Mechanism and scope of salen bifunctional catalysts in asymmetric aldehyde and α-ketoester alkylation

Metal complexes of C-2-symmetric Lewis acid/Lewis base salen ligands provide bifunctional activation resulting in rapid rates in the enantioselective addition of diethylzinc to aldehydes (up to 92% ee). Further experiments probed the reactivity of the individual Lewis acid and Lewis base components of the catalyst and established that both moieties are essential for asymmetric catalysis. These catalysts are also effective in the asymmetric addition of diethylzinc to alpha-ketoesters. This finding is significant because of alpha-ketoesters alone serve as their own ligands to accelerate racemic 1,2-carbonyl addition of Et2Zn and racemic carbonyl reduction. The latter proceeds via a metalloene pathway. and often accounts for the predominant product. Singular Lewis acid catalysts do not accelerate enantioselective 1,2-addition over these two competing paths. The bifunctional amino salen catalysts, however, rapidly provide enantioenriched 1,2-addition products in excellent yield, complete chemoselectivity, and good enantioselectivity (up to 88% ee). A library of the bifunctional amino salens was synthesized and evaluated in this reaction. The utility of the alpha-ketoester method has been demonstrated in the synthesis of in opiate antagonist. (c) 2005 Elsevier Ltd. All rights reserved.