In-depth structure–selectivity investigations on asymmetric, copper-catalyzed oxidative biaryl coupling in the presence of 5-cis-substituted prolinamines

Thirteen new and 25 known prolinamines carrying an additional 5- cis substituent were evaluated as the chiral ligands in asymmetric copper-catalyzed, oxidative biaryl coupling of 3-hydroxy-2-naphthoates. Comprehensive structure–selectivity investigations revealed that a phenyl group in the 5- cis position and a small substituent at the pyrrolidine nitrogen ( e.g. , Me) are essential for high levels of chirality transfer. The sense of the asymmetric induction depends on the steric demand of the exocyclic amino function. In the coupling of methyl 2-hydroxy-3-naphthoate, a primary amino group permitted up to 36% ee in favor of the P -enantiomer, while up to 64% ee in favor of the M -enantiomer was reached with secondary and tertiary amino functions ( e.g. NMe 2 , ( S )-NHCH(Me)Ph). A fully linear relationship between the enantiomeric excess of the prolinamine and the binaphthol was observed. A mechanism consistent with all stereochemical findings is proposed, indicating that 3-hydroxy-2-naphthoates with bulkier ester groups should permit better stereocontrol. Indeed, the enantiomeric excess was raised to good 87% when tert -butyl 3-hydroxy-2-naphthoate was used as the substrate.