Organocatalytic Asymmetric Michael Addition in Aqueous Media by a Hydrogen-Bonding Catalyst and Application for Inhibitors of GABAB Receptor

Jae Ho Shim,Deok-Chan Ha,Ji Hae Kim,Yeonsun Hong,Hyeon Soo Kim

doi:10.3390/catal11091134

Abstract

Catalysts based on (R, R)-1,2-diphenylethylenediamine are, as chiral organic catalysts, applied to the asymmetric Michael addition to α, β-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 GABAB agonists in an optically pure manner. Additionally, GABA (γ-aminobutyric acid) analogs such as baclofen and phenibut were synthesized as R-type S-type with high optical purity.

Highlights

Organic catalysts composed of carbon, hydrogen, sulfur, and other nonmetal elements are commonly referred to as “organocatalysts.” Stereoselective organocatalysts have been extensively studied, metal-catalyzed asymmetric reactions tend to exhibit higher enantioselectivities than organocatalysts [1].metal catalysts incur higher processing costs, and the metals are often retained in the products in ppm-level concentrations, thereby lowering the pharmaceutical purity of the products
The reaction was investigated by applying it to the Michael reaction of nitroalkene, malononitrile, and nitro ester through a chiral hydrogen-bonding catalyst used for asymmetric C-C Michael reaction
We report the development of catalysts based on (R, R)-1,2-diphenylethylenediamine for use as chiral bifunctional organocatalysts in asymmetric Michael additions to α, β-unsaturated nitroalkenes under neutral conditions

Summary

Introduction

Organic catalysts composed of carbon, hydrogen, sulfur, and other nonmetal elements are commonly referred to as “organocatalysts.” Stereoselective organocatalysts have been extensively studied, metal-catalyzed asymmetric reactions tend to exhibit higher enantioselectivities than organocatalysts [1].metal catalysts incur higher processing costs, and the metals are often retained in the products in ppm-level concentrations, thereby lowering the pharmaceutical purity of the products. Organic catalysts composed of carbon, hydrogen, sulfur, and other nonmetal elements are commonly referred to as “organocatalysts.” Stereoselective organocatalysts have been extensively studied, metal-catalyzed asymmetric reactions tend to exhibit higher enantioselectivities than organocatalysts [1]. Metal catalysts are unstable in the presence of moisture. To overcome such disadvantages, research on stereoselective synthesis using organocatalysts has gained significant attention [2,3]. Since the conceptual establishment of organocatalysts, the application of organocatalytic reactions in asymmetric synthesis has been widely investigated, leading to significant advances in the area of organic synthesis [4,5,6]. Numerous examples of organic reactions using water as a solvent have been reported, and water-based asymmetric catalytic reactions exhibiting high yields and good stereoselectivities have been investigated [9,10,11,12,13]

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Results

Conclusion