The Second-Generation, Gram-Scale Total Synthesis of (+)-Gliocladin C and The First Total Syntheses of (+)-Plectosphaeroic Acids B and C

In Chapter 1, epipolythiodioxopiperazine (ETP) natural products are introduced. Focus is directed toward the subclass of tryptophan-derived ETPs and a closely related trioxopiperazine natural product, (+)-gliocladin C, which is proposed to serve as a common synthetic precursor of these ETPs. A review of previous synthetic approaches to ETP toxins is provided, and recent total syntheses of (+)-gliocladin C are described.;In Chapter 2, the development of the second-generation, gram-scale total synthesis of (+)-gliocladin C is described. The convergent route features two key steps. The first is a catalytic, enantioselective O- to C-carboxyl transfer reaction that constructs the all-carbon quaternary stereocenter of an oxindole precursor. The second is a demanding aldol condensation, which in conjunction with an N-acyliminium ion cyclization, unites two advanced intermediates of matched polarity.;In Chapter 3, the first total syntheses of plectosphaeroic acids B and C are described. A late-stage copper-mediated cross-coupling is used to forge the congested, central C&ndashN bond linking the two fragments of these natural products. Critical to the success of these syntheses is the elaboration of the di-(tert-butoxycarbonyl) derivative of gliocladin C to intermediates poised for introduction of the epipolythio- or dimethylthio functionality of these ETP natural products.