Synthesis of O-linked Carbasugar Analogues of Galactofuranosides and N-linked Neodisaccharides

• Main Author: Frigell, Jens
• Format: Doctoral Thesis
• Language: English
• Published: Stockholms universitet, Institutionen för organisk kemi 2010
• Subjects: carbasugar; galactofuranose; mycobacterium; tuberculosis; ring-closing metathesis; GlfT2; galactan; epoxide-opening; pseudodisaccharide; etherification; regioselective; carbohydrate; carbocycles; glycomimetics; glucosidase; neodisaccharides; Mitsunobu; Organic synthesis; Organisk syntes
• Online Access: http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-43561; http://nbn-resolving.de/urn:isbn:978-91-7447-168-7

In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes. Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use. The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed. The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity. === At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.