Date of Award

Summer 2019

Project Type

Thesis

Program or Major

Chemistry

Degree Name

Master of Science

First Advisor

Marc Boudreau

Second Advisor

Richard Johnson

Third Advisor

Patricia Wilkinson

Abstract

As a result of the constant overuse and misuse of antibiotics, bacteria have developed a variety of resistance mechanisms against them. One of the most effective forms of resistance are β-lactamase enzymes that work by hydrolyzing β-lactam antibiotics. There are four classes of β-lactamase enzymes: A, B, C and D. Class B enzymes, also known as metallo-β-lactamases (MBLs), are unique because they contain one or two Zn(II) ions in their active site. In order to combat these enzymes, scientists have developed inhibitors to be co-prescribed with already known antibiotics. The inhibitors preferentially bind to the β-lactamases while the antibiotics are able to kill the bacteria. Unfortunately, there are no known clinical inhibitors for MBLs, which have been known to hydrolyze last resort antibiotics. Our goal is to synthesize a library of novel phosphonamide compounds to be used as possible MBL inhibitors.

A four-step synthetic strategy to synthesize the phosphonamide compounds was designed and optimized. Arbuzov chemistry was used to form a library of six compounds with varying functional groups. Optimal monodealkylation techniques were investigated; these included the use of NaOH, LiBr, NaI, and t-BuNH2. Running the reaction with NaOH yielded pure, desired products in the highest yields. The most effective reaction conditions for the chlorination reactions were determined and each phosphonochloridate was reacted with D-Proline ethyl ester · HCl to form the target compounds. phosphonamide, P-[(2-(4-morpholinyl)ethyl-D-proline ethyl ester]-, monoethyl ester (6) was isolated as a 1:1 mixture of diastereomers in a 74% yield, which is the highest among the final compounds. phosphonamide, P-[vinyl-D-proline ethyl ester]-, monoethyl ester (7), phosphonamide, P-[(pentafluorophenyl)methyl-D-proline ethyl ester]-, monoethyl ester (10) and phosphonic acid, P-[[4-(trifluoromethyl)phenyl]methyl-D-proline ethyl ester]-, monoethyl ester (11) were formed in 17, 20 and 15% yields respectively. Unlike 7 and 10, target compound 11 was isolated as a single diastereomer. phosphonamide, P-[(3-nitrophenyl)methyl-D-proline ethyl ester]-, monoethyl ester (8) and phosphonamide, P-[ethyl-D-proline ethyl ester]-, monoethyl ester (9) were also a mixture of diastereomers and were made in yields of 33 and 47% respectively. The structures of the final compounds were confirmed using 1H, 13C, and 31P NMR as well as numerous 2D NMR studies. They were further analyzed using high resolution electron spray ionization mass spectrometry (ESI-MS). The optimized synthetic strategy can be used to produce more final products and further expand upon the target compound library with the goal of discovering an effective MBL inhibitor.

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