Prolinamides derived from 2-aminocyclohexanols as organocatalysts for asymmetric List-Lerner-Barbas aldol reactions

Starting from Cbz-L-proline and either racemic trans-2-aminocyclohexanol or racemic cis-2-aminocyclohexanol, new chiral prolinamides containing 2-aminocyclohexanols have been made available in an effective manner. They are demonstrated to be capable of catalyzing the List-Lerner-Barbas aldol reaction between ketones and aldehydes. While they generally show moderate catalytic activity, they provide diastereomeric ratio up to 97:3 (anti/syn) and 96% ee in the reaction of cyclohexanone with benzaldehyde. Computational studies reveal that the electrophile (e.g. aldehyde) is activated by two-point hydrogen bonding with the amide NH and the OH protons of the catalyst.