The oligo- (poly-) sialic acids formed by α(2,8)-linkages are involved in various biological events in nerve tissues. To elucidate their biological roles, the chemical synthesis of α(2,8)-linked oligo-sialic acids is of great importance. However, it remains a challenge due to the difficulty of α-selective sialylation at poorly reactive C8 hydroxyl of sialic acid, which is affected by the hydrogen bonding with the acetamide group at the C5 position. Very recently, we have developed a complete stereoselective glycosidation method using macrobicyclic sialic acid donors as synthetic equivalent of the bridgehead oxonium cation, in which the C1 and C5 positions were tethered with an alkyl chain. In this study, we have extended our methodology to the synthesis of α(2,8)-linked oligo-sialic acids. Previously, we have shown that the reactivity of the C8 hydroxyl of sialic acid was ameliorated by forming a lactam at the C1 and C5 positions, which allowed for α(2,8)-linkage formation. Based on this result, we designed a macrobicyclic sialyl acceptor, which was expected to be less likely prone to hydrogen bonding between the C8 hydroxyl and the C5 amino groups. To ensure the conversion into a sialyl acceptor after glycosidation, chloroacetyl (CAc) groups were chosen as transient protecting groups for both C7 and C8 hydroxyl groups. To prepare a bicyclic sialic acid, a C5-NH2 intermediate was conjugated with a tether part, which then underwent Shiina’s macrolactonization reaction to provide 7,8-di-O-CAc bicyclic donor. The bicyclic donor was glycosidated with a Gal acceptor, followed by removal of CAc groups with 1-selenocarbamoylpiperidine, giving a 7,8-OH acceptor. The glycosidation of the bicyclic donor with the 7,8-OH bicyclic acceptor in CH2Cl2 produced a sialic acid dimer in 95% yield with complete stereoselectivity. The result strongly demonstrated a high reactivity of the C8 hydroxyl of the bicyclic acceptor. The sialic acid dimer was then successfully converted into a 7,8-OH glycosyl acceptor again by selective removal of CAc groups in high yield. Repeating the cycle of sialylation (~95% yield) and selective removal of CAc groups (~96% yield) three times, a pentasialoside was synthesized in high overall yield. Finally, selective cleavage of the tether parts with Zn in AcOH provided a corresponding C5-NH2 intermediate quantitatively, which was followed by the global deprotection to deliver a α(2,8)-linked pentasialoside.

Stereoselective synthesis of α(2,8)-linked oligo-sialic acids using bicyclic sialic acids

2019 Fall National Meeting

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