Over 50 percent of all drugs on the world market are based on chiral molecules and their sales exceeded $100 billion in 2000. The Food and Drug Administration requires that both enantiomers of new chiral drugs are fully characterized separately with respect to pharmacological activity, in vitro and in vivo pharmacokinetic profile, and toxicology. Consequently, most chiral pharmaceuticals will be sold as enantiomerically pure compounds. The current challenge for the pharmaceutical industry is to devise cost-effective, environmentally benign and hazard-free processes for the synthesis of chiral non-racemic drugs. Of the various methods available for the preparation of enantiomerically pure compounds, asymmetric catalytic processes are the most attractive. While several highly effective and useful catalytic asymmetric processes that utilize transition metal compounds have been developed in recent years, purely organic compounds, despite their enormous potential, are rarely used in asymmetric catalysis. The long-term goal of this proposal is to fill this need by designing and identifying highly enantioselective amine based catalysts for use in asymmetric carbon-carbon bond forming reactions. These asymmetric aminocatalysts could complement existing metal-based catalytic strategies in the future. Ideally, the products of this research will be non-toxic, environmentally benign, and highly efficient catalysts for the synthesis of chiral non-racemic biologically active molecules and drugs. Specifically, this proposal aims at (1) Studying the mechanism of proline-catalyzed asymmetric aldol and Mannich reactions to gain a better understanding of reactivity and selectivity in aminocatalysis. (2) Designing novel aminocatalysts for aldol, Mannich, and Michael reactions. (3) High-throughput screening of aminocatalytic libraries. (4) Synthesizing biologically active natural products and drugs using aminocatalysis.
