Highly enantioselective immobilized prolinamide-catalyzed aldol reactions in continuous-flow systems: effect of water on the catalyst lifetime and application in the synthesis of a chiral fenpentadiol analogue

Catalytic enantioselective aldol reactions of trifluoroacetophenones with ketones under continuous-flow conditions have been developed for the first time by using polystyrene-supported prolinamides. The robustness of the flow system was demonstrated by the continuous synthesis of a variety of trifluoromethyl carbinols in high yields with high enantioselectivities. The unusually long lifetimes (>195 h) of this flow process were achieved by facilitating H2O-promoted hydrolysis of iminium intermediates on the polymer. Mechanistic study revealed a racemization phenomenon and an inherent reversible property of the aldol reactions in a conventional batch system, both of which were suppressed under continuous-flow conditions. The synthetic utility of this flow process was further demonstrated by the formal continuous-flow synthesis of a chiral fenpentadiol analogue.

Automated summary

For the first time, catalytic enantioselective aldol reactions of trifluoroacetophenones with ketones were successfully developed under continuous-flow conditions using polystyrene-supported prolinamides. The robustness of the flow system was demonstrated by the continuous synthesis of various trifluoromethyl carbinols with high yields and enantioselectivities. Through mechanistic studies, it was revealed that the racemization phenomenon and reversible property of the aldol reactions in a conventional batch system could be suppressed under continuous-flow conditions.