Graduation Term

2024

Degree Name

Master of Science (MS)

Department

Department of Chemistry

Committee Chair

Shawn R. Hitchcock

Abstract

The Curtius rearrangement is an important synthetic transformation in organic chemistry and is named in honor of Theodore Curtius who developed this reaction in the late 19th century. The rearrangement involves the conversion of a carboxylic acid into a primary amine through an isocyanate intermediate. The isocyanate is formed by the thermal decomposition of an acyl azide intermediate formed from the carboxylic acid starting material. The thermal decomposition is accompanied by the migration of the substituent bound to the carboxyl group of the acyl azide. When exposed to different nucleophiles, these isocyanates can then be converted to the corresponding amines, carbamates, or substituted urea derivatives.This thesis describes the work that has been conducted on developing the Curtius reaction to follow an alternate synthetic pathway. Mechanistically, the Curtius reaction generates multiple intermediates that can be exploited for their reactivity to generate products that are not expected. This exploration led to the formulation of the central thought of this project: By utilizing carboxylic acids bearing suitable leaving groups in the alpha-position, the scope of the Curtius rearrangement can be expanded in such a way that the final products will be the dehomologated aldehydes or ketones depending on the level of substitution of the alpha carbon of the substituted carboxylic acid. The second part of this thesis describes the work that was conducted towards the total synthesis of a novel antiplasmodial compound developed by Singh, Rathi, and co-workers and described in the prestigious Journal of Medicinal Chemistry in 2021. This compound has shown very high activity against resistant strains of malaria in in vitro and in vivo studies. Retrosynthetically, the synthetic target is envisioned to potentially come from an anti-selective asymmetric glycolate aldol addition reaction. The synthetic pathway that was designed was based on the successful formation of the anti-aldol addition product by Crimmins and coworkers, but it was discovered that it was not possible to obtain this product via the modified approach that was taken. Specifically, this thesis will describe the efforts taken to optimize the formation of the anti-aldol addition isomer and propose a mechanistic explanation for why the syn-isomer was the dominant isomer observed through these studies.

Access Type

Thesis-Open Access

DOI

https://doi.org/10.30707/ETD2024.20240827063557736135.999970

Download

Share

COinS