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Open Access Publications from the University of California

Total Syntheses of Akuammiline Alkaloids and Nickel-Catalyzed Heck Cyclizations of Amide Derivatives

  • Author(s): Moreno, Jesus
  • Advisor(s): Garg, Neil K
  • et al.

This dissertation is divided into two projects concerning natural product synthesis and methodology development. The importance of natural product synthesis in chemistry and medicine cannot be overstated. In addition to providing a complex setting to test and apply new synthetic methodologies, natural products play a vital role in public health. Their influence in the pharmaceutical industry is profound, as approximately half of all chemical entities to treat disease come from natural product mimics, derivatives, or natural products themselves. With new natural products being discovered daily, there exists an ongoing need to develop efficient syntheses of these compounds and their derivatives.

Chapters One, Two, and Three focus on a particularly interesting and important class of indole-containing natural products called the akuammiline alkaloids. Specifically, Chapter One provides a historical overview of this family of compounds that ultimately demonstrates how these challenging structures, along with their encouraging pharmacological profiles, render them formidable synthetic targets that have been the subject of synthetic chemists’ efforts for the past decade.

Chapters Two and Three describe our lab’s own synthetic efforts to members of the akuammiline family: picrinine, strictamine, 2(S)-cathafoline, and aspidophylline A. Central to our approach was the use of modern variants of the classic Fischer indolization reaction to generate high levels of complexity and the cores of the natural products. Ultimately, these efforts culminated in the first total synthesis of picrinine, strictamine, and 2(S)-cathafoline, as well as an enantioselective, second-generation synthesis of aspidophylline A.

Chapter Four describes the development of the first Mizoroki–Heck cyclizations of amide derivatives. This work highlights the potential of amides, which were once thought to be unreactive due to their resonance stability, as building blocks to prepare complex structures. Through this method, various products containing quaternary centers can be formed.

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