Single and dual glycoside clustering around calix[4]arene scaffolds via click thiol–ene coupling and azide–alkyne cycloaddition (original) (raw)

We present the first synthesis of calix[4]arene-based S-glycoclusters via photoinduced multiple thiol-ene coupling of tetra-and octa-allyl calix[4]arenes with peracetylated glucosyl thiol (67-88% yields). Moreover we describe the dual clustering at the upper and lower rim of a calix[4]arene with two different sugars (galactose and glucose) via sequential copper(I)-catalyzed azide-alkyne cycloaddition and photoinduced thiol-ene coupling. Ever since we reported in the mid-1990s on the first synthesis of calix[4]arene O-glycosides, 1 increasing interest has been focused by us 2 and others 3,4 on multiple glycosylation of calix[4]arene platforms to give glycoclusters. The final goal of those synthetic efforts was the preparation of structurally well-defined clusters to be used as probes in carbohydrate-lectin molecular recognition processes. Thus, in view of the fact that non-natural C-glycosides are impervious toward hydrolytic degradation, 5 subsequent research in our laboratory was carried out on the assembly of calix[4]arene-based C-glycoclusters. Accordingly, we first synthesized compounds in which the carbohydrate fragments were grafted to the macrocycle through a carbon chain formed by Wittig reaction of calix[4]arene aldehydes and sugar phosphoranes. 2c In a second instance we prepared C-glycoclusters via N-heterocycle ring formation, namely tetrazole from thermal azide-nitrile cycloaddition (ANC) 6 and triazole from Cu(I)-catalyzed azidealkyne cycloaddition (CuAAC). 7 Recently, we took advantage of the efficiency of the latter reaction, the quintessential click process, 8 for anchoring up to eight sialyl residues to calix[4]arene scaffolds in a one-pot process. 3 In this case S-sialoclusters were formed because all sialyl residues featured an anomeric thioether linkage. S-Linked glycoconjugates are known to display low susceptibility to enzymatic hydrolysis because the rate of hydrolysis of the thioglycosidic bond by glycohydrolases is several order of magnitudes slower than that of the corresponding O-glycosides. 9 The calix[4]arene-based S-sialoclusters proved to be active at submillimolar concentrations against BK (etiological agent of nephropathies) and influenza A viruses. Hence, giving the need to prepare calix[4]arene-based glycoclusters with robust tethers by the use of simple and efficient ligation reactions, we would like to report here on calixarene glycoclustering through sulfide bridges