Browsing by Author "Homayonia, Saba"

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    Towards a Fully Synthetic Glycoconjugate Vaccine: Synthesis of Antigenic Oligosaccharides Related to Campylobacter jejuni HS:4c
    (2024-01-18) Homayonia, Saba; Ling, Chang-Chun; Back, Thomas George; Derksen, Darren Jason; Fraser, Marie Elizabeth; Monteiro, Mario
    Campylobacter jejuni is a bacterial pathogen that causes hundreds of millions of cases of food-borne gastroenteritis worldwide annually. The infection caused by this bacterium is also associated with several forms of post-infectious autoimmune sequelae that can be very serious, including the life-threatening Guillain-Barré syndrome. The capsular polysaccharides (CPS) of C. jejuni HS:4c consist of a unique repeating disaccharide unit that is characterized with a β-1,4-linked 6-deoxy-β-D-ido-heptopyranose and an N-acetyl-β-D-glucosamine. The 6-deoxy-ido-configuration of the heptose combined with its β-anomeric configuration makes the chemical synthesis of the disaccharide very challenging. Interestingly, the bacterial CPS is found to be partially modified with an O-methyl phosphoramidate (MeOPN) functionality at the O-2 or O-7 position of the 6-deoxy-β-D-ido-heptopyranosides. Building upon our previously established methodologies, in chapter Two the first synthesis of three analogues of β-D-ido-octopyranosides that contain a 6,7-dideoxy-functionality and either a terminal methyl ester or carboxylic acid or amide is reported. Since carboxylic acids have been reported as bioisosteres of a phosphate group, these analogues can be regarded as carbon-based bioisosteres of 6-deoxy-β-D-ido-heptopyranoside containing a MeOPN group without a chiral center. The three octopyranosides were efficiently synthesized from a O-2 activated β-D-galacto-octopyranuronate that was smoothly converted to the desired β-D-ido-octopyranuronate configuration using an elegant one-pot process. Furthermore, an efficient synthetic scheme to obtain oligosaccharides related to CPS structures of C. jejuni HS:4c is developed in chapter Three. The synthesis is featured with a highly efficient, one-step stereo and regioselective conversion of β-D-galacto-heptopyranosides to 6-deoxy-β-D-ido-heptopyranosides via an intermediate 2,3-anhydro-β-D-talo-heptopyranoside. The key repeating disaccharide and its analog in reverse order plus a trisaccharide were synthesized as the target compounds. Originated from the fact that enzyme-resistant thioglycosides are highly valuable immunogens due to their enhanced metabolic stability, in chapter Four the first synthesis of a family of thiooligosaccharides related to the capsular polysaccharides (CPS) of Campylobacter jejuni HS:4c for potential use in conjugate vaccines is reported. So far, no synthesis of the thioanalogues of the CPS antigens have been reported. The unprecedented synthesis presented in this work is built on an elegant approach by using β-glycosylthiolates as a glycosyl donor to open the 2,3-epoxide functionality of pre-designed 6-deoxy-β-D-talo-heptopyranosides. The results illustrated that this key transformation can be designed in a modular and highly regio and stereo-selective manner. Built on the success of this novel approach, I succeeded in the synthesis of a family of thiooligosaccharides including a thiohexasaccharide which is considered to have the suitable length and complexity for use as an antigen in future immunizations. The first direct conversion of base-stable but acid-labile 2-trimethylsilylethyl glycosides to glycosyl-1-thioacetates in a one-pot manner is also reported. MeOPN-containing carbohydrates are important targets as such structures can play a critical role in understanding the biosynthetic pathway and immunological importance of this phase-variable modification. As a result, in chapter Five the synthesis of two β-D-ido-heptopyranose monosaccharides with the MeOPN functionality either on O-2 or O-7 position is commenced which mimics the native repeating disaccharide unit related to the CPS structures of C. jejuni HS:4c.