Polyfunctional organic molecules play an integral role in the chemotherapeutic treatment of disease. Synthetic chemistry plays a key role in providing researchers and physicians with the biologically active substances they require. The overwhelming majority of these synthesis efforts depends critically on the selective derivatization of reactive sites on polyfunctional structures containing multiple reactive groups. The dominant strategy for this task to date is the repetitive use of """"""""protective groups."""""""" Protective groups, by definition, mask the reactivity of one site while allowing reactions to take place at another site. Yet, protective groups are inefficient - they require a reaction to be introduced, a reaction to be cleaved, and both of these steps usually proceed in less than 100% yield. The costs in terms of time, reagents, waste removal and overall yields of desired products are tremendous. The capacity to selectively functionalize very similar sites in polyfunctional structures without the use of protecting groups would dramatically improve the efficiency with which synthetic chemists assemble complex targets. Simultaneously, improved efficiency would reduce the cost and environmental stress of synthesis efforts. Yet, systematic, general solutions to this problem have not been reported. In many circles, the problem is represented as intractable. We intend to pursue a systematic program targeted at the site-selective functionalization of polyfunctional molecules. Our approach will depend on the development of chiral catalysts that perform enantio- and regioselective reactions. Among the catalytic processes we will study will be site-selective phosphorylation, acylation and deoxygenation. The catalysts we discover will be derived from both rationally designed catalyst libraries, as well as from combinatorial libraries developed in our lab. The utility of the catalysts will be demonstrated through the target-oriented syntheses of complex polyfunctional targets in the phosphoinositide family. In addition, these new catalysts will be applied to the synthesis of natural product-like libraries through the selective modification of important polyfunctional natural products of demonstrated biomedical significance. The end result will be both new tools for the selective synthesis of complex biologically active compounds, as well as important samples for use in biological screens.
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