Studies on the Synthesis of Bacterial Glycans

• Author / Creator

  Wang, Lei

• Glycans play essential roles in the life cycle of bacteria and often modulate interactions with their environment. Chemical synthesis provides a useful tool to access structurally well-defined bacterial glycans. These molecules can serve as probes for elucidating the biological function of these glycans and can also be helpful tools in providing an understanding of their biosynthesis. This thesis is focused on the synthesis of three types of bacterial glycans: rhamnolipids, lipooligosaccharides and lipopolysaccharide biosynthetic intermediates. In the first project, I focused on the synthesis of four rhamnolipid analogs. Rhamnolipids can modulate the immune response of hosts that they infect. However, the structural features in these molecules required for their immunomodulatory activity is not well understood. The molecules consist of one or more rhamnose residues linked to an ester-containing lipid. Because the ester functionality is relatively unstable in biological systems, I was interested in making analogs in which this functionality was replaced with more stable species as they may have better biological activities due to longer survival times. In this study, I synthesized amide, ketone, ether and hydrocarbon rhamnolipid derivatives. In the second project, a convergent strategy was developed for the stereoselective synthesis of four unusual N-acylated monosaccharides, which are fragments of lipooligosacchride IV (LOS IV) from Mycobacterium marinum. A critical substrate-controlled cyclization of an amino acid derived oxazolidine was the key step for synthesis of three of the targets. The fourth target was assembled from 3-butynol; the key step was a one-pot oxidation–cyclization–oxidation of a Boc-protected amino alcohol that led to the formation of lactam. This work represents the first synthesis of these unusual motifs, which have been shown to be essential to the bioactivity of LOS IV. In Chapter 4, I synthesized large, lipid-linked glycans related to lipopolysaccharide biosynthetic intermediates in Escherichia coli O9a. Our targets are structures that contain from 2, 6, 10, 14 or 18 tetrasaccharide repeating units, linked through a pyrophosphate moiety to farnesol. The approach I developed involves assembly of the carbohydrate chain, formation of a glycosyl phosphate intermediate, coupling with a lipid phosphate and finally deprotection. Using this approach, I successfully synthesized targets with two and six repeating units, containing 11 and 27 monosaccharide residues, respectively.

• Subjects / Keywords

  • lipooligosaccharide IV
  • glycan
  • rhamnolipid
  • synthesis
  • lipopolysaccharide

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3XS5JZ9K

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.