Electronic Theses and Dissertations

Date of Award

2010

Document Type

Dissertation

Degree Name

Ph.D. in Chemistry

First Advisor

John M. Rimoldi

Second Advisor

Marc Slattery

Third Advisor

Franck Dayan

Abstract

Quorum sensing bacteria produce and release chemical signal molecules (like N-acyl homoserine lactones, AHL) that increase in concentration as a function of cell density. The responses cover a large spectrum of process such as the virulence in Staphylococcus aureus, competence for DNA-uptake in Bacillus subtilis and Streptococcus pneumoniae, sporulation in Bacillus subtilis, conjugal plasmid transfer in Enterococcus faecalis, and bacteriocin production in lactic acid bacteria. The collapse of (AHL) signaling system in bacteria represents an attractive therapeutic approach towards the development of new antibiotics. Recently, a new extracellular modulator was isolated from a symbiotic bacterium (Bradyrhizobium japonicum) that nodulates soybean. This quorum sensing molecule, containing a novel oxetane ring, was partially characterized and named bradyoxetin (2-{4-[[4-(3-aminooxetan-2-yl)phenyl](imino)methyl]phenyl}oxetan-3-ylamine). The objective of this dissertation research was to confirm the absolute stereochemistry of bradyoxetin by total synthesis, with the production of the four possible stereoisomers. Novel chemical strategies for the efficient formation of oxetane rings were developed, using the inexpensive chiral drug chloramphenicol as a starting material. Employing a five-step protocol, suitable oxetane intermediates were synthesized and characterized as precursors to the final step of bradyoxetin synthesis. Approaches towards the synthesis were also developed for the construction of the natural product oxetin. New scaffolds bearing an oxetane ring were created for the future development of new antibiotics.

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