Highly Enantioselective Aza Morita−Baylis−Hillman Reaction Catalyzed by Bifunctional β-Isocupreidine Derivatives

Abstract

The aza-MBH reaction of imines 1 and beta-naphthyl acrylate 2 in the presence of C-6' modified beta-isocupreidine derivative 1c (0.1 equiv) and beta-naphthol 5 (0.1 equiv) afforded the corresponding (3S)-aza-MBH adducts 4 in high yield and excellent enantiomeric excess. These catalytic conditions allowed the aliphatic imines to be employed for the first time as electrophilic partners of the aza-MBH reaction. The coexistence of two H-bond donors with different acidic strengths was found to be crucial for the observed high enantioselectivity.

Total Synthesis of Biologically Active Natural Products Based on Highly Selective Synthetic Methodologies

“…This reaction tendency is the same as that observed for β-ICD-catalyzed reactions. 7,8) To demonstrate the utility of α-ICPN, we examined aza-MBH reactions of aromatic imines 12 with β-naphthyl acrylate (13) employing catalyst 14 27) derived from α-ICPN and β-naphthol under the dual catalysis conditions developed by Masson and colleagues [28][29][30] As summarized in Chart 6, the reactions of 12 and 13 produced aza-MBH adducts 15 with high R-selectivity in the range of 80% ee to 96% ee, which is opposite to that observed in the reactions catalyzed by the corresponding β-ICD-derived catalyst. 28) The observed R-selectivity can be explained by assuming zwitterionic intermediates 16 28) stabilized by hydrogen bonding, from which a six-membered proton transfer followed by E1cb elimination of the catalyst takes place to give R-aza-MBH product 15.…”

Chiral Amines Derived from Asymmetric Aza‐Morita–Baylis–Hillman Reaction

“…Aliphatic imines were poor substrates for the reaction and this is believed to be due to their extremely labile nature. Very recently, Zhu and coworkers have developed a novel catalysis that was applicable to the reaction of acrylate with both aromatic and aliphatic imines [21]. The 6 0 -OH group in b-ICD provided a handle for the introduction of other H-bond donors that were capable of modulating both the steric and electronic parameters.…”

“…General Procedures of Aza-MBH Reactions Involving Aliphatic Imines [21] To a solution of corresponding imine freshly prepared (1.0 equiv) in dried dichloromethane at 0 C, catalyst (13c) (0.1 equiv), b-naphthol (0.1 equiv), and b-naphthyl acrylate (2.0 equiv) were added. The reaction mixture was stirred under argon atmosphere at 0 C for the required time indicated in the tables.…”

Enantioselective Aza‐Morita–Baylis–Hillman Reaction Using Aliphatic α‐Amidosulfones as Imine Surrogates

“…[7] Although the enantioselectivity was excellent, the yield remained moderate at best. As a continuation of this research program, we assumed that generating the imine in situ under conditions conducive to the aza-MBH reaction could be a solution to the problem.…”

“…The inclusion of achiral b-naphthol 2 was thought to increase the enantioselectivity of the aza-MBH reaction in accord with our earlier observations. [7] To validate this hypothesis, we carried out the aza-MBH reaction of N-p-methoxybenzenesulfonyl-aamidosulfone 3a with b-naphthyl acrylate 4a in the presence of a catalytic amount of 6'-deoxy-6'-benzamido-b-isocupreidine 1a (Ar = Ph) and b-naphthol 2 (Table 1). At room temperature, the reaction of 3a with two equivalents of 4a provided indeed the desired product 5a in 44% yield with 88% ee, along with ethyl 3-phenylsulfonylpropionate (10) in quantitative yield based on 3a (cf.…”