Mechanistic insight into benzylidene-directed glycosylation reactions using cryogenic infrared spectroscopy

The stereoselective formation of 1,2-cis glycosidic linkages is challenging. The currently most widely used strategy for their installation uses 4,6-O-benzylidene-protected building blocks. The stereoselectivity of this reaction is thought to be driven by a covalent intermediate, which reacts via an SN2 mechanism. However, the role of cationic SN1-type intermediates in this reaction is unclear. Here we elucidate the structure of glycosyl cations carrying 4,6-O-benzylidene groups using cryogenic infrared ion spectroscopy and computational methods. The data reveal that the intermediates form anhydro cations, which correlates well with the stereoselective outcome of SN1-type glycosylations. The study highlights how cryogenic infrared spectroscopy can elucidate the role of intermediates in sugar chemistry and how these structural data can be linked to reactions in solution. The role of cationic intermediates in the benzylidene-directed synthesis of 1,2-cis glycosidic linkages is unclear. Now cryogenic infrared spectroscopy provides insight into the SN1 mechanism of benzylidene-directed glycosylation reactions. The analysis reveals that cationic intermediates form anhydro cations through a two-step process, which correlates with the observed stereochemical outcome.