Synthesis of Complex Alkaloids Using New C–N bond Formation Methods

This dissertation describes our syntheses of natural product scaffolds and alkaloid natural products, with a focus on the development of new and interesting methods for carbon–nitrogen (C–N) bond formation. The first chapter discusses our synthesis of the pentacyclic core of arboflorine, a Kopsia indole alkaloid. Our synthetic sequence features the use of an efficient Heck coupling and a regioselective Ir-catalyzed C–H borylation to form a highly substituted methoxypicoline derivative and a convergent Suzuki–Miyaura cross coupling of a 2-bromo tryptamine derivative. For our key step in the synthesis, we report an unusual transannular, radical-mediated, dehydrogenative C(sp2)–N bond formation to furnish the pentacyclic core of arboflorine. In the second chapter, we discuss our formal syntheses of the poly-alkylated indole natural products, cis-trikentrin A and herbindole B. Given their modest complexity, these molecules have been the target of syntheses by numerous groups mainly to highlight new synthetic methods. We investigated a divergent approach, using a common meso hydroquinone intermediate. En route to synthesizing the target compounds, we discovered a new chemical transformation—using Pd-catalyzed C–H activation conditions developed by Jin-Quan Yu and co-workers, we were able to transform an ortho-ethyl aniline to the corresponding indole in one step. This bond formation method allowed us to exploit the pseudo-symmetry of the target compounds by using a symmetrical hydroquinone precursor. In the third chapter, we investigate the possibility of making our syntheses of cis-trikentrin A and herbindole B enantioselective. We explored methods of asymmetric desymmetrization of the meso hydroquinone intermediate used for both syntheses. These methods were explored in collaboration with different people and groups including Dr. Caroline Bischof from our lab, Dr. Ana Hurtley from Prof. Scott Miller’s lab at Yale University, and Luke Latimer and Zachary Russ from Prof. John Dueber’s lab in the Department of Bioengineering at UC Berkeley