Establishment of Guidelines for the Control of Glycosylation Reactions and Intermediates by Quantitative Assessment of Reactivity

Abstract

Stereocontrolled chemical glycosylation remains am ajor challenge despite vast efforts reported over many decades and so far still mainly relies on trial and error.Now it is shown that the relative reactivity value (RRV) of thioglycosides is an indicator for revealing stereoselectivities according to four types of acceptors.Mechanistic studies show that the reaction is dominated by two distinct intermediates:glycosyl triflates and glycosyl halides from N-halosuccinimide (NXS)/TfOH. The formation of glycosyl halide is highly correlated with the production of a-glycoside.These findings enable glycosylation reactions to be foreseen by using RRVs as an a/b-selectivity indicator and guidelines and rules to be developed for stereocontrolled glycosylation.

Guidelines for O-Glycoside Formation from First Principles

“…Guideline 1: Experimental parts and reaction schemes for glycosylation reactions should report molar concentrations of all reactants and reagents and not simply stoichiometry in terms of equivalents. So-called empirical optimization schemes for glycosylation reactions 25 − 28 must specify concentration and conversion, and ideally include optimization of concentration.…”

“… 30 − 32 The guidelines we present are general considerations for reactions conducted at the S N 1/S N 2 interface 18 without the assistance of neighboring group participation, which fall under a different kinetic regime. 19 Finally, we note that while the choice of nonparticipating groups for both glycosyl donors and acceptors can significantly influence the overall rate of a glycosylation reaction under a given set of conditions by shifting the S N 1/S N 2 interface, 25 − 27 , 29 , 33 − 35 the guidelines that we offer are general, and their application should improve reproducibility whatever the protecting group regime.…”

“…Both Wang and co-workers and Seeberger and co-workers have made significant contributions, with additional input from Jensen and co-workers, 24 with similar goals in mind recently, but do not take into account the kinetic differences between reactions proceeding through associative as opposed to dissociative mechanisms in their, in some cases, necessarily empirical approaches. 25 − 29 We limit ourselves to the formation of O -glycosides, believing them to be more central to glycobiology, and do not anticipate that the guidelines we offer will extrapolate directly to C -glycoside formation, which operate more closely to the S N 1 end of the mechanistic spectrum and appear to depend heavily on the conformational dynamics of the putative oxocarbenium ion. 30 − 32 The guidelines we present are general considerations for reactions conducted at the S N 1/S N 2 interface 18 without the assistance of neighboring group participation, which fall under a different kinetic regime.…”

Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions

“…2b) features benzyl ethers and benzoate esters (10)(11)(12)(13)(14)(15)(16)(17)(18) used in a matrix of model glycosylation reactions, as these represent the most commonly used protecting groups in synthetic carbohydrate chemistry. The benzyl ether and benzoate esters are structurally very similar, while differing significantly in electronic properties and their ability to stabilize an oxocarbenium ion 35,36 .…”

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

“…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] Thus, 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.…”