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I. Total Synthesis of Smenochromene B and Halenaquinone and II. Studies on the Chemical and Biological Properties of Azobenzene Photoswitches

  • Author(s): Kienzler, Michael A
  • Advisor(s): Trauner, Dirk
  • et al.
Abstract

Part one of this dissertation describes synthetic efforts toward two separate but structurally related groups of marine sesquiterpene quinone natural products, the smenochromene/likonide family and halenaquinone, and culminates in the total synthesis of smenochromene B and halenaquinone. The total synthesis of smenochromene B and efforts towards likonide A centered around the use of smenochromene D as a synthetic intermediate. A macrocyclic ring contraction and double bond isomerization was the key transformation necessary to produce smenochromene B. During the optimization of the synthesis of smenochromene D, two different and remarkable oxidative dimers were isolated, and the mechanism by which they are formed is discussed. Additionally, density functional theory calculations were used to investigate the oxa-6π electrocyclization used to synthesize smenochromene D and are believed to be biologically relevant to the markedly different levels of enantiomeric excess observed within members of the structural family.

Halenaquinone, a biologically active pentacyclic quinone isolated from the marine sponge Xestospongia exigua, is biosynthetically related to the smenochromene/likonide family. The total synthesis of halenaquinone reported here features two key steps: a diastereoselective intramolecular Heck reaction, which sets the all-carbon quaternary stereocenter, and an intramolecular inverse-electron-demand Diels-Alder cycloaddition using a vinyl-orthoquinone methide as a diene. This is the first application of such a Diels-Alder cycloaddition to total synthesis. In order to better understand the Diels-Alder reaction, density functional theory calculations were performed to analyze two relevant transition states.

Part two describes several projects focused around the synthesis of photoswitchable azobenzene ligands. In order to build on previous work that demonstrated photoregulation of wild-type voltage-gated potassium channels by membrane permeable blockers, a new series of compounds was synthesized with red-shifted absorption maxima. Two new azobenzene containing blockers were identified as being able to regulate voltage-gated potassium channels by toggling between darkness and irradiation with 472 nm light; one compound blocked voltage-gated potassium channels in the trans form, the other in the cis form. Additionally, azobenzene compounds based on the drugs lidocaine and retigabine were synthesized, and preliminary biological data are reported. Finally, the syntheses of azobenzene analogs of the anti-cancer and life-extending (in lower organisms) compound resveratrol and a related protein-tyrosine kinase inhibitor piceatannol are reported.

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