Synthesis of hybrid ferrocene-proline amides as active catalysts for asymmetric aldol reactions in water

Ferrocenyl substituents were considered as lipophilic moieties to be introduced in prolinamide scaffold in order to obtain new catalysts suitable for use in "on water" conditions. Five proline amides incorporating a ferrocene unit were synthesized from easily accessible ferrocenylamines and evaluated as catalysts in the asymmetric direct aldol condensation of cyclohexanone with aldehydes in aqueous medium. Optimal substrate conversion and stereoselectivity were achieved in brine and in the presence of benzoic acid as additive. All the tested catalysts displayed good activity in 5 mol-% loading and best results in terms of enantioselectivity were obtained by using a ferrocenyl-prolineamide bearing an additional S-chiral center. In the presence of such catalyst a variety of aromatic aldehydes reacted in reasonable time with just 2 equiv. of cyclic ketones to give the expected aldols in high yields (65-98%) and stereoselectivities (up to 94% ee, up to 93:7 dr).