Earth abundant catalysts as an enabling tool for organic synthesis

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Project Summary Transition metal-catalyzed reactions have revolutionized chemical synthesis as applied to the preparation of bioactive molecules and drug compounds, yet new methods are needed to open new molecular space and overcome the structural biases that arise from current methods. Earth-abundant transition metals, by virtue of their increased ionicity in metal–carbon bonding and higher density of states, offer distinct reactivity as compared to state-of-the-art precious metal catalysts. This proposal describes a new approach to site selective C–H functionalization reactions that leverages the unique properties of iron, cobalt and manganese to predictably distinguish subtle differences in the properties of C–H bonds to achieve complementary selectivity to existing methods. By establishing and articulating the general principles of this approach, these methods will enable retrosynthetic analyses that will translate to rational design of new molecules outside the reach of current metal-catalyzed reactions. Specifically, methods for the meta-selective functionalization of arenes are proposed as are new routes for the selective elaboration of heterocycles that are commonly found in lead compounds. In addition, methods are proposed to synthesize 1,3,5-trisubstiuted arene derivatives, a valuable structural type that is been historically underexplored in drug discovery campaigns. Methods for the chemoselective functionalization of C(sp3)–H bonds in the presence of C(sp2)–H sites are also proposed that rely on the unique electronic properties of first-row transition metals supported by readily prepared and modular redox-active ligands.