Organocatalytic properties of polyhydroxylated prolines

The development of enantioselective reactions using water as a reaction medium and small organic molecules as organocatalysts is an important current goal.¹ Proline is a suitable organocatalyst, because its conformational rigidity, its ability to act as a base and as a Brönsted acid, both allowing it to act as an efficient bifunctional catalyst.² Nevertheless, it is not efficient in aqueous media, which require prolines substituted with hydrophobic groups, because most of the reactions take place in the interphase of biphasic systems.³. A representative example is the aldol condensation of p-nitrobenzaldehyde with cyclohexanone, using (2S,4R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (proline 1) as the catalyst and water as the solvent, Four stereoisomers resulted, with an overall yield of 86%, an anti/syn diastereomeric ratio of 20:1 and an enantiomeric excess of greater than 99%.

The organocatalytic properties of the similar (2S,3R,4R)-3,4-bis((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylic acid (proline 2), with two OH groups protected as OTBS, were now studied for the aldolic condensation of p-nitrobenzaldehyde with cyclohexanone, in the same conditions as for proline 1. The results obtained were almost similar. The enantiomeric yields and the enantiomeric excesses were also 86% and greater than 99%, respectively. But the diastereomeric anti/syn excess was now higher (25:1 versus 20:1)