1-Picolinyl-5-azido Thiosialosides: Versatile Donors for the Stereoselective Construction of Sialyl Linkages

With the picolinyl (Pic) group as a C-1 located directing group and N₃ as versatile precursor for C5-NH₂, a novel 1-Pic-5-N₃ thiosialyl donor was designed and synthesized, based on which a new sialylation protocol was established. In comparison to conventional sialylation methods, the new protocol exhibited obvious advantages, including excellent α-stereoselectivity in the absence of a solvent effect, broad substrate scope encompassing the challenging sialyl 8- and 9-hydroxy groups of sialic acid acceptors, flexibility in sialoside derivative synthesis, high temperature tolerance and easy scalability. In particular, the applicability to the synthesis of complex and bioactive N-glycan antennae when combined with the MPEP glycosylation protocol via the “latent-active” strategy has been shown. Mechanistically, the excellent α-stereoselectivity of the novel sialylation protocol could be attributed to the dramatic electron-withdrawing effect of the protonated Pic groups, which was supported by control reactions and DFT calculations.