Date of Graduation

5-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor/Mentor

Zheng, Nan

Committee Member

Durham, Bill

Second Committee Member

Kilyanek, Stefan M.

Third Committee Member

Allison, Neil T.

Keywords

Endoperoxide; Gem-difluoride Quinazolinone; Singlet Oxygen; TiO2; Unstrained C-C Bond Cleavage; Visible Light Photocatalysis

Abstract

The pharmaceutical industry has been focused on discovering new innovative drugs over the last decade, but the syntheses are either inefficient or the approach to environmental sustainability raises significant concerns. Photochemistry and photocatalysis have found widespread applications in organic synthesis as a result of this pressing issue. Our role as organic chemists is to improve environmental quality by creating a "greener" world through the development of efficient synthetic methods and strategies. Solar energy is now one of the most abundant and renewable natural resources. The emergence of environmental sustainability concerns has led to the development of new techniques for harnessing solar radiation. One critical solution involves efficiently converting solar energy to chemical energy. This has sparked interest among researchers in finding greener approaches to organic reactions using visible light. However, organic molecules typically have limited ability to absorb visible light effectively. To address this, photoredox catalysts, such as transition metal complexes like ruthenium or iridium polypyridyl complexes, are commonly utilized due to their exceptional ability to absorb visible light. Aliphatic rings are a vital structural element in various kinds of organic compounds including drugs, natural products, and functional materials. The C-C bond cleavage and functionalization constitutes a highly attractive scaffold hopping strategy in organic synthesis. However, the C-C bond cleavage of unstrained aliphatic rings has long been viewed as an extremely challenging problem owing to the high C-C bond dissociation energy. The first part of the works in this dissertation describes the first-ever aromatization-promoted, visible-light-assisted C-C bond cleavage and functionalization of aliphatic rings using diamines as an activator for the synthesis of remotely functionalized quinazolinones. The final products isolated in this work have quinazolinone scaffolds that have been in high demand due to their promising biological and therapeutic capabilities. These quinazolinones have also been distally functionalized with gemdifluoroalkene. Gem-difluoroalkene groups are highly sought after as synthetic targets due to their challenging nature to produce using traditional methods. They are considered valuable structural elements in pharmaceuticals, pesticides, and materials. In addition, the reaction exhibits a broad substrate scope, good to excellent product yields, and high regioselectivities. The second part of this work focuses on synthesis of amino endoperoxides using a semiconductor as a photocatalyst. Endoperoxides are a diverse group of compounds that exhibit various biological activities such as antimalarial, antiviral, and/or anticancer and have attracted attention in the field of natural products, organic synthesis, and drug discovery. Malaria incidence and mortality rates have remained relatively stable since 2015. Every year, hundreds of millions of people become infected, and more than 500,000 people die, primarily in Africa. Eliminating parasitic disease will necessitate the development of new methods as well as improved use of existing ones. The endoperoxide moiety responsible for its biological activity is always difficult to install. Researchers are stepping up to the plate. Inspired by The 2015 Nobel Prize in Physiology or Medicine awarded to Professor Youyou Tu for her key contributions to the discovery of artemisinin, and two separate reactions that led to endoperoxide formation as side products in the Zheng lab, our attention has been drawn to the usefulness and importance of these products and hence the desire to pursue this project. Heterogeneous photocatalysis using low-cost, recyclable metal-oxide catalysts such as TiO2 and visible light offers a promising alternative, but to date, there has been only one report on heterogeneous photocatalytic synthesis of endoperoxides using TiO2. This work even though boasts of the use of readily available, recyclable, cheap, and environmentally friendly photocatalyst, is the first work on amino endoperoxide synthesis utilizing TiO2, oxygen, and visible light.

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