Abstract
Glycosyl cations are the key intermediates during the glycosylation reaction that covalently links building blocks during the synthetic assembly of carbohydrates. The exact structure of these ions remained elusive due to their transient and short-lived nature. Structural insights into the intermediate would improve our understanding of the reaction mechanism of glycosidic bond formation. Here, we report an in-depth structural analysis of glycosyl cations using a combination of cold-ion infrared spectroscopy and first-principles theory. Participating C2 protective groups form indeed a covalent bond with the anomeric carbon that leads to C1-bridged acetoxonium-type structures. The resulting bicyclic structure strongly distorts the ring, which leads to a unique conformation for each individual monosaccharide. This gain in mechanistic understanding fundamentally impacts glycosynthesis and will allow to tailor building blocks and reaction conditions in the future.
Highlights
The glycosylation reaction follows, for the most part, a textbook SN1 mechanism that proceeds via a carbocation intermediate
Structural details concerning the exact type of interaction, which could range between oxocarbenium-type and acetoxonium-type ions have remained elusive (Fig. 1)
The experimental setup where m/z-selected ions generated by nanoelectrospray ionization are accumulated in a hexapole ion trap and picked up by superfluid helium droplets traversing the trap was described previously[9,11]
Summary
The glycosylation reaction follows, for the most part, a textbook SN1 mechanism that proceeds via a carbocation intermediate. C2 acyl groups such as 2-O-acetyl or 2-O-benzoyl interact with the anomeric carbon and promote the formation of 1,2-trans-glycosidic linkages. The interaction of participating groups with the anomeric carbon of a glycosyl cation is expected to substantially influence the ring conformation and in turn impact the kinetics and stereochemical outcome of the reaction[7,8]. The structures of three glycosyl cations of C2-acetylated and C3-, C4-, C6-methylated D-glucopyranose, D-mannopyranose, and D-galactopyranose (Supplementary Note 1) are determined in detail by cold-ion infrared spectroscopy. The glycosyl donors to be structurally examined were designed to decouple cation formation from other factors such as the influence of other participating or bulky protecting groups. Resolved IR spectra confirm the covalent character of participating group interactions with the anomeric carbon and pinpoint the structural details of glycosyl cations such as ring puckering
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