A general and convergent synthesis of diverse glycosylphosphatidylinositol glycolipids

Abstract

Glycosylphosphatidylinositol (GPI) glycolipids anchor a large number of proteins in the cell membrane of eukaryotic cells. Their conserved pseudopentasaccharide core carries additional phosphoethanolamine, saccharide and lipid substituents. These structural variations are characteristic for a species or a tissue but their functional significance remains largely unknown. Studies that would link a specific function to a structurally unique GPI rely on availability of homogeneous samples of these glycolipids. To address this need we have developed a general synthetic route to GPI glycolipids. Our convergent synthesis starts from common building blocks and relies on a fully orthogonal set of protecting groups that enables the regioselective introduction of phosphodiesters and efficient assembly of the GPI glycans. Here, we report on the development of this synthetic strategy, evaluation of the set of protecting groups with respect to phosphorylation methods, evaluation of the assembly plan for the GPI glycan, optimization of the glycosylation reactions, and the application of this strategy to the total syntheses of four structurally diverse branched GPI glycolipids.