Part I. Synthesis and conformational analysis of 6- C-methyl substituted 2-acetamido-2-deoxy-β-D-glucopyranosides. Part II. Design and strategies towards a unified synthesis of heparan sulfate oligosaccharides

Jihane Achkar, Purdue University

Abstract

The first part of this thesis pertains to the conformational analysis of 6-C-methyl-substituted 2-acetamido-2-deoxy-β- D-glucosamine derivatives (β-GlcNAc). A stereocontrolled synthesis of (6S)- and (6R)-C-methyl β-GlcNAc mono- and disaccharides derivatives is described. The effect of (6 S)- and (6R)-C-methyl-substitution on the conformational preference of the exocyclic C-5-C-6 bond in β-GlcNAc derivatives is analyzed by 1H and {1H}-coupled- 13C NMR. The stereodefined (6S)- and (6R )-C-methyl groups have a strong and predictable influence on sidechain conformations, as determined by 3 JH-H, 2JC-H, and 3JC-H coupling constants. Variable-temperature 1H NMR experiments in methanol-d4 produced ΔH and ΔS values based on two-conformer models indicating that both steric and solvation effects have an important influence on conformation. The second part of this thesis treats of the elaboration of a unified synthesis of heparan sulfate fragments. Heparin and heparan sulfate (HS) cell-surface proteoglycans are a class of complex structurally diverse sulfated polysaccharides that orchestrate numerous protein-carbohydrate recognition events and modulate protein function. Specific structural information within HS (chain length, sulfation pattern, monosaccharide sequence) play a critical regulatory role in numerous biological pathways. In order to determine those key structural motifs, we have designed and implemented a synthetic strategy that can potentially produce all of HS substructures from a common orthogonally protected disaccharide repeating unit precursor. A set of hydroxyl protecting groups that can be selectively cleaved was carefully chosen so that subsequent deprotection/sulfation-rounds generate thirty-two different sulfation patterns per HS disaccharide core. The synthetic efforts underlying this design are described and have led to the synthesis of a differentially protected HS disaccharide precursor.

Degree

Ph.D.

Advisors

Wei, Purdue University.

Subject Area

Organic chemistry

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