| A novel catalyst for the asymmetric cyanation of imines, the Strecker reaction, is discovered using combinatorial methods. The optimized structure consists of a substituted urea derivative bearing tert-leucine, diaminocyclohexane, and substituted salicylaldehyde diversity elements. The catalyst is highly effective for the addition of hydrogen cyanide to a wide range of N-allyl or N-benzyl aldimine and methyl ketoimine substrates, providing corresponding adducts in high yield and enantioselectivity. The enantioenriched a-amino nitrile products are readily converted to optically pure difunctional chiral building blocks, including tertiary and quaternary α-amino acids and 1,2-diamines. Practical aspects of the methodology, such as efficient catalyst synthesis, catalyst recycling, and protective group strategies are discussed.; A detailed mechnistic investigation of the catalytic Strecker reaction is described. Kinetic, structure-activity, structural, and computational studies point to the participation of an activated complex between the catalyst and the (Z)-stereoisomer of the imine substrate. The active site of the catalyst is shown to be the urea moiety, with imine coordination taking place through a novel dual hydrogen bonding interaction. This structural model serves as the basis for further rational optimization of the catalyst for the Strecker reaction, and for the application of this catalyst system to other asymmetric transformations of imines. |
