瑞香黄烷素A-D的全合成研究

发布时间：2018-03-06 01:02

本文选题：DaphnodorinsA-D　切入点：全合成　出处：《上海交通大学》2014年博士论文　论文类型：学位论文

【摘要】：Daphnodorins A-D具有抗肿瘤、抗病毒、抗炎、杀虫抑菌等多种生物活性，是理想的先导化合物。但是该类化合物在自然界中含量较低，分离纯化较困难。尽管双黄酮类化合物的合成已有较多报道，但Daphnodorin类化合物全合成尚未见报道。本文通过DaphnodorinsA-D的全合成研究，探索Daphnodorin类化合物的化学合成方法，为该类化合物更深入的活性和构效关系研究提供化学合成手段和化合物来源。本课题首先探索了Daphnodorin A和B的全合成，在第一代合成路线中，本文尝试了钯催化的插羰基环合反应构建Daphnodorin A和B结构中的2-芳基-3-羰基苯并呋喃环。尽管在模板反应中成功探索出构建2-芳基-3-羰基苯并呋喃环的最优反应条件，但应用到Daphnodorin A和B的全合成中效果不理想。在第二代合成路线中，本研究通过邻碘代酚与吸电子基活化的炔在碱性条件下的共轭加成和分子内Heck反应开发出2-取代-3-吸电子基取代的苯并呋喃环的构建方法，并应用该方法首次完成Daphnodorin A和B的全合成，所得Daphnodorin B与天然产物核磁、旋光及高分辨数据一致；而合成所得Daphnodorin A为消旋产物。为了防止Daphnodorin A手性中心在多步合成路线中消旋化，，本研究又尝试了另外两条路线完成了Daphnodorin A的合成：第二条路线所得终产物也为消旋体；第三条路线采用温和的反应条件脱去黄烷醇骨架的3-位羟基，明显提高了Daphnodorin A的光学纯度。接着，本文探索了Daphnodorin C的全合成，分别尝试了不对称环氧化物开环和炔的[2+2+2]反应构建A环的合成路线，但由于路线中间体收率过低等原因以失败告终，本文最终未能完成Daphnodorin C的合成工作。通过以上两条路线的尝试，提示我们Daphnodorin C的合成路线设计应尽量避免大位阻取代基团的使用、未来的合成路线设计应以解决含氧螺环核心结构的方法学研究为前提。最后，本课题探索出了有位阻取代基取代的芳基碘代物的硼酸酯化反应条件，能够高效合成硼酸酯取代的黄酮和三烷氧基取代苯，并通过探索连接方式相同的3,8″-双芹菜素的合成来指导Daphnodorin D的合成。我们选择位阻小的碘代查尔酮与硼酸酯取代的苯乙酮经Suzuki偶联、Claisen Schmidt缩合、选择性脱保护、碘调节的关环等反应，首次完成了3,8″-双芹菜素的全合成；并以相同的思路构建了Daphnodorin D的核心骨架。在Daphnodorin类化合物的合成研究过程中，本课题开发了Luche还原法还原α,β-不饱和乙酰基酚甲酸乙酯来制备2-烯丙基酚的合成方法。该方法为黄烷醇及Daphnodorin类双黄酮合成中的关键中间体2-烯丙基酚类化合物的高效合成提供了新方法；同时，本文开发出一种Pd(PPh3)4催化的酰氯与原位生成的炔基锌衍生物偶联合成呋喃双黄酮构建所需炔酮片段的方法。
[Abstract]:Daphnodorins A-D has many biological activities, such as anti-tumor, anti-virus, anti-inflammatory, insecticidal and bactericidal. Although there have been many reports on the synthesis of bisflavonoids, the total synthesis of Daphnodorin compounds has not been reported. In this paper, the chemical synthesis methods of Daphnodorin compounds are explored through the study of total synthesis of DaphnodorinsA-D. It provides chemical synthesis methods and sources for the further study of the activity and structure-activity relationship of these compounds. In this paper, we first explore the total synthesis of Daphnodorin A and B, in the first generation synthesis route, In this paper, palladium catalyzed cyclization of 2-aryl-3-carbonyl benzofuran in Daphnodorin A and B structures has been attempted, although the optimal reaction conditions for the construction of 2-aryl-3-carbonyl benzofuran ring have been successfully explored in the template reaction. But the application of Daphnodorin A and B in the total synthesis is not ideal. In the second generation synthesis route, In this paper, the method of constructing 2-substituted -3-electron-absorbing benzofuran ring was developed by conjugate addition and intramolecular Heck reaction of o-iodophenol and electron-absorbing group activated acetylene in alkaline condition. Daphnodorin A and B were synthesized by this method for the first time. The obtained Daphnodorin B was consistent with the nuclear magnetic field, optical rotation and high resolution data of natural products, while the synthesized Daphnodorin A was racemic product. In order to prevent the chiral center of Daphnodorin A from racemizing in the multi-step synthesis route, In this study, the synthesis of Daphnodorin A was carried out by two other routes: the end product of the second route was also racemate, the third route used mild reaction conditions to remove the 3-position hydroxyl group from the framework of flavanol. The optical purity of Daphnodorin A was improved obviously. Then, the total synthesis of Daphnodorin C was explored, and the synthesis route of A ring was constructed by asymmetric ring opening of epoxide and [222] reaction of acetylene, but the yield of intermediate was too low. In this paper, the synthesis of Daphnodorin C has not been completed. Through the attempts of the above two routes, it is suggested that the design of synthetic route of Daphnodorin C should avoid the use of large steric resistance substituents as far as possible. The future synthetic route design should be based on the methodology of solving the core structure of oxygen-containing snails. Finally, the boric acid esterification conditions of substituted aryl iodides with sterically hindered substituents were explored, which could efficiently synthesize borate substituted flavonoids and trialkoxy substituted benzene. In order to guide the synthesis of Daphnodorin D by exploring the synthesis of 3O8 "-bisapigenin in the same connection mode, we have selected Iodochalone with low steric resistance and acetophenone substituted by borate, which was condensed by Suzuki coupled with Claisen Schmidt and selectively deprotected. The complete synthesis of 3O8 "-diapigenin was completed for the first time, and the core skeleton of Daphnodorin D was constructed with the same thinking. In the process of synthesis of Daphnodorin compounds, In this paper, Luche reduction method was developed to reduce 伪, 尾 -unsaturated acetylphenol ethyl formate to 2-allylphenol, which is the key intermediate in the synthesis of flavanols and Daphnodorin bisflavonoids. A new method for high efficiency synthesis is provided. At the same time, a method of coupling acyl chloride catalyzed by Pd(PPh3)4 with in situ alkynyl zinc derivative to synthesize furan bisflavone was developed.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R914.5

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