Combinatorial chemistry has recently burst on the scene as a valuable tool for the discovery of new drug candidates. The ability to synthesize hundreds of compounds for screening is a useful complement to rational drug design. There are many similarities between the design of new therapeutic agents and the development of new asymmetric ligands, the most important of which is the limitation of a rational design strategy. The proposed research aims to develop a combinatorial approach to two classes of ligands that have proven to be useful in the past, diphosphines and phosphine-dihydrooxazole ligands. Amino acid building blocks that will allow for the synthesis of both types of ligands by known combinatorial technology will be discussed. Preliminary results will be presented that show that, amino acid derived phosphine/dihydrooxazole ligands capable of giving state of the art selectivities for palladium catalyzed pi-allyl alkylations, can be synthesized. A general method for the synthesis of libraries of both diphosphines and phosphine-dihydrooxazole ligands on solid supports will be covered. A method that permits the deprotection of the phosphine protecting group while the molecule is attached to the solid support will also be shown. Chemistry that allows for the metalation of the ligands will be presented. The screening of libraries of metal complexes will be covered. Initially three reactions will be screened, palladium catalyzed pi-allyl alkylation, the Heck reaction and a rhodium Catalyzed [4+2] cycloaddition reaction. These reactions were chosen because of their differing mechanisms and the fact that all are potentially useful carbon-carbon bond forming reactions.
