Synthesis of densely-functionalized multicyclic ring systems from bicyclobutanes
| dc.contributor.author | Woelk, Kyla | |
| dc.contributor.supervisor | Leitch, David | |
| dc.date.accessioned | 2024-12-19T21:51:42Z | |
| dc.date.available | 2024-12-19T21:51:42Z | |
| dc.date.issued | 2024 | |
| dc.degree.department | Department of Chemistry | |
| dc.degree.level | Doctor of Philosophy PhD | |
| dc.description.abstract | The discovery and development of novel small molecule drug candidates is essential to the advancement of the pharmaceutical industry. One area of focus for drug development is increasing the molecular complexity and number of Csp3 centers in pharmaceutical candidates. Saturated multicyclic structures have been proposed as bioisosteres to replace portions of pharmaceutical molecules that lack these Csp3 centers. Incorporating these bioisosteres in existing pharmaceuticals has been shown to improve pharmacokinetic properties and in some cases even increase the drug’s potency. The syntheses to access these bioisosteres is limited and thus, efforts to develop more syntheses of these motifs is crucial in progressing the development of new drugs. This thesis explores the development of new methods to access these saturated multicyclic bioisosteres, specifically bridging bicycloalkanes. Bicyclo[1.1.0]butanes are used as a common starting material to access the different bicyclic compounds. Focus is placed on the use of readily available starting materials and straightforward reaction conditions. Reaction discovery, optimization and viability is reported for a variety of different bicyclic compounds. The types of bicyclic compounds that were synthesized include 2-azabicyclo[2.1.1]hexanes, 2-oxo-bicyclo[2.1.1]hexanes and 3-azabicyclo[3.1.1]heptanes. High-throughput experimentation was used to aid in reaction discovery and optimization in a streamlined manner. Reaction scopes were developed to demonstrate the applicability of these methods. Finally, this thesis demonstrates the potential for application of these bicyclic bioisosteres in pharmaceuticals via target-based synthesis. This was done through the functionalization of the products synthesized. This demonstrates their ability to be modified so they can be incorporated into drug candidates. With more syntheses of these bioisosteres available to medicinal chemists, the ability for these motifs to be applied in future drug development processes can be improved. | |
| dc.description.embargo | 2025-11-29 | |
| dc.description.scholarlevel | Graduate | |
| dc.identifier.bibliographicCitation | Woelk, K. J.; Becica, J.; U, A.; Jenny, S. E.; Leitch, D. C. Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes. Angew. Chem. Int. Ed. 2022, 61, e202204719 | |
| dc.identifier.bibliographicCitation | Woelk, K. J.; Dhake, K.; Schley, N. D.; Leitch, D. C. Enolate addition to bicyclobutanes enables expedient access to 2-oxo-bicyclohexane scaffolds. Chem. Commun. 2023, 59, 13847–13850 | |
| dc.identifier.bibliographicCitation | Dhake K.; Woelk K. J.; Krueckl, L. D. N.; Alberts F.; Mutter, J.; Pohl, M. O.; Thomas, G. T.; Sharma, M.; Bjornerud-Brown, J.; Fern´andez, N. P.; Schley, N. D.; and Leitch, D. C. Diastereoselective dearomative cycloaddition of bicyclobutanes with pyridinium ylides: a modular approach to multisubstituted azabicyclo[3.1.1]heptanes. Chem. Commun., 2024, 60, 13008-13011 | |
| dc.identifier.uri | https://hdl.handle.net/1828/20871 | |
| dc.language | English | eng |
| dc.language.iso | en | |
| dc.rights | Available to the World Wide Web | |
| dc.subject | Bicyclobutane | |
| dc.subject | Bioisostere | |
| dc.subject | Bicyclic Molecules | |
| dc.subject | Organic Synthesis | |
| dc.subject | Bicyclohexane | |
| dc.subject | Bicycloheptane | |
| dc.title | Synthesis of densely-functionalized multicyclic ring systems from bicyclobutanes | |
| dc.type | Thesis |