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Progress Towards the Total Synthesis of (–)-Batrachotoxin, A Computationally Inspired Second-Generation Synthesis of (+)-Fastigiatine, Progress Towards the Total Synthesis of (–)-Himeradine A, and Strategies Towards the 4,5-Spirocyclic Fragment of Phainanoid F

  • Author(s): DeForest, Jacob
  • Advisor(s): Rychnovsky, Scott D
  • et al.

The first chapter of this dissertation focus on the history and syntheses of the bioactive steroidal alkaloid (–) batrachotoxin. Several notable partial syntheses are discussed, as well as two total synthesis. Previous efforts by the Rychnovsky group, as well as our current route towards batrachotoxin are described in Chapter 2. The successful synthesis of fully elaborated AB and DE steroidal fragments are disclosed, as well as the key reductive fragment coupling and Heck cyclization to form the steroidal core.

Chapters 3 provides a concise introduction to the Lycopodium family of natural products, while Chapters 4 and 5 describe our recent efforts towards the total synthesis of two Lycopodium alkaloids, (+)-fastigiatine and (–)-himeradine A. Following the successful first-generation synthesis of fastigiatine, we chose to pursue a modified second-generation route that was inspired by computationally modeling. Highlights of the synthesis include a diastereoselective reduction-ketalization, an optimized dibromocarbene mediated ring-expansion, and utilization of photoredox catalysis to perform a radical aminomethylene conjugate addition. In Chapter 5, our efforts towards the total synthesis of himeradine A are disclosed. A highly efficient racemic synthesis of an advanced tri substituted piperidine was achieved, and several methods to perform a late-stage resolution are discussed. A proof-of-concept Suzuki coupling between the quinolizidine precursor and pentacyclic core precursor was successful. Elaboration of the coupled intermediate through the remainder of the synthesis was accomplished, confirming the validity of our approach towards the synthesis of himeradine A.

Finally, several strategies towards the synthesis of the 4,5-spirocyclic fragment of phainanoid F are presented in Chapter 6. While initial efforts on a model system were unsuccessful due to unexpected carbocation rearrangements, a route involving the photochemical Wolff ring contraction proved to be an efficient method to access the cyclobutane moiety found in the natural product. This approach is currently being applied towards the enantioselective synthesis of the western fragment of phainanoid F.

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