Asymmetric Synthesis of 1,1-Diarylalkyl Units by a Copper Hydride Catalyzed Reduction: Differentiation Between Two Similar Aryl Substituents

An efficient method for the preparation of enantiomerically enriched 1,1-diarylalkyl units has been developed. The use of copper hydride complexed by the (R)-1-[(S)-2-diphenylphosphino)ferrocenyl]ethyidicyclo- hexylphosphine (Josiphos) ligand effects a highly enantioselective conjugate reduction of beta,beta-diaryl-substituted alpha,beta-unsaturated nitriles with aryl groups of similar steric demand and no secondary coordination site. A range of substrates with meta and para substituents on the aryl group were reduced with good to excellent enantioselectivities (up to 97% enantiomeric excess (ee)) and this methodology was applied to the formal synthesis of indatraline.