CaltechTHESIS
  A Caltech Library Service

Aryne annulation reactions toward the synthesis of heterocyclic molecules

Citation

Gilmore, Christopher Dennis (2012) Aryne annulation reactions toward the synthesis of heterocyclic molecules. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:03212012-034245395

Abstract

The last decade has seen an outgrowth in the development of synthetic methodologies exploiting benzyne. The unique ability of this reactive intermediate to directly furnish ortho-difuntionalized aromatic systems first stoked interest in this research group as a possible partner in asymmetric arylation reactions. Since our initial forays, we have expanded our synthetic strategies to include bond insertions, cycloadditions, condensations, and multicomponent reactions. The first project discussed in this volume is the development of an aryne annulation strategy for constructing common, synthetically useful heterocyclic structures in a convergent manner. We have developed a convergent approach to indoles and indolines. Likewise, through an orthogonal functional group intallation upon an enamine substrate, isoquinolines, quinolines, and isoquinolones can all be accessed as well. In this manner, we have been able to generate an array of functionalized heterocycles, including some that are prohibited by traditional means of synthesis. We have also begun to understand some of the reactivity trends in this context for the elusive aryne reaction partner. The development of the aryne annulation strategy for the synthesis of isoquinolines directly led to the shortest reported total synthesis of the opiate alkaloid papaverine, and the tetrahydroisoquinoline anticancer antibiotic quinocarcin. Our more recent, ongoing efforts toward the synthesis of the bis-tetrahydroisoquinoline antitumor molecule jorumycin and its many structural relatives are detailed herein. Jorumycin has been targeted through a combination of aryne annulation and acyl-alkylation/condensation methodologies aimed at the synthesis of a functionalized bis-isoquinoline intermediate. Reduction of this key bis-isoquinoline to a bis-tetrahydroisoquinoline and subsequent lactamization will provide the pentacyclic core of jorumycin and related natural products in only three steps from simple isoquinoline building blocks. The final project described is the development of several different aryne multicomponent reactions to form novel carbo- and heterocyclic scaffolds, including iminoisobenzfurans, iminoindenones, dibenzoketocaprolactams, and 2-quinolones.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Organic Synthesis, Synthetic Chemistry, Organic Chemistry, total synthesis, arynes, benzyne, reactive intermediate, alkaloids, three-component reaction, multicomponent reaction, isoquinoline, indole, indoline, tetrahydroisoquinoline, quinoline
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Mixed availability, specified at file level
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Bercaw, John E. (chair)
  • Dervan, Peter B.
  • Hsieh-Wilson, Linda C.
  • Stoltz, Brian M.
Defense Date:14 March 2012
Record Number:CaltechTHESIS:03212012-034245395
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:03212012-034245395
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6859
Collection:CaltechTHESIS
Deposited By: Christopher Gilmore
Deposited On:01 Jun 2012 17:57
Last Modified:26 Dec 2012 04:40

Thesis Files

[img]
Preview
PDF (Introduction) - Final Version
See Usage Policy.

326Kb
[img]
Preview
PDF (Ch. 1: Heterocycles by Aryne Annulation) - Final Version
See Usage Policy.

1955Kb
[img]
Preview
PDF (Ch. 2: Orthogonal Aryne Annulations to form Heterocycles) - Final Version
See Usage Policy.

2319Kb
[img] PDF (Appendix 1: Spectra for Ch. 2) - Final Version
Restricted to Caltech community only until 14 March 2018.
See Usage Policy.

12Mb
[img]
Preview
PDF (Ch. 4: Three-Component Aryne Reactions with Isocyanides) - Final Version
See Usage Policy.

2644Kb
[img] PDF (Appendix 3: Spectra for Ch. 4) - Final Version
Restricted to Caltech community only until 14 March 2018.
See Usage Policy.

13Mb
[img] PDF (Appendix 4: X-ray data for Ch. 4) - Final Version
Restricted to Caltech community only until 14 March 2018.
See Usage Policy.

567Kb
[img]
Preview
PDF (Bibliography and Index) - Final Version
See Usage Policy.

252Kb

Repository Staff Only: item control page