Prolinamides containing 2-(2-aminocyclohexyl)phenols as highly enantioselective organocatalysts for aldol reactions.

Effective synthesis of prolinamides of 2-(2-aminocyclohexyl)phenols has been accomplished. The novel prolinamides are demonstrated to catalyze the direct aldol reaction between ketones and aldehydes with high stereoselectivity, thus affording up to 99 : 1 / diastereomeric and 99 : 1 enantiomeric ratio. Experimental results as well as computational investigations have revealed that the electrophile ( aldehyde) is activated by dual hydrogen bonding with the amide NH and phenolic OH group of the catalyst. A rather large spacing between the H-bond donor groups and its conformational flexibility are remarkable structural features of the most enantioselective catalyst.