A highly diastereoselective and enantioselective Michael addition of enolizable ketones such as cyclohexanone and acetophenone to a variety of substituted trans‐β‐nitrostyrenes and chalcones was catalyzed by a novel chiral and unsymmetrical thiourea as organocatalyst in the presence of water or under neat reaction conditions. The anticipated Michael adducts, γ‐nitrocarbonyl adducts and 1,5‐dicarbonyl derivatives, were obtained in up to 98:2 diastereomeric ratio and up to 96 % enantiomeric excess. The application of this new chiral organocatalyst was extended to an asymmetric Michael addition‐proton transfer‐aldol reaction cascade process, a formal [3+3] cyclization reaction of cyclohexanone with arylidenepyruvates, with high stereoselectivity. The organocatalyst reported here is one of the very few able to promote the above cascade process, providing the important bicyclic framework that is found in many natural products.
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.
Novel organocatalysts derived from (R)- and (S)-proline and incorporating a chiral phosphoramide fragment were rationally designed and subsequently synthesized. These chiral compounds catalyze the enantioselective aldol addition reaction of cyclohexanone to prochiral isatins in the presence of water. These observations are particularly relevant since reports of asymmetric aldol reactions between cyclohexanone and isatins catalyzed by chiral secondary amines remain scarce, with primary amines being the most studied and successful catalysts. The present report includes a thorough evaluation of the new bifunctional catalysts that actually give rise to either enantiomer of the chiral product by proper selection of the configuration of the proline moiety.
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