Synthesis and Development of Methods for Preparation of Inositolphosphoglycans, Glycoglycerolipids and Glycerophospholipids

Abstract: This thesis describes the synthesis of a series of myo-inositol-containing oligosaccharides, and the exploration of using the chiral epoxide (S)-glycidol in short synthetic routes to glycoglycerolipids and glycerophospholipids.In chapter 2, synthesis of the core heptasaccharyl myo-inositol Galp(α1-6)Galp(α1 -3)Galf(β1-3)[Glcp(α1-P04-6)Manp](α1-3)Manp(α1-4)GlcNp(α1-6)Ins-1-P04, found in the lipophosphoglycans of Leishmania parasites, is described. This part primarily deals with problematic deprotections of complex carbohydrates. In this context, the stability of anomeric phosphodiesters towards hydrolytic cleavage was studied.In chapter 3, a short synthetic route to protected derivatives of 2-amino-2-deoxy-α-D-glucopyranosyl-(1➔6)-D-myo-inositol is presented. These derivatives are key building blocks in the synthesis of inositolphosphoglycans (IPGs) and glycosylphosphatidylinositol (GPI)-anchors.The building blocks were subsequently used for synthesis of IPGs, analogous to putative second messengers to insulin, to provide a small targeted library of compounds. A thiol-terminated spacer was introduced by radical elongation of allyl ethers with benzyl mercaptan, for immobilization of the IPGs by coupling to maleimide-functionalized solid phases, proteins or various probes. The aim of this project was to provide IPGs for evaluation of biological activity, isolation of antibodies, and identification of receptors for the second messengers to insulin.Chapters 4 and 5 describe syntheses of galactoglycerolipids and glycerophospholipids via glycosylation or phosphorylation of the three-carbon synthon (S)-glycidol. Using this approach, three galactoglycerolipids and the corresponding glycerolipid were synthesized and an oxidation-reduction procedure for tritiation of the glycerolipid was developed. Two of the galactolipids have recently been identified in the human colon carcinoma cell line HT29. The synthetic method developed for the galactolipids was subsequently used to explore a new efficient route to enantiomerically pure glycerophospholipids. Lysophosphatidic acids and phosphatidic acids were obtained in good overall yields from (S)-glycidol, in only three and four steps, respectively. Moreover, a strategy for synthesis of lysophosphatidylcholines, in only three steps, is also described.