Transition metal catalyzed reactions have revolutionized chemical synthesis as applied to the preparation of bioactive molecules and drug compounds. Most of these transformations rely on the least abundant elements in the Earth's lithosphere ? palladium, iridium and rhodium ? and raise concerns about toxicity and sustainability. This proposal describes catalysis with Earth abundant transition metals that, in addition to cost and environmental advantages, offers unique reactivity that will enable new methods to diversify lead compounds in medicinal chemistry and potentially streamline pharmaceutical synthesis. Cobalt and nickel complexes are proposed, as their high density of states, unique redox chemistry and smaller atomic radii than heavy metals congeners can be utilized to overcome long-standing challenges in site selective C-H functionalization. In addition, new polyfunctionalization methods are described whereby multiple C-H bonds on a single carbon are transformed into reactive and versatile functionality. Notably, the proposed methods do not rely on directing groups but rather inherent electronic and steric differences associated with specific carbon- hydrogen bonds. A third area of interest, conducted in collaboration with Bristol-Myers Squibb, explores new iron and cobalt catalysts as alternatives to palladium for the most widely applied carbon-carbon bond forming reactions utilized in the pharmaceutical industry. The structural similarity among ligand platforms culminates in a new method for one-pot site selective C-H arylation in the absence of directing groups using an Earth abundant metal catalyst.
This proposal describes new methods using Earth abundant transition metal catalysts designed to streamline drug discovery. New approaches to the site selective functionalization of C(sp2-H) and C(sp3-H) bonds are described that exploit the unique electronic properties of first row transition metals as compared to precious elements. Using structurally identical cobalt pre-catalysts for cross coupling provides a new method for direct arylation of important pharmaceutical building blocks.
