Reactions that are catalytic, proceed with outstanding selectivity, are efficient and use inexpensive materials can dramatically shorten the time between conception and large-sale preparation and marketing of a therapeutic agent. According, the objective of the proposed research is to develop new catalytic asymmetric carbon-carbon bond-forming processes that can be used in the preparations of molecules important to human health care. The proposed research will focus on catalytic asymmetric preparations of chiral amines and alcohols, particularly those not accessible through available catalytic methods. For example, our preliminary success with enantioselective additions of alkyl groups to aryl and alkyl imines to provide chiral amines will be extended to alpha-carbonyl-containing imines and ketimines. Catalytic asymmetric additions of alkyl, aryl, alkenyl, and alkynyl groups into these types of substrates will provide concise entries into biomedically important natural and unnatural amino acid and derivatives. Likewise, an intramolecular variation of this carbon-carbon bond forming process will be advanced. The addition of aromatic groups into tethered imines (Pictet-Spengler Reaction) will be developed into an asymmetric process catalyzed by Lewis acidic metals modified by chiral peptidyl ligands. In a related manner, the enantioselective addition of alkyl group into ketones to general chiral, non-racemic tertiary alcohols will be developed into a general catalytic asymmetric transformation. Given the lack of catalytic methods to synthesize chiral tertiary alcohols, success with this reaction will significantly enhance the availability and reduce the cost of preparation of numerous medicinally important compounds. In all segments of the proposed studies, the utility of new asymmetric catalytic transformations will be highlighted with efficient and selective synthesis of several medicinally important targets. Furthermore, once a catalytic asymmetric process has been demonstrated, the corresponding reaction mechanism will be probed to enhance further the overall selectivity and reactivity of the process. New reaction methods to be developed will involve catalysis by Lewis acidic metals modified by chiral peptidyl ligands that can serve as bifunctional catalysts. Amino acids are inexpensive, readily available in enantiomerically pure form, and peptide synthesis has been worked out in both solution and solid phase, simultaneous preparation of multiple ligand structures is straightforward. Accordingly, a unique and useful feature of the peptide-based chiral ligands is the facility with which they can be prepared and examined so that optimal levels of reactivity and selectivity can be achieved.
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