Competing C‐4 and C‐5‐Acyl Stabilization of Uronic Acid Glycosyl Cations

Abstract

Uronic acids are carbohydrates carrying a terminal carboxylic acid and have a unique reactivity in stereoselective glycosylation reactions. Herein, the competing intramolecular stabilization of uronic acid cations by the C-5 carboxylic acid or the C-4 acetyl group was studied with infrared ion spectroscopy (IRIS). IRIS reveals that a mixture of bridged ions is formed, in which the mixture is driven towards the C-1,C-5 dioxolanium ion when the C-5,C-2-relationship is cis, and towards the formation of the C-1,C-4 dioxepanium ion when this relation is trans. Isomer-population analysis and interconversion barrier computations show that the two bridged structures are not in dynamic equilibrium and that their ratio parallels the density functional theory computed stability of the structures. These studies reveal how the intrinsic interplay of the different functional groups influences the formation of the different regioisomeric products.

The Influence of the Electron Density in Acyl Protecting Groups on the Selectivity of Galactose Formation

“…By comparison with computed harmonic frequencies, the structure of the probed ion can be determined. This approach and others based on infrared multiple photon dissociation (IRMPD) spectroscopy have successfully been applied to probe the structure of glycosyl cations exhibiting remote and neighboring group participation. ,,,,,− …”

“…This approach and others based on infrared multiple photon dissociation (IRMPD) spectroscopy have successfully been applied to probe the structure of glycosyl cations exhibiting remote and neighboring group participation. 10 , 15 , 28 , 29 , 34 , 37 − 41 …”

“…On the other hand, it has been reported that the formation of β-triflates − can lead to α-selectivity upon the attack of a nucleophile. Evidence for remote participation has been provided indirectly by bridged side products extracted from glycosylation reactions , or directly by low-temperature NMR experiments in organic solvents , and gas-phase infrared spectroscopy. ,,, It should be noted that the intermediate showing remote participation in solution can only be observed under very limited circumstances, as the lifetime of the glycosyl cation is usually shorter than the relaxation time in NMR experiments . Furthermore, glycosyl cations with remote acetyl groups were stabilized in super acids .…”

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

“…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.…”

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

“…An example of this principle is neighboring group participation (NGP) of an acyl group at the C-2 position affording a bicyclic dioxolanium ion intermediate 3 that reacts in a stereospecific manner with a glycosyl acceptor to afford a 1,2- trans product (Figure A). − Extension of this principle to acyl functionalities positioned on the C-3, C-4, or C-6 hydroxyl groups via NGP has also been suggested to direct the stereoselectivity of glycosylation reactions. However, whether selectivity can be attributed to NGP of the acyl group or other stereoelectronic effects is a subject of much debate. − The second main strategy utilizes glycosyl donors that contain protecting groups that are less capable of neighboring group participation, e.g., benzyl ethers. In this case, the glycosyl cation is trapped by the promotor system counterion or a solvent additive to afford quasi- stable intermediates that can be displaced in an S N 2-like reaction pathway to afford a glycosylation product. − Most modern promotor systems give rise to the formation of glycosyl triflates and since these covalent adducts can exist in the α- ( 1 ) or β-form ( 6 ), reactions proceeding via these intermediates can in principle form the β- or α-product via an S N 2-like reaction pathway, respectively. , The nucleophilic displacement of α-glycosyl triflates 1 is likely to take place via an intermediate α-contact ion pair (CIP) 2 which maintains its stereochemical memory to form the β-product .…”