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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10011
標題: | 由D-絲胺酸進行克流感合成之探討 Study of Oseltamivir Synthesis from D-Serine |
作者: | Joshua Lai 賴怡禎 |
指導教授: | 方俊民(Jim-Min Fang) |
關鍵字: | 克流感,流感病毒,唾液酸水解酶,抑制劑, Tamiflu,Oseltamivir,Influenza,Neuraminidase, |
出版年 : | 2011 |
學位: | 博士 |
摘要: | 近來,新型流感數度襲捲全球,除了導致嚴重的經濟衝擊,更造成大量無辜生命的喪失。由於流感能藉由兩種主要的突變路徑---抗原漂移 (antigen drift) 及抗原轉移 (antigen shift) 來達到產生高致病性的新型流感病毒,因此人類缺乏對於這種新型流感的免疫能力,這樣不對等的關係也造成了整個社會的恐慌。
在過去的一些研究中,Hoffmann La-Roche Ltd. 及 GlaxoSmithKline 分別開發出針對唾液酸水解酶 (Neuraminidase) 的抑制劑---克流感 (Tamiflu) 及瑞樂沙 (Relenza),這兩種藥物藉由設計成模擬唾液酸水解酶的受質被水解時的過渡態,使得病毒即便在感染宿主細胞後,也無法順利的將其子代釋出,進而造成病毒的凋亡。然而由於瑞樂沙的分子設計,使得它的口服可利用率相當的低,它通常以鼻吸劑的方式被使用,這樣的方式對於年長者及嬰幼兒來說都相當不方便,因此克流感成為目前唯一可口服的唾液酸水解酶抑制劑,在克流感的工業法合成上是以莽草酸 (Shikimic acid) 為起始物,但是莽草酸取得主要是透過八角這一類天然草藥的萃取,由於對有限的天然草藥的依賴,使得此工業合成方式無法滿足在流感大爆發期間的需求。 為了滿足這樣的需求,我們嘗試開發出一個以可大量取得的原料為起始物的合成方法,藉由逆合成分析克流感的有效藥物成份---奧司他偉 (oseltamivir) 的結構,我們推導出一個以 D-絲胺酸為起始物的合成方法,經由環閉合置換來建構環己烯及共軛酯基的中心骨架,並利用 D-絲胺酸上的掌性中心來建構在奧司他偉上另外兩個掌性中心。 在這個合成方法中我們成功整合了以下幾個關鍵性步驟: (a) 透過 Zn2+ 與 Garner's 醛螯合作用的乙烯基加成, (b) 利用銦來促使丙烯酸基進行 Reformatsky 反應,以及 (c) 環閉合置換反應。 Recently, influenza has just swept worldwide and resulted in a severe crisis to human beings. Taking advantage of two mutation mechanisms---antigenic drift and antigenic shift, influenza virus can generate hybrid and highly pathogenic strains. The lack of immunities to these new influenza strains poses human into an unequal battle and even causes a worldwide panic. Hoffmann La-Roche Ltd. and GlaxoSmithKline have developed two neuraminidase inhibitors---Tamiflu and Relenza against influenza virus. By mimicking the transition state of neuraminidase in the cleavage of sialic acid, these two drugs can block the release of the budding progenitors of influenza virus. However, the oral bioavailability of Relenza is relatively low due to the highly polar functionalities. The administration of Relenza is therefore limited in nasal inhalation which is not convenient to the elders and the infants. As a result, Tamiflu is the only orally available drug in the treatment of influenza virus. The industrial manufacture of oseltamivir, the active pharmaceutical ingredient of Tamiflu, starts from shikimic acid, which is mainly produced by extraction of star anise, a natural herb. When there were a pandemic, the limited resource of natural herb may not satisfy the demand for manufacturing oseltamivir in sufficient amount. For this reason, we design a new synthetic route to oseltamivir using commercially available D-serine as the starting material. The stereogenic center of D-serine not only controls the syn stereochemistry in the vinyl addition to Garner's aldehyde but also secures the three consecutive chiral centers in anti--anti relationship for oseltamivir. In this synthesis, we successfully integrate the following key reactions: (a) Zn2+ chelated vinyl addition to Garner's aldehyde, (b) indium promoted Reformatsky reaction of $alphaup$-(bromomethyl)acrylate in aqueous media, and (c) ring-closure metathesis. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/10011 |
全文授權: | 同意授權(全球公開) |
顯示於系所單位: | 化學系 |
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