Theoretical study on the mechanisms of Proline-catalyzed Mannich reaction between acetaldehyde and N-Boc imines

The mechanisms of the single and double Mannich reactions between acetaldehyde and N-Boc imines are clarified by density functional theory calculations. For single addition of Mannich reaction, the energy difference between the transition states of different configurations correspond to an enantiomeric excess value of 90.58% (without solvent) and 98.46% (in acetonitrile) in favor of the (S)-configuration product. For bis-addition of Mannich reaction, the calculated enantiomeric excess value is 95.02% (without solvent) and 98.57% (in acetonitrile) in favor of the (S, S)-configuration product. These calculated results are in good agreement with the experimental results. The calculations clearly demonstrate that the hydrogen-bonding determine the stereochemistry of the reactions. Copyright (C) 2012 John Wiley & Sons, Ltd.