MSCE  Vol.5 No.8 , August 2017
An Efficient Synthesis of Enantiomerically Pure γ-Aminobutyric Acid (GABA) Derivatives

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.

Cite this paper: Liu, H. , Yuan, J. , Tian, Q. , Ji, N. and He, W. (2017) An Efficient Synthesis of Enantiomerically Pure γ-Aminobutyric Acid (GABA) Derivatives. Journal of Materials Science and Chemical Engineering, 5, 25-32. doi: 10.4236/msce.2017.58003.

[1]   Andersen, K.E., Braestrup, C., Gronwald, F.C., Jorgensen, A.S., Nielsen, E.B., Sonnewald, U., Knutsen, L.J., et al. (1993) The Syn-thesis of Novel GABA Uptake Inhibitors. 1. Elucidation of the Structure-Activity Studies Leading to the Choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic Acid (Tiagabine) as an Anticonvulsant Drug Candidate. Journal of medicinal chemistry, 3612, 1716-1725.

[2]   Krogsgaard-Larsen, P., Krogsgaard-Larsen, P., Arnt, J. and Arnt, J. (1979) GABA Receptor Agonists: Relationship between Structure and Biological Activity in Vivo and in Vitro. Advances in Experimental Medicine and Biology, 123, 303-321.

[3]   Shashoua, V.E., Jacob, J.N., Ridge, R., Campbell, A. and Baldessarini, R.J. (1984) Gamma-Aminobutyric Acid Esters. 1. Synthesis, Brain Uptake, and Pharmacological Studies of Aliphatic and Steroid Esters of Gamma-Aminobutyric Acid. Journal of Medicinal Chemistry, 275, 659-664.

[4]   Maier, N.M., Franco, P. and Lindner, W. (2001) Separation of Enantiomers: Needs, Challenges, Perspectives. Journal of Chromatography A, 9061-2, 3-33.

[5]   Dambrova, M., Zvejniece, L., Liepinsh, E., Cirule, H., Zharkova, O., Veinberg, G. and Kalvinsh, I. (2008) Comparative Pharmacological Activity of Optical Isomers of Phenibut. European Journal of Pharmacology, 5831, 128-134.

[6]   Baures, P.W., Eggleston, D.S., Erhard, K.F., Cieslinski, L.B., Torphy, T.J. and Christensen, S.B. (1993) The Crystal Structure, Absolute Configuration, and Phosphodiesterase Inhibitory Activity of (+)-1-(4-Bromobenzyl)-4-(3-(cyclopentyloxy)- 4-methoxyphenyl)-pyrrolidin-2-one. Journal of Medicinal Chemistry, 3622, 3274- 3277.

[7]   Schneider, H.H., Schmiechen, R., Brezinski, M. and Seidler, J. (1986) Stereospecific Binding of the Antidepressant Rolipram to Brain Protein Structures. European Journal of Pharmacology, 1271-2, 105-115.

[8]   Jin, H., Kim, S.T., Hwang, G.S. and Ryu, D.H. (2016) L-Proline Derived Bifunc-tional Organocatalysts: Enantioselective Michael Addition of Dithiomalonates to Trans- Beta-Nitroolefins. The Journal of organic chemistry, 818, 3263-3274.

[9]   Wang, J., Li, W., Liu, Y., Chu, Y., Lin, L., Liu, X. and Feng, X. (2010) Asymmetric Cyanation of Activated Olefins with Ethyl Cyanoformate Catalyzed by a Modular Titanium Catalyst. Organic Letters, 126, 1280-1283.

[10]   Kolarovic, A., Kaslin, A. and Wennemers, H. (2014) Stereoselective Synthesis of Indolines via Organocatalytic Thioester Enolate Addition Reactions. Organic Letters, 1616, 4236-4239.

[11]   Lapin I. (2001) Phenibut (Beta-Phenyl-GABA): A Tranquilizer and Nootropic Drug. CNS Drug Reviews, 74, 471-481.

[12]   Zvejniece, L., Vavers, E., Svalbe, B., Veinberg, G., Rizhanova, K., Liepins, V., Kalvinsh, I. and Dambrova, M. (2015) R-Phenibut Binds to the α2-δ Subunit of Voltage- Dependent Calcium Channels and Exerts Gabapentin-Like Anti-Nociceptive Effects. Pharmacology, Biochemistry, and Behavior, 137, 23-29.