The objective of this research program is to address the longstanding challenge of selective carbon-carbon bond formation. Accordingly, a novel, synergistic catalysis mode will be explored which facilitates the direct activation of C-H bonds en route to forming cross-coupled products. The functionalization of unreactive carbon atoms in a selective manner could fundamentally impact retrosynthetic analysis of natural product and drug targets, enabling drastically simplified syntheses. Herein, we present a unique construction of a ubiquitous moiety in Nature - the aliphatic-aryl C-C bond. Our approach harnesses the power of three catalyst working cooperatively in addition to the sufficient reactivity of radicals in order to achieve selective ?-amino C-H bond arylation. Previously, this bond formation could only be accomplished using a triple cocktail of expensive transition metals, flammable lithium bases, and high-temperature cross coupling reactions along with a strategically placed directing group. In our analysis, this venerable strategy can be dramatically improved by eliminating the sources of toxic metal byproducts and the requirement for activated substrates. Central to this new mode of activation is an organocatalyzed hydrogen atom abstraction triggered by photoredox catalysis, and an oxidatively versatile nickel catalyst, which mediates the unconventional coupling of a neutral radical with organohalides to furnish the desired product. This manifold permits the C-H activation and subsequent functionalization of non-readily oxidized compounds, i.e. those substrates that are unreactive under typical photoredox conditions. We will begin with the formidable coupling between a deactivated N-acylated heterocylce, N-Boc-pyrrolidine and an aryl halide. The ?-arylated products are prevalent motifs in drug molecules and natural products. After optimization of the initial protocol, we propose expansion of this reaction manifold to the ?-vinylation of amines followed by the examination of intramolecular oxidative cyclization reactions to afford complex alkaloids and spirolactams, key architectures in the development of new pharmaceuticals. Finally, an asymmetric variant of the ?-functionalization protocol will be explored using chiral nickel catalysis, further increasing reaction utility.
The proposed research program will address a longstanding challenge in organic synthesis- the organocatalyzed activation of sp3 hybridized C-H bonds. This new reaction will facilitate the direct linkage between the C-H bond of a prototypically unreactive carbon building block with a second, useful reaction partner to give a value-added product. The products we form are ubiquitous in medicinal chemistry and are inaccessible through available C-H bond functionalization protocols.
