UC Berkeley

This dissertation describes our efforts toward the total synthesis of complex natural products in the Lycopodium alkaloid and phomactin terpenoid families. The first chapter focuses on our strategy to construct fawcettimine-type Lycopodium alkaloids (such as palhinine A) that contain unique bridging ring systems. The synthesis of a model substrate to examine an atom- transfer radical cyclization is described, as well as the synthesis of a 6-5-9 tricycle that could serve as a common intermediate to access many fawcettimine-type natural products.

After observing an unprecedented hydroamination while working toward the synthesis of Lycopodium alkaloids, we explored the possibility that trimethylsilyl iodide (TMSI) could be a novel effector of this transformation. The second chapter describes our optimization studies of this hydroamination reaction on simple sulfonamides. We show that catalytic amounts of TMSI and water are unique in their ability to effect hydroamination and hydroetherification of unactivated olefins at room temperature. We found that the iodide anion is crucial to obtain high reactivity at low temperatures.

The third chapter of this dissertation provides background and initial strategies toward the synthesis of phomactin natural products. Biological activity and previous syntheses are described. Our general strategy for accessing the phomactin terpenoids by utilizing strategic C–C activation of a cyclobutanol-derived substrate is illustrated as well as initial strategies and model studies. These include investigating C(sp3)–H functionalization reactions with a ketone-derived directing group and assessing the ability to accomplish a hydrazine/aldehyde “traceless” bond construction.

The fourth chapter describes the development of our synthetic route to access several phomactin-like compounds. This has been accomplished through exploiting the unique properties of cyclobutanol-containing compounds. Both π-allyl cross-coupling and aldehyde addition reactions are efficient means of appending the linear fragment to the [3.1.1]bicycle. Templated macrocyclization was achieved in excellent yield, aided by the scaffolding ability of the rigid [3.1.1]bicycle. The cyclobutanol was selectively cleaved open through the action of rhodium catalysis. We’ve shown mechanistically that the products of this process are dependent on subtle changes to the substrate as well as the solvent. Final functionalizations include a reductive sulfone removal in the presence of an enone moiety via the intermediacy of an in situ generated cyclopropanol “protecting group”.