Development of water-soluble tetravalent glycoclusters based around a calix[4]resorcinarene core

Abstract

Calix[4]resorcinarenes functionalised with glycosidic ligands on their lower rim have received little interest compared to analogues bearing carbohydrates on the upper rim. In this study, series of novel macrocyclic glycoclusters bearing mono- or disaccharides on the lower rim of a calix[4]resorcinarene core were prepared. Calix[4]resorcinarenes can exist as conformational isomers so each glycocluster was isolated and characterised as the pure conformer, where possible.
Amongst the distinct features of this work is that Lewis acid catalysis was used for the synthesis of calix[4]resorcinarenes by condensation of resorcinol, or its 2-substitued analogues, with an aldehyde. Also, rather than linking the glycosidic moieties to the pre-formed calix[4]resorcinarene, the glycosidic aldehydes were assembled prior to condensation with the resorcinols. Significantly, acylation of the glycoclusters facilitated separation of each conformational isomer.
Amongst the aldehydes used for condensation were glycosylated derivatives of hydroxybenzaldehydes, compounds with a short alkyl spacer between the glycosidic aryl moiety and the aldehydic carbonyl group, and a number with an alkyl or polyether spacer that did not contain any aryl group. Following a study of the condensation products from the reaction of each series of aldehydes with resorcinol, 2-methylresorcinol or pyrogallol it became clear that the distribution of conformational isomers could be predicted, influenced greatly by the properties of the starting materials.
Finally, it was demonstrated that deprotection of a conformational isomer obtained during the initial studies gave a glycosylated calix[4]resorcinarene which is fully soluble in aqueous media. Such compounds may have great potential in solubilisation and the formulation of hydrophobic drugs.