Study on Organocatalytic Asymmetric Michael Addition in Aqueous Media by a Hydrogen-Bonding Catalyst and Application for Inhibitors of GABAB 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, provides fast reaction, high chemical yield, and mirror-image selectivity. This reaction allowed the preparation of GABA_B agonists in an optically pure manner. Besides, GABA (\(\gamma\)-aminobutyric acid) analogs such as baclofen and phenibut were synthesized as R-type S-type with high optical purity. We demonstrated that R-baclofen induced a higher intracellular Ca²⁺ release than RS-baclofen. Taken together, our data show that as a drug, baclofen RS-type may induce differential calcium release activity depending on R and S-types. This will in turn induce differential GABA_B receptor activation.