Reactive Heterocycle Usage in Methodology Development and Total Synthesis 98 views

This dissertation covers a wide body of research in the field of synthetic organic chemistry. The first three chapters involve the use or synthesis of reactive heterocyclic species for either the development of reaction methodologies or total synthesis. Analysis of recent U.S. FDA-approved drugs spanning the last 10 years reveals that 82% of new small-molecule drugs contain a nitrogen heterocycle, an increase from the previously reported 59%, as well as an increase in the total number of nitrogens per drug. There is an ever-present need to develop methodologies for the synthesis of heterocycles to address the needs of the pharmaceutical industry. The total synthesis of natural products from the breitfussin family are reported in chapter one while the total synthesis of colensolide A is reported in chapter two. Both natural product families are rich in heterocycles, and the methods used in these total syntheses leverage the high reactivity of two intermediate (oxazolones and acyl azide respectively) to form their heterocyclic cores. Chapter three introduces an underutilized class of aza-indole core that has been historically difficult to synthesize. A new synthesis for this core is outlined using highly reactive tetrazines and functionalizations are performed on all positions of the core. Chapters four and five depart from the central theme of heterocycle usage and instead explore drug discovery and synthetic organometallic methodologies respectively. A line of newly developed proteasome activators is reported in chapter four along with a meta-analysis of the chemical space and properties of proteasome activators currently used by the Tepe group. In chapter five, a collaboration with the Harman lab utilizing a dearomative technique for the synthesis of barrelenes and molecular editing of benzene rings is discussed.

PHD (Doctor of Philosophy)

Heterocycles; Organic Synthesis; Total Synthesis; Organic Chemistry; aza-indoles; Diels-Alder

English

2025-11-22