几个天然甾体分子的合成与修饰

发布时间：2018-05-04 16:30

本文选题：甾体 + 甾体生物碱　；参考：《贵州师范大学》2017年硕士论文

【摘要】：甾体是天然产物中一类重要化合物,具有多种生理活性,是重要的药物分子或药物原料。对具有活性的天然甾体分子进行合成和结构修饰,是开展甾体天然产物化学研究的重要工作。本论文开展了对几个天然甾体分子的合成与结构修饰,包含以下两部分:(1)茄啶solanidine的合成:茄啶是一种结构独特的甾体生物碱,具有多种生物活性。田伟生课题组曾以薯蓣皂甙元为原料,采用Schmidt重排为关键反应完成茄啶的合成。但在合成中出现了严重的C-25异构化问题。本论文中,通过调整合成路线解决了异构化反应问题,并以发散式的方式完成茄啶和22-epi-茄啶两个天然产物的合成。从薯蓣皂甙元醋酸酯出发,经开环置换的方式打开E环、C-25异构化、选择性内酯接力还原、Schmidt重排/氮烷基化/立体选择性亚胺盐还原等九步反应,以24%总收率合成了茄啶。按类似的路线,在内酯接力还原后,通过两次分子内氮烷基化反应等共九步反应,17%的总收率完成22-epi-茄啶的合成。(2)甾体-托吡酯缀合物的合成:托吡酯为一种新型的抗癫痫药,进入临床一线用药品种,而青阳参总苷可以与苯妥英钠共用临床,其活性成分是C21甾体酯糖苷。基于青阳参总苷中去氧糖组成的糖链部分与托吡酯的糖衍生物(糖中羟基部分被低极性基团覆盖)的结构特征,拟以托吡酯代替青阳参糖苷中的糖链部分,通过结构修饰合成甾体-托吡酯缀合物,并同时模拟托吡酯活性基团磺酰胺基,在甾体的C-3位置引入磺酰胺基。以青阳参C21甾体苷元告达庭和与其结构类似而易得的C27甾体苷元及孕甾烷醇作为甾体部分,对其结构改造和修饰,合成得到12个甾体新分子,其中包括了6个甾体-托吡酯缀合物和6个甾体氨基磺酸酯。
[Abstract]:Steroids are a kind of important compounds in natural products. They have many physiological activities and are important drug molecules or raw materials. The synthesis and structural modification of active natural steroids is an important work in the chemical research of steroids natural products. In this paper, the synthesis and structural modification of several natural steroids, including the following two parts: 1) Solanidine solanidine: Solanidine is a structurally unique steroidal alkaloid with a variety of biological activities. Tian Weisheng group used diosgenin as raw material and Schmidt rearrangement as the key reaction to complete the synthesis of solanidine. However, there is a serious problem of C-25 isomerization in the synthesis. In this paper, the isomerization reaction was solved by adjusting the synthesis route, and the synthesis of two natural products, Solanidine and 22-epi-solanidine, was completed in a divergent manner. Starting from diosgenin acetate and opening E-ring C-25 isomerization by ring-opening replacement, Solanidine was synthesized in 24% overall yield by selective lactone relay reduction, Schmidt rearrangement / nitroalkylation / stereoselective imine reduction. In a similar route, after lactone reduction, a total yield of 17% was obtained through two intramolecular nitrogen-alkylation reactions to complete the synthesis of 22-epi-solanidine steroid-topiramate conjugate: topiramate is a new antiepileptic drug. It can be shared with phenytoin sodium and its active component is C21 steroidal glucoside. Based on the structural characteristics of the sugar chain part of the total glucoside and the sugar derivative of topiramate (the hydroxyl group of the sugar is covered by the low polar group), topiramate is proposed to replace the sugar chain part of the glucoside. The steroid-topiramate conjugate was synthesized by structural modification, and the sulfonamide group of topiramate active group was simulated, and the sulfonamide group was introduced into the steroid C-3 position. Twelve steroidal new molecules were synthesized by modifying and modifying the steroidal glycosides of C21, C27 steroidal glycosides and pregnancy sterol, which are similar to the C21 steroidal glycosides. These include 6 steroidal-topiramate conjugates and 6 steroidal aminosulfonates.
【学位授予单位】：贵州师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O629.2

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