Synthesis of Glycolipid Probes for Elucidation of the Pathological Mechanism of Carbohydrate-Deficient Glycoprotein Syndrome

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Aiming at elucidation of pathological mechanism of carbohydrate-deficient glycoprotein syndrome (CDGS), we investigated the synthetic method for glycolipid probes such as "Lipid Intermediate" and its precursors, dolichyl glycosyl phosphates designated in the biosynthetic pathway for N-linked glycoproteins. The results are summarized on the following items.1) Preparation and utilization of a novel phosphorilating agent : We have developed an efficient entry to phospholipids and glycophosphates using bis (trimethylsilylethyl) phosphite (1) as a novel phosphorilating agent.2) Synthesis of dolichyl glycosyl phosphates : As a model reation we have synthesized citronellyl phosphate (2) and dolichyl phosphate (3) by the reaction of 1 with the respective lipid alcohols, namely citronellol and dolichol. On the other hand glucosyl fluoride was used for glucosylation of bis (trimethylsilylethyl) phosphate (4). The resulting glucosyl phosphate (5) was subjected to the condensation with 3, giving dolichyl glucosyl pyrophosphates (6). Reaction of dolichol with 2,3,4,6-tetra-O-acetylmammose in the presence of o-chlorophenyl phosphodichloride afforded dolichyl mannosyl phosphate (7) in one-pot process.3) Assembly of oligosaccharides containing beta-D-mannopyranoside : An efficatious route to the mannosylbeta1*4N-acetylglucosamine was developed by means of stereoselective reduction of glucosulosylbeta1*4N-acetylglucosamine, which was prepared by beta-selective glycosylation of GlcNAc with glucosulosyl bromide obtained from glucose by 6 steps in 39% overall yield.