Synthesis of a polyphosphorylated GPI-anchor core structure

Abstract

Using a linear assembly approach a highly differentially protected derivative of the common GPI-anchor core structure (α-D-Man-(1[Formula: see text]6)-α-D-Man-(1[Formula: see text]2)-α-D-Man-(1[Formula: see text]4)-α-D-GlcNH2-(1[Formula: see text]6)-D-myo-inositol) has been synthesized. All mannose donors were prepared from a common thioglycoside precursor (1), and coupled to GlcN3-myo-inositol acceptor 5 in a linear five-step glycosylation–deprotection sequence in 49% overall yield, to give the key intermediate 10, with orthogonal temporary protecting groups at the 6'', 2'', 6', and 2 positions of the trimannoside motif and at the 1 and 2 positions of the inositol part. Consecutive removal of the temporary protecting groups in the trimannoside moiety followed by phosphorylation, gave a tetraphosphosphate derivative in 60% overall yield. Removal of a camphor acetal afforded a 1,2-inositol diol, which was converted to a 1,2-cyclic phosphate using commercial methyl dichlorophosphate ([Formula: see text]17, 95%). One-step deprotection using sodium in liquid ammonia afforded the target polyphosphorylated core structure 18 (60%), which will be tested for metabolic insulin action.Key words: glycophosphatidylinositols, linear synthesis, glycosylations, inositolphosphoglycans, IPG.