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.