UC Berkeley

The medicinally relevant indole structure is frequently encountered in drug candidates and naturally occurring molecules. These indole alkaloids exhibit diverse molecular structures and exert exciting biological functions that are useful to human and plant health. Many of these important natural products lack effective means for their chemical synthesis, therefore limiting access. My dissertation focuses on the study of new strategies to synthesize indole alkaloids.

The first chapter describes my efforts at functionalizing the C2 position of brevianamide F, which is proposed to be a common intermediate in the unified synthesis of prenylated indole alkaloids, versicamide and carneamide natural products. Several synthetic routes to directly functionalize the indole C2 position of brevianamide F were investigated, and a C2-borylated brevianamide was prepared. Advancing this intermediate to reverse-prenylated brevianamide F, and optimizing its diborylation will be key to achieving the proposed syntheses.

In Chapter 2, the first synthesis of a pentacyclic ambiguine (ambiguine P) is discussed. As part of a team, we developed a strategy that takes advantage of sequential, robust, alkylative functionalizations of indole, leading to the rapid construction of the ambiguine core structure. Key to the success of the synthesis is the use of a Nicholas reaction to alkylate at C2, crafting a fused seven-membered ring that is characteristic of the pentacyclic ambiguines, as well as the use of an amide-directed functionalization at C12 to set a requisite quaternary center. A versatile late-stage intermediate was prepared that may be applicable to the synthesis of the other pentacyclic ambiguines. The first total synthesis of ambiguine P was completed in 21 steps from carvone via a late-stage C–H oxidation.

Chapter 3 describes the use of the synthesis strategy and knowledge acquired from the studies described in Chapter 2 to synthesize related ambiguines of higher oxygenation levels. From the advanced intermediate prepared in the synthesis of ambiguine P and described in Chapter 2, various synthetic sequences are examined to access ambiguines L, I, N, and J. Various strategies have been explored to install the C10 hydroxy group that is common to most members of the ambiguine family. Late-stage oxidation of the pentacyclic scaffold has proven to be a challenge due to the presence of the oxidation-sensitive indole moiety. Ultimately, the desired oxidation state at the C10 position was achieved through formation of an alkene, from which the seven-membered E ring of the scaffold is functionalized. The resulting C25 and C26 oxidation products map onto ambiguines N and O, respectively, thereby paving way for their completion.