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_N2-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.

Figure 1.

Relative Energetics of Participation by Vicinal and Distal Esters (Not to Scale).

Figure 2.

Conformational Equilibria of Esters

Figure 3.

Two Rationalizations of the Influence of p-Substituent Effects in Axial Benzoate Esters in Glycosylation.

Figure 4.

Recently conquered, structurally-complex oligosaccharides a) chorella virus N-glycan 57 and b) periploside A 58: the bond formation sequence follows the colors of the rainbow.

Figure 5.

Glycosyl Donors in the Neuraminic Acid and Ulosonic Series

Figure 6.

Definition of the Staggered Conformations about the Exocyclic Bond in the hexopyranosides (R = H) and higher pyranosides (R = C). The C6-O6 bond is either trans, or gauche to the C5-O5 bond and trans or gauche to the C5-C4 bond in that order.

Figure 7.

Predictive model for the conformation of the exocyclic bond in the higher carbon sugars (The pentose chain from C4–C7 is in bold).

Figure 8.

Laminaritriose 87 and the Thioether Mimetics 88 and 89

Figure 9.

Increased Potential for Hydrophobic Interactions on the α-Face of Hydroxylamine 86 as Compared to β-(1→3)-Glucans.

Figure 10.

Hydroxaloging of Kalkitoxin

Scheme 1.

General Glycosylation Mechanism.

Scheme 2.

Formation of oxacarbenium ions and a covalent glycosyl hexafluoroantimonate in superacid solution

Scheme 3.

Counterion-Directed Addition of Enol Ethers to the Tetrahydrofuranylium Ion.

Scheme 4.

Intramolecular Trapping of a Transient Oxacarbenium Ion.

Scheme 5.

Equilibrating Oxacarbenium and Dioxacarbenium Ions and Glycosyl Triflates

Scheme 6.

Protecting Group Dependence of Dioxalenium Ion Formation in Neighboring Group Participation.

Scheme 7.

Formation of a Fused but not a Bridged Dioxacarbenium Ion in Superacidic Medium

Scheme 8.

Participation by Remote Esters is Kinetically Disfavoured by a Multiplicity of Unfavourable Equilibria

Scheme 9.

¹⁸O Labelling Experiment Argues Against Remote Participation

Scheme 10.

Intramolecular Trapping of a Bridged Ion in the Presence of the Weakly Nucleophilic Triflimide Counterion.

Scheme 11.

Restriction of glucoimidazole and isofagamine side chain conformation by GHs

Scheme 12.

Partial X-ray crystal structures of termite GH1 β-glucosidase with (a) cellobiose (PDB ID 3VIK), (b) 1-deoxynojirimycin (PDB ID 3VIG), and (c) a glucose-Hepes conjugate (PDB ID 3VIO)

Scheme 13.

A Phostone Phostone Dimer Mimic of a Disaccharide

Scheme 14.

Asymmetric synthesis of polyhydroxy-N-alkoxypiperidines, with barriers to stereomutation of the hydroxylamine moiety.

Scheme 15.

Compatibility of the Hydroxylamine Moiety with Glycosylation.

Scheme 16.

Final stages of the synthesis of a trimeric β-(1→3)-glucan hydroxalog

Scheme 17.

Preparation of Hydroxalogs from O-acyl-N,N-dialkyl hydroxylamines

Scheme 18.

Hydroxalog synthesis by N-O Bond Formation

Scheme 19.

Synthesis of Propylamycin 116

Scheme 20.

Synthesis of the Advanced Apralog 123