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Abstract
This thesis presents the results of our investigation into the development of a modular approach for the synthesis of heparin and heparan sulfates. A suitable set of the protecting groups levulinoyl ester (Lev), 9-fluorenylmethyl carbonate (Fmoc), a tert- butyldiphenylsilyl ether (TBDPS), an allyl ether (All), and an acetyl (Ac) that may be suited for the assembly of a wide range of different heparinoid fragments were determined and evaluated in synthesis. It was shown that Lev ester could be used to protect all those hydroxyls within the molecule that will be sulfated in the final target, while acetyl esters protect the sulfated C-2 positions of hexuronic acid units. Using strategically chosen monosaccharides precursors (I-VI), a set of disaccharide building blocks (19-22) were synthesized. These disaccharides were derivatized into new set of disaccharides (24-27) by replacement of the TBDPS ether at C-6 by a Lev ester. In order to extent further the number of heparinoid structures with this approach, disaccharide 20 was transformed into glycosyl donor 29 and acceptor 30. Disaccharide 36 was synthesized, in order to explore the compatibility of the oxidation procedure and removal of protecting groups in the presence of sulfate ester. It was found that the introduction of the uronic acid group at the end of the synthetic sequence, using a TEMPO mediated oxidation, led to partial degradation. Therefore, an alternative approach was explored whereby an iduronic acid was introduced earlier than in the previous approach. In this study, it was found that glycosylation with a benzylidene donor (disaccharide 38) proceeded with an excellent yield than that of glycosylation with a uronate donor (disaccharide 41).