The broad application of well-defined synthetic oligosaccharides in glycobiology and glycobiotechnology is largely hampered by the lack of sufficient amounts of synthetic carbohydrate specimens. Insufficient knowledge of the glycosylation reaction mechanism thwarts the routine assembly of these materials. Glycosyl cations are key reactive intermediates in the glycosylation reaction, but their high reactivity and fleeting nature have precluded the determination of clear structure–reactivity-stereoselectivity principles for these species. We report a combined experimental and computational method that connects the stereoselectivity of oxocarbenium ions to the full ensemble of conformations these species can adopt, mapped in conformational energy landscapes (CEL), in a quantitative manner. The detailed description of stereoselective S N 1-type glycosylation reactions firmly establishes glycosyl cations as true reaction intermediates and will enable the generation of new stereoselective glycosylation methodology.

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The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an a,b unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR-based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen-containing C-aryl glycosides and C-alkyl glycosides under superacid and flow conditions, respectively.

An expansive NMR-based structural analysis of elusive glycosyl cations derived from natural and non-natural monosaccharides in superacids is disclosed. Forthe first time,it has been possible to explore the consequence of deoxygenation and halogen substitution at the C2 position in as eries of 2halogenoglucosyl, galactosyl, and mannosyl donors in the condensed phase.T hese cationic intermediates were characterizedu sing low-temperature in situ NMR experiments supported by DFT calculations.T he 2-bromo derivatives displayi ntramolecular stabilization of the glycosyl cations. Introducing as trongly electron-withdrawing fluorine atom at C2 exerts considerable influence on the oxocarbenium ion reactivity.I nasuperacid, these oxocarbenium ions are quenched by weakly coordinating SbF 6 À anions,t hereby demonstrating their highly electrophilic character and their propensity to interact with poor nucleophiles.

The Mukaiyama aldol reaction has been used to efficiently install a lateral chain at the C-9 position of the Wieland-Miescher ketone derivative 3 within two steps, representing a shortcut compared to that of the classical sequences. The treatment of the silylated enol ether 8 with a wide range of acetals in the presence of tin tetrachloride led to a the diastereoselective construction of the C-9 quaternary center of 33 new building blocks derived from the Wieland-Miescher ketone derivative 3.

The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an a,b unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR-based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen-containing C-aryl glycosides and C-alkyl glycosides under superacid and flow conditions, respectively.