The central theme of this
project is the development of methods for the synthesis of chemical
libraries that are derived from, or inspired by, biologically
relevant natural products and heterocycles. The generation of
natural product-like libraries is particularly important because
such products are commonly available either as single entities
or in small quantity in a complex mixture of derivatives. Thus,
the synthesis of libraries of compounds inspired by natural products
will not only expedite the identification of new biologically
active compounds, but will also facilitate the determination of
structure activity relationships, and perhaps mechanism of action.
Toward this end, we propose the synthesis of libraries of medium
ring compounds that resemble anti-cancer polyketides as well as
polyphenolic compounds including coumarins and flavans. Significantly,
biological data that validates the relevance of several of the
proposed libraries is already in hand.
In addition to the potential utility of the natural product-like
libraries synthesized, the development of new reactions and reaction
sequences will allow expeditious parallel synthesis of new heterocyclic
chemotypes. Examples of our proposed methodology include palladium-catalyzed
decarboxylative cycloadditions, iterative and CH-functionalization
of phenols, enyne metathesis/Diels-Alder sequences, and Paterno-Büchi
reactions. In addition to developing new reaction chemistry for
the construction of libraries, we will also develop new reagents
that 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 in utilizing unstable β-halocarbonyl
compounds in parallel synthesis. Thus, it is our hypothesis that
the use of N-vinypyridinium reagents will permit the
efficient construction of compounds that would be difficult to
make by conventional methodologies.
