4 of pyrrole. Subsequently, aldehyde homologation was accomplished by Wittig reaction followed by acidic hydrolysis. Meanwhile, 2-hydroxytryptamine was prepared from oxidization of indole by DMSO in hydrochloric acid. The spirooxyindole structure was constructed by imine-formation followed by intramolecular cyclization of 2-hydroxyindole with the aforementioned aldehyde to afford the two diastereomeric pentacyclic ring of the spiro[pyrrolidin-3,3'-oxindole] skeletons. Their relative stereo configurations were determined by X-ray crystallography. The structure of nauclealise A was finally obtained by formylation at the position 18 (pyrrole ring) followed by deprotection and their structures were analyzed and compared to the spectroscopic data of Yang's team.