Glycosyl Oxocarbenium Ions: Structure, Conformation, Reactivity, and Interactions

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Carbohydrates (glycans, saccharides, and sugars) are essential molecules in all domains of life. Research on glycoscience spans from chemistry to biomedicine, including material science and biotechnology. Access to pure and well-defined complex glycans using synthetic methods depends on the success of the employed glycosylation reaction. In most cases, the mechanism of the glycosylation reaction is believed to involve the oxocarbenium ion. Understanding the structure, conformation, reactivity, and interactions of this glycosyl cation is essential to predict the outcome of the reaction. In this Account, building on our contributions on this topic, we discuss the theoretical and experimental approaches that have been employed to decipher the key features of glycosyl cations, from their structures to their interactions and reactivity. We also highlight that, from a chemical perspective, the glycosylation reaction can be described as a continuum, from unimolecular S N 1 with naked oxocarbenium cations as intermediates to bimolecular S N 2-type mechanisms, which involve the key role of counterions and donors. All these factors should be considered and are discussed herein. The importance of dissociative mechanisms (involving contact ion pairs, solvent-separated ion pairs, solvent-equilibrated ion pairs) with bimolecular features in most reactions is also highlighted.The role of theoretical calculations to predict the conformation, dynamics, and reactivity of the oxocarbenium ion is also discussed, highlighting the advances in this field that now allow access to the conformational preferences of a variety of oxocarbenium ions and their reactivities under S N 1-like conditions. Specifically, the ground-breaking use of superacids to generate these cations is emphasized, since it has permitted characterization of the structure and conformation of a variety of glycosyl oxocarbenium ions in superacid solution by NMR spectroscopy.We also pay special attention to the reactivity of these glycosyl ions, which depends on the conditions, including the counterions, the possible intra-or intermolecular participation of functional groups that may stabilize the cation and the chemical nature of the acceptor, either weak or strong nucleophile. We discuss recent investigations from different experimental perspectives, which identified the involved ionic intermediates, estimating their lifetimes and reactivities and studying their interactions with other molecules. In this context, we also emphasize the relationship between the chemical methods that can be employed to modulate the sensitivity of glycosyl cations and the way in which glycosyl modifying enzymes (glycosyl hydrolases and transferases) build and cleave glycosidic linkages in nature. This comparison provides inspiration on the use of molecules that regulate the stability and reactivity of glycosyl cations.

Guidelines for O-Glycoside Formation from First Principles

“… 18 − 21 , 23 In brief, glycosyl oxocarbenium ions are highly destabilized by the presence of multiple electron-withdrawing C–O bonds to the extent that they might be considered borderline “superelectrophiles” 14 , 15 , 40 , 41 and have yet to be observed spectroscopically, with the exception of the 2-deoxy and 2-deoxy-2-bromo pyranose series lacking the C–O bond at the 2-position even in superacid media. 42 − 45 On the other hand, the NMR spectra of many activated covalent glycosyl donors in solvents typically employed for glycosyl reactions have been reported in the literature, 18 , 46 − 49 with the continual addition of new examples. 20 , 21 Modern kinetic analyses of glycosylation reactions, including computational studies when conducted in the presence of the counterion, come down on the side of associative mechanisms.…”

“…Glycosylation reactions, however, have long been depicted mostly as S N 1 reactions proceeding through intermediate oxocarbenium ions with the obligatory counterions considered as mere spectators and so typically omitted from reaction schemes. As we have discussed elsewhere, this viewpoint is no longer sustainable in the light of the current physical organic record. − , In brief, glycosyl oxocarbenium ions are highly destabilized by the presence of multiple electron-withdrawing C–O bonds to the extent that they might be considered borderline “superelectrophiles” ,,, and have yet to be observed spectroscopically, with the exception of the 2-deoxy and 2-deoxy-2-bromo pyranose series lacking the C–O bond at the 2-position even in superacid media. − On the other hand, the NMR spectra of many activated covalent glycosyl donors in solvents typically employed for glycosyl reactions have been reported in the literature, ,− with the continual addition of new examples. , Modern kinetic analyses of glycosylation reactions, including computational studies when conducted in the presence of the counterion, come down on the side of associative mechanisms. , The preponderance of evidence therefore suggests that typical homogeneous glycosylation reactions conducted in organic solution with rare exceptions − will hew to the S N 2 end of the mechanistic spectrum . On the basis of this understanding, we offer here a series of guidelines derived from first principles that are intended to help practitioners and nonpractitioners alike derive and execute O -glycosylation reactions with increased reproducibility.…”

Computational discoveries of reaction mechanisms: recent highlights and emerging challenges

“…43 Glycosyl oxocarbenium ions are highly reactive species whose very short lifetimes make them difficult to characterize, both experimentally and theoretically. 44 The difficulties for theory stem from the fact that the structures and energies of oxocarbenium ions strongly depend on the substituents, counterion, and solvent. The vast conformational flexibility of glycosyl donors (even the simplest ones) adds a further technical challenge.…”

Exhaustive Conformational Search for Sialyl Cation Reveals Possibility of Remote Participation of Acyl Groups

“…[24][25][26] Despite a number of successful attempts to establish the structure of glycosyl cations both with molecular modelling and physical methods in superacid [27,28] and in the gas phase, [29] the existence of glycosyl cations in general is still a subject of discussion [19,30] and consequently their conformations have been mostly deduced from computations. [31][32][33] The so-called "two-conformer hypothesis" is often applied in carbohydrate chemistry to account for the influence of the glycosyl cation conformations on the glycosylation outcome. [34,35] This hypothesis states that the glycosyl cation adopts at least two conformations which are related by inversion of the pyranose ring (Scheme 2).…”

“…The mechanism of glycosylation is best described as a continuum between S N 1‐ and S N 2‐like pathways [19] with glycosyl cation (oxacarbenium ion, for sialic acids called sialyl cation, also known in biochemistry as “sialosyl cation”, Scheme 1) or related structures (such as contact ion pair and solvent‐separated ion pair [20,21] ) as the key intermediates [22,23] whose conformations have significant influence on the glycosylation reaction outcome [24–26] . Despite a number of successful attempts to establish the structure of glycosyl cations both with molecular modelling and physical methods in superacid [27,28] and in the gas phase, [29] the existence of glycosyl cations in general is still a subject of discussion [19,30] and consequently their conformations have been mostly deduced from computations [31–33] …”