Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines

PROJECT SUMMARY/ABSTRACT Subtle structural modifications have the potential to dramatically alter the biological activity of small molecules. Consequently, the development of synthetic methods that allow for selective molecular editing has the potential to greatly accelerate the design and synthesis of novel therapeutics. Transition-metal catalyzed C–

H functionalization is a particularly compelling approach, as it circumvents the requirement for prior activation at the site of functionalization. However, C–H activation typically requires a high degree of preorganization of the agostic interaction between the metal and the target bond, usually through coordination of the metal to a directing

group. Unfortunately, efforts to use common functional groups and commonly used protecting groups to direct C(sp3)–H activation have met with limited success. Instead, specially designed directing groups are often necessary, limiting the synthetic utility of existing C–H functionalization methodologies.

In the proposed research, ligands will be designed to enable the use of common, weakly coordinating L-type donors, such as alcohols and carbamates, as directing groups for C(sp3)–H activation. We hypothesized that two main factors are responsible for the failure of existing ligands to promote these reactions: the intrinsically

weak binding of these functional groups to Pd, and the focus on L,X chelates in recent ligand design efforts, which are expected to disfavor agostic complex formation with L-type directing groups due to the lack of charge balance within the complex. Thus, we propose to design novel bis-anionic ligands, structures that are currently

underexplored in C–H activation chemistry, containing an internal base that can participate in C–H activation via concerted metalation-deprotonation. In order to compensate for the weak coordination of the desired directing groups to Pd, the proposed ligands will be designed to stabilize substrate-Pd complexes through the secondary

coordination sphere by serving as H-bond acceptors or donors matched to the desired directing group. In Aim 1, which is strongly supported by preliminary results, we will develop ligands that can enable alcohol-directed C(sp3)–H functionalizations through two reaction manifolds: C–H dehydrogenation reactions to form allylic

alcohols, which are exceedingly versatile synthetic intermediates, and direct C(sp3)–H arylations. Aim 2 will extend this ligand design strategy to develop α-arylations of Boc-amines, with a particular focus on methylene C–H activation in saturated N-Boc azacycles. The successful realization of these aims will provide powerful new

synthetic methodologies, directly facilitating the design and synthesis of novel therapeutics. In addition, validation of the underlying hypotheses and ligand design strategy will afford a conceptual advance that will contribute to the continued development of the field of C–H activation. The proposed work will be carried out under the mentorship of Professor Jin-Quan Yu, a preeminent scholar

in the field of transition-metal catalyzed C–H functionalization. The intellectual environment in the Yu lab and The Scripps Research Institute is ideally suited to enable the successful execution of these aims.