Studies of Intramolecular Cyanoamidation with Alkenes and Application Toward the Total Synthesis of Natural Products

Abstract

Chapter One. A brief discussion of the relevant background in intramolecular cyanoamidation. Examples from successive methodology studies are given. The proposed mechanism and published mechanistic experiments are presented, along with its applications in the synthesis of complex molecules. Chapter Two. A summary of the design, discovery, and optimization of the diastereoselective intramolecular cyanoamidation reaction is presented. Significant findings are discussed along with a preliminary substrate scope. A detailed description of our attempts to cleave the chiral directing group is given. Chapter Three. An overview of the Aspidosperma alkaloid family with an emphasis on quebrachamine is presented. A discussion is given of the isolation, biological activity, and previous total syntheses of quebrachamine. Strategies for the synthesis of the all–carbon quaternary center and formation of the nine–membered ring are specified. Chapter Four. A novel strategy for the total synthesis of quebrachamine via intramolecular cyanoamidation is proposed. Three routes to the key cyanoformamide intermediate are presented. Optimization of the intramolecular cyanoamidation is described along with reproducibility studies. Progress toward the final ring closure between indole and nitrile groups via one– and two–step methods is discussed, along with future work. Chapter Five. The application of a serendipitously discovered Bischler–Napieralski-type reaction toward the total synthesis of eburnamonine is proposed. Optimization of the reaction is discussed along with attempts to grow high-quality crystals of the product. Subsequent efforts to hydrogenate the iminium ion product are presented.