Date of Award

Winter 2018

Project Type

Thesis

Program or Major

Chemistry

Degree Name

Master of Science

First Advisor

Marc A Boudreau

Second Advisor

Eric B Berda

Third Advisor

Arthur Greenburg

Abstract

The design and synthesis of β-lactamase inhibitors is a constant area of study to overcome the growing problem of resistance to β-lactam antibiotics. Serine dependent β-lactamase enzymes, through a hydrolysis mechanism, can deactivate many traditional β-lactam antibiotics. Designing drugs to specifically target β-lactamases is of great interest because such drugs could be used in tandem with traditional β-lactam antibiotics. Aza-β-lactam molecules have been theorized to be less vulnerable to hydrolysis than the traditional β-lactams. Nucleophilic attack of the active-site serine of the β-lactamase on the aza-β-lactam ring would lead to a carbamoyl-enzyme intermediate, which would be partially stabilized due to the neighboring nitrogen atom and thus is expected to be more hydrolytically stable than the corresponding acyl-enzyme intermediate of a β-lactam.

The initial attempt to synthesize the aza-carbacepham 1 utilized a rhodium catalyzed N-H insertion as the key step to form the substituted piperidine ring fused to the aza-β-lactam ring. With the use of aldehyde 8, a Wittig reaction was conducted to extend the carbon chain, but problems arose with the removal of the N-acetyl group. Multiple pathways were attempted but all were unsuccessful in cleaving the N-acetyl group, so a different synthetic approach was explored that utilized an aldol reaction to form the respective ring.

The synthesis of aza-carbapenam 33 originally proceeded via enol-ether 34a/b followed by acid catalyzed conversion to the corresponding alcohol 35. But due to low yields, a different approach involving hydroboration of alkene 47 was explored. With the use of a model system, the Wittig conditions were optimized and applied to aldehyde 8 to form alkene 47. Traditional hydroboration conditions were then attempted with the formation of unexpected product 48.

Rapamycin has been found to potentiate oxacillin activity against several strains of methicillin-resistant Staphylococcus aureus (MRSA), but its mechanism of action is unknown. The interaction of rapamycin with oxacillin and MRSA are going to be studied with a photoaffinity labeling process. Diazirine linker 49 was synthesized and initial steps to alkylate rapamycin were attempted. NMR data of rapa-linker 50 is still inconclusive due to low isolated yields.

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