Ritts, Casey2024-04-302024-04-302023-12https://hdl.handle.net/11299/262881University of Minnesota Ph.D. dissertation.December 2023. Major: Chemistry. Advisor: Thomas Hoye. 1 computer file (PDF);ix, 232 pages.Annulation reactions of linear, unsaturated substrates construct cyclic products that can contain substantially greater amounts of molecular complexity. Designed processes that leverage high energy intermediates are advantageous for expanding methods development via myriad trapping reactions of the reactive species. Our research group’s long-standing interest in the biosyntheses of polycyclic natural products has also led to fundamental studies on the cyclization reactions of polyunsaturated compounds. Specifically, we have explored the versatility of the cycloisomerization of multi-alkynyl substrates into aryne intermediates via the hexadehydro- Diels–Alder (HDDA) reaction and their subsequent trapping. Using HDDA benzynes, access to other high energy intermediates can be incorporated into the reaction path to facilitate additional annulation events. The first chapter of this thesis will detail an example of this concept that forms hypervalent main group intermediates through trapping of HDDA arynes using sulfinyl and phosphinyl reagents. These fleeting intermediates – all-carbon-ligated s-sulfuranes and s- phosphoranes – undergo reductive eliminations that form helical heteroaromatic compounds through C(sp2)–C(sp2) coupling.The second chapter discusses the biosynthesis of (+)-ottelione A, a 4-methylene-2- cyclohexenone natural product that exhibits potent antiproliferative activity via tubulin polymerase inhibition. We believe this compound is formed through a one-of-a-kind biosynthetic process that involves a spontaneous [3,3] sigmatropic (i.e., Cope) rearrangement. The enzymatic oxidation of the nominal precursor to (+)-ottelione A, a novel (acyclic) diarylheptanoid, initiates the multistep formation of a highly strained cyclonona-1,5-diene that undergoes a rare ambient temperature Cope rearrangement. The de novo syntheses of the nominal precursor, along with other diarylheptanoid analogs, was accomplished. Overall, a synthesis involving 10 steps (6 steps longest linear sequence, 38% isolated yield) was developed to provide material for biological studies involving the Ottelia alismoides plant and its protein extracts. These works share a common theme of leveraging strained, unsaturated systems for inducing unorthodox annulation processes.enarynesdiarylheptanoidhexadehydro-Diels–AlderottelionephosphoranesulfuraneThesis or Dissertation