The Experimental Evidence in Support of Glycosylation Mechanisms at the S_N1–S_N2 Interface

Abstract

A critical review of the state-of-the-art evidence in support of the mechanisms of glycosylation reactions is provided. Factors affecting the stability of putative oxocarbenium ions as intermediates at the S1 end of the mechanistic continuum are first surveyed before the evidence, spectroscopic and indirect, for the existence of such species on the time scale of glycosylation reactions is presented. Current models for diastereoselectivity in nucleophilic attack on oxocarbenium ions are then described. Evidence in support of the intermediacy of activated covalent glycosyl donors is reviewed, before the influences of the structure of the nucleophile, of the solvent, of temperature, and of donor-acceptor hydrogen bonding on the mechanism of glycosylation reactions are surveyed. Studies on the kinetics of glycosylation reactions and the use of kinetic isotope effects for the determination of transition-state structure are presented, before computational models are finally surveyed. The review concludes with a critical appraisal of the state of the art.

Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides. Modulation of the Influence of Remote Substituents on Glycosylation?

“…9 This change in reactivity is usually understood in terms of the increased electron-withdrawing ability of the ester destabilizing nascent positive or partial positive charge at the reaction center (Scheme 4). 1,5,6,8,17,70 The results presented in Table 1 and summarized in Figure 7a indicate that this effect will be moderated by the change in side chain conformation in the galactopyranoside series. Thus, the increase in the gt conformation with its intermediate reactivity at the expense of the less reactive tg conformation on replacement of a benzyl ether by an alkanoyl or aroyl ester will partially offset the added electron-withdrawing effect of the ester group.…”

“…1 Thus, for example, galactopyranosides undergo both acid-catalyzed and spontaneous hydrolysis more rapidly than their gluco isomers (Figure 1); 2−5 the same pattern of reactivity is found in glycosylation reactions with a series of comparably protected thioglycosides. 6 The influence of protecting groups on the anomeric reactivity of glycosyl donors also is broadly appreciated, with the more electron-withdrawing (or disarming) esters retarding reaction rates compared to the less electron-withdrawing (or arming) ethers.…”

Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2‐Azidofuranoses, 2‐Fluorofuranoses and Methyl Furanosyl Uronates

“…The decoration pattern of carbohydrates plays an all‐important role in manipulations/transformations of the functional groups in the assembly of carbohydrate building blocks as well as in the union of two carbohydrates in a glycosylation reaction. During a glycosylation reaction a donor glycoside is generally activated to give an electrophilic species bearing significant oxocarbenium ion character . Although steric effects are often decisive in determining the overall shape of a neutral molecule, in charged molecules electronic effects become more important and they may in fact outweigh steric effects.…”

“…During ag lycosylationr eaction ad onorg lycoside is generally activated to give an electrophilics peciesb earing significant oxocarbenium ion character. [4] Although steric effectsa re often decisive in determiningt he overall shape of an eutral molecule, in chargedm olecules electronic effects become more important and they may in fact outweigh steric effects. For example, protonatedi minosugars, that is, carbohydrates having the endocyclic oxygen replaced by an itrogen, may change their conformation to place their ring substituents in as terically unfavourable (pseudo)-axial orientation to stabilise the positive charge on the ring nitrogen.…”

Gold-catalyzed synthesis of α-D-glucosides using an o-ethynylphenyl β-D-1-thioglucoside donor

“…As such, the stereochemistry of the newly formed glycosidic bond would in theory only depend on the anomeric configuration of a donor molecule (Scheme 1a). [2] S N 2 or “S N 2-like” reactions has been realized between deprotonated/anionic acceptors and glycosyl halide[17, 18] or sulfonate[19–25] donors and via a macrocyclic bisthiourea-catalyzed cooperative activation strategy,[26] but much advance in this area is still desired. We attempted to develop activation strategies to generate anomeric leaving groups that would permit S N 2-type glycosylations.…”