The objective of this research program is to develop new reaction methodology for synthesizing economically important and biologically relevant carbocyclic and heterocyclic molecules. Studies will focus on the elaboration and advancement of nickel-catalyzed annulations and cyclizations that function under user-friendly conditions and employ benign starting materials. These reactions will include regioselective cycloadditions of unsaturated hydrocarbons with heterocumulenes and new cyclization-based molecular rearrangements. These reactions will find utility in the synthesis of a variety of pharmaceuticals and biologically active substrates for which current synthetic approaches are either non-existent or inefficient. The initial phases will build upon previous accomplishments involving nickel-based catalysts for mediating carbon dioxide/diyne and isocyanate/diyne annulations to produce 2-pyrones and 2-pyridones, respectively. The substrate scope of this particular system will be expanded to include other heterocumulenes and other unsaturated hydrocarbons. Ultimately, this should afford a rich array of complex carbocyclic, heterocyclic, and fused-ring compounds. Key mechanistic steps will be explored through the use of model compounds permitting concomitant catalyst re-design (e.g., through use of new ligands and/or metals) to enhance reaction performance and scope. Parallel efforts will focus on nickel-catalyzed cyclization rearrangements of readily accessible unactivated cyclopropylen-ynes as atom-economical syntheses of heterocycles and carbocycles under mild conditions. Throughout the proposal, opportunities are described for preparing biologically or commercially important substrates or related analogues and will be pursued. This research program will reverberate across the scientific disciplines of organic and organometallic chemistry, chemical biology, and medicinal chemistry.
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