Development of carboxyl- and amide-directed C-H activation/C-C coupling reactions

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DESCRIPTION (provided by applicant): Unactivated C-H bonds are ubiquitous in biologically active compounds as well as intermediates in organic synthesis. Development of catalytic methods to functionalize these strong bonds selectively will offer unprecedented and efficient tools for making C-C and C-heteroatom bonds in organic synthesis and medicinal chemistry. A number of promising catalytic reactions have been developed using directed C-H activation as a key strategy. These reactions typically use pre-installed nitrogen-containing auxiliaries as directing groups via binding to metal catalysts. Considering the broad applications of auxiliaries in synthesis, auxiliaries developed for C-H insertion are not yet practical due to multiple steps and harsh conditions involved in their installation and removal. To overcome these drawbacks, we propose to develop catalytic C-H activation reactions of simple and synthetically useful carboxylic acids and amides at the 2-positions. These reactions are also applicable to simple amine derivatives. We will exploit these reactivities to develop an array of C-H activation/C-C coupling reactions using practical coupling partners such as organoboron reagents and olefins. To improve the practicality of C-H activation reactions, we propose to develop mild conditions (50-80¿C and pH = 4-12) that allow the use of O2 or air as the stoichiometric oxidant. These advantages will be exploited to site-selectively functionalize biologically active natural products including dehydroabietic acid, podocarpic acid and amino acids. The structurally diversified dehydroabietic acid derivatives will be tested for potentially improved biological activity as BK channel openers. Lastly, we have also discovered an effective ligand to achieve the first Pd(II)-catalyzed enantioselective coupling of sp2 and sp3 C-H bonds with organoboronic acids which will find widespread use in synthesis and medicinal chemistry. PUBLIC HEALTH RELEVANCE: The C-H activation/C-C coupling reactions described in this proposal will expedite the drug discovery process by providing unprecedented routes to access biologically active compounds. The enantioselective alkylation of sp2 and sp3 C-H bonds will provide new methods for the preparation of medicinally relevant chiral molecules. Research plans for applications of these reactions in medicinal chemistry are also outlined.