Mimicry of the proton wire mechanism of enzymes inside a supramolecular capsule enables β-selective O-glycosylations

Enzymes achieve high substrate and product selectivities by orientating and activating the substrate(s) appropriately inside a confined and finely optimized binding pocket. Although some basic aspects of enzymes have already been mimicked successfully with man-made catalysts, substrate activation by proton wires inside enzyme pockets has not been recreated with man-made catalysts so far. A proton wire facilitates the dual activation of a nucleophile and an electrophile via a reciprocal proton transfer, enabling highly stereoselective reactions under mild conditions. Here we present evidence for such an activation mode inside the supramolecular resorcin[4]arene capsule and demonstrate that it enables catalytic and highly β-selective glycosylation reactions—still a major challenge in glycosylation chemistry. Extensive control experiments provide very strong evidence that the reactions take place inside the molecular container. We show that this activation strategy is compatible with a broad scope of glycoside donors and nucleophiles, and is only limited by the cavity size. Proton wires in enzyme active sites enable stereoselective reactions under mild conditions by facilitating dual activation of a nucleophile and an electrophile through reciprocal proton transfer. Now it has been shown that such an activation mode can be mimicked inside a supramolecular capsule, enabling a general approach to β-glycosides.