UC Berkeley

Innovative carbon-carbon bond forming reactions have been integral to the synthesis of a myriad of complex molecules such as densely functionalized terpene natural products. Key to this effort is the development of novel methodology to generate strategic carbon-carbon bonds to rapidly access complex scaffolds. This dissertation describes a novel approach to the quassinoid natural products and the development of new methodology to help realize this goal. In Chapter 1 we provide an introduction to the quassinoid family of natural products including isolation, structural elucidation, the proposed biosynthesis, biological activity, and previous syntheses. In this chapter, we seek to provide the context with which our synthetic approach is based. Previous total syntheses of quassinoid natural products were hampered by lengthy oxidation sequences following construction of the carbon scaffold. To this end, in Chapter 2, we proposed to leverage the pseudo-symmetry of quassin to construct the carbon scaffold in tandem with the oxidation. To implement this strategy, we developed a novel copper-catalyzed double coupling of epoxy ketones to generate highly diastereo- and regioselective pseudo-symmetric products. We then extended this methodology to couple two different units in a three-component coupling. Finally, to conclude this chapter, the previously developed methodology was applied to the synthesis of the quassinoid core architecture. Having laid the foundation, in Chapter 3, we seek to extend our copper-catalyzed methodology to the construction of quaternary centers and ultimately the full quassinoid carbon skeleton; however, an unexpected rearrangement occured during dioxene cross coupling making a tandem allylic substitution/cross- coupling transformation unfeasible. We therefore surmised that any approach moving forward would need to first generate the quaternary center at the A/B-ring junction prior to dioxene cross-coupling. Accordingly, we first constructed a bicyclic using an ene/condensation/alkylation sequence before elaborating our system with dioxene. Finally, we are able to rapidlyassemble an advanced intermediate containing all the carbons necessary for construction of C19 quassinoids and set the foundation for future work in this area.