Date of Award

Spring 5-2020

Degree Type

Dissertation

Degree Name

Ph.D.

Degree Program

Chemistry

Department

Chemistry

Major Professor

Dr. Mark L Trudell

Second Advisor

Dr. Branko Jursic

Third Advisor

Dr. Viktor Poltavets

Fourth Advisor

Dr. Steven Rick

Abstract

SCP-1, a potent derivative of acetaminophen, exhibits significantly diminished hepatotoxicity and nephrotoxicity relative to acetaminophen and nitrate ester derivatives of acetaminophen. It was therefore of interest to explore the development of nitric oxide donor analogs of SCP-1 to identify compounds that could have enhanced analgesic and/or antipyretic activity while taking advantage of the very low liver and kidney toxicity inherent to SCP-1. In this project, a series of nitrate ester analogues of the SCP-1 were prepared as potential nitric oxide donors. The synthesis of SCP analogs was achieved by triflic acid catalyzed O-acylation of SCP-1 with chloroalkanoyl chlorides followed by nitration with silver nitrate. The chloroesters and corresponding nitrate esters were obtained in high yields (>90%). Preliminary hepatotoxicity studies revealed the nitrate esters to be well tolerated by human hepatocytes and had little effect on the three cytochrome P450 enzymes tested (CYP3A4, CYP2E1 and CYP2D6). In addition, the nitrate esters exhibited antipyretic activity similar to acetaminophen.

With the emerging interest in 3,3-diarylazetidines as novel motifs in drug discovery programs, an easy, efficient, scalable synthetic method that could accommodate the introduction of both electron-rich and electron-deficient aryl groups for preparation of diversely substituted 3,3-diarylazetidines would be valuable to medicinal chemists. In this second project, a versatile synthesis of 3,3-diaryl azetidines from N-Boc-3-aryl-3-azetidinols using Friedel-Crafts arylation conditions with AlCl3 is described. A series of substituted diaryl azetidines were readily prepared and isolated as the oxalate salts in high yield and high purity. The 3,3-diaryl azetidine oxalates were then easily converted into N-alkyl and N-acyl analogues in high overall yields (>85%).

In the last project, A general synthesis of pyruvate esters was developed. Using this method, a series of alkyl pyruvate esters were synthesized in moderate to high yields (56-93%). This was achieved in four steps starting from the readily available triethyl-2-phosphonopropionate which was converted to the alkene ethyl 2,3-dimethyl-2-butenoate using Horner-Wadsworth-Emmons reaction. The ethyl ester was hydrolyzed to the corresponding carboxylic acid after which a series of esters were prepared using Steglich esterification. The esters were then converted to their corresponding pyruvate esters via ozonolysis.

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The University of New Orleans and its agents retain the non-exclusive license to archive and make accessible this dissertation or thesis in whole or in part in all forms of media, now or hereafter known. The author retains all other ownership rights to the copyright of the thesis or dissertation.

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