title: Synthesis of a malaria candidate glycosylphosphatidylinositol (GPI) structure: a strategy for fully inositol acylated and phosphorylated GPIs.
abstract: 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 axial diastereomer being formed predominantly, even more so in the case of long-chain acyl derivatives. The myoinositol precursor was prepared from methyl alpha-d-glucopyranoside by the biomimetic procedure of Bender and Budhu. For the glycan array, advantage was taken of the fact that (a). n-pentenyl ortho ester donors are rapidly and chemospecifically activated upon treatment with ytterbium triflate and N-iodosuccinimide and (b). coupling to an acceptor affords alpha-coupled product exclusively. A strategy for obtaining the GPI's alpha-glucosaminide component from the corresponding alpha-mannoside employed Deshong's novel azide displacement procedure. Thus all units of the glycan array were obtained from a beta-d-manno-n-pentenyl ortho ester, this being readily prepared from d-mannose in three easy, high-yielding steps. The "crowded environment" at positions 1 and 2, noted above, could conceivably be relieved by migration of the acyl group to the neighboring cis-O-3-hydroxyl in the natural product. However, study of our synthetic intermediates and prototypes indicate that the O-2 acyl group is quite stable, and that such migration does not occur readily.
authors.affiliation: Natural Products and Glycotechnology Research Institute, Inc, 4118 Swarthmore Road, Durham, North Carolina 27707, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: K N
authors.initials: KN
authors.lastname: Jayaprakash
authors.forename: Urs
authors.initials: U
authors.lastname: Schlueter
authors.forename: Bert
authors.initials: B
authors.lastname: Fraser-Reid
mesh_terms: D000215:Acylation; D000818:Animals; D002240:Carbohydrate Sequence; D017261:Glycosylphosphatidylinositols / Q000138:chemical synthesis* / Q000737:chemistry; D007294:Inositol / Q000737:chemistry*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000737:chemistry*
chemical_list: D017261:Glycosylphosphatidylinositols; D007294:Inositol