UC Irvine

This dissertation chronicles the development of a metal-hydride hydrogen atom transfer(MHAT) initiated annulation and its implementation in the synthesis of terpenoid natural products. Chapter 1 introduces the concept of MHAT and relevant transformations developed within this reactivity manifold. The second half of Chapter 1 details our development of a novel MHAT-initiated annulation between α,β- and γ,δ-unsaturated carbonyls to access sterically congested terpenoid motifs. Chapter 2 begins with a brief overview of the biosynthesis and bioactivity of the labdane diterpenoid forskolin. Specific attention is paid to the utility of forskolin as a biological tool to stimulate adenylyl cyclase and its corresponding analogs as therapeutics. The latter half of Chapter 2 focuses on prior total syntheses of this secondary metabolite, highlighting the challenges associated with constructing the carbocyclic core and establishing the stereochemically complex array of oxidation found in the natural product. Chapter 3 details our synthetic efforts towards forskolin, which leveraged the previously described MHAT-initiated annulation culminating in a 14-step synthesis of the target compound. Chapter 4 begins with a brief overview of the biosynthesis and bioactivity of quassinoid natural products. This section focuses on some of most biologically potent congeners and their antimalarial and anticancer properties. The latter portion of this chapter covers the prior syntheses of the congener quassin, which serves as a logical entry point for groups aiming to establish a general synthetic route to the quassinoids. Specific attention is paid to the challenges associated with introducing the extensive oxidation found in quassin. Chapter 5 details our synthetic efforts towards quassin and the evolution of the MHAT-initiated annulation in a synthetic setting, which led to a 14-step synthesis of the target compound.