Date of Award

2021

Document Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

Andrei G. Kutateladze

Second Advisor

Brian Michel

Third Advisor

Michelle Knowles

Fourth Advisor

Daniel Linseman

Fifth Advisor

Brady Worrell

Keywords

Azaxylylenes, Organic chemistry, Photochemistry

Abstract

Natural products remain the most common source for drug leads, although diversity-oriented synthesis of unnatural complex molecules is gaining momentum. Our lab has been developing experimentally simple and straightforward approaches to complex molecular architectures via photochemical reactions involving a minimal number of experimental steps. In order to achieve this, photoprecursors were assembled via high yielding reactions. Next, we deployed photoinduced cycloadditions to create complex 3-dimentional structures. Lastly, with this obtained primary photoproduct, post-photochemical transformations were used to further grow its scaffold complexity.

One method to increase scaffold complexity is the [4+2] intramolecular cycloadditions of azaxylylenes, which are developed through standard amide bond-forming reactions. The intermediates are produced by the excited state intramolecular proton transfer (ESIPT) from photoprecursors that could be trapped intramolecularly by tethered unsaturated pendants. Understanding intramolecular cycloaddition of azaxylylenes allows for the access to other derivatives of these complex molecules, with a particular focus on heterocycles. Also, the awareness of photoassisted intermediates via excited state intramolecular proton transfer helped us implement [4+2] cycloadditions, which gave us rapid access to complex nitrogen heterocycles possessing natural product-like privileged substructures. The primary photoproducts were introduced to post-photochemical transformations, including classical elimination of the scaffold and decarboxylative elimination. Through this base-catalyzed modification, we were able to access flat, aromatic, and complex heterocycles.

With underutilization of photochemistry and the need of aromatic polyheterocycles, we tailored photoprecursors to target specific compounds that have never been synthesized before but are targeted for biological testing. In addition to unnatural polyheterocycles, we targeted natural products that are biologically active. We continued our studies to modulate the biological activity of final compounds through methylation of the pyridine; all these products were submitted to National Cancer Institute for NCI-60 testing against 60 most common human cancer cell lines. During our studies, we derived an unusual rearrangement that undergoes a retro-Claisen condensation producing pyridopyrimidine.

Our focus in the synthesis of photoassisted intramolecular cycloadditions will help develop complex compounds in drug discovery. Method development for synthesis of these highly sought-after sp3 carbon rich photoprecursors has the potential to lead to the discovery of new materials. Photochemistry is slowly earning its deserved place in the arsenal of synthetic methods, and our successful synthetic photochemistry research program will further encourage the utilization of these methods in medicinal chemistry and make a greater impact in the academic and industrial community.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Provenance

Received from ProQuest

Rights holder

Tina Alanna Holt

File size

195 pgs

File format

application/pdf

Language

en

Discipline

Chemistry

Available for download on Saturday, October 01, 2022

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