Semester

Spring

Date of Graduation

2025

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Gregory Dudley

Committee Co-Chair

Brian Popp

Committee Member

Brian Popp

Committee Member

Steven Valentine

Committee Member

Hacer Karatas Bristow

Committee Member

Margaret Hilton

Abstract

While benzene rings and their derivatives are among the most frequently encountered ring systems in natural products, pharmaceuticals, agrochemicals, dyes, and functional materials, polysubstituted arenes are relatively scarce. The analysis of FDA-approved small molecules provides valuable insights into the characteristics of successful drugs while also highlighting gaps in the availability of synthetic methods capable of efficiently accessing diverse substitution patterns on aromatic rings. Highly substituted arenes are typically synthesized through sequential modification of a pre-existing benzene core; however, this stepwise approach becomes increasingly challenging with each additional substitution. An alternative strategy involves the direct construction of benzene rings via annulation reactions, which offer significant advantages over traditional methods in terms of efficiency, versatility, and atom economy.

In our study, we explored the medicinal chemistry of the sesquiterpene natural product Illudalic acid (IA1), which contains a hexa-substituted aromatic ring constituting its trifunctional pharmacophore for protein tyrosine phosphatase (PTP) inhibition. Using benzannulation chemistry to install the polysubstituted benzene core, we developed synthetic routes to IA1 and its analogs to evaluate their selective inhibition of LAR-PTP enzymes.

Additionally, we investigated a cationic Rh(I)-catalyzed diyne-alkyne cyclotrimerization reaction for the synthesis of polysubstituted benzenoids. By modifying the functionalities on the reactants, we achieved regioselective control over this cycloaddition reaction and applied it to the concise synthesis of a penultimate precursor of the norilludalane sesquiterpene, puraquinonic acid.

Furthermore, we developed a streamlined process for synthesizing neopentylene-tethered (NPT) 1,6-enynes in three steps from the inexpensive and readily available material dimedone via tandem fragmentation/olefination. NPT 1,6-enynes are crucial intermediates for reaction discovery and target-oriented synthesis due to their strategic importance in accessing complex chemical architectures.

The development of novel synthetic approaches for the construction of highly substituted arenes is crucial for advancing organic synthesis. Strategies that address the limitations of traditional methods, improve regioselectivity, and broaden the range of accessible substitution patterns will have far-reaching implications in medicinal chemistry, materials science, and beyond.

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