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Development of Versatile Strategies for Aryne Annulation: Applications in Methodology and Natural Product Total Synthesis


Allan, Kevin McCormack (2010) Development of Versatile Strategies for Aryne Annulation: Applications in Methodology and Natural Product Total Synthesis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/VPEN-7M75.


Since the elucidation of its structure in 1953, benzyne has been the focus of intense interest within the chemical community. Due to an unusually high degree of ring strain, benzyne displays reactivity uncharacteristic of common alkynes, including a tendency to react under mild metal-free conditions. This reactivity is exploited in the development of three novel methods for the synthesis of heterocyclic structures.

The first synthetic methodology includes two orthogonal annulation reactions taking place between functionalized enamines and arynes. The substitution at the nitrogen atom of the enamine determines the path of reactivity. Carbamates undergo a formal [3 + 2] cycloaddition with arynes to give rise to indolines, while amides undergo a formal [4 + 2] cycloaddition and dehydration to form isoquinolines. The latter reaction is applied to a three-step synthesis of the antispasmotic pavine alkaloid, papaverine.

This isoquinoline-forming aryne annulation reaction is further employed in a concise asymmetric total synthesis of the tetrahydroisoquinoline antitumor antibiotic, (–)-quinocarcin. In addition to this key transformation, the synthetic route features an auxiliary-mediated diastereoselective dipolar cycloaddition to set the absolute stereochemistry and a novel two-step reduction to form the tetrahydroisoquinoline. In total, this strategy has enabled the shortest total synthesis of this important alkaloid reported to date.

The second methodology involves the synthesis of 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones from β-ketoesters using an aryne acyl-alkylation reaction in combination with an in-situ condensation. This technology enables the preparation of highly functionalized polyaromatic ring systems in two steps from readily available carboxylic acid starting materials. As a demonstration of its utility, this method is employed in a rapid synthesis of the P,N-ligand, QUINAP.

Finally, the development of a pair of three-component coupling reactions between arynes, isocyanides, and a third relay species is described. Phenyl esters and quinones lead to iminoisobenzofurans, while alkynes furnish iminoindenones. Procedures for the subsequent hydrolysis of these products are provided, thereby giving access to synthetically useful ortho-ketobenzamide and indenone compounds.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Synthesis; Aryne; Alkaloid; Isoquinoline; Quinocarcin
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Bercaw, John E. (chair)
  • Reisman, Sarah E.
  • Dervan, Peter B.
  • Virgil, Scott C.
  • Stoltz, Brian M.
Defense Date:25 March 2010
Record Number:CaltechTHESIS:04272010-110655339
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5744
Deposited By: Kevin Allan
Deposited On:07 May 2010 21:58
Last Modified:08 Nov 2023 00:39

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