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

Abstract

AbstractGlycoconjugate 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.