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.

Auf dem Weg zur automatisierten Oligosaccharid‐ Synthese

“…Diese Studie wird gegenwärtig von Ancora Pharmaceuticals (Medford, MA, USA) klinisch evaluiert. [272] Bemerkenswert ist noch, dass die synthetischen GPI-Strukturen [273] von Plasmodium nicht nur die Mçglich-keit zur Impfstoffentwicklung erçffnen, sondern auch zur Grundlagenforschung über Malariaimmunpathogenese beitragen.…”

Recent trends in the synthesis of O-glycosides of 2-amino-2-deoxysugars

“…[126][127][128][129][130][131][132][133][134] The triflate moiety is typically introduced by reaction of an alcohol with Tf 2 O and pyridine in dichloromethane, see for example, the synthesis of 2-O-triflate 64 from 2-hydroxyl derivative 63 (Scheme 12). [135][136][137][138][139][140][141][142][143][144][145] As to the triflate displacement reaction, many modifications have emerged [135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152] since the pioneering work by van Boom and co-workers. 153 For example, the treatment of 64 with NaN 3 in DMF afforded 14b in 86% yield.…”

Synthetic Studies of Glycosylphosphatidylinositol (GPI) Anchors and GPI-Anchored Peptides, Glycopeptides, and Proteins

“…Since then, several GPI anchors have been prepared by the Fraser-Reid [22-25], Ley [26,27], Martin-Lomas [28,29], Nikolaev [30], Schmidt [31-34], Seeberger [35-38], and Vishwakarma [39,40] groups, as well as ours [41-44]. Therefore, GPI chemical synthesis has witnessed great progresses in the past two decades.…”