An Orthogonal ‘Clickable’ Xyloside Scaffold in 4C1 and 1C4 Conformation

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Abstract
Glycoclusters are important molecular tools for studying carbohydrate–protein interactions. It is advantageous to derive glycoclusters from carbohydrate-based scaffolds. Modulating the chair conformation of the scaffolding monosaccharide between 4C1 and 1C4 enables the variation in the spatial organisation of the resulting glycoclusters, allowing the consequences for carbohydrate recognition in biological systems to be studied. Recently, we introduced a xylose derivative capable of adopting two complementary chair conformations, which was conjugated to glycoligands via Suzuki–Miyaura cross-coupling to afford homobivalent glycoclusters. Here, we expand this approach by further exploring the potential of xylose as a conformationally ‘switchable’ carbohydrate scaffold. Two additional features were introduced, (i) alkyne groups to facilitate conjugation reactions through click chemistry, and (ii) orthogonal protection to enable the synthesis of heterobivalent glycoclusters in addition to homobivalent analogues. This strategy enabled the synthesis of a focused library of homo- and heterobilvalent glycoclusters, which were subjected to preliminary biological evaluation. Notably, inversion of the chair conformation of the xyloside scaffold exerted a significant effect on the potency of the respective compounds as inhibitors of mannose-specific bacterial adhesion.

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