Over the decade, our research group has been focused on the chemical synthesis of highly complex sialic acid-containing glycoconjugates, especially gangliosides. We have achieved the total syntheses of nine gangliosides and the glycan part syntheses of four gangliosides since 2009. Furthermore, we have developed a series of fluorescently labeled gangliosides for the single molecule imaging of gangliosides in cell membranes and revealed specific interactions between gangliosides and proteins during assembly of lipid raft domain. However, the synthesis of sialoglycans remains a challenge primary due to the difficulty of the stereocontrol of sialidation. Very recently, we have developed a robust method for α-sialidation, which ensured the full stereocontrol in a substrate-controlled manner. In this presentation, I will share and discuss outcomes obtained in our study into α-sialidation. To achieve complete stereocontrol, we envisioned harnessing bridgehead cation chemistry for sialidation. A bridgehead oxonium cation of sialic acid would completely restrict the site of nucleophilic attack and provide a strong driving force for glycoside bond formation due to its high potential energy caused by ring strain. Our proof-of-concept study using model bicyclic sialic acid donors revealed that the bicyclo[12.2.2] system produced the α-glycoside with the highest efficiency and complete stereoselectivity. Next, the bicyclic sialic acid donors were modified to ensure the selective opening of the macrocyclic moiety for further modification of the C5 amino group. With the modified donors, we performed α-selective O- and C-glycosidations with coupling partners possessing various levels of complexity. Furthermore, the iterative couplings of bicyclic sialic acid derivatives allowed for the synthesis of oligomeric sialic acid with complete stereoselectivity.

Rewriting the synthesis strategy toward sialic acid-containing glycans

2019 Fall National Meeting

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