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Title: The synthesis of azadisaccharides and aminopyrrolidines as potential glycosidase inhibitors
Author: Curtis, Kim Louise
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2005
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Azadisaccharides e.g. 399 (Figure 1) are known to be potent selective inhibitors of glycosidases and thus have potential as anti-viral, anti-cancer and anti-diabetic agents. We have developed new, efficient, versatile and stereoselective routes to azadisaccharides using non-carbohydrate starting materials. Pinacol methodology has been successfully used to synthesise two (2→6) linked homoaza-O-disaccharides mimics and due to the versatility of the synthetic route, modification has enabled the synthesis of a (2→6) linked homoaza-O-trisaccharide. Complementary to this, RCM (Grubbs catalyst) and stereoselective dihydroxylation (OSO4) has been utilised in the synthesis of (1→6) linked 5-deoxy-pyrrolidine and piperidine homoaza-O- and N- disaccharides as single diastereoisomers. Preliminary biological screening of these compounds has identified 399 as a weak selective inhibitor of naringinase. Aminopyrrolidines are compounds of great chemical and biochemical interest and are versatile chiral intermediates in the synthesis of compounds of considerable therapeutic value. Three novel diastereomeric 2-hydroxymethyl-3-amino-4-hydroxylpyrrolidines have been synthesised from one key homoallylic carbamate. Using a tethered aminohydroxylation and a regio- and stereoselective intramolecular epoxide opening the novel (2S, 3S, 4R) isomer 488 and (2S, 3S, 4 S) isomer 489 (Figure 2) have been synthesised respectively. Access to a third (2S, 3R, 4R) isomer was also achieved using an unprecedented regioselective intermolecular epoxide opening. Preliminary biological screening of 488 and 489 has identified both as weak inhibitors of beta-galactosidase.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available