Modern drug discovery is facing critical challenges. Rapid advances in human biology are revealing new biomolecular targets and processes, for which existing chemical compound libraries can provide only limited success in the identification of novel bioactive agents. This deficiency has been attributed primarily to the relative lack of structural diversity within the libraries. The three-dimensional world of biological macromolecules has been continuously interrogated with generally similar planar, aromatic, and structurally simple compounds. Contemporary diversity-generating methods have never been implemented for the preparation of large libraries, as an increase in the number of diverse members requires a corresponding increase in the number of synthetic steps, or a continuous supply of different staring materials. This proposal details a strategy for developing a chemically sustainable diversification method, by tapping into our largest source of organic compounds: arenes.
The proposed research aims to develop new methods that can rapidly convert simple aromatic entities into highly functionalized, complex small molecules. By integration of this strategy with many different chemical operations, numerous distinctive and independent dearomative programs will generate a diverse set of multiplex small molecules. This simplicity-to-complexity approach will provide a practical platform for the rapid, controlled access to a functionally diverse set of compounds, ranging from anticancer to anti-infective agents. This research will also deliver methods for dearomative diversification of existing aromatic compound libraries to provide new members with unique physiochemical properties. Given the broad scope of possible dearomative programs that will be developed, and the vast amount of aromatic compounds accessible, this will ultimately provide a sustainable source of diverse molecules for the next generation of compound libraries.
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