Thermal Cycloisomerizations of 1,6-Enynes for the Synthesis of Illudinine and Other High-Value Polycyclic Aromatic Structures

The longstanding challenge of constructing polysubstituted benzene derivatives has benefited from over one-hundred years of imaginative solutions to the same problem. This dissertation focuses on the many evolutions of benzannulation strategy with an emphasis on how evolving cycloaddition methodology has paved the way for insightful improvements and creative applications to complex synthetic challenges. Here, we (Dudley Group) describe efforts to harness increasingly unsaturated variations of the Diels-Alder cycloaddition to develop methodology for the synthesis of natural products and other high-value aromatic scaffolds. A cascade (cyclo)isomerization / elimination process is discussed which produces novel isoquinoline derivatives and polycyclic aromatic structures of potential interest for pharmaceutical, biomedical, and energy-related research. Mechanistic experiments support a putative allenylpyridine (reminiscent of the Garratt–Braverman cyclization) as a key intermediate in the cascade process. Finally, a concise total synthesis of the illudalane sesquiterpene illudinine was realized in eight steps and 14% overall yield from commercially available dimedone. The synthesis demonstrates the benefits of evolving benzannulation methodology in the context of synthetic efficiency. The approach features tandem fragmentation / Knoevenagel-type condensation and microwave-assisted oxidative cycloisomerization to establish the isoquinoline core. Completion of the synthesis involves a recently reported cascade SNAr / Lossen rearrangement on a densely functionalized aryl bromide and an optimized procedure for O-methylation of 8-hydroxyisoquinolines. The oxidative cycloisomerization proceeds by way of a novel inverse-demand intramolecular dehydro-Diels–Alder cycloaddition, which has a potentially broader appeal for preparing substituted isoquinolines.