Date of Award
Doctor of Philosophy (PhD)
Stephen P. Waters
Nitrogen-containing heterocycles have great utility in the biomedical and medicinal fields and one such heterocycle is the 5-membered pyrrolidine ring. The synthesis of pyrrolidine rings has been studied extensively with the routes relying on anodic oxidation, transition metals and dipolar cycloadditions with azomethine ylides. Previous work in the Waters group has been focused on new routes to azomethine ylides through a domino sequence. Through a thermal aza-Cope rearrangement followed by [3+2] dipolar cycloaddition the synthesis of a library of 2-allyl pyrrolidines was accomplished. It was discovered that by using allylic amines and glyoxals at room temperature a cycloadduct was isolated bearing a 5-vinyl moiety.
The results were promising and the first part of the project was to optimize the reaction followed by substrate scope expansion to build a library of compounds. The new cycloadducts could not have been synthesized under traditional methods due to side reactivity difficulties and therefore this work circumvents the problems associated with the classical routes. This is the first report of azomethine ylides derived from allylic amines and glyoxals to date. Many cycloadducts were synthesized and they all contained the 5-alkenyl group with many of them closely matching pyrrolidine containing natural products.
The natural product, spirotryprostatin B, is an ideal target for featuring the developed methodology in total synthesis. Spirotryprostatin B was found to inhibit the G2/M phase in the cell replication pathway, suggesting a possible anti-cancer treatment. Using allylamine, ethyl glyoxylate, and appropriate dipolarophile under the optimized reaction conditions would afford a highly substituted cycloadduct that could be transformed into the final target. The core of the structure was synthesized in just three steps with only two steps requiring purification. The regio- and stereochemistry of the cycloadducts were analyzed using NOE enhancement and DFT studies to conclude that the [3+2] dipolar cycloaddition proceeded through the exo transition state.
The total synthesis of the anti-cancer compound peducularine was also studied. Many different dipolarophiles were tested, but the ideal dipolarophile was not identified. The results of these experiments were important in defining the scope of the methodology.
Number of Pages
Machamer, Natalie Kay, "I. A New Route To Azomethine Ylides: Shifting The Reliance On Amino Ester Precursors II. Applications In Total Synthesis" (2015). Graduate College Dissertations and Theses. 407.