asymmetric catalysis β’ copper β’ homogeneous catalysis β’ Michael addition
Copper-catalyzed asymmetric conjugate addition reactions of organometallic reagents to Michael acceptors have been an important research topic for two decades. New procedures developed by careful tuning of the reaction conditions, the organometallic reagent, and the chiral ligand provide the conjugate adducts with very high enantioselectivities. This brief overview of copper-catalyzed asymmetric conjugate addition reactions highlights some of the most important recent contributions.
Copper-catalyzed enantioselective conjugate addition reactions were first studied with Grignard reagents. With chiral ferrocene ligands, such as taniaphos [3] or josiphos, [4] EtMgBr underwent Michael addition to unsaturated esters, such as 1 a and 1 b. In the presence of the regioisomeric copper-ligand complex 2 a (0.5 mol %) or 2 b (1.5 mol %), the expected adducts 3 a and 3 b were formed in 99 % yield with 93 and 96 % ee, respectively (Scheme 1). Interestingly, the use of (S)-Tol-binap (4) in combination with CuI (1 mol %) enables stereoselective addition reactions to E-and Z-unsaturated esters to be carried out. For example, (E)-5 and (Z)-5 were converted into the two enantiomeric Michael adducts 6 and ent-6 in 93 and 94 % ee, respectively. No isomerization of the sensitive unsaturated ester (Z)-5 was observed during the reaction.
This methodology could be used directly for the addition of MeMgBr to the a,b-unsaturated ester 7 in the presence of (S)-Tol-binap (4) and CuI. The conjugate adduct 8 was formed in 68 % yield with 96 % ee (Scheme 2). By using an iterative reaction sequence, it was possible to synthesize both [*] T.