(R)- and (S)-Proline-Derived Chiral Phosphoramides as Organo­catalysts for the Enantiodivergent Aldol Reaction of Isatins with Cyclohexanone in the Presence of Water

Abstract

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.

Aldol Insights: The Route to Chiral Synthesis of 3‐Substituted 3‐Hydroxy‐2‐Oxindoles

“…This study, alongside the diverse catalytic approaches employed in the asymmetric aldol reactions of isatin derivatives, contributes to the multifaceted strategies available for the synthesis of valuable chiral compounds. The utilization of distinct catalysts such as urea derivatives broadens the toolkit of methodologies, further enriching the field of asymmetric synthesis Nakano and colleagues introduced an enantioselective crossed aldol reaction between isatin derivatives (1) and acetaldehyde (53), employing di-amino alcohol-type catalysts XXXII. This method yielded 3-substituted 3-hydroxyindolin-2ones with high chemical yields (up to 95 %) and optical purity (up to 92 % ee) (Scheme 29).…”

“…The use of water or brine as solvents, or under neat conditions, showed promising results in terms of yield and stereoselectivity. The addition of Brønsted acids as additives further enhanced the efficiency of the enantioselective aldol addition reaction of cyclohexanone to prochiral isatins, to afford aldol adduct 50 a in 45-94 % yield with up to 86 : 14 er and 90 : 10 dr. [53] (Scheme 30). The authors explored the scope of the reaction by varying the substitution pattern in the isatin substrate and using catalysts with different configurations.…”