Date of Award
Doctor of Philosophy (PhD)
Rhett C. Smith
Molecules containing N-heterocycles are prevalent in pharmaceutical settings. The ability to generate highly functionalized molecules containing N-heterocycles in very few synthetic operations is valuable for drug discovery. Our group has developed a two-step synthesis to access a rarely studied diazacyclobutene scaffold via a formal [2+2] cycloaddition between 4-phenyl-1,2,4-triazolinedione and electron-rich thioalkynes. Our interest in this scaffold increased exponentially from promising preliminary biological evaluations against a protozoan parasite, Trypanosoma brucei. While we were able to double the number of historical examples of this scaffold, there were significant limitations in our methodology. The most notable limitations were the lack of structural diversity through the triazolinedione substrate as well as the chalcogen position of the electron-rich alkyne.
Overall, this dissertation describes two distinct methodologies and diversification of the diazacyclobutene scaffold that were developed to circumvent the limitations. The first chapter of this thesis reviews the entire experimental and computational history of diazacyclobutenes and the preliminary biological relevancy of diazacyclobutenes against Trypanosoma brucei. The second chapter describes the telescoped oxidation and cycloaddition of electron-rich alkynes and R3 -substituted triazolinediones. The third chapter details our efforts to diversify electron-rich alkynes to nitrogen bearing alkynes, ynamides. The fourth chapter describes our efforts to develop methodology to synthesize electron-rich 1-en-3-ynes to afford tetrahydroindoles and pyrroles through iii cascade reaction of a diazacyclobutene intermediate. The fifth and final chapter will detail our efforts to expand biological evaluations of diazacyclobutenes against other protozoan parasites. The chapter describes our efforts to establish an in-house assay to test diazacyclobutenes against protozoan parasite, Trichomonas vaginalis
Miller, Brock Alexander, "Expansion of the Diazacyclobutene Motif for Antiparasitic Evaluation" (2023). All Dissertations. 3392.
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