Studies towards ß-turn mimetics, synthesis of kedarosamine from threonine, and synthesis of glycopeptides from mucins and gp120

University dissertation from Organic Chemistry 2, Center for Chemistry and Chemical Engineering, Lund Institute of Technology, Lund University, P.O. Box 124, S-221 00 Lund , Sweden

Abstract: The secondary structure of proteins is crucial for proper function of the protein in biological systems. Peptide T, an octapeptide from the envelope glycoprotein gp120 of the HIV virus, has previously been shown to be responsible for binding to the CD4 receptor on T helper/inducer lymphocytes. NMR studies showed that the four C-terminal amino acid residues of peptide T adopted a beta-turn conformation. In this thesis a beta-turn mimetic was proposed in which the hydrogen bond between the first and fourth amino acid of the peptide T beta-turn was exchanged for a two carbon bridge. Key attempts to incorporate the second amino acid of the beta-turn in the mimetic failed, either due to difficulties in forming imines or in their subsequent reactions. The kedarcidin chromophore, a member of the enediyne antitumour antibiotic family, cleaves double stranded DNA thereby causing apoptosis. The synthesis of a kedarcidin chromophor analogue, containing one of the carbohydrates, is described. Kedarosamine, the sugar moiety of the chromophore, was synthesised starting from D-threonine by chain elongation. The key reactions were diasteroselective ketone reduction and glycosylation. Diastereselective reduction of a ketone derived from D-threonine was accomplished with excellent selectivity (>300:1) using tetramethylammonium triacetoxyborohydride. The kedarosamine precursor was converted into an 1-O-acetyl glycosyl donor, which under BF3·Et2O promotion gave exclusively the desired alpha-glycoside. In the attempted preparation of a thiomethyl kedarosamine donor an azasugar was formed as the major product, most likely via a bridged bicyclic intermediate. A mechanism involving this bicyclic intermediate was proposed and used to explain the high alpha-slectivity obtained in glycosylations with the kedarosamine donor. The envelope glycoprotein gp120 of the HIV virus is one of the most highly glycosylated viral proteins known. Three glycpopetides from the V3-loop of gp120, each having one GalNAc moiety, and two glycopeptides derived from a partial sequence of ovine submaxillary mucin and the 23 amino acid tandem repeat of the human intestinal mucin Muc2, respectively, carrying six GalNAc moieties, were prepared. In the solid phase synthesis of these glycopeptides piperidine was used for all Fmoc deprotections and was shown to be preferable to morpholine which earlier was recomended for glycopeptide synthesis.

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