Verdazyl radicals, discovered in 1963, are a family of exceptionally stable radicals defined by their 6-membered ring containing four nitrogen atoms. Verdazyl radicals are highly modular compounds with a large assortment of substitution patterns reported. Their stability and high degree of structural variability has been exploited in the fields of materials, inorganic, polymer and physical chemistry; however their deliberate use as starting materials towards organic synthesis had only been reported in recent years by the Georges lab.
In 2008, the Georges group reported a disproportionation reaction that was observed to a occur with 6-oxoverdazyl radicals resulting in azomethine imines capable of undergoing 1,3-dipolar cycloaddition reactions. With this discovery, the door to using verdazyl radicals as substrates towards organic synthesis had been opened. Their utility in synthesis was soon discovered not to be limited to just the cycloadducts their azomethine imine derivatives could generate but also the increasing number of N-heterocycles that could be generated from these cycloadducts via unique rearrangement reactions, a major theme of this thesis. In addition, triphenyl verdazyl radicals, a distinct class of verdazyl radicals, has been shown to react with alkynes by direct radical addition and rearrangement to afford isoquinolines.
As part of this thesis, a new synthetic methodology of generating 6-oxoverdazyl radicals is reported that does not rely on the use of phosgene or hydrazines. This new synthesis allows for the expansion of available alkyl substituents possible on N1 and N5 positions of 6-oxoverdazyl
radicals, as well as, generation of unsymmetrical examples of 6-oxoverdazyl radicals with non-identical N1 and N5 alkyl substituents. Employing the new 6-oxoverdazyl radicals synthesized via this method, a study on the effects of different alkyl substituents on the disproportionation reaction of 6-oxoverdazyls was undertaken.
Lastly, given the assortment of N-heterocyclic molecular scaffolds capable of being synthesised starting from verdazyl radicals as precursors, the applicability of verdazyl radicals in making a diversity oriented synthesis (DOS) based library was explored. In a group effort with other Georges lab members, a small library composed of various classes of verdazyl radical derived compounds was synthesized and non-specifically tested for cytotoxicity against acute myeloid leukemia and multiple myeloma cell lines in collaboration with The Princess Margaret Hospital. One example was shown to effectively kill cancer cells in both these lines in 250 μM concentration pointing out the potential of using verdazyl radical based chemistry in drug discovery.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/43376 |
| Date | 12 December 2013 |
| Creators | Bancerz, Matthew |
| Contributors | Georges, Michael |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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