Highly efficient α-sialylation with ortho-(1-phenylvinyl)benzoates as leaving groups: One-pot assembly of α-sialoglycans

Sialic acid represents one of the most important monosaccharides in mammals. However, because of the unique structure of sialic acid with the anomeric center flanked by methylene and carboxyl groups, efficient synthetic access to sialoglycans remains a difficult task, thus hindering in-depth biological studies. Here, we report one-pot α-sialylation protocol for efficient synthesis of various α-sialoglycans, using sialyl ortho-(1-phenylvinyl)benzoates (PVB) as donors. This α-sialylation method enjoys broad substrate scope and high yields. In particular, this α-sialylation protocol has been successfully applied in one-pot synthesis of several α-sialoglycans, including bioactive ganglioside Hp-s1 and ST_N antigen with reduced steps and improved efficiency. Furthermore, density functional theory calculations provide the mechanistic insights of much higher reactivity of sialyl PVB donors than the corresponding thiosialoside donors in the presence of N-iodosuccinimide (NIS) and trifluoromethanesulfonic acid (TfOH). The enhanced reactivity arises from favorable noncovalent interactions and effective stabilization of the carbocation intermediate by the two phenyl groups within the PVB moieties.