Saturated Heterocycle Synthesis through a Novel Base-Promoted Cascade Protocol

Abstract

Over the past century, advances in medicinal chemistry have established nitrogen-containing heterocycles as key structural motifs in pharmaceuticals, owing to their prevalence in numerous biologically active compounds and marketed drugs. As technology has advanced, human society has entered a new golden age of medicine wherein 75-80% of all FDA-approved small-molecule drugs contain at least one nitrogen-containing heterocycle. Specifically, saturated analogues exhibited characteristic trends that were associated with an increased likelihood of biological activity and, consequently, the discovery of new drug candidates. The emergence of these trends upon incorporation of saturated heterocycles highlights the importance of such motifs in medicinal chemistry. For these reasons, current research efforts are focused on developing new approaches to access a diverse range of saturated heterocycles and on expanding the methods available for the synthesis of their novel heterocyclic structures. This thesis describes a new method where a base-promoted cascade oxidation is developed and utilized to approach the synthesis of highly valuable nitrogen-containing saturated heterocycles in one step from common and commercially available chemicals, highlighting the method’s immediate value and implementation. Chapter One provides an overview of the value of nitrogen-containing saturated heterocycles in synthetic and medicinal chemistry. The remainder of this thesis focuses on three key classes of heterocycles, beginning with aziridines, which are discussed highlighting their value in medicinal and synthetic chemistry, together with the methodologies available for their synthesis and the associated synthetic challenges. It then discusses piperazines and morpholines, emphasizing their importance, applications, existing synthetic methodologies, and remaining synthetic challenges. Chapter Two describes the discovery and development of a direct aziridination method based on a base-promoted oxidative cascade reaction. It provides an overview of the base-promoted halogen transfer methodology developed by the Bandar group and its evolution into a cascade process, culminating in the aziridination method, followed by its optimization. The scope of this process addresses several gaps in existing literature and is established as the only method that can access these motifs directly from common and commercially available amines and styrenes. This is followed by the mechanistic studies that further confirmed our hypothesis along with computational studies. Next, the knowledge gained from this method, specifically the mechanistic and computational studies, allowed access to N-H aziridines, consequently establishing new reactivity concepts such as “Base-Promoted Intramolecular Oxidative Cyclization” and further studies towards “Amide -C-H Oxidative Coupling”. Thus, a small overview is presented on the value of the new reactivity observed which is currently being further developed by my colleagues, highlighting the intrinsic value of the reported method. Chapter three describes the discovery and development of the synthesis of six-membered saturated heterocycle rings, specifically piperazines and morpholines, along with their respective discovery and optimization process and their further extension towards the synthesis of unsymmetric piperazines and regioselectivity and diastereoselectivity trends. Additionally, a small overview is provided on deprotection methods for the products synthesized to further extend the value of the method developed. In the final part of the chapter, I will summarize my contributions and discuss the future outlooks on this chemistry.