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Synthesis of the Leishmania LPG core heptasaccharyl myo-inositol
Department of Chemistry, Linkoping University, Linkoping SE-581 83, Sweden.
Department of Chemistry, Linkoping University, Linkoping SE-581 83, Sweden.
Department of Chemistry, Linkoping University, Linkoping SE-581 83, Sweden.
Department of Chemistry, Linkoping University, Linkoping SE-581 83, Sweden.
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2000 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 122, no 45, p. 11067-11072Article in journal (Refereed) Published
Abstract [en]

Total synthesis of the core heptasaccharyl myo-inositol, Galp(a1-6)Galp(a1-3)Galf(ß1-3)[Glcp(a1-PO4-6)Manp](a1-3)Manp(a1-4)GlcN p(a1-6)Ins-1-PO4, and the corresponding hexasaccharyl myo-inositol, Galp(a1-6)Galp(a1-3)Galf(ß1-3)Manp(a1-3)Manp(a1-4)GlcNp(a1-6)Ins-1-PO4 , found in the lipophosphoglycans of Leishmania parasites are described. The target molecules contain synthetic challenges such as an unusual internal galactofuranosyl residue and an anomeric phosphodiester. The synthesis was accomplished using a convergent block synthetic strategy. Four building blocks, a trigalactoside, a dimannoside, a glucosyl inositolphosphate, and a glucosyl-a-1-H-phosphonate, all appropriately protected, were used. The trigalactoside was linked to the dimannoside followed by glycosylation with the glucosyl inositolphosphate to produce the fully protected hexasaccharyl myo-inositol. Subsequent oxidative coupling of the glucosyl-H-phosphonate formed the anomeric phosphodiester linkage to produce the protected heptasaccharyl myo-inositol. Both the assembly order of the subunits and sequence of deprotection were essential for the successful synthesis of these complex molecules. The deprotection was accomplished by deacetylation and clevage of benzyl ethers with sodium in liquid ammonia, followed by acidic deacetalization/desilylation to produce the target molecules.

Place, publisher, year, edition, pages
2000. Vol. 122, no 45, p. 11067-11072
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-47539DOI: 10.1021/ja001515tOAI: oai:DiVA.org:liu-47539DiVA, id: diva2:268435
Available from: 2009-10-11 Created: 2009-10-11 Last updated: 2021-10-01
In thesis
1. Synthesis and Development of Methods for Preparation of Inositolphosphoglycans, Glycoglycerolipids and Glycerophospholipids
Open this publication in new window or tab >>Synthesis and Development of Methods for Preparation of Inositolphosphoglycans, Glycoglycerolipids and Glycerophospholipids
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the synthesis of a series of myo-inositol-containing oligosaccharides, and the exploration of using the chiral epoxide (S)-glycidol in short synthetic routes to glycoglycerolipids and glycerophospholipids.

In chapter 2, synthesis of the core heptasaccharyl myo-inositol Galp(α1-6)Galp(α1 -3)Galf(β1-3)[Glcp(α1-P04-6)Manp](α1-3)Manp(α1-4)GlcNp(α1-6)Ins-1-P04, found in the lipophosphoglycans of Leishmania parasites, is described. This part primarily deals with problematic deprotections of complex carbohydrates. In this context, the stability of anomeric phosphodiesters towards hydrolytic cleavage was studied.

In chapter 3, a short synthetic route to protected derivatives of 2-amino-2-deoxy-α-D-glucopyranosyl-(1➔6)-D-myo-inositol is presented. These derivatives are key building blocks in the synthesis of inositolphosphoglycans (IPGs) and glycosylphosphatidylinositol (GPI)-anchors.The building blocks were subsequently used for synthesis of IPGs, analogous to putative second messengers to insulin, to provide a small targeted library of compounds. A thiol-terminated spacer was introduced by radical elongation of allyl ethers with benzyl mercaptan, for immobilization of the IPGs by coupling to maleimide-functionalized solid phases, proteins or various probes. The aim of this project was to provide IPGs for evaluation of biological activity, isolation of antibodies, and identification of receptors for the second messengers to insulin.

Chapters 4 and 5 describe syntheses of galactoglycerolipids and glycerophospholipids via glycosylation or phosphorylation of the three-carbon synthon (S)-glycidol. Using this approach, three galactoglycerolipids and the corresponding glycerolipid were synthesized and an oxidation-reduction procedure for tritiation of the glycerolipid was developed. Two of the galactolipids have recently been identified in the human colon carcinoma cell line HT29. The synthetic method developed for the galactolipids was subsequently used to explore a new efficient route to enantiomerically pure glycerophospholipids. Lysophosphatidic acids and phosphatidic acids were obtained in good overall yields from (S)-glycidol, in only three and four steps, respectively. Moreover, a strategy for synthesis of lysophosphatidylcholines, in only three steps, is also described.

Place, publisher, year, edition, pages
Linköping: Linköping University, 2002. p. 59
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 770
National Category
Organic Chemistry
Identifiers
urn:nbn:se:liu:diva-179768 (URN)9173734209 (ISBN)
Public defence
2002-09-13, Planck, Fysikhuset, Linköpings Universitet, Linköping, 13:15
Opponent
Note

All or some of the partial works included in the dissertation are not registered in DIVA and therefore not linked in this post.

Available from: 2021-10-01 Created: 2021-10-01 Last updated: 2023-03-07Bibliographically approved

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