rdf-syntax-grammar
mods:
  schema location: http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
  title info:
    title: Development of Lewis base catalyzed stereoselective methods for synthesis of [beta]-lactones and dyotropic rearrangements of tricyclic [beta]-lactones
  name:
    name part: Purohit, Vikram C.
    role:
      role term: creator
  name:
    name part: Romo, Daniel
    role:
      role term: thesis advisor.
  type of resource: text
  genre: bibliography
  origin info:
    place:
      place term: txu
    date issued: 2010
    issuance: monographic
  language:
    language term: eng
  physical description:
    form: electronic
    form: remote
    extent: 1 online resource.
  abstract: The recent finding that the FDA-approved antiobesity agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-beta-lactones. The well-documented upregulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl- beta -lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facialselective hydrogenation leading to cis-substituted- beta -lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent R-epimerization and R-alkylation or acylation led to trans- beta - lactones and beta -lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-lactones displayed antagonistic activity (apparent Ki in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis- beta -lactone, displayed an apparent Ki (2.5 ( 0.5 muM) of only 10- fold lower than that of orlistat (0.28 ( 0.06 muM). In addition, mechanistic studies of the ketene dimerization process by Reaction View infrared spectroscopy support previous findings that ketene formation is rate determining. A highly diastereoselective, nucleophile-promoted bis-cyclization process, employing readily available and tractable keto-acid substrates, is described. This methodology provides concise access to bicyclic- and tricyclic-beta-lactones bearing tertiary carbinol centers and quaternary carbons, greatly extending the scope of previous routes to bicyclic-beta-lactones from aldehyde acid substrat…
  note: by Vikram Chandrakant Purohit.
  note: "Major Subject: Chemistry"
  note: Title from author supplied metadata (automated record created 2010-03-12 12:08:51).
  note: Electronic resource.
  note: Doctor of Philosophy Texas A&M University 2008 http://hdl.handle.net/1969.1/ETD-TAMU-2008-12-199
  note: Includes bibliographical references.
  note: Text (Dissertation)
  subject:
    topic: Major chemistry
  subject:
    topic: Lewis base catalysis
  subject:
    topic: Beta lactones
  subject:
    topic: Dyotropic rearrangements
  identifier: http://hdl.handle.net/1969.1/ETD-TAMU-2008-12-199
  record info:
    record content source: TXA
    record creation date: 100428
    record change date: 20151201150137.0
    record identifier: in00002595316