There is a fundamental need to rapidly and efficiently build complex molecules from simple building blocks. The long-term goal of this program is to construct such molecules from readily accessible starting materials through dual-metal catalysis with organo Gold intermediates. The value of this dual-catalytic strategy is that it reduces the number of synthetic steps required, while also giving access to new synthetic bond disconnections and unique chemo- and regioselectivities. This strategy therefore substantially enriches the toolkit of bond- forming strategies available in pharmaceutical development. This approach is innovative because it combines the power of gold catalysts to rearrange and activate substrates with the selectivity of other metal catalysts to form new bonds. The rationale for this approach is the demonstrated cooperative catalysis of gold and palladium, through which the PI established the synthetic potential of these dual-catalytic methods in the construction of butenolides, isocoumarins, and nitrogen-containing heterocycles, three classes of molecules with known biological activity. This concept first will be applied to reactions that construct carbon-oxygen and carbon-carbon bonds in one synthetic transformation in order to synthesize other biologically relevant heterocycles. This strategy is efficient because it does not require the separate synthetic preparation and manipulation of a stoichiometric organometallic reagent;instead, the reactive compounds are generated in situ, allowing for faster and more economical development of pharmaceutical targets. Once this strategy is demonstrated through its application to oxygen-containing heterocycles, we will apply it to develop a variety of other significant dual-catalyzed reactions. The following expected outcomes are anticipated: First, the unique bond disconnections and chemoselectivities of the reactions are expected to provide access to biologically active compounds not easily available through traditional pathways. Second, the dual-catalytic pathways are expected to increase the efficiency of the synthesis of therapeutic agents used to treat human disease by removing the need for separate synthetic preparation of stoichiometric organometallic reagents. These outcomes are expected to have an important positive impact because they significantly expedite drug discovery at the same time that undesired chemical waste byproducts are minimized. As advances in chemical biology continue to spur the identification of new therapeutic targets, this ability to quickly and efficietly assemble complex molecules through dual catalysis will ensure the timely development of new pharmaceuticals for the benefit of human health.
The new catalytic methods that will result from the proposed research will provide efficient routes from simple building blocks to biologically active compounds, significantly facilitating the preparation of these compounds for drug discovery. The increased accessibility of these pharmaceutical candidates will permit the rapid development of compounds that improve human health.
