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標題: | 經由一鍋化途徑合成神經胺酸酶抑制劑「零流感」 Synthesis of Anti-Influenza Neuraminidase Inhibitor Tamiphosphor by “One-Pot” Sequence |
作者: | Yi-Wei Lo 羅翊瑋 |
指導教授: | 方俊民(Jim-Ming Fang) |
關鍵字: | 有機催化劑,不對稱合成,零流感,一鍋化合成途徑, organocatalyst,asymmeric synthesis,tamiphosphor,one-pot synthesis, |
出版年 : | 2013 |
學位: | 碩士 |
摘要: | 流行性感冒對人類的健康造成極大的威脅,近幾年來曾爆發出H5N1禽流感且2013年也出現H7N9新型流感,而在克流感普遍地被用來抑制流感病毒後,目前也出現了因服用克流感所產生的抗藥性危機。因此,開發出新型的藥物以對抗流感病毒是目前相當重要的課題。
我們實驗室透過將克流感的羧酸置換成磷酸,以提昇對神經胺酸酶活性區域中S1位置上三組精胺酸(Arg118、Arg292、Arg371)的作用力,而活性測試結果也顯示零流感(tamiphosphor)有相當大的潛力開發做為新一代的流感抑制劑。然而在過往我們使用D-木醣與二羥基環己二烯作為起始物的合成途徑,在進行大量化的開發時卻不如預期中容易。 2012年,Lu教授的研究團隊發表了透過兩個一鍋化途徑進行克流感的合成,且總產率高達35%。因此,本論文以一鍋化的合成途徑提昇合成效率來進行零流感的合成,而為了證明文獻中一鍋化合成策略的可行性,我們首先成功地驗證了Lu教授研究團隊所提供之以一鍋化合成克流感的策略,再根據此一鍋化的策略對零流感進行合成上的分析。使用磷試劑103作為Michael acceptor,以利接續進行分子內的Horner–Wadsworth–Emmons合環反應,完成three-component coupling反應,並於環己烯結構中引入磷脂基,成功的合成出化合物104。而在此關鍵步驟中,我們也意外地發現於硝基位置上同時發生了nitro-Michael反應而得到相當多量的副產物119。為了解決此問題,我們透過於反應過程中加入NaOEt,進行retro-Michael反應,讓副產物119成功地轉為化合物104。接著進行硝基還原並對胺基進行保護,完成一鍋化的合成操作,成功的合成出磷酯化合物93,而文獻63已報導使用TMSBr對磷酯基進行水解並完成去Boc保護後,即可完成零流感的合成。 因此,我們認為以一鍋化的合成途徑可以進行零流感的大量合成,亦有機會作為工業上的製程,以協助開發零流感成為新的抗流感藥物。 Influenza remains a major health problem. The recent emergence of H7N9 influenza and H5N1 avian flu has caused serious concern of the potential for global influenza pandemics. Tamiflu is the most widely-used drug for treatment of influenza infection; however, the drug resistant has emerged. Thus, development of new influenza inhibitors is urgently needed. Our team has recently reported that tamiphosphor is a promising drug against both avain and human influenza. Tamiphosphor, designed by replacing the carboxyl group in oseltamivir with a phosphonate group, interacts strongly with the three arginine residues (Arg118, Arg292, and Arg371) in the active site of neuraminidases of H1N1 and H5N1 viruses. D-Xylose and bromoarene cis-1,2-cyclohexadienediol as starting materials to synthesize tamiphosphor. However, some problems were encountered when we tried to synthesize this drug in large scale. In 2012, Lu and coworkers have accomplished an efficient asymmetric total synthesis of oseltamivir by two one-pot reaction sequences in 35% overall yield. Based on this simple and high-yielding synthetic strategy, we first validated the synthetic strategy of Lu’s team, and then undertook the synthesis of tamiphosphor. We used vinyl phosphonate 103 as the Michael acceptor for a three-component coupling reaction, followed by an intramolecular Horner–Wadsworth–Emmons reaction to construct the cyclohexene phosphonate 104. Unexpectedly, we also got an appreciable amount of side product 119. Fortunately, we found that addition of NaOEt rendered a retro-Michael reaction for effective conversion of 119 to the desired product 104 in the one-pot process. After reduction of the nitro group, the amine intermediate was directly protected as an NHBoc group, giving 93. According to literature63, treatment of 93 with trimethylsilyl bromide would afford tamiphosphor by hydrolysis of the phosphonate group with concomitant removal of the Boc group. Thus, this one-pot synthesis of phosphonate 93 might be suitable for synthesis of tamiphosphor in large scale and will be useful for the development of anti-influenza drugs. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/61397 |
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