NIH-National Institute of General Medical Sciences

Project 2

Libraries Based on Natural Products and Privileged Structures

This project develops methods for synthesis of chemical libraries that are related to biologically relevant natural products and heterocycles. These libraries are important because such products are often available only as single entities or as part of a complex mixture. Thus, the synthesis of natural product inspired libraries will expedite the identification of new bio-activity and facilitate both SAR and mechanistic studies. To this end we prepare medium ring compounds that resemble anti-cancer polyketides as well as polyphenolic compounds including coumarins and flavans. Significantly, available data validates the relevance of several of the libraries.

In addition to the utility of the described libraries, the development of new synthetic methods allows rapid parallel synthesis of new heterocyclic chemotypes. Examples of our methodology include palladium-catalyzed decarboxylative cycloadditions, iterative CH-functionalization of phenols, enyne metathesis/Diels-Alder sequences and Paterno-Büchi reactions. We develop not only new chemistry but also new reagents to facilitate parallel synthesis. For example the use of N-vinypyridinium salts as versatile coupling partners in Suzuki and Nozaki-Hiyama-Kishi reactions overcomes the difficulties of utilizing unstable ß-halocarbonyl compounds. We believe that using N-vinypyridinium reagents permits efficient construction of compounds that would be otherwise difficult to make.

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