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Topic

Studies Toward a Unified Synthesis of 6,11-Dioxasteroids

Department of Chemistry

Date & location

• Monday, April 28, 2025
• 3:30 P.M.
• Elliott Building, Room 226

Examining Committee

Supervisory Committee

• Dr. Jeremy Wulff, Department of Chemistry, University of Victoria (Supervisor)
• Dr. Heather Buckley, Department of Chemistry, UVic (Member)
• Dr. David Leitch, Department of Chemistry, UVic (Member)
• Dr. Peter Wan, Department of Chemistry, UVic (Member)
• Dr. Caren Helbing, Department of Biochemistry and Microbiology, UVic (Outside Member)

External Examiner

• Dr. Glenn Micalizio, School of Pharmacy & Pharmaceutical Sciences, University of California, Irvine

Chair of Oral Examination

• Dr. Simon Devereaux, Department of History, UVic

Abstract

Steroid molecules have many essential biological functions. Some steroids (e.g. cholesterol) are key components of cell membranes, while others (e.g. steroid hormones) regulate vital signalling pathways. Given their physiological importance, steroids have long served as starting points for the development of new drug molecules. Steroidal drugs are accessed through peripheral modifications to the hydrocarbon skeleton or through deep-seated structural changes to the core framework itself. Heterocyclic steroids—steroidal molecules that have one or more heteroatoms (typically oxygen, nitrogen, or sulfur) embedded in their core skeleton—have unique physicochemical, metabolic, and biological profiles compared to their (natural) carbocyclic counterparts. Many classes of heterocyclic steroids have been synthesized, including the 6- and 11-oxasteroids. In contrast, the higher order 6,11-dioxasteroids have garnered very little attention. Only one synthetic study has been documented in the literature, and as of yet no biological data have been reported for the 6,11-dioxasteroids. Efficient access to these molecules could potentially lead to the discovery of new drug candidates or biological tool compounds. This thesis describes our quest toward achieving a unified synthesis of 6,11-dioxasteroids. Herein, we provide a thorough account of how we charted a course to synthesizing the most advanced 6,11-dioxaestranes known to date. As a distinctive feature, we routinely capitalized on the chemistry of vinyl ether intermediates. Importantly, this also motivated us to develop new synthetic methodology. In addition to synthesizing advanced 6,11-dioxaestranes, we also developed a protocol for the copper-catalyzed Chan–Evans–Lam synthesis of trisubstituted vinyl ethers. Although we encountered many pitfalls during the course of our synthetic campaign, we eventually devised a stepwise sequence for constructing the tetracyclic 6,11-dioxaestrane skeleton. Of note, a Schenck-ene photooxygenation was employed early in the synthesis to set the stage for a crucial C-ring annulation step. Recognizing the importance of functionalizing the D-ring prior to tetracycle formation, we implemented a singlet oxygen-mediated cascade reaction on a vinyl ether-containing cyclopentadiene intermediate. This chemo-, regio-, and diastereoselective transformation enabled access to highly functionalized bicyclic CD-ring building blocks. The A-ring was introduced using a convergent Mitsunobu coupling. Finally, we secured access to advanced 6,11-dioxaestranes by identifying mild conditions for a Friedel–Crafts cyclization. We anticipate that the work described in this thesis will serve as a launching point for future discovery efforts in medicinal chemistry and chemical biology.