Cu‐Catalyzed Enantioselective 1,4‐Additions of Aryl‐Grignard Reagents to Cyclohexenone in the Presence of TADDOL‐Derived Phosphane‐Phosphite Ligands

Asymmetric conjugate additions (1,4‐additions) of aryl‐Grignard reagents to cyclohex‐2‐enone, currently a more or less unsolved challenge, were investigated. For this purpose, a small library of phenol‐derived chiral phosphane‐phosphite ligands containing TADDOL‐ or BINOL‐based phosphite moieties was evaluated. These ligands are easily prepared by a short modular scheme previously developed in this laboratory. Two particularly powerful ligands ( 4a and 4b , both TADDOL‐derived and each possessing a bulky tert ‐butyl substituent ortho to the phosphite group) were identified. Conditions were optimized with use of the addition of (4‐methoxyphenyl)magnesium bromide to cyclohexenone as a standard reaction system. Under optimized conditions [CuBr · SMe 2 (4 mol‐%), ligand 4a (6 mol‐%), 2‐methyl‐THF, –78 °C, slow addition of Grignard reagent] the 1,4‐product was obtained with high enantioselectivity (up to 95 % ee ) and good regioselectivity (r.r. = 90:10). The scope of the method was probed with different aryl‐Grignard reagents. It was found that reagents with electron‐donating substituents in meta ‐ or para ‐positions performed particularly well, whereas the presence of F or CF 3 substituents led to decreased ee values. Only ortho ‐substituted aryl‐Grignard reagents did not give rise to useful results. A series of phosphane‐phosphite ligands were also tested in the Rh‐catalyzed 1,4‐addition of phenylboronic acid to cyclohexenone, but enantioselectivities did not exceed 70 % ee in this case.