Synthesis of a Malaria Candidate Glycosylphosphatidylinositol (GPI) Structure: A Strategy for Fully Inositol Acylated and Phosphorylated GPIs.

A congener of the glycosylphosphatidylinositol (GPI) membrane anchor present on the cell surface of the malaria pathogen Plasmodium falciparum has been synthesized. This GPI is an example of a small number of such membrane anchors that carry a fatty acyl group at O-2 of the inositol. Although the acyl group plays crucial roles in GPI biosynthesis, it rarely persits in mature molecules. Other notable examples are the mammalian GPIs CD52 and AchE. The presence of bulky functionalities at three contiguous positions of the inositol moiety creates a very crowded environment that poses difficulties for carrying out selective chemical manipulations. Thus installations of the axial long-chain acyl group and neighboring phosphoglyceryl complex were fraught with obstacles. The key solution to these obstacles in the successful synthesis of the malarial candidate and prototype structures involved stereoelectronically controlled opening of a cyclic ortho ester. The reaction proceeds in very good yields, the desired ax...