TEMPLATE DIRECTED COMBINATORIAL SYNTHESIS

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The objective of this project is the design and discovery of new catalyst systems for enantioselective organic synthesis, directed toward an exo-selective catalyst of the Diels-Alder reaction. A parallel objective is the creation of a new methodology for the generation of catalysts and other targets of combinatorial chemistry. Based on the molecular recognition studies on organic molecules as well as the advances in antibody catalysis, libraries of molecules will be synthesized which are pre-organized for catalytic activity. The libraries will be synthesized by the addition of diverse pools of building blocks whose addition to the supported compound will be templated via binding to a compound which models the transition state of interest. In this way, the building blocks which most effectively bind the reaction transition state-mimic will be incorporated at the expense of those least effective. The selective enrichment of the potential catalysts will allow a large potential diversity of catalytic compositions to be sampled, and will add a degree of selection and amplification to the synthetic combinatorial library. The compounds obtained will be screened for binding and catalytic activity, identified, and independently synthesized and characterized. Based on the lead structures discovered and the kinetic, chemical and structural analysis of the catalyst and its substrates, optimized catalysts will be synthesized which incorporate the mechanistic knowledge obtained.