NEW CATALYTIC AND ENANTIOSELECTIVE REACTIONS

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The primary goal of the proposed research project is to develop two new asymmetric catalytic carbon-carbon bond forming processes. The overall objective is to increase the opportunities for efficient and enantioselective construction of molecules important to human healthcare. Reactions that are catalytic, that proceed with outstanding selectivity, that are efficient and use inexpensive materials can dramatically diminish the time span between the conception of a therapeutic candidate and its large scale preparation and marketing. In this regard, the utility of the new asymmetric catalytic transformations will be highlighted with efficient and selective synthesis of several medicinally important agents. The first reaction to be explored is the asymmetric addition of trimethylsilylcyanide to epoxides. Preliminary results have shown the feasibility of this new transformation. Subsequent studies will optimize the process through convenient yet systematic modifications to the peptidyl ligand structure of the novel catalytic system; developing a better mechanistic understanding of the reaction, and applying this transformation toward the synthesis of various anti-HIV agents. Similarly, the addition of trimethylsilylcyanide to imines (Strecker reaction) will be developed into a general catalytic asymmetric transformation. Again the scope of the reaction will be delineated with catalysts containing metals coordinated to peptidic ligands. Reaction mechanism will be probed and applications toward important molecules will be demonstrated. Both of the reactions to be developed will employ Lewis acidic metals that are modified with chiral peptidyl ligands as catalysts. Of particular significance is the speed at which the new catalysts can be prepared and optimized. This unique and useful feature is the direct result of using amino acids as the chiral building blocks of the ligand system. Since amino acids are readily available and peptide synthesis has been worked out in both solution and solid phase, simultaneous preparation of multiple ligand structures is relatively straightforward. The large number of ligands that can be prepared and screened for both reactivity and selectivity in a systematic manner allows for the rapid selection of an optimal catalytic system.