University of Illinois Urbana-Champaign

Dearomative transformations in synthesis: I. Dearomative dihydroxylation with arenophiles II. Total synthesis of lycoricidine and narciclasine III. Towards the total synthesis of collybolide

Southgate, Emma Helen

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SOUTHGATE-DISSERTATION-2019.pdf

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https://hdl.handle.net/2142/104966

Description

Title
Dearomative transformations in synthesis: I. Dearomative dihydroxylation with arenophiles II. Total synthesis of lycoricidine and narciclasine III. Towards the total synthesis of collybolide
Author(s)
Southgate, Emma Helen
Issue Date
2019-02-19
Director of Research (if dissertation) or Advisor (if thesis)
Sarlah, David
Doctoral Committee Chair(s)
Sarlah, David
Committee Member(s)
  • Denmark, Scott E.
  • Hergenrother, Paul J.
  • van der Donk, Wilfred A.
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Date of Ingest
2019-08-23T20:28:07Z
Keyword(s)
  • Dearomatization
  • arene
  • lycoricidine
  • narciclasine
  • total synthesis
  • collybolide
  • dearomative
  • dihydroxylation
Abstract
Dearomatization reactions represent a powerful tool for the conversion of readily-available arenes into structurally complex, high-value intermediates in synthesis. Although there are many classic and modern approaches for overcoming the resonance stability inherent in these compounds, the technologies reported in the literature have limitations in terms of substrate scope and bonds constructed. In particular, there is a paucity of reactions for dearomative installation of functionality into simple arenes in a selective and mild fashion. The first chapter of this dissertation describes the development of a dearomative functionalization reaction developed by our laboratory for the regio- and stereoselective formation of cis-dihydrodiol and diaminodiol derivatives of simple arene substrates. Using a photochemical cycloaddition between arenes and small molecules termed arenophiles, we have accomplished a one-pot process for dearomatizing benzene, naphthalene, and higher order aromatic systems and trapping the dearomatized intermediates with osmium-catalyzed dihydroxylation. Through this approach, we have accessed a number of dihydrodiol and diaminodiol compounds with functionality not tolerated in tradition dearomatization methodologies, and we have applied this strategy to the synthesis of high value small molecules. The second chapter describes the synthesis of lycoricidine and narciclasine, two Amaryllidaceae alkaloids with potent anti-cancer activity. Through the application of a Narasaka variant of our dearomative dihydroxylation reaction and a key Suzuki reaction, we have enabled concise access to a key intermediate encompassing all of the carbon atoms present in these isocarbostyril alkaloids. In addition to completing the synthesis of lycoricidine via a nitroso-Diels–Alder reaction and protecting group cleavage, we utilized an aryl C–H hydroxylation strategy for the conversion of a late-stage lycoricidine intermediate into a compound en route to narciclasine. Finally, we were able to synthesize a range of biaryl dihydrodiol compounds through the application of our dearomative dihydroxylation-Suzuki coupling process, using commercially available boronic acids and bromobenzene as starting materials. The third chapter discusses approaches to the fungal natural product collybolide. This compound is of interest due to the increasing need for alternative opioid pharmaceuticals to treat pain and addiction caused by the current opioid crisis. As collybolide has been identified as a potent, biased κ-opioid receptor agonist, it has the potential to be developed into therapeutics for the treatment of pain, itch, addiction, and depression. No total syntheses of this compound have been reported; we have thus far explored two routes to the natural product. While the first route, using an intramolecular conjugate addition as a key step, failed, the current route employs a dearomative hydrogenation reaction to access key stereocenters in the natural product from a symmetrical arene starting material. The use of enzymatic desymmetrization will allow for the conversion of this symmetrical hydrogenated product into an enantiopure intermediate suitable for collybolide synthesis, and synthetic access to this compound will allow for further biological testing and analogue development.
Graduation Semester
2019-05
Type of Resource
text
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http://hdl.handle.net/2142/104966
Copyright and License Information
Copyright 2019 Emma Southgate

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