Synthesis of Cardiotonic Steroids Oleandrigenin and Rhodexin B and Studies Toward the Synthesis of Bufalin

Abstract

Organic chemistry is an ever-evolving field, which produces constant development of new synthetic methods featuring novel technologies. This is critical in driving innovation, especially in total synthesis. Total synthesis is an ever-present topic, with nature still providing new discoveries of natural compounds that can unlock newly discovered therapeutic understandings. However, the natural world can often provide only limited quantities of materials for biological explorations. With most isolation techniques requiring extraction of once living material, natural sources are finite. Total synthesis methods allow scientists the opportunity to preserve natural life by producing natural products with commercially abundant materials. Total synthesis also takes inspiration from the literature to modify and improve upon existing methods for making targets more efficiently. Nature makes specific products for a variety of reasons that are necessary for survival, while boasting the means to achieve regio- and stereoselectively. Described herein is the development of novel strategies for building late-stage, poly-functionalized steroid cores, containing sensitive substituents, including bufadienolide core-scaffolds, thereby allowing the development of more efficient methods to synthesize steroids in general. The first chapter will focus on introducing the relevance of bufadienolides by discussing their unique structural motif and describing their endogenous production in human tissues and the regulatory processes they engage in. This will continue to overview sources of bufadienolides found in nature and provide a brief summary of the progression of synthetic routes that were developed leading to the present-day literature. From there, chapter 2 will describe methods regarding our investigations into developing a strategy for synthesizing bufadienolides via selective hydrogenation. This will advance toward a brief discussion of subsequent oxidation studies of the resulting reduced lactone through applying recently discovered literature methods and Saegusa and Wacker-type oxidations developed in our research group. Chapter 2 will also discuss an investigation on improving known methods of synthesizing pyrone moieties via a photooxidation of carbonyl furans, toward a more stream-lined method from the reported literature. This chapter will also offer some additional strategies and future directions for optimization studies. Chapter 3 will discuss the synthesis and novel methods utilized to generate the second, and most efficient synthesis to date, of oleandrigenin through a House-Meinwald rearrangement strategy. To complete the synthesis of oleandrigenin, a similar photooxidation procedure is used to transform a furan into a butenolide moiety from optimizations based on literature precedent. The synthesis of oleandrigenin provides the foundation for developing a novel glycosylation protocol towards the first synthetic route of rhodexin B (vida infra). The glycosylation method described herein is the first reported strategy of glycosylating in the presence of sensitive C-16 oxidized and protected functionalities, followed by selective orthogonal deprotection. Chapter 4 will describe current strategies and methods for developing site-selective glycoside cleavage under mild reaction conditions. The preliminary studies and optimizations describe how using catalytic amounts of superacid reagents can be used in anhydrous organic solvent, can induce selective anomeric cleavage of a mixture of pseudo-disaccharides. This chapter concludes by discussing future directions of using chiral Bronsted super acidic catalysts to induce selective glycoside cleavage via inherent site recognition of glycoside linkages. Finally, chapter 5 will provide a brief overview of the present gaps in the field of the synthesis of bufadienolides and how this dissertation describes efforts to close these gaps. This concluding chapter will also provide future objectives that are currently being investigated.