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

Anomeric Triflates versus Dioxanium Ions: Different Product-Forming Intermediates from 3-Acyl Benzylidene Mannosyl and Glucosyl Donors

“…The conformational restriction enforced by the benzylidene ring, thus, prevents the benzylidene mannosyl 1,3dioxolenium ion to adopt the electronically most-favorable geometry (the 1 C 4 conformation), rendering the formation of the 3-O-benzoyl benzylidene mannosyl 1,3-dioxanium more difficult than the formation of its 4,6-dibenzyl counterpart, explaining the results we previously obtained in our CEST-NMR studies. 29,41 The identified lowest energy conformers of the dioxanium and oxocarbenium cations were subsequently used to compute reference IR-spectra to aid in interpretation of the experimentally obtained spectra. 26,42 Figure 1a,b shows the computed spectra (filled) and the experimental spectra (black line) to confirm the formation of the dioxanium ions, as indicated by a characteristic dioxanium −[C−O] + stretch (∼1550 cm −1 ) and the absence of the oxocarbenium [C1� O5] + (∼1565 cm −1 ) and benzoyl C�O (∼1775 cm −1 ) stretches.…”

“…The formation of the two different reactive intermediates accounts well for the dichotomy in the stereochemical outcome for the 3-O-benzoyl benzylidene mannose and glucose systems. The mannosyl dioxanium ion, detected by 13 C CEST NMR, 29,41,45 is responsible for the stereoselective formation of the α-mannosyl glycosylation products. In contrast, the glucosyl 1,3-dioxanium ion could be formed and characterized in the gas phase, but no evidence was found in solution.…”

“…Indeed, Asensio and co-workers have previously been able to detect the β-glucosyl triflate by NMR spectroscopy of an 13 C-labeled glycosyl triflate . We have also been able to detect the elusive β-mannosyl triflate by 1 H/ 19 F CEST, urging us to revisit the anomerization reaction in both cases. As shown in the reaction profiles for the glucosyl and mannosyl triflates (Figure a, left pathways), the activation energy ( TS IV ) for the formation of the anomeric β-triflate ( R β ) is slightly higher for the mannoside (+16.5 kcal mol –1 ) than that for the glucoside (+15.8 kcal mol –1 ).…”

“…There has been significant debate as to the origin of the high α-selectivity in the 3-acyl benzylidene mannose case. − While Crich and co-workers have initially postulated long-range participation as a reasonable explanation for this stereoselectivity, they have more recently argued strongly against the possible formation of the 1,3-dioxanium ions as this would require the formation of a highly strained dioxanium ion from a C-3-acyl rotamer that is hardly populated requiring an intramolecular substitution reaction on a high-energy ring conformer. − Rather they argued that the C-3-ester destabilizes the anomeric triflate, promoting reactions through an oxocarbenium ion intermediate. , To investigate the formation of 1,3-mannosyl dioxanium ions, we recently investigated these glycosylation reactions with chemical exchange saturation transfer (CEST) NMR. We have forwarded spectroscopic evidence for the generation of 1,3-dioxanium ions from 3-acyl-4,6-benzylidene mannosyl α-triflates that can account for the formation of the observed α-products. − With these CEST-NMR studies, we have not been able to detect the corresponding glucosyl 1,3-dioxanium ions.…”

“…To unravel the origin of the contrasting behavior of the 3-acyl benzylidene mannosyl and glucosyl donors, we here report a combination of systematic glycosylation reactions, using a series of alcohol nucleophiles of gradually changing nucleophilicity, with gas-phase IR spectroscopy to study the potential formation of the 1,3-dioxanium ions and computational experiments investigating different reaction paths of the anomeric triflates . Combined with our previous NMR studies that have revealed the formation of mannosyl 1,3-dioxanium ions and the absence of these species from the corresponding glucosyl systems, a picture emerges on the diverging reaction pathways followed in the mannose and glucose systems. The computational studies pinpoint the structural features responsible for the contrasting behavior of the mannosyl and glucosyl donors and illuminate the delicate balancing act between the various reactive intermediates.…”