UC Riverside

The total synthesis of natural products allows organic chemists the opportunity to develop new methodologies and strategies to access targets with highly valuable and interesting biological activities with medicinal applications that could benefit the scientific and global community. Inspired and motivated by intriguing structural complexities and compelling biological activities, this dissertation work is centrally focused on total synthesis of fraxinellone, a limonoid natural product, and annotionlides A and B, which are lycopodium alkaloid natural products. Fraxinellone is a valuable natural product due to its interesting neuroprotective activity against glutamate toxicity, which is suggested to be involved in the pathogenesis of Alzheimer’s disease and other CNS diseases. Similarly, annotinolides A and B are also structurally and biologically intriguing because they have each been found to inhibit beta-amyloid protein aggregation which is also suggested to be involved in the pathogenesis of CNS diseases such as Alzheimer’s. Through both total synthesis projects, there is an emphasis on developing novel methodologies and strategies to access the complex carbon-carbon frameworks. Chapter 1 describes an overview of the most significant historical accomplishments and contributions to the subfield of limonoid total synthesis, including pioneering total synthesis strategies and methodologies to highly complex limonoid natural products. Herein is described the development of a γ-butenolide arylation methodology designed for the total synthesis of fraxinellone and progress of the synthetic route that ultimately led to the successful total synthesis and future directions of this work. Chapter 2 describes an overview of the most significant pioneering synthesis strategies for the synthesis of lycopodium alkaloids as well as an in-depth discussion of the biosynthesis pathway and the immense medicinal interest in the family of lycopodium alkaloids. Herein is described the progress towards the total synthesis of annotinolides A and B through an exciting and efficient divergent route featuring a redox neutral Heck reaction, an intramolecular Mannich-type cyclization, a biomimetic radical cyclopropanation and a reverse-selectivity [2 + 2] photocycloaddition. Chapter 3 describes the history the of Morita-Baylis-Hillman (MBH) reaction and enolate coupling reactions as our foundation and inspiration to develop a methodology for the α-functionalization of α,β-unsaturated ketones accomplishing a reverse-selectivity Heck reaction.