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Preparation and Application of Cyclic Chiral Organoboron Compounds for the Stereoselective Synthesis of Vacquinol-1 Analogs, and Trisubstituted Cyclobutylboronates

  • Author / Creator
    McDonald, Rory
  • Boron is a versatile atom in synthetic organic and medicinal chemistry. The formation of a variety of carbon-carbon and carbon-heteroatom bonds, and the ability to act as a pharmacophore makes boron a powerful tool in drug discovery. An area of drug discovery that remains underexplored with boron is the application and preparation of cyclic chiral boronates to synthesize bioactive scaffolds of interest. The use of chiral boronates is particularly appealing for the preparation of privileged scaffolds, as a greater amount of synthetic diversity can be become available, which has important implications in drug repurposing, and discovering new biological activity with common molecular scaffolds. With such great potential, the chemistry and applications of chiral boronates warrant further study. To study the application of cyclic boronates, a rapid library of analogs for vacquinol-1 (vac-1)—a preclinical candidate against glioblastoma multiforme (GBM)—was synthesized using racemic allylic piperidinyl boronates and quinoline aldehydes. This library was generated to try and find a more potent and efficient analog, as vac-1 has now been abandoned as a clinical candidate, largely due to its poor in vivo activity in mice transplanted with GBM tumours. For the preparation of chiral boronates, a variety of cyclobutenones were synthesized using an optimized route. This library of cyclobutenones were subjected to a catalytic enantioselective conjugate borylation reaction to examine the generality of the reaction and limitations of substrates. This project is particularly noteworthy, as it is one of the first successful examples of preparing tertiary trisubstituted cyclobutylboronates using conjugate borylation chemistry. Since these cyclobutylboronates are unknown, they represent a wonderful opportunity to discover potential drug candidates incorporating a polysubstituted cyclobutane motif.

  • Subjects / Keywords
  • Graduation date
    Spring 2020
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-srr2-sj80
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.