Doctor of Philosophy
Kerr, Michael A.
This thesis focuses on the synthesis of a variety of heterocycles and carbocycles such as pyrrolidines, dihydrofurans, dihydropyrroles, cyclopentenes, and 2,5-dihydrooxepines. Traditional synthetic methods are discussed first, followed by the manipulation of donor-acceptor cyclopropanes towards the above-mentioned compounds. This leads to a discussion about an important pyrrolidine-containing natural product known as kainic acid. Kainic acid has been studied in the neuroscience field for its biological properties which have led to a better understanding of common human neurological disorders like epilepsy, Huntington’s disease and the after-effects of strokes.
Chapter two focuses on a common rearrangement of donor-acceptor cyclopropanes known as the Cloke-Wilson reaction. Without isolating the desired cyclopropane, two modes of reactivity were observed which depended solely on the choice of starting reagent. The first was the traditional Cloke-Wilson rearrangement generating dihydrofurans and the second was a vinylogous variant forming 2,5-dihydrooxepines. It was discovered that with careful choice of Lewis acid or transition metal catalysts, each of the obtained compounds can be manipulated to other dihydrofuran derivatives or dihydropyrrole heterocycles. One of the dihydropyrrole compounds obtained was deemed as a viable synthetic precursor towards kainic acid.
Chapter three describes the synthetic efforts towards kainic acid utilizing the methodology from chapter two. The difficulties towards this natural molecule will be presented with the major issue resulting from stereochemical constraints. This resulted in the successful synthesis of β-allokainic acid which is one of the less active isomers of naturally occurring kainic acid.
Chapter four discloses a single-step manipulation of the dihydrofurans synthesized via Cloke-Wilson rearrangement to their corresponding cyclopentenes. Extensive screening of Lewis acids and solvents provided insights into the possible mechanism of this reaction.
Summary for Lay Audience
This thesis describes the synthesis of molecules known as carbocycles and heterocycles. These types of compounds are abundant in products obtained from natural sources and are highly sought in the pharmaceutical industry. Finding new ways of synthesizing carbocycles and heterocycles is always in high demand. Common synthetic procedures are discussed, followed by how cyclopropanes can be utilized towards the mentioned compounds. This leads to a discussion about a heterocycle-containing natural product known as kainic acid. The biological properties of this compounds were studied which lead to a better understanding of common human neurological disorders such as epilepsy, Huntington’s disease and the after-effects of strokes.
Chapter two focuses on a common reaction involving cyclopropanes and their rearrangement to heterocycles of value. The reaction proceeds by a famous transformation known as the Cloke-Wilson rearrangement. It was discovered that with a careful choice of catalyst, each of the compounds can be manipulated to other heterocycles that are seen in desired pharmaceuticals and natural products. We determined one of the compounds to be a useful starting reagent towards the synthesis of kainic acid.
Chapter three describes the synthetic efforts towards kainic acid. Initial synthetic problems are discussed with the most significant issue arising once the relative three-dimensional arrangement of atoms on a specific intermediate was determined, also known as stereochemistry. Attempts at obtaining the correct stereochemistry failed which resulted in the synthesis of one of the isomers of kainic acid known as β-allokainic acid.
Chapter four discloses the rearrangement of products obtained in chapter two to their corresponding cyclopentene derivatives. An extensive testing of catalysts and solvents were performed which helped obtain the cyclopentenes in high yields and provided insights into the possible mechanism of the rearrangement.
Piotrowski, Mathew L., "The Synthesis of Heterocycles and Carbocycles and Work Towards Kainic Acid" (2019). Electronic Thesis and Dissertation Repository. 6641.