Study of the Stereoselectivity of 2-Azido-2-deoxygalactosyl Donors: Remote Protecting Group Effects and Temperature Dependency

Abstract

The stereoselectivity of glycosylation reactions is affected by many factors. Synthesis of 1,2-cis glycosidic linkages (such as α linkages in glucose and galactose like monosaccharides) is challenging due to lack of control of the stereoselectivity. Our systematic study of GalN(3) donors with different combination of protecting groups indicated that acetyl groups at the 3- and 4-positions are particularly important for high α-selectivity. Temperature is also recognized as a major factor in control of stereoselectivity. Mechanisms responsible for these experimental results are discussed and explored using computational methods. A remote participation model of the acetyl groups is proposed to explain the directing effects of the acetyl groups.

A propos of glycosyl cations and the mechanism of chemical glycosylation; the current state of the art

“…Not surprisingly, in view of the greater delocalization of the positive charge the bridged species uniformly were found to be the more stable. 21 Stabilization by participating 3- and 4- O- acetyl groups were computed to be of comparable magnitude (≤ 1 kcal.mol −1 difference) while that afforded by a participating 6- O -acetate was found to be considerably smaller (Fig. 3).…”

Stereoselective Synthesis of Natural and Non-natural Thomsen-nouveau Antigens and Hydrazide Derivatives

“…13 Other studies have examined structural aspects of sugar donors including the nature of protecting groups, 14 leaving groups, 15 and reaction conditions. 16 Electronics of glycosyl acceptors are also a major contributing factor dictating stereoselectivity. 17 Although a number of amino acid protecting groups have been explored in peptide synthesis, 18 glycopeptide conjugation has largely been limited to Fmoc and Cbz, 19 yet even after extensive optimization of reaction conditions, the glycosylation of D-GalN 3 can often yield a mixture of α/β anomers.…”

“…With two possible half-chair conformations, as shown in Figure 1, conformer 4 H 3 has been reported to be more stable than 3 H 4 ( Figure 1). 25 A nucleophile will approach the half-chair oxocarbenium ion conformer following a pseudoaxial trajection that allows for the formation of a more stable chair-oriented product rather than the less stable twist boat conformer. 26 Therefore, attack through b on conformer 3 H 4 is more favorable and will give the β-product, whereas attack through a on 4 H 3 will result in the α-product.…”

Automated solid-phase synthesis of oligosaccharides containing sialic acids

“…In order to install the cis -glycoside formed by the union of the galactosamine and the linker, galactosamine building block 8 relies on remote participating protecting group effects of esters at C3 and C4 [23–24]. The selectivity of the cis -glycosylation improved with higher reaction temperatures due the strongly deactivating effect of three electron withdrawing ester and carbonate protecting groups [23,25]. The addition of dioxane to CH 2 Cl 2 resulted in preferred formation of the α-anomer, an effect that is well known from solution phase syntheses [26] (Table S6, Figure S1 in Supporting Information File 1).…”