Through this award funded by the Chemical Synthesis Program of the Division of Chemistry, Prof. Daesung Lee of the University of Illinois at Chicago explores a new synthetic method evolved from the formation of an unconventional strained aromatic intermediate. This method has many applications for the synthesis of biologically active natural products, pharmaceuticals, drugs, and other functional materials containing aromatic substructures. The reaction discovery, exploration of its utility and general scope, and application to the synthesis of natural and medicinally relevant compounds, provides an effective research platform for equipping students with the knowledge and skills to become competitive researchers in the work force. Importantly, because most students trained through these research areas are expected to pursue careers in either academia or industrial settings, their contributions will range from basic science to human health.
This research exploits a method for the formation of reactive arynes directly from acyclic multiyne precursors. The favorable reactivity of these arynes and their congeners generated in unconventional manners allows their subsequent functionalization to undergo Alder-ene reactions, nucleophilic addition, hydrohalogenation, and haloalkylation. In the presence of transition metal catalysts, these arynes also can promote an efficient functionalization of unactivated C-H bonds on alkyl groups, which can be further extended to aromatic systems, providing a formal hydroarylation. The reactivity profiles and mechanisms of these aryne-based transformations are further investigated by DFT-based theoretical calculations. These new aspects of aryne reactivity, in combination with a mechanistic understanding, provide an alternative approach to the limitations of current methods involving 1,2-elimination of functionalized benzene derivatives. Through the direct construction of arynes from non-aromatic precursors, a versatile new synthetic tool is evolved for the synthesis of various functionalized aromatic systems, including indoles, indolines, carbazoles, and many other aromatic structures.