Abstract
Chiral γ-aminobutyric acid (GABA) derivatives are the normal inhibitory neurotransmitters in the mammalian central nervous system. In this paper, enantiopure GABA derivatives 6 were synthesized via reduction/cyclization/hydrolysis cascade reactions from the highly enantioselective β-aryl-γ- ni-troalkanes Michael adducts 4, which was obtained from asymmetric Michael addition of S, S’-diphenyldithiomalonate 2 to trans-β-nitroolefins 1, using novel chiral cinchona alkaloid-derived thioureas 3 as the organocatalysts. This synthesis represents an efficient, highly selective and environmental benign methodology for GABA derivatives.
Highlights
IntroductionGABA is the most common inhibitory neurotransmitters in the mammalian central nervous system (CNS) where it exerts its effects through inhibiting GABA receptors channels
Enantiopure GABA derivatives 6 were synthesized via reduction/cyclization/hydrolysis cascade reactions from the highly enantioselective β-aryl-γnitroalkanes Michael adducts 4, which was obtained from asymmetric Michael addition of S, S’-diphenyldithiomalonate 2 to trans-β-nitroolefins 1, using novel chiral cinchona alkaloid-derived thioureas 3 as the organocatalysts
GABA is the most common inhibitory neurotransmitters in the mammalian central nervous system (CNS) where it exerts its effects through inhibiting GABA receptors channels
Summary
GABA is the most common inhibitory neurotransmitters in the mammalian central nervous system (CNS) where it exerts its effects through inhibiting GABA receptors channels. In pharmacological tests of locomotor activity, antidepressant and pain effects, (S)-phenibut was inactive in doses up to 500 mg/kg, but in contrast, (R)-phenibut turned out to be two times more potent than racemic phenibut in most of the tests. We report the asymmetric Michael addition of S, S’-diphenyldithiomalonate 2 to trans-β-nitroolefins 1, catalyzed by chiral cinchona alkaloid-derived thioureas organocatalysts 3, to give a series of corresponding chiral β-aryl-γ-nitroalkanes 4 in moderate to good yields, along with excellent stereoselectivities. Their transformations into biologically attractive chiral GABA derivatives 6 via reduction/cyclization/hydrolysis cascade reactions were reported
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