Constrained Bicyclic β-Proline Analogues in Aldol Reaction

Significance

A bicyclic amino acid (C) was prepared in enantiopure form and evaluated as catalyst in the intermolecular aldol reaction of acetone and 4-nitrobenzaldehyde. A comparative DFT study of proline (A), β-proline (B) and bicyclic amino acid (C) was also conducted and unveiled the importance of the spatial relationship between the secondary amine and acid functionalities and the constraining effect of the pyrrolidine ring in stabilizing the transition states of the tested aldol reaction. Predicted enantiomeric ratios using DFT methods were in good agreement with experimental results and consistent with the List-Houk model (J. Am. Chem. Soc. 2003, 125, 2475).