Photo-mediated One-Pot Glycosylation-Deprotection-Glycosylation Strategy for Synthesis of Histo-blood Group Antigens

Abstract

Glycans that are widely distributed in nature possess diverse biological activities. However, the inherent structural microheterogeneity of natural glycans impedes their functional evaluation. Chemical glycosylation serves as a powerful approach to access well-defined complex glycans for structure-activity relationship studies. In particular, one-pot multistep glycosylation enables the efficient assembly of complex glycans by eliminating intermediate purification and minimizing protecting-group manipulations. Nevertheless, a key limitation of this traditional approach is its inefficient late-stage coupling, which might result in the loss of valuable advanced donors. Here, we developed a photolabile ester-mediated one-pot glycosylation–deprotection–glycosylation strategy for the rapid assembly of both linear and branched oligosaccharides. Based on the photolabile ortho-nitro-benzyloxycarbonyl (oNBC) ester-mediated one-pot strategy from the reducing end to non-reducing end, efficient and stereoselective synthesis of oligomannoside, oligofucoside, and five types of HBGAs including A_tri, B_tri, H1, H3 and Le^b antigens was achieved. Various glycosyl leaving groups including ynenoates, trichloroacetimidates, N-phenyl trifluoroacetimidates, and thioglycosides were successfully employed in these photo-mediated one-pot reactions, with solvent and temperature identified as critical factors for stereoselective glycosidic bond formation. In contrast to the photolabile o-nitrobenzyl (oNB) group, the photolabile oNBC group could be readily introduced on the primary and secondary hydroxyls of sugar building blocks under mild basic conditions, which were fully compatible with common ester protecting groups. When installed at the C-2 position of glycosyl donors, the oNBC group typically favored the formation of β-glycosidic bonds. The binding results indicated that the H1 receptor exhibited superior binding to norovirus-like particles relative to the H3 receptor, thereby serving as a valuable tool for assessing norovirus vaccine-elicited antibodies. The photolabile ester-mediated one-pot strategy provides a versatile platform for the streamlined assembly of architecturally complex and branched glycans.

Keywords

Glycosylation / Oligosaccharides / Glycans / Glycosides / One-pot synthesis / Photolabile group / Norovirus / Histo-blood group antigens

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