En Route to the Transformation of Glycoscience: A Chemist’s Perspective on Internal and External Crossroads in Glycochemistry

Abstract

Carbohydrate chemistry is an essential component of the glycosciences and is fundamental to their progress. This Perspective takes the position that carbohydrate chemistry, or glycochemistry, has reached three crossroads on the path to the transformation of the glycosciences, and illustrates them with examples from the author's and other laboratories. The first of these potential inflexion points concerns the mechanism of the glycosylation reaction and the role of protecting groups. It is argued that the experimental evidence supports bimolecular S N 2-like mechanisms for typical glycosylation reactions over unimolecular ones involving stereoselective attack on naked glycosyl oxocarbenium ions. Similarly, it is argued that the experimental evidence does not support long-range stereodirecting participation of remote esters through bridged bicyclic dioxacarbenium ions in organic solution in the presence of typical counterions. Rational design and improvement of glycosylation reactions must take into account the roles of the counterion and of concentration. A second crossroads is that between mainstream organic chemistry and glycan synthesis. The case is made that the only real difference between glycan and organic synthesis is the formation of C−O rather than C−C bonds, with diastereocontrol, strategy, tactics, and elegance being of critical importance in both areas: mainstream organic chemists should feel comfortable taking this fork in the road, just as carbohydrate chemists should traveling in the opposite direction. A third crossroads is that between carbohydrate chemistry and medicinal chemistry, where there are equally many opportunities for traffic in either direction. The glycosciences have advanced enormously in the past decade or so, but creativity, input, and ingenuity of scientists from all fields is needed to address the many sophisticated challenges that remain, not the least of which is the development of a broader and more general array of stereospecific glycosylation reactions.

Guidelines for O-Glycoside Formation from First Principles

“… 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. 16 , 18 The preponderance of evidence therefore suggests that typical homogeneous glycosylation reactions conducted in organic solution with rare exceptions 50 − 52 will hew to the S N 2 end of the mechanistic spectrum. 16 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.…”

“… 16 , 18 The preponderance of evidence therefore suggests that typical homogeneous glycosylation reactions conducted in organic solution with rare exceptions 50 − 52 will hew to the S N 2 end of the mechanistic spectrum. 16 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. These guidelines are not intended to be specific to any specific class of glycosidic bond, nor to any particular set of nonparticipating groups; rather, they provide what we consider to be solid foundations onto which selectivity for many classes of glycosidic bonds can be built through the informed choice of protecting groups.…”

Zirconium-catalysed direct substitution of alcohols: enhancing the selectivity by kinetic analysis

“…Depending on the nature of the substrate it can be assumed that a carbocationic intermediate may form in solution as a more or less tight ion pair. 102 Consequently, the degree of S N 1character of the mechanism may vary between substrates. In addition to direct etherification, 2b can form by transetherification of 2a with 1b under the catalytic conditions (see Supporting Information).…”

Progress and challenges in the synthesis of sequence controlled polysaccharides

“…Similar to chemical polymerization, the removal of the PGs is a significant bottleneck. Additionally, several transformations remain challenging due to the poor reactivity or limited stereocontrol of certain BBs [33][34][35][36][37].…”