A novel approach to access N-Aryl nitrones via copper catalyzed coupling of benzyl alcohols with nitrosobenzenes is described. The results of mechanistic studies are conflicting but suggest this reaction proceeds through either redox process or a nucleophilic nitroso hydrate intermediate formed in situ, which was previously unprecedented. The unique electronics of this process allow access to nitrones with excellent step and atom economy, which are otherwise difficult to make using conventional methods. In this work, a total of 22 nitrones have been made. 15 of which from pure starting materials with yields ranging from 26 - 89 % and another 7 from two step, one pot reactions where the nitrosobenzenes were made in situ from commercially available anilines and reacted in a subsequent step to produce the nitrone in 8 - 46 % yield. In addition to the nitrone forming reaction occurring in the second step of a two-step sequence, we have also shown that subsequent reactions can be done on newly formed nitrones in one pot. This was demonstrated with a newly synthesized nitrone and a donor-acceptor cyclopropane in a [3+3] annulation reaction forming the cycloadduct in 90% yield. / Thesis / Master of Science (MSc) / With over 250 000 cases of resistant bacterial infections reported, and more than 5 400 directly causing Canadian deaths in 2018, we are currently facing an antibiotic crisis[67]. A particularly worrying class of resistance involves Gram-negative bacteria, as their highly impermeable outer membrane poses added complexity to their evolved resistance mechanisms[68]. The outer membrane restricts the chemical matter able to cross, making the bacteria intrinsically resistant to small molecule antibiotics and other compounds which may have intracellular targets[69],[70]. This barrier is therefore a major bottleneck for cellular mechanistic studies and compound mechanism of action, as these small molecules cannot gain entry to the cell. To circumvent this issue, outer membrane permeabilizing compounds must be discovered so that these systems can be more effectively studied. Commonly used membrane active compounds such as colistin and its derivatives, interact with both the outer and inner membranes of Gram-negative bacteria, and are toxic to cells[71]. Therefore, molecules that are outer membrane selective and nontoxic to Gram negative bacteria would be useful tools to expedite the study of biological systems.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27127 |
| Date | January 2021 |
| Creators | Borrillo, Louie |
| Contributors | Magolan, Jakob, Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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