Date of Award
Master of Science (MS)
Department of Chemistry
Timothy A Mitchell
Cycloaddition reactions are valuable synthetic tools, providing efficient reaction pathways toward the formation of complex three-dimensional polycyclic structures from planar precursors, often in a regio- and stereoselective fashion.1 Previously, the Mitchell research group has reported differing reactivity of acetoxypyranones and silyloxypyrones in the exploration of base- and thermal-mediated oxidopyrylium-alkene [5+2] cycloadditions.2 Oxidopyrylium-based [5+2] cycloadditions allow efficient access toward bridged polycyclic ethers and related seven-membered ring systems via dipolar, aromatic oxidopyrylium intermediates, affording common structural motifs present in biologically active compounds.3 Through our investigation of these and related systems, our group aims to garner mechanistic insight to allow for further development of this synthetic methodology.
Unlike the heavily-studied Diels Alder [4+2] cycloaddition, oxidopyrylium-based [5+2] cycloadditions are not well understood at a mechanistic level, and the resulting deficit of fine mechanistic detail hinders the effective application and overall potential of this powerful transformation. Work in the Mitchell research group towards expanding the utility of [5+2] cycloadditions emphasizes the following three aims: uncovering mechanistic insight, examining complex synthetic applications, and developing novel reaction strategies.
Specifically, investigation of oxidopyrylium [5+2] cycloadditions in silyloxypyrone-alkene systems has revealed several factors impacting the rate of cyclization, including: the composition of silyl transfer groups, steric implications of molecular tethers, and the electronic nature of tethered olefins. Implementation of several mechanistic probes, such as kinetic isotope effect (KIE) studies and molecular modeling computations, has allowed for the identification of mechanistic scenarios contrasting the commonly accepted mode of reactivity of activation toward zwitterionic oxidopyrylium intermediates followed by rate-determining, concerted [5+2] cycloaddition for these systems. Additionally, the application of [5+2] cycloadditions towards the synthesis of natural product scaffolds was investigated in efforts towards the target toxicodenane A. Finally, an exploration of temporary molecular tethers to overcome inherent limitations of intermolecular [5+2] cycloadditions has led to the development of novel strategies utilizing boron-based tethers, allowing for successful net intermolecular [5+2] cycloadditions.
Grabowski, Jake, "Investigation and Application of Oxidopyrylium-Based [5+2] Cycloadditions and the Development of Novel Synthetic Strategies" (2021). Theses and Dissertations. 1437.
Available for download on Wednesday, October 15, 2025