Transition metal-catalyzed enantioselective sp3 C-H activation reactions can provide new synthetic routes for the expedient construction of bioactive molecules and drug compounds. Despite the great potential of such reactions, the development of enantioselective sp3 C-H functionalizations via an organometallic approach is in its infancy when compared to other more advanced methods of asymmetric catalysis. This proposal is centered on the development of novel enantioselective sp3 C-H activation reactions that would broaden the scope of transition metal-catalyzed asymmetric C-H functionalizations. The key strategy for achieving this goal is via the design and development of ligand scaffold that cooperates with the weak coordination between the substrate and the metal center to promote C-H activation. Additionally, we will relay our efforts through collaborations to biomedical research in identifying new drug candidates for the treatment of human diseases. Furthermore, we will strive to overcome the inherent need for the formation of 5-membered palladacycles in sp3 C-H activation to access remote methyl and methylene C-H bonds. Our key strategy is to design a template that relies on weak coordination to direct the metal towards the desired distal C-H bond. This approach would not only provide unprecedented access to a variety of ?- and ?-substituted aliphatic carboxylic acid derivatives, but also provide a platform for the late-stage diversification of drug molecules via functionalization of previously inaccessible remote C-H bonds.
This proposal centers on utilizing the asymmetric cleavage of carbon-hydrogen bonds to develop new reactions for the enantioselective construction of carbon-carbon bonds. Such reactions will allow for the rapid construction of bioactive chiral compounds and drug molecules from inexpensive and readily available chemicals. In a collaborative effort, we will use our proposed chemistry to discover promising new drug candidates for the treatment of human diseases.
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