Novel Base-Labile Linkers for Convenient Purification and Functional Group Introduction in Solid-Phase Glycan Synthesis

Glycans are essential biomolecules across species, but their structure-property relationships remain poorly understood. Pure oligosaccharide samples are crucial for studying these properties, and their preparation heavily relies on chemical synthesis. The linker used for attaching the oligosaccharide to the solid support is essential during solid-phase glycan synthesis. Here, we present three base-labile linkers compatible with Merrifield resin. The first type of resin, containing a hydroxyhexanoic acid linker, can be prepared in a one-step synthesis and releases glycans with a terminal carboxylic acid after methanolysis and hydrolysis. Linkers on the second and third types of resin can be synthesized through simple chemical reactions and cleaved to reveal either a free reducing end of the oligosaccharide or a terminal amine with a C5-spacer. The phthalate structure in the second and third types of resin is sensitive to sodium methoxide and can also be cleaved during hydrazinolysis. Hydrazinolysis, rather than methanolysis, enables the isolation of oligosaccharide with pivaloyl ester protection and facilitates the purification process compared to partially protected compounds. Using these resins, we prepared nine tetrasaccharides and one octasaccharide, including α (1-6) mannan, α (1-4) glucan, β (1-4) glucan, and β (1-3) glucan. Glycans with terminal functional groups can be converted into glycoconjugates for further applications.