Domino Azide-Metallocarbene Coupling and Nucleophilic Trapping: Synthetic Applications and Mechanistic Studies.

• Author / Creator

  Atienza, Bren Jordan Perez

• Metallocarbenes are a class of reactive intermediates used in many strategic and complementary carbon-carbon and carbon-heteroatom bond forming reactions. The Stevens [1,2]-rearrangement of ammonium ylides is an example of a transformation typically involving metallocarbenes. The replacement of the amine with azide in this metallocarbene-mediated process results to the formation of an electron-deficient imine; this imine can then be trapped with variety of nucleophiles. During the course of our study using electron-rich arenes as nucleophilic traps, a key step in the proposed total synthesis of isatisine A, we began to have issues with regioselectivity. In an effort to trouble-shoot this process, we encountered some seemingly anomalous results. Highly inquisitive, mechanistic studies were then undertaken to understand the progress of the reaction. These mechanistic studies resulted in the elucidation of a novel dual catalysis mechanism for this domino process. A library of compounds (truncated analogs of isatisine A) was then made using the newly developed reaction conditions. The mechanism was then used as a guide to develop asymmetric versions of the transformation. While attempting to apply the newly developed reaction transformation to the synthesis of isatisine A, another opportunity arose. We began exploring the possibility of expanding the existing chemical library through umpolung (reversal of polarity) reactivity. Although we were unable to induce umpulong reactivity of nucleophiles with our rigid electrophilic C-acylimines, a different regiodivergent functionalization was developed, opening the door to a greater variety of compounds. This library of new compounds was then submitted to be screened for potential antiviral activity. After several rounds of structure activity relationship studies, new lead structures were found. This dissertation has many important implications: (1) the potential of the western fragment of isatisine A as a novel antiviral lead, (2) a novel dual catalysis in metallocarbene chemistry utilizing the concept of electrophilic metalation.

• Subjects / Keywords

  • Mechanism
  • Metallocarbene
  • Azide Trapping
  • Electrophilic Metallation

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R33N20W6N

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.