Abstract: 

Paxilline indole diterpenoids constitute a family of structurally complex natural products that exhibit a broad range of biological activities, including BK channel inhibition and anti-flea activity. These congeners share a common pentacyclic indoloditerpenoid core featuring vicinal quaternary stereocenters, while structural diversity arises from variations in the heterocyclic motif of the terpene fragment and substitution pattern on the indole moiety. Previous synthetic efforts have identified the construction of these vicinal quaternary stereocenters as a principal challenge in developing efficient synthetic routes to these complex natural products. The Pronin laboratory addressed this challenge through the development of a novel polycyclization reaction that efficiently constructs the vicinal quaternary stereocenters and rapidly building structural complexity. This strategy provided efficient access to advanced intermediates for the synthesis of emindole SB and nodulisporic acid C. Building on this work, I investigated the expansion and broader synthetic utility of the polycyclization reaction and demonstrated its application to the preparation of previously inaccessible, highly functionalized intermediates relevant to the paxilline indole diterpenoid family. These intermediates provide a platform for the introduction of the structural features and oxidation states characteristic of the more complex members of the family. Application of this strategy ultimately enabled the first synthesis of penerpene D in 11 steps and established substantial progress toward the synthesis of paxilline.