Bicyclobutane reactivity enables access to densely functionalized aza-multicyclic compounds
| dc.contributor.author | Dhake, Kushal | |
| dc.contributor.supervisor | Leitch, David | |
| dc.date.accessioned | 2025-08-21T19:30:18Z | |
| dc.date.available | 2025-08-21T19:30:18Z | |
| dc.date.issued | 2025 | |
| dc.degree.department | Department of Chemistry | |
| dc.degree.level | Doctor of Philosophy PhD | |
| dc.description.abstract | For over two decades, medicinal chemists have aimed to "Escape from Flatland" by increasing (stereogenic) Csp3-rich centers in target molecules. One such strategy involves bioisosterism, where aromatic units are replaced with rigid, saturated, multicyclic systems, such as small bicyclic rings. This has improved the pharmacokinetic and physicochemical properties of drug candidates and approved active pharmaceutical ingredients (APIs). However, despite the prevalent use of nitrogen heterocycles in investigational and approved compounds, there are far fewer examples utilizing azabicyclics as bioisosteres. This thesis outlines various methods for constructing a library of multisubstituted bicyclic compounds, utilizing bicyclo[1.1.0]butane (BCB) as a versatile and readily accessible substrate. The approaches prioritize minimizing synthetic steps to generate these compounds efficiently. A key focus is on the reactivity of BCBs, exploring their use in synthesizing azabicyclo[2.1.1]hexanes and cyclobutenyl methanamines, azaspiro[3.3]heptenones, 3 azabicyclo[3.1.1]heptanes, and tetrasubstituted cyclobutanes. A common theme across all experimental chapters is the dependence of reactivity on the catalytic system. Chapters 2 and 3 show that synthesizing desired azabicyclohexanes and spirolactams requires a Lewis acid catalyst. In contrast, chapters 4 and 5 demonstrate that reactivity is not dependent on Lewis acids, allowing access to azabicycloheptanes and tetrasubstituted amino-iodine functionalized cyclobutanes. Collectively, this work establishes a vital foundation for medicinal chemistry by providing access to Csp3-rich, three-dimensional bicyclic structures. These compounds potentially function as saturated bioisosteres for aromatic rings, expanding chemical space and offering expedited pathways for drug synthesis and diverse applications in the pharmaceutical industry. | |
| dc.description.embargo | 2026-08-06 | |
| dc.description.scholarlevel | Graduate | |
| dc.identifier.uri | https://hdl.handle.net/1828/22630 | |
| dc.language | English | eng |
| dc.language.iso | en | |
| dc.rights | Available to the World Wide Web | |
| dc.subject | organic synthetic methodology | |
| dc.subject | bicyclic rings | |
| dc.title | Bicyclobutane reactivity enables access to densely functionalized aza-multicyclic compounds | |
| dc.type | Thesis |