Towards a modular approach for heparin and heparan sulfate synthesis
Haller, Friedrich Michael
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This work 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 protecting groups that allows the assembly of a wide range of different heparinoid fragments was determined and evaluated in synthesis. Disaccharide 108 was synthesized as a first module to determine the feasibility of our approach. It was found that the assembly of 108 using donor 107 proceeded only in medium yields and the reproducibility of the reaction was low. This was attributed to undesired side reactions of the azido moiety with the vinylic group. However, these problems could be circumvented by conversion of 107 into trichloroacetimidate 112 or fluoride 113, respectively. Extension of disaccharide 108 at the non-reducing end gave trisaccharide 117. Through conversion of 117 into heparinoid fragment 122 it was demonstrated that the fully protected oligosaccharide could be converted into unsulfated heparinoids and that multiple primary hydroxyl groups could be selectively oxidized in presence of secondary ones using a published TEMPO-catalyzed oxidation procedure. Conversion of disaccharide 108 into heparinoid fragment 133 proved that this procedure could be applied for the synthesis of selectively sulfated fragments. It was also possible to remove the TBDPS protecting group in presence of sulfate esters using HF·pyridine in pyridine as reagent. In order to extend further the number of heparinoid structures accessible with our approach, disaccharide 143 was synthesized as model compound to investigate the use of acetyl esters and levulinoyl esters as protecting groups in the context of our general approach. The conversion of 143 into fragment 150 established, that levulinoyl esters can be used as temporary protecting groups for all those hydroxyl functionalities that remain unsulfated in the final product, while acetyl esters can be used to protect the unsulfated C-2 position of hexuronic acid precursors. It was also demonstrated, that the acetyl ester can be efficiently cleaved in presence of sulfate groups using lipases.