This thesis is primarily focused on the development of Wittig methodologies and the applications of the product alkenes in organocatalysis and drug discovery. Herein is described an aqueous Wittig methodology for the synthesis of α-methylstilbenes and their use in the preparation of novel triazole stilbene inhibitors of aromatase, a clinically validated target for the treatment of estrogen receptor positive breast cancer. As well, a one-step, stereoselective synthesis of alkenyl phenols was developed. The method provides easy access to a variety of compounds that contain this synthetically and biologically important functionality, including natural product phenolic stilbenes. In turn, alkenyl phenols were used as a key component in a novel organocatalytic methodology for the synthesis of cyclobutanes in good yields and high enantioselectivity. Notably, this is one of relatively few asymmetric, catalytic methods for cyclobutane synthesis. Preliminary biological activity of some of these cyclobutane derivatives is reported, including promising anti-cancer activity. Finally, a ten-step total synthesis of the Amaryllidaceae alkaloid (+)-trans-dihydronarciclasine was completed. The synthesis features an organocatalytic Michael-aldol cascade on a cinnamaldehyde derivative, which was prepared using a Wittig methodology previous reported by the McNulty group. Importantly, this compound was found to be one of the most potent anti-Zika compounds reported to date. Future work should focus on improving the potency and selectivity of the various aforementioned chemotherapeutics, with concurrent efforts to build upon the novel methodologies discussed herein. / Thesis / Doctor of Philosophy (PhD) / The Wittig reaction is one of the best ways to make alkenes, a type of reactive bond between two carbon atoms. A new Wittig reaction was developed and used in the preparation and discovery of potent inhibitors of aromatase, an enzyme responsible for the proliferation of many breast cancers. As well, another Wittig methodology was created for the straightforward synthesis of an otherwise difficult to prepare class of alkenes. In turn, these types of alkenes were used in a novel preparation of cyclobutanes, a chemical structure that is difficult to make but can impart useful properties to drugs and materials. Finally, a Wittig reaction previously reported by the McNulty group was used as part of a chemical synthesis of trans-dihydronarciclasine, a rare natural product isolated from daffodils. Trans-dihydronarciclasine was discovered to have antiviral activity and is one of the most potent inhibitors of the Zika virus discovered to date.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24463 |
| Date | January 2019 |
| Creators | Nielsen, Alexander J. |
| Contributors | McNulty, James, Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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