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Radical-Polar Crossover Cyclizations in the Total Synthesis of Paxilline Indole Diterpenes

  • Author(s): Schatz, Devon
  • Advisor(s): Pronin, Sergey V
  • et al.
Creative Commons 'BY' version 4.0 license
Abstract

In Chapter 1, a thorough overview of the paxilline indoloterpenoids will be covered with an emphasis on the diterpene congeners. Their notable biological activities will be discussed, as well as their challenging structural features from a synthetic organic chemistry standpoint. A brief discussion on the biosynthetic origin of the natural product family is also provided. Prior synthetic art will then be discussed at length, with an emphasis on the terpene core, as knowledge of synthetic challenges intrinsic to this system has intimately guided the work discussed in Chapters 2 and 3.

Chapter 2 describes our lab’s efforts towards a total synthesis of (–)-nodulisporic acid C. Development of a key radical-polar crossover cascade and an enantioselective conjugate addition permitted expedient access the terpene core. Completion of the highly convergent synthesis was facilitated by an efficient, intermolecular ketone a-arylation between two complex fragments that required extensive optimization. Taken together, a 12-step, asymmetric synthesis of (–)- nodulisporic acid C was completed.

Chapter 3 describes recent efforts to elaborate on the utility of the key radical-polar crossover cyclization to access additional paxilline indole diterpene congeners, particularly flagship congener paxilline itself. Various strategies were assessed for transforming the original polycyclization product into the desired oxidation pattern. The lack of success in this endeavour forced a revision of the polycyclization substrate altogether. Proof of concept with this strategy has been demonstrated towards the core of paxilline.

In Chapter 4, a brief review of carbon-carbon bond forming processes enabled by hydrogen atom transfer is described. Our labs methodology expanding the radical-polar crossover cascade to a well-functioning annulation is then discussed. Highly decorated cyclohexanols, complementary to Diels-Alder adducts, were efficiently accessed. The methodology permitted a facile synthesis of labdane diterpene forskolin.

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