The Mechanism of the Stetter Reaction - A DFT Study

On the basis of Breslow's mechanism for benzoin condensation, a model asymmetric Stetter reaction has been investigated using DFT methods. In contrast to the concerted benzoin condensation, after formation of the Breslow intermediate the Stetter reaction is found to be a two-step process in which the rate-determining C-C coupling of the Breslow intermediate and the Michael acceptor precedes final proton transfer. In addition, the enolamine is found to play a significant role in the stereochemistry of the product, with the energy difference between stereoisomers of this intermediate reflected throughout the remainder of the reaction sequence. Consequently, electronic and steric control of the stereochemistry of this intermediate should directly enhance the ee values of the product. © Wiley-VCH Verlag GmbH & Co. KGaA, 2008.