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

Andrés G Santana,Gonzalo Jiménez-Osés,Jesús Jiménez-Barbero,Laura Montalvillo-Jiménez,Juan Luis Asensio,Pedro Merino,Laura Díaz-Casado,Ana M Gómez,Francisco J Cañada,Francisco Corzana

doi:10.1021/jacs.0c05525

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 α- and β-glycosyl triflates, or even increasingly unstable glycosyl oxocarbenium-like species, among which only α-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 α-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 β-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 β-close ion pair (β-CIP) species, the formation of the α-glycoside is necessarily preceded by a bimolecular α → β triflate interconversion, which under certain circumstances becomes 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 α- and β-glycosyl triflates against neutral and anionic acceptors.

Highlights

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
Central to many of these processes is the role played by glycosyl triflates. These highly reactive species are formed upon activation of common sugar donors, such as glycosyl sulfoxides or thio-glycosides among others,[16] and are believed to exist as a mixture of - and - anomers in a fast exchange equilibrium
Chemical glycosylations with poorly nucleophilic acceptors seem to proceed, in all cases, with an enhanced -selectivity as shown by Codée and col., which could reflect the dominant role played in these circumstances by the minor, yet more reactive intermediates, such as -triflates or even glycosyl oxocarbenium-like species present in the reaction mixture (Figure 1b).11a

Summary

Introduction

The acknowledgment of the relevance of glycoconjugates in biological processes has run parallel to the development of new methods for glycosidic bond formation.[1,2,3,4,5,6,7,8,9] the last few decades have witnessed a burgeoning progress in the area of glycosyl donor engineering, with a more recent focus on the understanding of glycosylation mechanisms.[10,11,12,13,14,15] Central to many of these processes is the role played by glycosyl triflates These highly reactive species are formed upon activation of common sugar donors, such as glycosyl sulfoxides or thio-glycosides among others,[16] and are believed to exist as a mixture of - and - anomers in a fast exchange equilibrium. Chemical glycosylations with poorly nucleophilic acceptors seem to proceed, in all cases, with an enhanced -selectivity as shown by Codée and col., which could reflect the dominant role played in these circumstances by the minor, yet more reactive intermediates, such as -triflates or even glycosyl oxocarbenium-like species present in the reaction mixture (Figure 1b).11a

Results

Discussion

Conclusion