Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

Abstract

A practical enantioselective N-selective nitroso aldol reaction of α-methylmalonamates with a nitrosoarene is reported. The reaction employs the Takemoto thiourea catalyst for the induction of enantioselectivity, and the corresponding optically active oxyaminated malonamates were obtained in reasonably good yields.

Challenges and recent advancements in the synthesis of α,α-disubstituted α-amino acids

“…A disadvantage of this technique, however, is the limitation in nitrogen reagents that can be utilized, as the nitrogen center needs to be turned electrophilic. Additionally, to obtain the unmasked amine, generally, a reductive N-N or N-O bond cleavage is performed using SmI 2 or Zn after the reaction 46 , 47 . Furthermore, asymmetric electrophilic amination has also been established via the formation of a chiral enamine that can sterically hinder one enantiomer by attacking the nitrogen electrophile in a selective manner 48 , 49 .…”

“…More recently, the Mohanan group employed the Takemoto chiral thiourea catalyst for the electrophilic amination of α-methylmalonamates with nitrosoarenes to construct N -alkyl- N -arylhydroxylamines 47 . Through bifunctional hydrogen bonding, the catalyst activated both the nitrosoarene and the malonamate substrate which induced enantioselectivity.…”

“…Moreover, atom in molecule analysis of Ni/Cu and Pd/Cu complexes were performed and it was found that the former was more stable than the latter, suggesting that the Ni/Cu complex enabled the reaction under base-free conditions room temperature. This strategy also enabled the facile construction of several drug candidates, including the key intermediate of the NK1 receptor antagonist PD154075 (47) and CI-988 (48), which is used as a CCK-B receptor antagonist (Fig. 6b).…”