本文選題：DaphnodorinsA-D　切入點(diǎn)：全合成　出處：《上海交通大學(xué)》2014年博士論文　論文類型：學(xué)位論文

【摘要】：Daphnodorins A-D具有抗腫瘤、抗病毒、抗炎、殺蟲抑菌等多種生物活性，是理想的先導(dǎo)化合物。但是該類化合物在自然界中含量較低，分離純化較困難。盡管雙黃酮類化合物的合成已有較多報(bào)道，但Daphnodorin類化合物全合成尚未見報(bào)道。本文通過DaphnodorinsA-D的全合成研究，探索Daphnodorin類化合物的化學(xué)合成方法，為該類化合物更深入的活性和構(gòu)效關(guān)系研究提供化學(xué)合成手段和化合物來源。 本課題首先探索了Daphnodorin A和B的全合成，在第一代合成路線中，本文嘗試了鈀催化的插羰基環(huán)合反應(yīng)構(gòu)建Daphnodorin A和B結(jié)構(gòu)中的2-芳基-3-羰基苯并呋喃環(huán)。盡管在模板反應(yīng)中成功探索出構(gòu)建2-芳基-3-羰基苯并呋喃環(huán)的最優(yōu)反應(yīng)條件，但應(yīng)用到Daphnodorin A和B的全合成中效果不理想。在第二代合成路線中，本研究通過鄰碘代酚與吸電子基活化的炔在堿性條件下的共軛加成和分子內(nèi)Heck反應(yīng)開發(fā)出2-取代-3-吸電子基取代的苯并呋喃環(huán)的構(gòu)建方法，并應(yīng)用該方法首次完成Daphnodorin A和B的全合成，所得Daphnodorin B與天然產(chǎn)物核磁、旋光及高分辨數(shù)據(jù)一致；而合成所得Daphnodorin A為消旋產(chǎn)物。為了防止Daphnodorin A手性中心在多步合成路線中消旋化，，本研究又嘗試了另外兩條路線完成了Daphnodorin A的合成：第二條路線所得終產(chǎn)物也為消旋體；第三條路線采用溫和的反應(yīng)條件脫去黃烷醇骨架的3-位羥基，明顯提高了Daphnodorin A的光學(xué)純度。 接著，本文探索了Daphnodorin C的全合成，分別嘗試了不對(duì)稱環(huán)氧化物開環(huán)和炔的[2+2+2]反應(yīng)構(gòu)建A環(huán)的合成路線，但由于路線中間體收率過低等原因以失敗告終，本文最終未能完成Daphnodorin C的合成工作。通過以上兩條路線的嘗試，提示我們Daphnodorin C的合成路線設(shè)計(jì)應(yīng)盡量避免大位阻取代基團(tuán)的使用、未來的合成路線設(shè)計(jì)應(yīng)以解決含氧螺環(huán)核心結(jié)構(gòu)的方法學(xué)研究為前提。 最后，本課題探索出了有位阻取代基取代的芳基碘代物的硼酸酯化反應(yīng)條件，能夠高效合成硼酸酯取代的黃酮和三烷氧基取代苯，并通過探索連接方式相同的3,8″-雙芹菜素的合成來指導(dǎo)Daphnodorin D的合成。我們選擇位阻小的碘代查爾酮與硼酸酯取代的苯乙酮經(jīng)Suzuki偶聯(lián)、Claisen Schmidt縮合、選擇性脫保護(hù)、碘調(diào)節(jié)的關(guān)環(huán)等反應(yīng)，首次完成了3,8″-雙芹菜素的全合成；并以相同的思路構(gòu)建了Daphnodorin D的核心骨架。 在Daphnodorin類化合物的合成研究過程中，本課題開發(fā)了Luche還原法還原α,β-不飽和乙�；蛹姿嵋阴碇苽�2-烯丙基酚的合成方法。該方法為黃烷醇及Daphnodorin類雙黃酮合成中的關(guān)鍵中間體2-烯丙基酚類化合物的高效合成提供了新方法；同時(shí)，本文開發(fā)出一種Pd(PPh3)4催化的酰氯與原位生成的炔基鋅衍生物偶聯(lián)合成呋喃雙黃酮構(gòu)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 偽, 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.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R914.5

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