藉由不對稱Aza-Henry Reaction進行抗流感試劑瑞樂沙及殺流感之全合成

Total Synthesis of Anti-Influenza Agents Zanamivir and Zanaphosphor via Asymmetric Aza-Henry Reaction

林隆誌(Long-Zhi Lin)

指導教授 ： 方俊民

國立臺灣大學/理學院/化學研究所/博士(2017年)

https://doi.org/10.6342/NTU201700686

摘要

流行性感冒一直是很嚴重的健康問題，不論是區域性的或是全球性的大流行，通常都會帶走許多病患的生命以及嚴重導致經濟上的損失。神經胺酸酶(neuraminidase)為病毒表面上重要的膜蛋白，負責切斷宿主細胞與子代病毒的連結，而釋放子代病毒進行其他感染。因此神經胺酸酶抑制劑像是瑞樂沙(zanamivir)、克流感(oseltamivir)與peramivir都被開發出來並廣泛地使用在臨床治療上。也由於克流感的過度使用，近年來已有抗藥性的病毒株產生，因此目前抗藥性較不嚴重的瑞樂沙也成了治療流感病患所必要的藥物。
過去二十多年來，工業上生產zanamivir時，都是利用唾液酸(sialic acid)作為起始物進行合成，但也導致zanamivir的合成途徑無法有更多的改善。像是結構上四號位置的胺基，一直以來僅能藉由疊氮基團的還原來合成，而這樣的方法在進行大量生產時有爆炸的風險。
近年來也有一些新的zanamivir合成方法被開發出來，這些方法雖然都不再以價格較高的唾液酸作為起始物，但不可避免的在部分合成路徑中仍舊有使用到較危險的疊氮試劑。因此我們想要開發出一個不需要經由疊氮試劑的新合成路徑，同時也希望能利用這方法合成出zanaphosphor，其抑制神經胺酸酶的能力更優於zanamivir。
因此在我們的合成工作中，我們使用價格較低的D-glucono-δ-lactone作為起始物，並且藉由手性亞胺化合物的不對稱aza-Henry反應，建構出四號及五號位置上的含氮基團。其中四號位置的胺基是利用硝基的還原來得到，進而避免了疊氮試劑的使用。最後我們成功地開發出新的合成路徑，以建構出帶有許多取代基的二氫吡喃結構，進而合成出zanamivir與zanaphosphor。

關鍵字

流感 ； 瑞樂沙 ； 殺流感 ； 不對稱亨利反應

並列摘要

Seasonal influenza epidemic is a serious health problem to humans. Local and global influenza infections usually claim a vast number of lives and cause huge economic losses. Neuraminidase is an essential glycoprotein on influenza virus membrane responsible for cleaving the binding between newly formed virus particles and the host cells. Neuraminidase inhibitors, such as zanamivir, oseltamivir and peramivir, are widely applied to clinical treatment of influenza patients. Owing to the emergence of oseltamivir-resistant viruses, zanamivir would be indispensable to fight against influenza epidemics.
Over two decades, zanamivir has been prepared from sialic acid in manufacturing process. However, using sialic acid as the starting material also limits the variability of synthetic strategy to construct the densely substituted dihydropyran core structure of zanamivir with five consecutive stereogenic centers. Furthermore, the 4-amino group of zanamivir is only derived by reduction of azide group. Precaution must be taken when using explosive azide reagents.
Recently, some new synthetic methods without using the relatively expensive sialic acid as the starting material have been developed, but the employment of azide reagents still cannot be completely avoided. Therefore, we intended to develop a new azide-free process for the synthesis of zanamivir. Moreover, this process should be applicable to synthesize zanaphosphor, which has been shown to possess higher anti-influenza activity than zanamivir.
In our work, a cost-effective starting material of D-glucono-δ-lactone is employed, and the nitrogen-containing groups at the C4- and C5-positions are installed by asymmetric aza-Henry reaction of a chiral imine. Instead of using azide reagent, the key tactic is to utilize a nitro group as the latent amino group at C4-position. Finally, we successfully developed an efficient way to construct the densely substituted dihydropyran core, and achieved the syntheses of zanamivir and zanaphosphor.

並列關鍵字

influenza ； zanamivir ； zanaphosphor ； asymmetric Aza-Henry reaction

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