Functionalization of C?H bonds in arenes and heteroarenes can provide shortcuts en route to drug molecules. While C?H bonds proximate to coordinating groups have been successfully activated through directing effect to form a wide range of C?C and C?H bonds, remote C?H bonds in a given molecule are difficult to activate due to either distance (>six bonds away) or geometry (meta and para), thus greatly limiting the utility of C?H activation reactions in synthesis. This widely recognized challenge escalates with heterocyclic substrates where the heteroatoms coordinates strongly to the metal catalysts leading to either catalyst poisoning or limiting C?H activation to the sites that are proximal to the heteroatoms. Since the majority of aryl C?H bonds are distal to existing functional groups, functionalization of these C?H bonds, present at different distance and location will raise the applicability and scope of C?H activation reactions to the next level. These reactions, capable of modifying molecules at the previously inaccessible sites, will offer synthetic chemists greater flexibility to design the shortest synthetic route to achieve both complexity and diversity starting from simple and abundant chemicals. We propose two new and complementary strategies to promote remote meta-C?H activation reactions, namely template-assisted and norbornene-mediated meta-C?H activation. The former strategy features catalytic pyridine-based U-shaped templates to overcome the inherent limitations in substrate scope and transformations associated with our earlier generation nitrile template while the latter utilizes norbornene as a transient mediator to relay initial ortho-C?H activation to the meta position. The multi-pronged approach presented here fills a major gap in current synthetic methodologies by providing methods to functionalize previously inaccessible remote C?H bonds of a wide range of synthetically useful substrates including heterocycles. To achieve this overall goal, catalytic templates, ligands and reagents will be invented and commercialized through our industrial partner Sigma-Aldrich. These meta-C?H activation reactions of arenes and heteroarenes will be applied to drug discovery and chemical biology programs with research teams at the Scripps Research Institute and Harvard Medical School to deliver drug candidates and chemical probes in a timely manner.
New approaches are developed to functionalize C?H bonds of arenes and heteroarenes at the sites that are not accessible by existing methodologies. These technologies allow for late-stage diversification of bioactive heterocycles as well as expedient syntheses of novel heterocycles from simple arenes. The obtained arenes and heteroarenes containing novel substitution patterns that are difficult to construct will be used in chemical biology and drug discovery programs in collaboration with both academia and pharmaceutical industry.
Showing the most recent 10 out of 25 publications
