DESIGN AND USE OF ASYMMETRIC HYDROGENATION CATALYSTS

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DESCRIPTION: The main objectives of this revised application are to design and develop general and highly enantioselective hydrogenation methodologies that may be used for the preparation of various classes of biologically important compounds. The principal investigator notes that growing concern over the health risks associated with racemic drug development has greatly increased the demand for new effective strategies for enantioselective synthesis and that asymmetric catalytic methods are particularly appealing from the standpoint of efficiency, versatility, and economic feasibility. The principal investigator reports that his preliminary studies indicate that he may have discovered the most selective and broadly effective catalysts known for the hydrogenation of alpha-enamides to alpha-amino acid derivatives and that on the basis of these results, he proposes to employ his DuPHOS-Rh catalysts for the preparation of valuable beta- amino acids and alpha- aminophosphonic acids and that moreover, to expand the utility of his hydrogenation process for the production of nonproteinaceous alpha-amino acids, he proposes to fully develop a tandem catalysis procedure involving catalytic asymmetric hydrogenation of functional alpha-enamides, followed by palladium-catalyzed cross- coupling. He is to prepare a series of boronic acid- and tributyltin- substituted arylalanines, which are to provide simple access to a very diverse range of novel ring-substituted alpha-amino acids through cross- coupling with readily available organobromides and triflates. It is noted that incorporation of dihydroxyboryl-arylalanines into peptides could lead to a powerful method for the multiple, simultaneous synthesis of many analogous peptides from a single peptide intermediate. The principal investigator indicates that these studies will facilitate his long-term goals involving the design of novel bioactive peptides, such as chemoattractant receptor antagonists and peptides capable of sequence-specific binding to DNA. The second main objective is the development of general catalytic strategies for the production of enantiomerically pure hydrazines and amines. The principal investigator reports that he recently has achieved high enantioselectivity in hydrogenation of the C=N double bond of numerous N-benzoylhydrazones and that methods that should greatly improve the present process are proposed in an effort to develop a truly practical catalytic asymmetric reductive animation procedure for the conversion of prochiral ketones into chiral hydrazine and amine derivatives. He notes that he will exploit the unique suitability of this reaction for the preparation of specific alpha-hydrazino acids. It is further indicated that a second potentially general route to chiral amines also is proposed and involves enantioselective hydrogenation of the C=C double bond of enamides. The development of a broadly effective catalyst for the highly enantioselective hydrogenation of alpha-keto esters and simple, unfunctionalized ketones is said to remain an important goal. It is indicated that rhodium and ruthenium catalysts containing newly designed chiral bidentate and polydentate chiral ligands will be examined for activity and selectivity and that once optimized, these catalysts will be employed in an efficient asymmetric catalytic synthesis of the potent ACE inhibitor benazepril.