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Progress Toward the Kopsia Family of Indole Alkaloids and The Synthesis of Fused Pyrroles and Dihyrdoazepines via Intramolecular Cyclopropanation and Rearrangement

  • Author(s): Schultz, Erica Elizabeth
  • Advisor(s): Sarpong, Richmond
  • et al.

Chapter 1. An overview of multi-drug resistance (MDR) and the possibility of small molecule tools to elucidate the biological mechanism of MDR are outlined. The Kopsia family of natural products related to lapidilectine B is introduced, and previous synthetic efforts are discussed. Two synthetic strategies and the progress made toward the natural product are detailed. In the first route, the tetracyclic core of these molecules is accessed through a Friedel-Crafts type acylation. The second route employs an Ugi four-component coupling to introduce all the carbons found in the core of the natural product and accesses the tetracycle core in three ways.

Chapter 2. Rh-bound trimethylenemethane (TMM) variants generated from the interaction of a Rh-carbenoid with an allene have been applied to the synthesis of substituted 3,4-fused pyrroles. An overview of the synthetic variants of TMM is given and access to rhodium carbenoid centers from 1,2,3-triazoles is discussed. A range of allenes bearing different substituents is tolerated in this reaction. The pyrrole products are useful starting points for the syntheses of various dipyrromethene ligands.

Chapter 3. A method for the direct formation of dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles possessing a tethered diene is reported. Discussion of aza-Cope rearrangements and cyclopropanation from the decomposition of 1,2,3-triazoles into metallocarbenoids is given. The methodology involves an intramolecular cyclopropanation of an α-iminocarbene, leading to a transient 1-imino-2-vinylcyclopropane intermediate which rapidly undergoes a 1-aza-Cope rearrangement to generate fused dihydroazepine derivatives, mechanistic support is provided.

Chapter 4. The methodology described in Chapter 2 for the synthesis of substituted 3,4-fused pyrroles has been applied to a synthesis of the natural product cycloprodigiosin, which demonstrates antitumor and immunosuppressor activity. A history of the prodiginine family of natural products is given. The modes of action and the role of structure in regards to cycloprodigiosin's antitumor activity are also discussed.

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