Defense Date
8-29-2024
Graduation Date
Winter 12-20-2024
Availability
One-year Embargo
Submission Type
dissertation
Degree Name
PhD
Department
Chemistry and Biochemistry
School
School of Science and Engineering
Committee Chair
Thomas D. Montgomery
Committee Member
Jeffrey D. Evanseck
Committee Member
Paul A. Lummis
Committee Member
Kevin J. Tidgewell
Keywords
Total Synthesis, Method Development, Cycloadditions, Natural Product Synthesis, Heterocyclic Compounds
Abstract
Nitrogen-containing heterocycles are ubiquitous in bioactive molecules, pharmaceutical drugs, and natural products. For this reason, finding new and efficient ways to make such compounds remains a high priority for the organic and medicinal community. Our current endeavors build upon previously established work by our group, where we generated 1,2-diamines by coupling commercially available aldehydes with trimethylamine N-oxide (TMAO) in two steps. This route proved to be effective in generating 20+ novel 1,2-diamines and imidazolidines with a demonstrated ability to undergo transformations. Using this chemistry, we have developed a diastereoselective synthesis of 50+ novel 7-azanorbornanes using tertiary amine N-oxides and substituted alkenes. The 7-azanorbornane core is found in the natural product epibatidine, a non-opioid analgesic that demonstrates potency four times greater than morphine. Our method uses an efficient [3 + 2] cycloaddition, starting from either commercially available or easily accessible precursors to generate yields up to 97% and diastereomeric ratios up to > 20:1. To complement our synthetic work, density functional theory (DFT) calculations were performed, suggesting that the observed diastereoselectivity is likely due to steric considerations. Additionally, chrysosporazines are a family of newly isolated natural products that have demonstrated an ability to reverse chemotherapeutic resistance in cancer cell lines. To date, the chrysosporazines are only produced by the Chrysosporium sp. fungus found within an Australian Mugil mullet fish’s gastrointestinal tract, thus limiting future studies. Herein, we report the first total synthetic route towards chrysosporazine D following a convergent strategy using a palladium-catalyzed cyclization to generate the piperazine core motif. This 14-step route is flexible, enabling chrysosporazine E to also be synthesized with slight modification.
Language
English
Recommended Citation
Cocolas, A. (2024). METHOD DEVELOPMENT OF [3 + 2] CYCLOADDITIONS USING TERTIARY AMINE N-OXIDES AND EFFORTS TOWARDS THE FIRST TOTAL SYNTHESIS OF CHRYSOSPORAZINE D (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/2400