The work described in this proposal is aimed at the development of new methods of general utility in organic synthesis. Specifically, techniques to effect carbon-nitrogen, carbon-oxygen and carbon-sulfur bond formation will be developed or improved. In addition, these techniques will be applied to the synthesis of a number of different interesting and important heterocyclic species. Chemistry of this type is of importance in both academic and pharmaceutical (and other) settings. For example, a great number of pharmaceutically important compounds have aryl amines or aryl ethers as structural components. The ability to access the widest variety of these compounds, in an efficient manner, from readily available precursors is of great interest. The generation of new compounds is key to the development of new lead compounds, an integral part of drug discovery. One powerful means of discovering new leads is combinatorial chemistry. The success of combinatorial chemistry depends on the availability of new, general and efficient synthetic methods. Once a lead compound has been identified, it is often important to prepare derivatives in order to overcome problems in the original lead compound such as toxicity, solubility or bioavailability. The ability to do this is based on what techniques are available. Once a compound has been identified to go forward, it is necessary to make increasingly large quantities for testing and for clinical trial. The ability to prepare this material rapidly and efficiently is increasingly important for many reasons, including minimizing the cost involved in drug evaluation. If the drug actually becomes commercial, the techniques for its synthesis must be high yielding and reliable. The chemistry which we propose can impact all of the issues mentioned above. Our goals are to create high yielding, general and reliable methods for use in organic synthesis. We seek methods which access the widest number of structural variations and which can be carried out on both very small and very large scale.
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