Dissecting the mechanisms of a class of chemical glycosylation using primary 13C kinetic isotope effects

Abstract

Although arguably the most important reaction in glycoscience, chemical glycosylations are among the least well understood of organic chemical reactions resulting in an unnecessarily high degree of empiricism and a brake on rational development in this critical area. To address this problem primary 13C kinetic isotope effects now have been determined for the formation of β- and α-manno- and glucopyranosides by a natural abundance NMR method. In contrast to the common current assumption, for three of the four cases studied the experimental values concur with those computed for associative displacement of the intermediate covalent glycosyl trifluoromethanesulfonates. For the formation of the α-mannopyranosides the experimentally determined KIE differs significantly from that computed for an associative displacement, which is strongly suggestive of a dissociative mechanism that approaches the intermediacy of a glycosyl oxocarbenium ion. The application of comparable experiments to other glycosylation systems should shed further light on their glycosylation mechanisms and thus assist in the design of better reactions conditions with improved stereoselectivity.

A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art

“…1). 14 In this manner the formation of benzylidene protected β-gluco- and mannopyranosides was found to take place via loose S N 2 type transition states from the α-triflates. α-Glucopyranoside formation was found to occur in a similar manner from the less stable β-glucopyranosyl triflate thereby necessitating rapid interconversion of the α- and β-triflates in a Curtin-Hammett kinetic scheme.…”

“…14 In both series displacement of the α-triflate was found to take place via a B 2,5 conformation of the pyranosyl ring, while that of the β-triflates involved the a 4 H 3 conformation of the ring. In each case the C1-OTf and C1-O(H) i Pr partial bonds at the transition states were 2.2Å or longer, again suggestive of exploded transition states (Fig.…”

“…The single exception to the concordance between experimental and calculated KIE values was that of the displacement of the β-mannosyl triflate, which, with an experimental primary 13 C KIE of 1.005 at 25 °C, is more consistent with a stepwise mechanism involving a discrete oxocarbenium ion intermediate. 14 Bennet and coworkers studied the solvolysis of α-D-glucopyranosyl fluoride in hexafluoroisopropanol and on the basis of NMRdetermined KIE measurements suggest that the reaction either proceeds through a solvent-separated ion pair or via an S N i mechanism. 15 …”

Automated Chemical Synthesis of Oligosaccharides and Glycoconjugates

“…The synthesis began by the coupling of the fluoride donor (45) with the diol acceptor (44) in the presence of AgOTf as the promoter. This reactions proceeded regioselectively at the C-4 position, and the resulting pentasaccharide equipped with the anomeric thiophenyl leaving group was used as the glycosyl donor for the coupling with the glycosyl acceptor (46), which was added along with NIS/TfOH to affect the activation. Finally, the remaining 3′-OH of the resulting hexasaccharide intermediate was fucosylated by the addition of a donor (47) and NIS/TfOH.…”

Computational Chemistry on Chemical Glycosylations

“…For further discussion, let us look into the case of 4,6-Obenzylidene mannosyltriflate, which undergoes β-mannosylation reaction with good stereoselectivity (3,83,84). In a S N 2 mechanism, a pyranoside ring should be flexible enough for the Walden inversion, transiting from a 4 C 1 conformation to a pseudo-rotation plane.…”