First synthesis of a malarial prototype: a fully lipidated and phosphorylated GPI membrane anchor

A strategy is described for syntheses of a fully lipidated and phosphorylated prototype of the GPI of Plasmodium falciparum, the causative agent of lethal cerebral, drug-resistant malaria. Orthoesters, prepared in four steps from d-mannose, and methyl α-d-glucopyranoside are the key starting materials. The latter furnishes the inositol moiety using Bender’s procedure, while the former gives the other four units of the pseudo-pentasaccharide. The strategy for installing the three biologically important acyl units of the phosphoinositide has been worked out. The critical, biosynthetically important C2-O-acyl group of the inositol is exceptionally stable, showing no tendency to migrate to the cis-related C3-OH in several test substrates.