Kushal Dhake

Topic

Bicyclobutane reactivity enables access to densely functionalized aza-multicyclic compounds

Department of Chemistry

Date & location

• Wednesday, August 6, 2025
• 8:00 A.M.
• Clearihue Building, Room B017

Examining Committee

Supervisory Committee

• Dr. David Leitch, Department of Chemistry, University of Victoria (Supervisor)
• Dr. Jeremy Wulff, Department of Chemistry, UVic (Member)
• Dr. Nelson Lam, Department of Chemistry, UVic (Member)
• Dr. Jennifer Cobb, Department of Biochemistry and Microbiology, UVic (Outside Member)

External Examiner

• Dr. Stephen Newman, Department of Chemistry and Biomolecular Sciences, University of Ottawa

Chair of Oral Examination

• Dr. Kristan Jensen, Department of Physics and Astronomy, UVic

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-ring 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 of 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. Collectively, this work establishes a promising foundation for medicinal chemistry by providing access to Csp3-rich, three-dimensional bicyclic structures. These compounds function as saturated bioisosteres for aromatic rings, expanding chemical space and offering expedited pathways for drug synthesis and diverse applications in the pharmaceutical industry.