Computational Chemistry on Chemical Glycosylations

Abstract

The glycosylation reaction, which makes glycosidic linkages to develop a sugar chain, is one of the essential reactions in the realms of glycoscience. An understanding of mechanistic details of this key reaction will not only give researchers deeper insights on the nature of biochemical glycosylation reactions but will further the development of synthetic strategies in a rational way. In the present article we will overview the studies on mechanisms of glycosylation reactions, focusing on those using computational approaches. We review theoretical studies on general mechanistic issues, extensively discussing them in conjunction with the influence of neighboring groups and solvents, as well as stereoelectronic effect. The influence of a glycosyl donor's conformational flexibility on its reactivity/stereoselectivity and the debate about exocyclic or endocyclic cleavage of pyranoside rings are also described.

Controlling the stereoselectivity of glycosylation via solvent effects

“…Various efforts in the field of synthetic experiments and theoretical methods have been made to understand the mechanism and the stereoselectivity of the reaction. 4 In most cases reactions are catalyzed or promoted by an activator which helps the departure of a leaving group to form an oxocarbenium cation intermediate. Most glycosylation reactions proceed through tight ion-pair rather than a free oxocarbenium ion.…”

“…15 For example, donors with an ether group on C-2 are armed (more reactive), and those with esters or amides at the same position are disarmed (less reactive) because the activated donoractivator complex leads to a full and a partial positive charges resulting in increase in the kinetic energy barrier. 4,16,17 Protecting groups on the donor also have substantial impact on the stereoselectivity. For instance, an acyl group at the C-2 can work as a participating group to attack the oxocarbenium ion to form an acyloxonium ion, locking the face cis to the acyl group, directing the stereochemistry of the product as 1,2-trans mainly ( Figure 2).…”

1,3-syn-Diaxial Repulsion of Typical Protecting Groups Used in Carbohydrate Chemistry in 3-O-Substituted Derivatives of Isopropyl d-Idopyranosides

“…55 The idea that the influence of solvent polarity on the oxacarbenium ion conformation and, hence, on selectivity can be mediated by 1,3-syn-diaxial interaction correlates well with the hypothesis that the stereoselectivity is explained by solvent-induced variations in conformational preferences of the oxacarbenium cation. 56,47 Applicability of 3 J C,H Couplings for Study of Conformational Equilibria in Idopyranosides. Although knowledge of 3 J H,H couplings allows for estimation of conformer ratio, in case of idopyranosides 2a−c and 12a−c even thorough examination of J H3,H4 , J H4,H5 , and J H5,H6 couplings provided little information about real torsional angles at C3−C5.…”

“…The dielectric constant of solvent was shown to influence the conformational equilibrium of pyranosides by way of modulating the 1,3- syn -diaxial repulsion. − , This may consequently have an effect on stereoselectivity of glycosylations through the influence on the conformational equilibrium of oxacarbenium ions, when one of the putative conformers has 1,3- syn -diaxial substituent arrangement. Although the influence of solvents on the selectivity of glycosylations has been comprehensively investigated, − we suggested that 1,3- syn -diaxial repulsion may be one of the driving forces that define the pattern of solvent effects.…”

“…However, the resulting selectivities are overshadowed by the presence of modulating DMF additive . The idea that the influence of solvent polarity on the oxacarbenium ion conformation and, hence, on selectivity can be mediated by 1,3- syn -diaxial interaction correlates well with the hypothesis that the stereoselectivity is explained by solvent-induced variations in conformational preferences of the oxacarbenium cation. , …”