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New Aspects of Nazarov Reaction: Additive Effects, Gold Catalysis and Application Toward the Synthesis of Taxinine

  • Author / Creator
    Joy, Shaon
  • Methods involving efficient and stereoselective carbon-carbon bond formation enable chemists to synthesize bioactive natural products and drugs. The Nazarov reaction is a versatile tool for the construction of functionalized cyclopentenones. This 4π-electrocyclization provides easy and efficient access to multi-substituted cyclopentenones with excellent stereocontrol at two contiguous ring carbons and opportunities to link to additional bond-forming events. Typically, the Nazarov cyclization involves 1,4-pentadien-3-ones. However, development of unconventional initiation protocols to access the key pentadienyl cation in the Nazarov reaction has gained considerable popularity over the past decade. Chapter 1 describes the recent activity in the area of alternate activation protocols for Nazarov cyclization. One rapidly expanding area of homogeneous gold catalysis is the Au(I) catalyzed rearrangements of propargylic carboxylates, leading to domino reaction sequences. Chapter 2 discusses the synthesis of bridged bicyclic enynyl acetates and their use as dienone surrogates. The compounds undergo a [3,3]-rearrangement followed by a 4π-electrocyclization under Au(I) catalysis to form cyclopentenones in a regioselective fashion. Chapter 3 recounts our comprehensive investigation on the effects of additives in the silicon-directed Nazarov cyclization. We have found that the presence of hydroxylic additives can lead to facile and clean cyclizations of β-silyl substituted dienones. Successful cyclization of some lightly substituted dienones have been reported, which are otherwise highly unreactive under standard conditions. In chapter 4 our continued efforts toward the synthesis of taxinine are reported. The completion of the synthesis requires a six-membered ring annulation method to a previously established bicyclo[5.3.1]undecene core. Our attempts at the six-membered ring annulation involving a late-stage C-H insertion via metal-carbenoid chemistry has been presented. Some novel reactivities of the late-stage intermediates have also been explored. Prion diseases are a group of infectious neurodegenerative disorders that affect both humans and animals. They are invariably fatal due to the lack of proper treatment or cure. Current research relies heavily on the hypothesis that prion pathogenesis coincides with the cellular prion protein (PrPC) undergoing conformational change to the β-sheet enriched isoform PrPSc. Chapter 5 elaborates our efforts in the development of multivalent PrPSc binding compounds. Three classes of compounds were synthesized and tested for anti-prion activity.

  • Subjects / Keywords
  • Graduation date
    2013-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3Q38F
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Chemistry
  • Supervisor / co-supervisor and their department(s)
    • Dr. West, Frederick (Chemistry)
  • Examining committee members and their departments
    • Dr. Clive, Derrick (Chemistry)
    • Dr. Zhang, Liming (Chemistry)
    • Dr. Cairo, Christopher (Chemistry)
    • Dr. Klobukowski, Mariusz (Chemistry)
    • Dr. Lowary, Todd (Chemistry)