Biomimetic asymmetric Michael addition reactions in water catalyzed by amino-containing β-cyclodextrin derivatives

Abstract

Nine β-cyclodextrin derivatives containing an amino group were synthesized via nucleophilic substitution from mono(6-O-p-tolylsulfonyl)-β-cyclodextrin and used in asymmetric biomimetic Michael addition reactions in water at room temperature. The mechanism responsible for the moderate activity and enantioselectivity of the β-cyclodextrin derivatives was explored using nuclear magnetic resonance spectroscopy, namely 2D 1H rotating-frame overhauser effect spectroscopy (ROESY), ultraviolet absorption spectroscopy, and quantum chemical calculations, which provide a useful technique for investigating the formation of inclusion complexes. The effects of the pH of the reaction medium, the β-cyclodextrin derivative dosage, the structure of the modifying amino group, and various substrates on the yield and enantioselectivity were investigated. The results indicated that these factors had an important effect on the enantiomeric excess (ee) in the reaction system. Experiments using a competitor for inclusion complex formation showed that a hydrophobic cavity is necessary for enantioselective Michael addition. A comparison of the reactions using 4-nitro-β-nitrostyrene and 2-nitro-β-nitrostyrene showed that steric hindrance improved the enantioselectivity. This was verified by the optimized geometries obtained from quantum chemical calculations. An ee of 71% was obtained in the asymmetric Michael addition of cyclohexanone and 2-nitro-β-nitrostyrene, using (S)-2-aminomethylpyrrolidine-modified β-CD as the catalyst, in an aqueous buffer solution, i.e., CH3COONa-HCl (pH 7.5).