Nachweis des entfernten Nachbargruppeneffekts in Glykosylierungen durch kalte Infrarotspektroskopie

Controlling the stereochemistry during glycosynthesis is usually achieved by using elaborate protecting group techniques. For example, 1,2-trans-glycosidic bonds are formed by the introduction of participating protecting groups at the neighboring C2-position. This reaction is believed to proceed via a glycosyl cation, where the protecting group interacts with the positive charge at the anomeric carbon, effectively shielding the cis-side from nucleophilic attack, leading to the concept of neighboring group participation. The formation of 1,2-cis-glycosidic bonds remains, however, a major hurdle to date. Empirical studies have shown that their formation can be aided by the introduction of participating protecting groups at the remote C4- or C6-positions, leading to the phenomenon of remote participation. Due to the short-lived nature of glycosyl cations, they cannot be studied readily in the condensed phase. The gas-phase environment inside a mass spectrometer, however, can be used to isolate them. In a recent publication, cryogenic infrared spectroscopy was used to unravel the structure of glycosyl cations. Evidence for the existence of neighboring group participation was found in various monosaccharide building blocks, as the acetyl protecting group at the C2-position forms a covalent bond with the anomeric carbon. While these results enable a better understanding of neighboring group participation, the structural motifs underlying remote participation remain poorly understood. Their study would help optimizing reaction conditions aiding the formation of 1,2-cis-glycosidic bonds. Here, a combination of first-principles theory and cryogenic infrared spectroscopy in the low-temperature environment of superfluid helium droplets (0.4 K) is used to decipher the structure of galactose building blocks exhibiting remote participation. Galactose building blocks carrying an acetyl protecting group at the C4-position form α-selective dioxolenium-type structures, exhibiting a covalent bond between the anomeric carbon and the oxygen atom of the carbonyl group of the acetyl protecting group. Contrary, galactose carrying an acetyl group solely at the C6-position does not exhibit remote participation and forms non-selective oxocarbenium-type structures. Furthermore, a novel type of interaction between benzyl protecting groups and the anomeric carbon, leading to α-selective oxonium-type structures, is observed. The recorded data can be used by algorithms based on artificial intelligence to predict the best reaction conditions for performing glycosylation reactions with a defined stereochemical outcome