Ligand-Controlled Stereoselective Synthesis and Biological Activity of 2-Exomethylene Pseudo-glycoconjugates: Discovery of Mincle-Selective Ligands

Abstract

Glycoconjugate analogues in which the sp³ -hybridized C2 position of the carbohydrate structure (normally bearing a hydroxy group) is converted into a compact sp² -hybridized exomethylene group are expected to have unique biological activities. We established ligand-controlled Tsuji-Trost-type glycosylation methodology to directly prepare a variety of these 2-exomethylene pseudo-glycoconjugates, including glucosylceramide analogues, in an α- or β-selective manner. Glucocerebrosidase GBA1 cleaves these synthetic pseudo-β-glucosylceramides similarly to native glucosylceramides. The pseudo-glucosylceramides exhibit selective ligand activity towards macrophage-inducible C-type lectin (Mincle), but unlike native glucosylceramides, are inactive towards CD1d.

Keywords: Glucosylceramides; Glycan Analogues; Immune Receptors; Reagent-Controlled Glycosylation; Tsuji-Trost Allylation.