Characterization of elusive rhamnosyl dioxanium ions and their application in complex oligosaccharide synthesis.

Attaining complete anomeric control is still one of the biggest challenges in carbohydrate chemistry. Glycosyl cations such as oxocarbenium and dioxanium ions are key intermediates of glycosylation reactions. Characterizing these highly-reactive intermediates and understanding their glycosylation mechanisms are essential to the stereoselective synthesis of complex carbohydrates. Although C-2 acyl neighbouring-group participation has been well-studied, the reactive intermediates in more remote participation remain elusive and are challenging to study. Herein, we report a workflow that is utilized to characterize rhamnosyl 1,3-bridged dioxanium ions derived from C-3 p-anisoyl esterified donors. First, we use a combination of quantum-chemical calculations and infrared ion spectroscopy to determine the structure of the cationic glycosylation intermediate in the gas-phase. In addition, we establish the structure and exchange kinetics of highly-reactive, low-abundance species in the solution-phase using chemical exchange saturation transfer, exchange spectroscopy, correlation spectroscopy, heteronuclear single-quantum correlation, and heteronuclear multiple-bond correlation nuclear magnetic resonance spectroscopy. Finally, we apply C-3 acyl neighbouring-group participation to the synthesis of complex bacterial oligosaccharides. This combined approach of finding answers to fundamental physical-chemical questions and their application in organic synthesis provides a robust basis for elucidating highly-reactive intermediates in glycosylation reactions.

Detection and Characterization of Rapidly Equilibrating Glycosylation Reaction Intermediates Using Exchange NMR.

The stereoselective introduction of glycosidic bonds (glycosylation) is one of the main challenges in the chemical synthesis of carbohydrates. Glycosylation reaction mechanisms are difficult to control because, in many cases, the exact reactive species driving product formation cannot be detected and the product outcome cannot be explained by the primary reaction intermediate observed. In these cases, reactions are expected to take place via other low-abundance reaction intermediates that are in rapid equilibrium with the primary reaction intermediate via a Curtin-Hammett scenario. Despite this principle being well-known in organic synthesis, mechanistic studies investigating this model in glycosylation reactions are complicated by the challenge of detecting the extremely short-lived reactive species responsible for product formation. Herein, we report the utilization of the chemical equilibrium between low-abundance reaction intermediates and the stable, readily observed α-glycosyl triflate intermediate in order to infer the structure of the former species by employing exchange NMR. Using this technique, we enabled the detection of reaction intermediates such as ß-glycosyl triflates and glycosyl dioxanium ions. This demonstrates the power of exchange NMR to unravel reaction mechanisms as we aim to build a catalog of kinetic parameters, allowing for the understanding and eventual prediction of glycosylation reactions.