THE TOTAL SYNTHESIS OF COMPLEX MOLECULES VIA ELECTROCYCLIC RING CLOSURES OF DIVINYLPYRROLINES AND DIVINYLOXAZOLINES

Open Access
Author:
Huntley, Raymond
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
December 22, 2008
Committee Members:
  • Raymond Lee Funk, Dissertation Advisor
  • Raymond Lee Funk, Committee Chair
  • Steven M Weinreb, Committee Member
  • Ken S Feldman, Committee Member
  • Hasan Koc, Committee Member
Keywords:
  • Dragmacidin
  • Natural Products
  • Trikentrin
Abstract:
The total syntheses of the indole alkaloid natural products cis-trikentrin A and cis-trikentrin B, as well as the indolizidine natural product ã-lycorane are discussed in chapters 1 and 2. The key step in each of these syntheses is a thermal 6ð-electrocyclic ring closure reaction of a divinylpyrroline. This chemistry extends our existing methodology for the synthesis of 3,4-annulated indoles to a much wider range of substitution patterns, particularly the preparation of indoles substituted at the 4, 5, 6 and 7 positions. The diastereoselective preparation of 2,4-dialkylated cyclopentanones was also examined as part of this work. Chapters 3-5 describe our work towards the synthesis of the natural product dragmacidin E. Chemistry for the preparation of 3,4-annulated-7- hydroxyindoles, a key structural feature of dragmacidin E, was initially developed. This chemistry employed our earlier indole synthesis methodology, modified using lessons learned from our studies toward the trikentrin natural products. Pyrazine annulation chemistry was then examined, ultimately leading to the development of a 7-exo-Heck cyclization approach to the central 7-membered ring of dragmacidin E. This allowed for the preparation of the core ring system of the natural product. The introduction of the remaining methyl and bromide substituents was then effected, requiring the development of conditions for a challenging halogenselective Heck reaction. Finally, efforts were directed towards the spirocyclic guanidine ring of dragmacidin E, via either nitrile or aminonitrile intermediates.