| Summary: | 博士 === 國立臺灣大學 === 化學研究所 === 105 === 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.
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