Advances towards Highly Active and Stereoselective Simple and Cheap Proline‐Based Organocatalysts

Ten 4‐acyloxy‐L‐prolines were screened as catalysts at loadings of 2–0.1 mol‐% for the direct asymmetric aldol reaction in water by using variable amounts of water. Among them, a new catalyst, the L‐proline carrying a trans‐4‐(2,2‐diphenylacetoxy) group, and a catalyst previously synthesized by us, the L‐proline carrying a trans‐4‐(4‐phenylbutanoyloxy) group, were found to be excellent catalysts for the aldol reaction between cyclohexanone or cyclopentanone and substituted benzaldehydes when employed in only 1 and 0.5 mol‐%,respectively, at room temperature without additives. For such catalysts, high turnover numbers were obtained, which are among the highest values obtained for enamine organocatalysis. Finally, these catalysts can be synthesized by direct O‐acylation from inexpensive molecules and successfully used in scaled‐up reactions.