Development of Stereoselective Cyanoamidation Reactions and Their Application to Natural Product Total Synthesis

Abstract

Chapter 1. A survey of the literature to date on the palladium-catalyzed cyanoamidation reaction, both in terms of synthesis and mechanism. Details of work expanding the substrate scope of diastereoselective alkene cyanoamidation, as well as studies toward the removal of the chiral directing group, which necessitated development of a method for chemoselective reduction of hindered lactams in the presence of nitriles. Chapter 2. A review of the literature regarding the synthesis of asymmetric Aspidosperma alkaloids quebrachamine and eburnamonine. Approaches to scalemic material by a wide variety of routes. Chapter 3. A discussion of work towards an enantioselective cyanoamidation of a highly functionalized aliphatic-tethered alkene towards the synthesis of Aspidosperma alkaloids is presented. Efforts toward the functionalization of cyanoamidation products towards quebrachamine, including attempts at forming the alkaloid’s nine-membered ring and the application of diastereoselective cyanoamidation, are discussed. A successful total synthesis of (+)-eburnamonine in four steps from the scalemic cyanoamidation product. Chapter 4. A review of the literature published to date on the synthesis of madangamine alkaloids, including approaches to the diazatricyclic core, macrocyclic rings, and completed total syntheses of various members of the madangamine family. Chapter 5. A discussion of the variety of approaches undertaken towards the synthesis of a di(cyanoformamide) thought to be a viable substrate for a cyanoamidation-based C–C bond activation cascade for making the madangamine core. Details of the development of said cascade reaction and successful synthesis of a madangamine core derivative.