Dissecting the Essential Role of Anomeric β-Triflates in Glycosylation Reactions

Abstract

Glycosylations promoted by triflate-generating reagents are widespread synthetic methods for the construction of glycosidic scaffolds and glycoconjugates of biological and chemical interest. These processes are thought to proceed with the participation of a plethora of activated high energy intermediates such as the and glycosyl triflates, or even increasingly unstable glycosyl oxocarbenium-like species, among which only -glycosyl triflates have been well characterized under representative reaction conditions. Interestingly, the remaining less accessible intermediates, yet to be experimentally described, seem to be particularly relevant in -selective processes, involving weak acceptors. Herein, we report a detailed analysis of several paradigmatic and illustrative examples of such reactions, employing a combination of chemical, NMR, kinetic and theoretical approaches, culminating in the unprecedented detection and quantification of the true -glycosyl triflate intermediates within activated donor mixtures. This achievement was further employed as a stepping-stone for the characterization of the triflate anomerization dynamics, which along with the acceptor substitutions, govern the stereochemical outcome of the reaction. The obtained data conclusively show that, even for highly dissociative reactions involving -close ion pair (-CIP) species, the formation of the -glycoside is necessarily preceded by a bimolecular → triflate interconversion, which under certain circumstances does become the rate-limiting step. Overall, our results rule out the prevalence of the Curtin-Hammett fast-exchange assumption for most glycosylations and highlight the distinct reactivity properties of and glycosyl triflates against neutral and anionic acceptors.

How do Various Reaction Parameters Influence Anomeric Selectivity in Chemical Glycosylation with Thioglycosides and NIS/TfOH Activation?

“…Under the assumption, that the α/β‐selectivity is a direct result of an S N 2‐type displacement of an anomerically bound triflate an additional explanation could be given. Both the rate of interconversion between α‐ and β‐triflate and the position of equilibrium will be expected to be altered by temperature [25] . A higher reaction temperature would favour more of the β‐triflate in equilibrium according to the principle of Le Châtelier and a faster equilibrium, which would result in more α‐glycoside and an eroded selectivity in the present case, which is in accordance with the findings.…”

“…Both the rate of interconversion between αand β-triflate and the position of equilibrium will be expected to be altered by temperature. [25] A higher reaction temperature would favour more of the β-triflate in equilibrium according to the principle of Le Châtelier and a faster equilibrium, which would result in more α-glycoside and an eroded selectivity in the present case, which is in accordance with the findings. This effect would additionally be strengthened by the common ion effect, which would increase the amount of covalently attached triflate over the S N 1 path going through an oxacarbenium ion/triflate ion pair.…”

Statistical Analysis of Glycosylation Reactions

“…According to recent work by Asensio et al., [22] a multidisciplinary approach of combining NMR spectroscopy with kinetic and theoretical calculations illustrates that α‐glycosides can be formed by S N 2‐like substitution from a β‐covalent intermediate (such as β‐triflate) in triflate‐promoted conditions, such as NIS/TfOH. Although bimolecular α→β triflate interconversion is a rate‐limiting step, the highly reactive and unstable intermediate of β‐triflate quickly converts into α‐glycoside if the acceptor is involved.…”

“…However, it is a very difficult process because glycosyl intermediates are usually acid labile and can easily decompose into side products [16c,d] . Recently, the comprehensive analysis of covalent intermediate 9 through low‐temperature NMR spectroscopy was reported by the groups of Crich, [16c, 17a–c] Yoshida, [19] Bennet, [20] Codée, [6, 21] and Asensio [22] . The in‐depth structural analysis of counterion 11 was further conducted by the groups of Seeberger, [12c, 23] Pagel, [12c, 23, 24] Codée [25] and Boltje [25, 26] through mass spectrometry in combination with collision‐induced dissociation (CID) and IR ion spectroscopy.…”

Single‐Step Glycosylations with 13C‐Labelled Sulfoxide Donors: A Low‐Temperature NMR Cartography of the Distinguishing Mechanistic Intermediates

“…Interestingly, on many occasions triflate anions have been shown to facilitate the reaction, probably by promoting the formation of reactive glycosyl triflate species through nucleophilic catalysis [23] . For sulfoxide‐promoted glycosylations, numerous activated entities have been postulated to coexist upon pre‐activation of the donor, above which glycosyl triflates seem to occupy a hierarchical position, both mechanistically and concentration‐wise, acting as either true glycosylating species towards the acceptor or as reservoirs of even more reactive cationic intermediates [24] . However, this scenario might not hold when the acceptor alcohol is present in the reaction mixture from the beginning.…”