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

• Published in: European Journal of Organic Chemistry 2012-02, Vol.2012 (6), p.1179-1185
• Main Authors: Naeemi, Qaseem, Dindaroğlu, Mehmet, Kranz, Darius P., Velder, Janna, Schmalz, Hans-Günther
• Format: Article
• Language: English
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Asymmetric catalysis; C-C bond formation; Chemistry; Condensed benzenic and aromatic compounds; Conjugate addition; Copper; Exact sciences and technology; Noncondensed benzenic compounds; Organic chemistry; Organometalloidal and organometallic compounds; P derivatives; P ligands; Preparations and properties
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201101258

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·SMe2 (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 CF3 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. The difficult task of employing aryl‐Grignard reagents in Cu‐catalyzed enantioselective 1,4 addition reactions was achieved with the assistance of readily accessible chiral modular P,P ligands. High enantioselectivities were obtained in a number of synthetically relevant cases.