Synthesis of inhibitors for ER [alpha]-mannosidase I and stereoselective glycosylations using (R)- or (S)-(ethoxycarbonyl) benzyl chiral auxiliaries at C-2 of glycopyranosyl donors

Abstract

ER ±-mannosidase I plays a pivotal role in the quality control of glycoprotein folding within the endoplasmic reticulum (ER), a process that is commonly referred to as endoplasmic reticulum associated degradation (ERAD). A considerable number of genetic diseases are associated to the proceseses of ERAD. Kifunensine and 1-deoxymannojirimycin are well known inhibitors of this enzyme but they also inhibit Golgi mannosidase I, an enzyme that is essential for the maturation of N-linked glycoproteins to hybrid and complex type glycoproteins. Using these compounds as lead compounds, analogues were synthesized to improve their inhibitory activity and selectivity for ER ±-mannosidase I. The stereoselective introduction of a glycosidic bond is one of the greatest challenges to complex oligosaccharide synthesis. Important developments such as automated polymer supported oligosaccharide synthesis will not achieve their full potential until this problem is solved. Here, a novel approach for stereoselective glycosylations is described whereby a chiral auxiliary at C-2 of a glycosyl donor controls the anomeric outcome of a glycosylation. It was found that participation of an (S) ethoxycarbonylbenzyl auxiliary led to the formation of 1,2-cis glycosides, probably through a trans-fused dioxolenium ion intermediate. On the other hand, the use of an auxiliary with (R) configuration formed 1,2-trans glycosides, and this glycosylation proceeds through a cis-fused dioxolenium ion intermediate