Free and Cr(CO)3-Complexed Aminophosphine Phosphinite Ligands for Highly Enantioselective Hydrogenation of α-Functionalized Ketones

The synthesis and characterization of a new series of aryl- and cycloalkyl-substituted aminophosphine phosphinites ( 1 − 8 ) obtained from the reaction of the three precursors ( S )-2-hydroxymethyl azetidine, ( S )-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline, and ( S )-2-hydroxymethylindoline and chlorophosphines is described. The aromatic ring in ( S )-2-hydroxymethylindoline has allowed the synthesis and isolation of tricarbonyl chromium complexed amino alcohols syn -10 and anti -10, which were similarly converted into the corresponding aminophosphine phosphinites 11 − 13, presenting a stereogenic center and a planar chirality. Ligand 5 (( S )-Cp,Cp-IndoNOP) revealed an unprecedented 31 P NMR fluxional behavior related to a rotation inhibition around the P-heteroatom (N and O) bonds. These new AMPP ligands were used in the enantioselective hydrogenation of various α-functionalized ketones, i.e., dihydro-4,4-dimethyl-2,3−furandione 14, N -benzyl benzoylformamide 15, ethylpyruvate 16, and 2-( N,N -dimethyl)aminoacetophenone hydrochloride 17 . The stereoelectronic effects generated by the presence of the tricarbonyl chromium moiety onto the hydrogenations have been assessed. The beneficial effect of the matching chiralities in ligand syn -12 associated with the use of the most appropriate nonchiral ligand Cl has resulted in a win of 13% of ee for the rhodium-based hydrogenation of 15 . While using the most suitable new chiral AMPP ligand from this study, the four above-mentioned substrates were converted into the corresponding optically active alcohols in >99% ee ( l4 / 5 ), >99% ee ( 15 / 6 ), 87% ee ( 16 / 5 ), and >99% ee ( 17 / 5 ), respectively.