University of Illinois Urbana-Champaign

Methodology and total synthesis enabled by cycloadditions

Hooper, Annie Rebecca

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HOOPER-DISSERTATION-2023.pdf

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https://hdl.handle.net/2142/120204

Description

Title
Methodology and total synthesis enabled by cycloadditions
Author(s)
Hooper, Annie Rebecca
Issue Date
2023-02-24
Director of Research (if dissertation) or Advisor (if thesis)
Sarlah, David
Doctoral Committee Chair(s)
Sarlah, David
Committee Member(s)
  • Mitchell, Douglas A
  • van der Donk, Wilfred A
  • White, Christina
Department of Study
Chemistry
Discipline
Chemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
  • Cycloaddition
  • total synthesis
  • dearomatization
Abstract
Cycloaddition reactions represent one of the most powerful methods for the construction of cyclic molecular frameworks. One such example is the Nobel prize-winning Diels-Alder reaction, first reported in 1928. This fundamental pericyclic reaction has been applied in the synthesis of countless natural products and medicinally relevant compounds. Transition metal-catalyzed cycloadditions, in contrast to thermally driven ones, provide an opportunity for unactivated substrates and challenging or theoretically forbidden cycloadditions. The first chapter of this dissertation describes the use of N-methyl-1,2,4-triazolin-3,5-dione (MTAD) for the dearomatization of arenes via palladium-catalyzed syn-1,4-carboamination. The value of this methodology was highlighted by a 4-step synthesis of the FDA-approved antidepressant Sertraline from naphthalene. The second chapter of this dissertation describes a protecting group strategy for acrylamides. Protected acrylamides can be accessed with the use of TMS-cyclopentadiene (TMS-CP) for a Diels-Alder with acrylic acid followed by coupling with the amine of choice. The ,-unsaturated amides can be unveiled in less than one hour at 160 °C. This methodology was applied to seven different FDA-approved amine containing drugs; and its potential utility was demonstrated by improving the yield of a nucleophilic aromatic substitution, as compared to an unprotected acrylamide. The third chapter of this dissertation describes the synthesis of pyritide A1, a natural product predicted through genome mining but unisolable from the native producer. The synthesis featured a Reissert-Henze cyanation and a T3P-mediated macrolactamization. Comparison of our chemically synthesized sample to one prepared chemoenzymatically by collaborators proved identical, thus confirming the structural prediction of the pyritide family. The fourth chapter of this dissertation describes a second-generation synthesis of pyritides wherein all natural products of this family could be accessed as well as diverse analogues. This diversity-oriented strategy was demonstrated by a 10-step synthesis of pyritide A2, which featured a bioinspired pyridine formation through an aza-Diels-Alder/retro-[4+2] of a 1,2,4-triazene and a chemoselective trimethyl tin hydroxide-mediated hydrolysis of an ethyl ester. Additionally, the oxidation/aza-Diels-Alder sequence was extended to several other amino acid derived diacyl ylides, demonstrating the generality of the developed methodology.
Graduation Semester
2023-05
Type of Resource
Thesis
Handle URL
https://hdl.handle.net/2142/120204
Copyright and License Information
Copyright 2023 Annie Hooper

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