Wang, Tao2017-03-142017-03-142016-12http://hdl.handle.net/11299/185113University of Minnesota Ph.D. dissertation. December 2016. Major: Chemistry. Advisor: Thomas Hoye. 1 computer file (PDF); xiii, 246 pages.Part I: Paracaseolide A, a natural product characterized by a tetracyclic dilactone core structure containing six adjacent stereocenters, has an unprecedented skeleton and occupies unique structural space among the >200,000 characterized secondary metabolites. Researchers from six different groups have published a chemical synthesis of this compound; five used a thermal, net Diels–Alder cycloaddition and dehydration at high temperature under neat and O2-free condition to access this target by dimerization of a simple butenolide precursor. In my study, I found (i) that this dimerization proceeds under much milder (ambient temperature) conditions and with a different stereochemical outcome (exo instead of endo), rationalizable by a bis-pericyclic transition state, than previously recognized; (ii) that spontaneous epimerization, necessary to correct the configuration at one key stereocenter, is viable; and (iii) that natural paracaseolide A is racemic—a fact that directly points to the absence of enzymatic catalysis (namely, Diels–Alderase activity) in the cycloaddition. Together these results strongly suggest that a non-enzyme-mediated dimerization of butenolide monomer is the actual event by which paracaseolide A is produced in Nature. Part II: The hexadehydro-Diels–Alder (HDDA) reaction has recently grown as a powerful alternative in the generation of benzyne intermediates as well as a de novo approach in accessing highly substituted aromatic systems. Like other members of the venerable Diels–Alder cycloaddition, HDDA reaction starts from linear precursors and is also highly atom economical. I have contributed to several projects in this area of study. These includes (i) mechanism of cycloisomerization step (concertedness of reaction), (ii) origin of distortion in the geometry of benzyne, (iii) mechanism in the trapping reactions of tethered silyl ether, tethered arene and intermolecular trapping of alcohols, and (iv) synthesis of dichloroarene and carbazole derivatives via a HDDA-based strategy.encarbazolyneHDDAparacaseolideThesis or Dissertation