Chemical Investigations in Complex Alkaloid Synthesis

Abstract

The concise and efficient synthesis of complex biologically active natural products often requires the elaboration of innovative chemical design paired with the development of modern chemical methods to push the forefronts of chemical space to further biochemical investigations. Complex alkaloids have been of interest to synthetic chemists for decades where their intriguing chemical structures have led to the development of new reactions as well as provided biologically relevant compounds for potential therapeutic use. The growing Myrioneuron and Sarpagine- related alkaloid classes are only a small fraction of the larger realm of complex alkaloid space, however, chemical investigations into these families will hopefully provide insight to the synthetic community as a whole through new chemical methods, synthetic design, and expand further biochemical understandings. Thus, Chapter 1 will serve to introduce the Myrioneuron alkaloids, beginning by detailing their breadth of biological activity, followed by their proposed biosynthetic origins. Lastly, the reported synthetic approaches to this family will be described, starting with early efforts towards simpler congeners, leading to recent, elegant approaches to the more elaborate family members. Next, Chapter 2 will describe the evolution of our synthetic approach to the complex tetracyclic Myrioneuron alkaloid myrioneurinol, a strategy leveraging the hidden symmetry within the molecule to assemble the core scaffold. To begin this chapter, I will discuss our strategic plan towards the complex myrioneuron scaffold, then the early efforts to assemble the required symmetrical intermediate, an in-depth investigation into the key desymmetrizing double reductive amination, efficient elaboration of the scaffold, issues surrounding a challenging hydrogenation and our topologically controlled solution, and finally, the completion of myrioneurinol. Also described will be the development of a formal asymmetric synthesis, the first asymmetric entry towards this complex Myrioneuron alkaloid. Chapter 3 will serve to introduce a similarly complex, yet structurally distinct, subset of indole alkaloids, the Sarpagine-related alkaloids. This chapter will cover this broad family's chemical diversity and wide range of biological activity, their biosynthetic origins, as well as discuss selected synthetic studies within the sarpagine-type alkaloids. Finally, in Chapter 4, our efforts to develop a concise asymmetric approach to the unusual Sarpagine-type alkaloid rauvomine B will be described. First, I will introduce the strategic approach to the distinct sarpagine alkaloid, the challenges of achieving the preparation of the core methyl-containing scaffold will be discussed, including adjustments to the synthetic design. Lastly, the formation of the signature cyclopropane and associated quaternary carbon center via a key late- stage Rh-catalyzed cyclopropanation will be detailed, allowing for completion of this alkaloid target