Semester

Spring

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Gregory Dudley

Committee Member

Brian Popp

Committee Member

Jessica Hoover

Committee Member

Carsten Milsmann

Committee Member

Mark McLaughlin

Abstract

Natural products are the foundation of modern medicine and an inspiration for chemical innovation. Developing new synthetic strategies to complex natural products drives synthetic innovation and promotes pharmacological exploration. As bioactive secondary metabolites of fungi, illudalic acid and associated analogs have unrealized medicinal potential due to synthetic limitations. Illudalic acid is notably the first selective covalent inhibitor of the LAR-PTPs, a class of enzymes linked to many human illnesses, including stimulant addiction. The chemistry herein focuses on optimizing synthetic routes to illudalic acid and associated analogs toward exploring their pharmaceutical potential. We report a second-generation synthesis of illudinine (55% overall yield), the alkaloid congener of illudalic acid, through the insertion of a small, linear nitrile. We also enhance our current 4-step illudalic acid synthesis via regioselective Vilsmeier- Haack formylation, taking advantage of bulky formamides. The high-yielding and regioselective Wolff rearrangement diazodimedone is another attractive way to assemble the illudalane core, but further exploration is needed to maximize it efficacy. Using an adapted benzannulation strategy, 25 illudalic acid analogs (illudalogs) containing a naphthalene core were prepared and screened against the LAR-PTP family. These are the most potent inhibitors reported to date, and coupled with their ease of synthesis (4-steps), make the illudalogs attractive chemotherapeutic scaffolds.

Embargo Reason

Publication Pending

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