AbstractThe first part of this thesis is dedicated to the study and the development of new debenzylative cyclization reactions to construct five-membered ring glycomimetics with various applications in bio-organic chemistry. Although benzyl ethers constitute a major class of protecting groups, debenzylative cyclization may occur when a 1,4-relationship exist between an electrophilic center and a benzyl ether, to yield a tetrahydrofuran unit. The cyclization is highly stereo- and regio-selective in favor of the five-membered ring over the tetrahydropyran isomer, thus suppressing the need of protecting group manipulation to ensure regioselective cyclization. Herein, we intended to demonstrate the utility and the versatility of the DBCE reaction through the synthesis of various C-glycosides. Many reaction parameters were investigated to further understand the properties that impact the cyclization. On the other hand, the synthesis of γ-lactone glycosides through debenzylative lactonization (DBL) reaction has been investigated. The two cyclizations are mechanistically different as the etherification proceeds through a SN2 mechanism and the lactonization through a stepwise addition-elimination on sp2-hybridized electrophile.
The second part deals with the multi-step synthesis of difluorinated substrate analogues of UDP-Galactopyranose Mutase (UGM). This enzyme is involved in the biosynthesis of the bacterial cell wall of mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Despite the availability of treatments, TB still remains a major threat for public health, mainly due to the emergence of multidrug resistant strains. UGM enzyme is absent in mammals and catalyzes the interconversion of UDP-Galactopyranose (UDP-Galp) into UDP-Galactofuranose (UDP-Galf). The enzyme is a validated target for the discovery of new therapeutic agents against TB. Then, mono- and tetra-fluorinated substrate analogues have been synthesized to study the binding mode of the enzyme and to design new inhibitors. Polyfluorinated analogues showed good inhibition properties while the UGM-ligand complex could be crystallized. The impact of fluorination on the protein-ligand interaction still needs some investigation and the gem-difluorinated substrate analogues were identified as the next target structures. Therefore, various synthetic strategies were developed along this project in order to prepare UDP-CF2-galactose analogues with the objective to evaluate their biological properties towards the enzyme UGM.
|Date of Award||20 Nov 2018|
|Sponsors||Fund for Research Training in Industry and Agriculture (FRIA)|
|Supervisor||Stephane Vincent (Supervisor), Steve Lanners (President), Guillaume Berionni (Jury), Michael Sprimont Singleton (Jury) & Matthieu Sollogoub (Jury)|
- Fluorinated glycosides
- Multi-step synthesis
- difluorinated analogues
- De novo synthesis