Proline-Glycine Dipeptidic Derivatives of Chiral Phosphoramides as Organocatalysts for the Enantiodivergent Aldol Reaction of Aryl Aldehydes and Isatins with Cyclohexanone in the Presence of Water

Abstract

The synthesis of several novel organocatalysts derived from (R)- and (S)-proline-glycine dipeptides and incorporating a chiral phosphoramide fragment was accomplished. These chiral compounds catalyze the enantioselective aldol addition reaction of cyclohexanone to prochiral aryl aldehydes and isatins in the presence of water. These chiral organocatalysts represent some of the few proline-derived compounds capable to catalyze aldol-type addition of cyclohexanone to isatins, a C–C bond forming transformation for which chiral primary amines are usually more successful. Additionally, these phosphoramide-containing catalysts afforded excellent results in the addition of cyclohexanone to aryl aldehydes, as anticipated by the presence of the proline moiety. The present report includes a detailed evaluation of the new multifunctional catalysts that are able to afford either enantiomer of the chiral product by adequate selection of the configuration of the proline residue.

New Mesoporous Silica-Supported Organocatalysts Based on (2S)-(1,2,4-Triazol-3-yl)-Proline: Efficient, Reusable, and Heterogeneous Catalysts for the Asymmetric Aldol Reaction

“…Organocatalysts (2S,4R,1 S)-18 and (2S,4R,1 R)-18 incorporate an amide functional group in the (S)-proline-framework. This structural feature has proved rather successful in other organocatalysts derived from (S)-proline [42][43][44]. Furthermore, the fragment of (R)-or (S)-phenylethylamine was introduced to examine the potential effect of an additional center of chirality in the organocatalytic system.…”

“…In this context, several representative organocatalysts present two or more functional groups that act in cooperative or bifunctional strategies [12][13][14][15][16][17][18]. Several research groups have used natural and unnatural amino acids and peptides [19][20][21][22][23][24][25][26][27][28][29][30][31], chiral ureas and thioureas [32][33][34][35][36][37][38][39][40], and chiral amides [41][42][43][44][45] as building blocks or templates in organocatalyst design. In this context, a significant number of (S)-proline derivatives have been developed while searching for an improvement in the catalytic efficiency and stereoselectivity [46][47][48][49][50][51][52][53].…”