Linkage-Editing of β-Glucosylceramide and β-Glucosylcholesterol: Development of β-Selective C -Glucosylation and Potent Mincle Ligands

Despite recent advances, highly stereoselective C-glucosylation for the synthesis of glycan analogs with diverse C-glycoside linkages (linkage-edited pseudoglycans) remains a considerable challenge. Here, we present a β-selective C-glucosylation method using a 2,4-bis(triisopropylsilyl)-protected glucosyl bromide donor. Direct coupling with ceramide and cholesterol-derived bromofluoroolefins provides access to analogs of β-glucosylceramide (pseudo-β-GlcCer) and β-glucosylcholesterol (pseudo-β-GlcChol) containing CH2-, (R)–CHF-, and (S)–CHF-linkages. Pseudo-β-GlcCers activated immune responses in mouse bone marrow-derived macrophages and dendritic cells more potently than native β-GlcCer, with distinct immune activity patterns, depending on the linkage type.