Friday, April 26, 2024
4/26/2024
Project Summary Site-selective functionalization of C–H bonds in arenes and heteroarenes can potentially transform the synthesis of bioactive molecules, as it can enable the flexible molecular editing of a scaffold to rapidly generate a diverse set of structures. While C–H bonds proximate to coordinating groups have been successfully activated through its directing effect to form a wide range of C–C and C–X bonds, the majority of C–H bonds in a given molecule are incompatible with this conventional approach. The limitation arises from two factors: 1) distance - the directing effect of a coordinating group diminishes at distances greater than six bonds, and 2) geometry - meta and para positions on arenes are geometrically inaccessible, which greatly restricts the utility of C–H activation in synthesis. These widely recognized challenges escalate with heterocyclic substrates, as heteroatoms coordinate strongly to metal catalysts. This strong binding interaction either limits the utility of C–H activation to proximate sites, or leads to deleterious catalyst poisoning. Therefore, the development of new approaches to achieve selective functionalization of these previously inaccessible C–H bonds is of great value to drug discovery. To achieve the goal of site-selective remote C–H functionalizations of arenes and hetereocycles, we propose three complementary approaches to overcome the two aforementioned challenges. These are 1) the use of transient and catalytic templates, 2) the use of ligand-promoted site-selective C–H activation, and 3) employing a norbornene-mediated relay strategy to expand the first two methods to more distal sites. The first strategy features the use of novel transient directing templates for amine and ketone substrates, as well as employing reversible bifunctional bimetallic directing templates for heterocycles. The second approach is based on our previous finding that phenanthroline-type ligands can promote C-3 selective C–H activation of pyridines, albeit requiring super-stoichiometric amounts of starting material. We propose to redesign this ligand by using additional weak interactions to stabilize the transition states, thereby accelerating the C–H activation reaction. Finally, we propose to utilize norbornenes as a transient mediator to relay the initial remote C–H palladation from the first two approaches to an adjacent, more distal position. The multi-pronged approach presented here fills a major gap in current synthetic methodology. To achieve this overall goal, novel templates, ligands and reagents will be invented. These remote site-selective C–H activation reactions of arenes and heteroarenes will be applied to expedite drug discovery and chemical biology programs in collaboration with the Cravatt and Kelly labs, as well as with Bristol-Myers Squibb.
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