STRATEGIC COMBINATION OF TRANSITION METAL-CATALYZED REACTIONS FOR ECONOMICAL ONE-POT SYNTHESES OF N-HETEROCYCLES
University of Kansas
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There has been extraordinary progress in the field of chemical synthesis over the last couple of decades. Innovative methodologies and robust catalysts are emerging. Propelled by all these inventions the evolution of the field has reached the state when the principle concern of a synthetic chemist is not whether a molecule can be synthesized, but how rapidly and economically can it be produced. In this regard the development and application of one-pot reactions and multicomponent reactions play a major role because of their excellent overall economy of operation. The goal of this dissertation is to expand our understanding of regiocontrol of known transition metal-catalyzed reactions, and design one-pot protocols towards syntheses of medicinally relevant heterocycles. The first project described in chapter 2 of this dissertation, demonstrates the development of a synthetic method utilizing a Pd-catalyzed multicomponent reaction (MCR) previously developed in our laboratory for synthesis of highly substituted pyrrolidines and tetrahydrofurans. The project also helped us to unequivocally assign the relative stereochemistry of the precursors proposed in our previous reports. Methodology reported herein opens up possible future application towards synthesis of potent ETA antagonist-atrasentan and natural products like kainic acid and acromelic acid. The second project described in chapter 3, illustrates the concept of strategic sequencing of a MCR with transition metal-catalyzed annulation reactions. Herein, Cu-catalyzed MCR of imine, acid chloride and terminal alkyne was used to assemble highly functionalized enynes which upon ring closing enyne metathesis and Heck cyclization delivered N-heterocycles such as benzoindolines, dihydro pyrroloquinolines, cyclopropane fused dihydro indenopyridines and phenanthrolines. Divergence in an unexpected 5-exo vs 6-endo pathway during the Heck cyclization of homologous or isosteric substrates was observed. We believe the substrate conformation and the chelation are the factors which govern the regiodivergent Heck cyclization. A plausible mechanism for this regiodivergent Heck annulation is proposed. The third project described in chapter 4, presents efforts towards the successful design of a sequential one-pot protocol for the enyne metathesis and Heck cyclization illustrated in project two. A sequential one-pot methodology was realized for Ru/Pd catalyzed annulation reactions. Optimization of a common solvent for dual metal catalysis and a suitable base for Pd catalysis proved to be critical. The yields of pure heterocycles obtained via one-pot protocol were 2-22% higher in comparision with the stepwise procedure.
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