Graduation Term

Summer 2025

Degree Name

Master of Science (MS)

Department

Department of Chemistry

Committee Chair

Shawn Raynard Hitchcock

Committee Member

Timothy D. Lash

Committee Member

Susil Baral

Abstract

Acquired Immune Deficiency Syndrome (AIDS) and malaria are two devastating infectious diseases caused by HIV and Plasmodium parasites. AIDS is caused by HIV-1 and HIV-2, transmitted through sexual contact, blood transfusions, needle sharing, and perinatal routes. Malaria, caused by plasmodium parasites through mosquito bites. Today, millions of people around the world have been infected with HIV and malaria and much research has been done to treat it. However, despite advancements in therapeutic options, these diseases remain a significant global health threat, particularly in developing countries due to the emergence of drug-resistant strains for both HIV and malaria complicating eradication efforts. To develop new antimalarial drugs, Plasmepsin X (PMX), an aspartyl enzyme has been identified as a promising target. Both HIV-1 and the Plasmodium falciparum parasite utilize aspartyl proteases to propagate viral and parasitic life, making these enzymes crucial targets for drug development. TMC-126, an antiviral medication for HIV-1, has shown effectiveness in inhibiting these enzymes and preventing drug-resistant mutations. This thesis describes the effort taken to synthesize inhibitors for both HIV protease and PMX using an asymmetric glycolate aldol addition approach which would ultimately become a potential new pathway for synthesizing protease inhibitors (PI’s) to combat infectious diseases, addressing the challenges posed by drug resistance viral and parasite strains.

The latter part of this thesis is focused on redefining the Curtius rearrangement reaction. The Curtius rearrangement is a chemical reaction that converts carboxylic acids into to isocyanates under mild conditions, resulting in the formation of an acyl azide intermediate. The name comes from German chemist Theodor Curtius, who first proposed the reaction in 1885. The isocyanate can be treated with different nucleophiles, transforming into primary amines, carbamate, urea derivates, and urethanes. This reaction has been widely used in organic synthesis for over 130 years due to its versatility and stability. The isocyanate is highly reactive, making it susceptible to nucleophilic attack. The reaction retains the stereochemistry of the migrating carbon, forming chiral nitrogen-containing compounds with broad applications in natural product synthesis, pharmaceuticals, and bioactive molecules. The Curtius rearrangement produces intermediates that can be exploited to alter the classical mechanistic pathway. The Hitchcock group has developed a new synthetic method to generating these intermediates. This method introduces an alpha-leaving group onto the carboxylic acid, modifying the reaction's mechanistic pathway and allowed us to explore new application for the Curtius rearrangement to synthesize dehomologated carbinolamides as the final product depending on the substitution level at the alpha-position of the carboxylic acid.

Access Type

Thesis-Open Access

DOI

https://doi.org/10.30707/ETD.1763755359.018244

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