Synthesis of conformationally restricted beta-turn mimics
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Nijmegen : [S.n.]
Number of pages
Radboud University Nijmegen,, 30 oktober 2006
Promotor : Rutjes, F.P.J.T. Co-promotor : Delft, F.L. van
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Synthetic Organic Chemistry
SubjectSynthetic Organic Chemistry
This thesis aims at developing methods for introducing conformational restriction in Beta-turns, the turn elements present in Beta-sheets. A conformationally restricted peptide might either be formed via incorporation of a bridging diamino acids in a growing peptide chain, or via covalent bond forming processes after folding into a turn structure. Practical synthetic pathways are detailed to pepare amino acid amides, which form an extension of research that has been previously carried out in our group. Enzymatic resolution on these substrates then leads to the enantiomerically pure amino acids which are used throughout this thesis. The application of inter- and intramolecular copper-catalyzed 1,3-dipolar cycloaddition reactions (click-reactions) to introduce conformational restriction in peptide strands. Reaction of acetylenic amino acids with a variety of azides resulted in several potentially biologically relevant compounds such as mimics of the amino acid citrulline. However, in our hands, formation of triazoles via intramolecular cycloaddition in peptides remained unsuccessful. Ring-closing alkyne metathesis (RCAM) on suitable acetylene-equipped peptides is the subject of research. The preparation of the required catalyst and several precursor oligopeptides are discussed. Depending on the particular amino acids and the length of the peptide, various constrained oligopeptides were successfully prepared under RCAM conditions. Furthermore, the conformational properties of these constrained peptides were analyzed by NMR and compared to those of comparable cystine-stabilized peptides.
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