Synthetic studies toward 6-deoxy-ß-D-ido-heptopyranosides related to capsular polysaccharides of Campylobacter jejuni
Date
2013-10-16
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Abstract
Campylobacter jejuni is a leading cause of bacterial infection resulting in symptoms such as diarrhea, fever, and abdominal cramping. This pathogen is also associated with the development of Guillain-Barré Syndrome, an autoimmune condition that results from the development of antibodies elicited against the bacterial lipopolysaccharides that can cross-react with human gangliosides present on nerve tissue, resulting in neurological complications (e.g. acute paralysis) from immune-mediated destruction of the nervous system.
The capsular polysaccharide (CPS) of C. jejuni contains a unique repeating disaccharide unit which includes an unusual idopyranoside (6-deoxy-D-ido-heptose); we hypothesized that re-directing the immune response towards bacterial CPS may potentially decrease the risk of eliciting a harmful autoimmune reaction. Therefore, the primary goal of the thesis was to develop an efficient synthetic method to obtain β-linked idopyranosides which could eventually be incorporated into a CPS-based vaccine against C. jejuni.
A method was developed to obtain β-D-idopyranosides via an alkoxide-mediated regio- and stereoselective di-inversion of the C-2 and C-3 centres of 4,6-O-benzylidene-2,3-di-O-sulfonyl-β-D-galactopyranoside (Chapter 2). The method was the first to allow for installation of the challenging β-1,2-cis-linked D-idopyranosyl into oligosaccharides, and enabled access to orthogonally protected substrates.
An investigation into the mechanism of the 2,3-di-inversion was performed (Chapter 3), and confirmed that a regioselective O-transsulfonylation at O-3 enabled formation of 2,3-anhydro-talopyranoside, which underwent a trans-diaxial epoxide opening to afford the desired β-D-idopyranoside as the only product. The regioselectivity was attributed to the coordination of a counter-cation to one of the sulfonate oxygens with the help of a neighboring cis-oxygen. The role of the 4,6-O-acetal protecting group in the di-inversion reaction was explored (Chapter 4), and our results indicate that it imposes conformational restraint on the pyranose ring to facilitate O-transsulfonylation and also allows the subsequent opening of the intermediate epoxide to occur at a much improved rate. Finally, homologation of the β-D-idopyranoside at C-6 was studied which enabled access to two analogues of target β-D-ido-heptopyranoside (Chapter 5). Future work will involve the development of efficient methodologies to introduce the 6-deoxy-7-hydroxy functionalities.
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Immunology, Chemistry--Organic, Chemistry--Pharmaceutical
Citation
Hevey, R. (2013). Synthetic studies toward 6-deoxy-ß-D-ido-heptopyranosides related to capsular polysaccharides of Campylobacter jejuni (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27961