Ligand‐Controlled Stereoselective Synthesis and Biological Activity of 2‐Exomethylene Pseudo‐glycoconjugates: Discovery of Mincle‐Selective Ligands
Takahiro Ikazaki, Eri Ishikawa, Hiroto Tamashima, Hisako Akiyama, Yusuke Kimuro, Makoto Yoritate, Hiroaki Matoba, Akihiro Imamura, Hideharu Ishida, Sho Yamasaki, Go Hirai
Abstract
Abstract Glycoconjugate analogues in which the sp 3 ‐hybridized C2 position of the carbohydrate structure (normally bearing a hydroxy group) is converted into a compact sp 2 ‐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.