Date of Completion

1-21-2016

Embargo Period

7-20-2016

Keywords

Septanose, Oxepine, Synthesis, Glycosylation, Septanosyl bromide, FimH ligands, Conformational Flexibility, Expanded carbohydrates

Major Advisor

Mark W. Peczuh

Associate Advisor

Michael B. Smith

Associate Advisor

Ashis K. Basu

Field of Study

Chemistry

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

An efficient seven-step synthesis of carbohydrate-based novel oxepines has been accomplished using reductive elimination reactions. Classical Fisher-Zack synthesis of glycals via reductive eliminations of glycosyl bromides was adapted to develop a simple and efficient route to oxepine synthesis. The scope of the synthesis was evaluated by varying both the pyranose starting materials and protecting groups incorporated into the oxepine products. The efficiency, economy and simplicity of this method made it amenable to a practical, scalable synthesis of per-O-acetyl oxepines. Interestingly, this study incorporated the synthesis of di-O-acetyl septanoses and per-O-acetyl septanoses. We expect that the reactivities of these two systems are analogous to the respective pyranose derivatives. Bromination reactions of di-O-acetyl septanoses using HBr in AcOH provided the un-expected 1,4-anhydroseptanoses. These intramolecular cyclizations of di-acetyl systems were not affected with the change in ring configuration. The unusual reactivity of the septanoses is linked to the formation of kinetically favoured five-memebered ring and stereoselectivity. Alternatively, sequential bromination and glycosylation on per-O-acetyl septanoses gave access to the β-septanosides such as O-, N-, and S-glycosides exclusively.

A two-step synthesis of C-septanosides from protected pyranoses has been developed. Vinyl addition to tetra-O-benzyl D-glucose, D-galactose and D-mannose gave the corresponding allylic alcohols. Electrophilic cyclization of the allylic alcohols followed by iodination gave iodomethyl C-septanosides. The route is comparable to those that convert furanoses to C-pyranosides. The cyclization reactions were highly diastereoselective, giving cis-1,2 configured C-septanosides. The selectivity is rationalized based on inside alkoxy model for electrophilic cyclizations that correlates reactivity with the conformation of the allylic system. Substitution on the iodomethyl group of the cyclization products provided the C-septanose derivatives. The approach should be generally applicable for the synthesis of a variety of C-septanosides.

In the seperate study, septanose carbohydrates and related a polyhydroxylated oxepanes were studied as a ligands for the mannose-specific lectin FimH. Lectin Protein FimH at the tip of the E. coli is a bacterial adhesion that was primarily responsible for Urinal Tract infections (UTIS). Blocking of these bacterial adhesions by modified Carbohydrates was able to cure UTIS. Competitive binding assays and isothermal titration calorimetry (ITC) indicated an approximately ten-fold lower affinity for the 3-n-heptyloxy oxepane derivative compared to n-heptyl α-D-mannopyranoside, resulting exclusively from a loss of conformational entropy. Further investigations by solution NMR, X-ray crystallography and molecular modeling revealed that the oxepane ligand establishes an identical H-bond network compared to the prototypical mannoside ligand, but at the price of a high entropic penalty due to loss of its conformational flexibility. Overall, the observations made on the oxepane-FimH interaction can guide the design of ligands for other therapeutically important protein-small molecule interactions.

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