Dissertations, Theses, and Capstone Projects

Date of Degree


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Stephen P. Fearnley

Subject Categories

Organic Chemistry


Studies directed toward the total synthesis of (+/-)-Gephyrotoxin 287C are described herein. Even though the target alkaloid has been synthesized four times to date, it still presents an interesting synthetic challenge. Our ultimate goal is to develop an efficient enantioselective synthetic route utilizing oxazolone chemistry in order to demonstrate its utility as a dienophilic component in intramolecular Diels-Alder reactions. This is part of a greater ongoing study aimed at a range of suitable alkaloid targets.

Chapter 1 provides introduction to frog toxins as secondary metabolites and subsequently shifts to the target alkaloid. (+/-)-Gephyrotoxin 287C was originally described by Daly and Witkop in 1974 following isolation from the skin of the southwestern Columbian poison arrow frog Dendrobates histrionicus.29 Its discovery, isolation structure elucidation and biological activity are discussed.

Chapter 2 delivers detailed accounts of four total and seven formal synthesis of the target alkaloid to date. Previous synthetic works were an abundant source of valuable ideas that expedited our synthetic efforts.

Chapter 3 describes overall retrosynthetic approach to (+/-)-Gephyrotoxin 287C buoyed by successful completion of (+/-)-2-epi-Pumiliotoxin C in our lab.164 The initial stage of the synthesis (formation of cis-cycloadduct) mimics approach developed by Dr. Thongsornkleeb164, a post-doc in our laboratory, but diverges entirely afterwards.

Chapter 4 presents the synthetic methods employed to tackle the challenge of (+/-)-Gephyrotoxin 287C synthesis. It begins with preparation of the key triene followed by experimental and theoretical studies of intramolecular [4 + 2] Diels-Alder cycloaddition to generate desired cis-decahydroquinoline framework. Afterwards it splits into a model study of formation of the pyrrolidine C-ring via tandem elimination/ring closure and cyclopropanation studies. The bulk of presented work, however, is dedicated to rather simple, one might say, cyclopropane rupture. In spite of numerous attempts and subsequent model studies which proved vain reiteratively the last "to be or not to be" struggle provided genuinely desired ring rupture in regiospecific manner.

Chapter 5 concludes completed synthetic efforts and offers a detailed plan for future studies, partially completed, that would lead to the total synthesis of (+/-)-Gephyrotoxin 287C.