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系統識別號 U0007-1704200714554160
論文名稱(中文) Denbinobin 簡捷合成之研究
論文名稱(英文) A Concise Synthesis of Denbinobin
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 93
學期 2
出版年 94
研究生(中文) 王郁傑
研究生(英文) Yu-Chieh Wang
學號 M301092010
學位類別 碩士
語文別 中文
口試日期
論文頁數 105頁
口試委員 指導教授-陳繼明
中文關鍵字 Denbinobin  選擇性  催化劑  化合物  總產率  衍生物 
英文關鍵字 Denbinobin 
學科別分類
中文摘要 Denbinobin(1),為一種phenanthrene quinone 結構的天然物,其最早被發現於Dndrobium nobile 的成分之中。而最近有報導指出denbinobin(1)具有抗氧化、抗血小板凝聚、抗發炎以及抗惡性腫瘤方面的活性,為提供本化合物對其藥理作用機轉之探討,並進一步製備並研究其衍生物及類似物。本研究係先行設計一種化學全合成的簡捷方式以取得此天然物。在化學合成上,我們選擇以市售的2-bromoisovanillin(22)為起始物,進行七步反應以得到denbinobin(1)。首先,我們先將起始物2-bromoisovanillin(22)的OH基接上TBDMS保護基,並另將3,5-dimethoxybenzyl bromide(17)接上triphenyl- posphine形成phosphonium ylide 18,然後兩者以Wittig反應結合,得到olefins trans-24及cis-25。接著對cis-25以Bu3SnH/AIBN進行自由基環化反應形成化合物26,再以TBAF摘除先前的保護基得到化合物27,並以Fremy`s salt作氧化劑形成quinone 11,最後進行TMSI選擇性的去甲基反應而得到denbinobin(1),總產率為15 %。其中,以AIBN作催化劑而使用Bu3SnH進行自由基環化反應,與以Fremy`s salt氧化形成quinone結構為此一denbinobin(1)合成之重要關鍵化學反應。
英文摘要 Denbinobin(1) containing an phenanthrene quinone skeleton is a minor constituent isolated from Dendrobium nobile. Previous studies indicated that denbinobin(1) exhibited anti-inflammatory activity, anti-oxidant, anti-platelet aggregation and anti-tumor activity in vitro and in vivo. In order to prepare denbinobin analogs for structure -activity relationship and action mechanism studies, a concise synthesis of denbinobin(1) is developed in this research. Denbinobin(1) is prepared in 7 steps from two commercial available starting materials, 2-bromoisovanillin (22) and 3,5- dimethoxybenzyl bromide (17). The hydroxyl group of 22 was protected by treating with TBDMSCl to yield the protected 23. 3,5-Dimethoxybenzyl bromide (17) was reacted with triphenylposphine to form phosphonium ylide 18. By using Witting reaction, Compound 23 was reacted with 18 in thepresence of n-butyllithium to produce a mixture of olefins ,trans-24 and cis-25. The cis-25 isomer was treated with Bu3SnH/AIBN to form the desired phenanthrene 26. The TBDMS-protecting group of 26 was removed by tetra-n-butylammonium fluoride (TBAF) to yield 27, which was then oxidized to the phenanthrene- quinone 11 by Fremy`s salt. Finally, Compound 11 was selective demethyled with trimethylsilyl iodide (TMSI) to form denbinobin(1). The total yield of denbinobin(1) synthesis in the present study was 15 %.
論文目次 目錄 頁次 目錄...........................................................Ⅰ 流程目錄.......................................................Ⅳ附表目錄.......................................................Ⅴ 附圖目錄.......................................................Ⅵ中文摘要.......................................................Ⅷ 英文摘要.......................................................Ⅹ壹、緒論.........................................................1 一、前言.....................................................1 二、臨床之抗癌藥物...........................................3 三、癌症與細胞週期(cell cycle)................................5 四、微小管(microtubules).....................................8 五、作用於微小管之抗癌藥物...................................9 六、Denbinobin(1)之化學及藥理作用...........................10 七、研究目的................................................16 貳、結果與討論..................................................19 一、Denbinobin(1)之全合方法成回顧...........................19 (一)、經P4-tBu為催化劑進行分子內環化反應.................20 (二)、以Diels-Alder reaction進行環化反應.................23 二、Denbinobin(1)逆合成之設計...............................25 (一)、PIFA mediated intramlecular cyclization..............26 (二)、Bu3SnH/AIBN intrmolecular cyclization...............28 三、Denbinobin(1)之簡捷合成方法.............................33 (一)、以PIFA進行分子內環化反應...........................36 (二)、以Bu3SnH/AIBN進行分子內自由基環化之一..............37 (三)、以Bu3SnH/AIBN進行分子內自由基環化之二..............38 四、結論....................................................49 參、實驗部分....................................................52 一、實驗儀器................................................52 二、試藥及試劑..............................................54 三、化學合成部份............................................56 1. 3,5-Dimethoxybenzyltriphenylphosphonium bromide(18)...56 2. 2-Bromo-3-(tert-butyldimethylsilanyloxy)-4- methoxybenzaldehyde(23).................................57 3.2-Bromo-3-[2-(3,5-dimethoxyphenyl)vinyl]-6-methoxy- phenoxy-tert-butyldimethylsilane(E-24 ﹠Z-25).........59 4.3,5,7-trimethoxy-4-tert-butyldimethylsilanoxyl phenanthrene(26)......................................62 5.3,5,7-Trimethoxy-4-hydroxyphenanthrene(27)............64 6.3,5,7-Trimethoxy-1,4-phenanthrenequinone(11)..........66 7.5-Hydroxy-3,7-dimethoxy-1,4-phenanthrenequinone (denbinobin)(1).......................................68 肆、參考文獻....................................................70 伍、附圖........................................................77 流程目錄 頁次 流程一、Denbinobin(1)全合成方法(1)..............................20 流程二、化合物6之製備..........................................21 流程三、Denbinobin(1)全合成方法(2)..............................23 流程四、逆合成denbinobin(1)路徑(1)..............................27 流程五、逆合成denbinobin(1)路徑(2)..............................30 流程六、逆合成denbinobin(1)路徑(3)..............................32 流程七、以PIFA環化之denbinobin(1)合成方法......................33 流程八、以Bu3SnH/AIBN環化之denbinobin(1)合成方法(1).............34 流程九、以Bu3SnH/AIBN環化之denbinobin(1)合成方法(2).............35 流程十、化合物24及25之製備與作用機轉...........................39 流程十一、化合物26之製備與其自由基環化反應之作用機.............40 流程十二、化合物11之製備與作用機轉.............................46 流程十三、化合物1之製備與作用機轉..............................48 流程十四、以光化學反應進行trans- 24與cis-25之轉換..............49 附表目錄 頁次 表一、民國92年國人平均每日死亡人數..............................2 表二、數種中草藥成分對k562癌細胞抑制作用之篩選.................18 表三、Bu3SnH/AIBN環化反應條件與產率關係表.......................42 附圖目錄 頁次 圖一、細胞週期(cell cycle).......................................6 圖二、微小管(microtubules)示意圖.................................8 圖三、P4-tBu之化學結構..........................................22 圖四、化合物23之紅外光圖譜.....................................78 圖五、化合物23之氫核磁共振圖譜.................................79 圖六、化合物23之碳核磁共振圖譜.................................80 圖七、化合物24之氫核磁共振圖譜(1)..............................81 圖八、化合物24之氫核磁共振圖譜(2)..............................82 圖九、化合物24之碳核磁共振圖譜.................................83 圖十、化合物25之氫核磁共振圖譜(1)..............................84 圖十一、化合物25之氫核磁共振圖譜(2)............................85 圖十二、化合物25之碳核磁共振圖譜...............................86 圖十三、化合物26之紅外光圖譜...................................87 圖十四、化合物26之氫核磁共振圖譜(1)............................88 圖十五、化合物26之氫核磁共振圖譜(2)............................89 圖十六、化合物26之碳核磁共振圖譜...............................90 圖十七、化合物27之紅外光圖譜...................................91 圖十八、化合物27之氫核磁共振圖譜(1) ............................92 圖十九、化合物27之氫核磁共振圖譜(2) ............................93 圖二十、化合物27之碳核磁共振圖譜...............................94 圖二十一、化合物27之質譜圖.....................................95 圖二十二、化合物11之紅外光圖譜................................. 96 圖二十三、化合物11之氫核磁共振圖譜(1) ..........................97 圖二十四、化合物11之氫核磁共振圖譜(2) ..........................98 圖二十五、化合物11之碳核磁共振圖譜.............................99 圖二十六、化合物11之質譜圖.....................................100 圖二十七、化合物1之紅外光圖譜.................................101 圖二十八、化合物1之氫核磁共振圖譜(1) ..........................102 圖二十九、化合物1之氫核磁共振圖譜(2) ..........................103 圖三十、化合物1之碳核磁共振圖譜...............................104 圖三十一、化合物1之質譜圖.....................................105
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