Paul B. White

The stereoselective synthesis of 1,2‐ cis glycosidic bonds is a significant challenge in carbohydrate chemistry. 1,2‐ Cis galactosides can be obtained by using C‐4 acyl protection groups as a stereodirecting group, yet the underlying mechanism that steers selective galactosylation has remained elusive. Herein, we investigate the stereodirecting effect of C‐4 acyl groups in galactosides using glycosylation reactions, exchange NMR spectroscopy and DFT‐calculations. We found no experimental evidence for C‐4 dioxepanium ion formation through C‐4 acyl neighboring group participation. Instead, β‐glycosyl triflates were detected using exchange NMR which could afford α‐galactosides via S _N 2‐like displacement. Computational studies of the product‐forming transition state geometries reveal that the C‐4 benzoate group shields the β‐face of the galactosyl donor, thereby disfavoring reactions that proceed via the α‐glycosyl triflate pathway. These findings can explain the stereodirecting effect of C‐4 acyl groups on galactosyl donors, and provides fundamental insights for the development of stereoselective glycosylation methods in the future.

The stereoselective synthesis of glycosidic bonds can be promoted by the addition of stereodirecting solvents. In particular, nitrile and ether based solvents are known to promote the selective production of β- or α-glycosides, respectively. Even though the application of co-solvents in glycosylation protocols is well-established, the understanding of their impact on the glycosylation mechanism as well as the reaction intermediates formed upon their addition, remains incomplete. As the exact mechanism of solvent stereo direction remains debated, this limits the ability to develop stereoselective glycosylation methods. Herein, we report the application of relaxation and exchange NMR techniques to establish that acetonitrile and tetrahydrofuran form covalent glycosyl-nitrilium and glycosyl-oxonium ions, respectively. In contrast, other ethereal solvents such as diethyl ether and 1,4-dioxane were not able to do so. This work highlights the potential of exchange NMR to study reaction mechanisms, provides evidence for the formation of glycosyl-solvent adducts despite their very low populations, and improves our ability to develop better stereoselective glycosylation protocols.

One of the main challenges in oligosaccharide synthesis is the stereoselective introduction of the glycosidic bond. In order to understand and control glycosylation reactions, thorough mechanistic studies are required. Reaction intermediates found by NMR spectroscopy often cannot explain the glycosylation's stereochemical outcome. Hence, reactions may proceed through low-abundance reaction intermediates that are difficult to detect, according to a Curtin-Hammett scenario. We have previously observed that manno-type sugars can engage in C-3 acyl neighboring group participation. Herein, we report the detection of glycosyl dioxanium ions that result from C-3 neighboring group participation in mannuronic acid donors. Using a suite of exchange NMR techniques, we were able to dissect the kinetics of the conformational ring-flip that precedes C-3 acyl participation and the participation event itself in various manno-type sugars. Hence, this study provides a complete picture of mannosyl dioxanium ion formation.

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.

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 β-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.

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 β-glycosyl triflates and glycosyl dioxanium ions. This demonstrates the power of exchange NMR to unravel reaction mechanisms as we aim to build a catalogue of kinetic parameters allowing for the understanding and the eventual prediction of glycosylation reactions

The stereoselective introduction of the glycosidic bond remains one of the main challenges in carbohydrate synthesis. Characterizing the reactive intermediates of this reaction is key to develop stereoselective glycosylation reactions. Herein we report the characterization of low‐populated, rapidly equilibrating mannosyl dioxanium ions that arise from participation of a C‐3 acyl group using chemical exchange saturation transfer (CEST) NMR spectroscopy. Dioxanium ion structure and equilibration kinetics were measured under relevant glycosylation conditions and highly α‐selective couplings were observed suggesting glycosylation took place via this elusive intermediate.