Organocatalytic Asymmetric Michael Addition in Aqueous Media by a Hydrogen-Bonding Catalyst and Application for Inhibitors of GABA(B) Receptor

Abstract

Catalysts based on (R, R)-1,2-diphenylethylenediamine are, as chiral organic catalysts, applied to the asymmetric Michael addition to alpha, beta-unsaturated nitroalkenes under neutral conditions. The role of an aqueous medium for organic catalytic activity can be reversed concerning hydrophilic-hydrophobic function depending on the reaction conditions. In this study, to provide an environmentally friendly system, the thiourea-based catalyst substituted with 3,5-(CF3)(2)-Ph was used in water solvents. The hydrophobic effect of the substituent provided fast reaction, high chemical yield, and mirror-image selectivity. This reaction allowed the preparation of GABA(B) agonists in an optically pure manner. Additionally, GABA (gamma-aminobutyric acid) analogs such as baclofen and phenibut were synthesized as R-type S-type with high optical purity.