Synthetic studies toward 6-deoxy-ß-D-ido-heptopyranosides related to capsular polysaccharides of Campylobacter jejuni

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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Chemistry

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2013

Author dc:creator

• Hevey, Rachel

Advisor dc:contributor.advisor

• Ling, Chang-Chun

• Immunology
• Chemistry--Organic
• Chemistry--Pharmaceutical

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/27961

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/1149