Direct functionalization of unprotected carbohydrates <i>via</i> anomeric <i>N</i>-linkages to produce glycan probes.

Abstract

Carbohydrates are essential to many processes of life, but the biological activities of these biomolecules remain difficult to discern due to their complex and heterogeneous structures. Chemically defined glycan probes have been invaluable for establishing structure-function relationships that explain these activities. Nevertheless, probe production by de novo carbohydrate synthesis is challenging due to the lack of universal methods for glycan assembly. Here, we describe methods to access glycan probes through the direct functionalization of unprotected, reducing sugars at their anomeric position using nitrogen nucleophiles. We outline how reductive amination, amidation, hydrazide condensation, hydroxylamination, and azidation enable rapid N -functionalization with moderate to high chemo- and stereoselectivity. Using both classical and modern examples, we highlight how this large collection of distinct mono- and oligosaccharide probes enables the detection, modification, and isolation of glycan-binding proteins. Overall, these methods for glycan probe development, along with new approaches to expedite the production of reducing sugars, provide a strong complement to bottom-up glycan synthesis and continue to improve accessibility for these important tool compounds across the broader scientific community.

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