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 anti/syn diastereomeric and 99 : 1 enantiomeric ratio. Experimental results as well as computational investigations have revealed that the electrophile (e.g. 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.