Strategies for the Synthesis of Highly Oxygenated Isoryanodane Diterpenoids

Natural products and the synthetic pursuit of their complex frameworks have remained a core tenet of organic chemistry since its inception as a field. Highly oxygenated isolates, perhaps, remain one of the most formidable classes of natural products. Beyond the general difficulty in managing oxidation state and undesired reactivity, these isolates often present unconventional frameworks, inspiring innovation. Outside of synthetic motivation, highly oxygenated natural products often feature desirable bioactivities, with famous examples being Taxol, ingenol, and pleuromutilin. While these more popular isolates have received significant attention, there are many frameworks which possess promising bioactivity that remains undiscovered due to lack of natural abundance. Herein, we first discuss the current strategies towards highly oxygenated terpenes, and second, disclose promising efforts toward understudied rearranged 1,2-seco-isoryanodane diterpenoids. Chapter 1 offers a review of the current strategies which dominate recent approaches to highly oxygenated terpenes. Here, it is revealed that the same families of natural products routinely emerge as targets. This leads us to the question of whether these strategies are applicable to a broader range of natural products or are limited to the families they are developed for. Of particular interest are the isoryanodane diterpenoids, featuring a densely oxygenated 5/6/5 fused core. These isolates have received minimal attention (with only one completed synthesis), especially in comparison to their biogenic precursor the ryanodane diterpenoids, which feature a highly oxygenated 6/5/5 fused core. A review of the biogenesis and related bioactivity of these natural products follows. Synopsis of the previous synthetic efforts toward this family of natural products, covering four separate approaches which, surprisingly, all feature similar points of disconnection, provides insight to the current strategies being deployed. In chapter 2, we describe efforts toward the 1,2-seco-isoryanodane diterpenoids. Of particular note is the development of a strategy which outlines the importance of building rigidity into the system as the synthesis progresses. This successful strategy has enabled access to late-stage intermediates featuring a fully functionalized core of cinncassiol F via a substrate-controlled SmI2-mediated radical cyclization, demanding Conia-ene, and finally an unexpected bridgehead oxygenation. Exploratory model system studies provide insight to the synthesis of the challenging hemiketal/ketal motif. Preliminary elaboration of these model system studies on the real scaffold provide promising results toward the inaugural synthesis of the 1,2-seco-isoryanodane diterpenoids.