UC Irvine

This dissertation describes our development of an efficient and scaleable synthesis of the antiviral diterpenoids wickerols A and B. Chapter 1 introduces the isolation, biosynthesis, and anti-influenza activity of the wickerol/trichodermanin natural products in the context of efforts towards combating pandemic influenza. Comparisons between the anti-influenza activity of the wickerols and other anti-influenza agents are provided, and a hypothesized mechanism of action underlying the biological activity of the wickerols is proposed. Prior synthetic efforts towards the wickerols by Richards, Trauner, and Gui are described with a view towards identifying key structural features that informed our synthetic efforts. Chapter 2 discusses our first-generation total synthesis of wickerols A and B, enabled by a synthetic strategy translated from one used for the synthesis of a simplified model system. Notable contributions include the development of conditions for a diastereoselective of cuprate conjugate addition to construct a key quaternary stereogenic center, the optimization of a reductive samarium(II) iodide-mediated ketyl radical cyclization of a keto-enoate progressing through divergent reaction mechanisms depending on additive selection, the development of a Claisen-rearrangement-based sequence to install a methyl-bearing stereogenic center with simultaneous formal homologation of an aldehyde that was recalcitrant to traditional enolate methylation, and the development of an interrupted chlorinative Prins/controlled dehydrochlorination process for bridging ring construction in the face of deleterious, strain-driven carbocation rearrangements. Chapter 3 describes our motivations for pursuing a second-generation total synthesis of the wickerols, and our efforts towards implementing a concise, hydrogen atom transfer-initiated tandem radical bicyclization-based approach for rapid construction of the wickerol framework. Notable contributions include the gram-scale synthesis of a key dienyl trans-hydrindanone cyclization precursor bearing all of the carbons posessed by the wickerol framework through a mixed organocuprate conjugate addition, the discovery of a deleterious 1,5-hydrogen atom transform pathway precluding our proposed radical bicyclization, and the discovery of conditions for the formation of a fused 5/6/7 tricyclic core through a samarium(II)-iodide-mediated ketyl radical cyclization proceeding with undesired 7-endo regiochemistry. A redesigned second-generation synthetic strategy informed by these results is discussed in Chapter 4. A linear route to a suitable precursor for a polarity-matched regiocontrolled samarium(II)-iodide-mediated ketyl radical cyclization was implemented utilizing a chemoselective Mukaiyama type aldol reaction after extensive investigation of convergent conjugate allylation-based approachs. Conditions to effect a ketyl radical cyclization for construction of the fused 6/6/5 ring system embedded in the tetracyclic framework were developed. Elaboration to intermediates suitable for closure of the final, bridging ring of the wickerols through deoxygenative radical generation followed by intramolecular Giese addition and our initial investigation of this ring closure are described.