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-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. This synthesis represents an efficient, highly selective and environmental benign methodology for GABA derivatives


Introduction
GABA is the most common inhibitory neurotransmitters in the mammalian central nervous system (CNS) where it exerts its effects through inhibiting GABA receptors channels.And decreased GABA biological activity results in the excessive excitement of CNS (namely Neuronal Firing).The dysfunction of the Ar NO 2 Et 2O, r.t.Journal of Materials Science and Chemical Engineering central GABA system is responsible for the development and outbreak of epilepsy [1], Huntington's, Parkinson's diseases [2] and other psychiatric disorders, such as anxiety and pain [3].Various GABA derivatives and analogs are widely recognized as CNS depressants, for example: Phenibut, Baclofen (Lioresal and Baclon®), Vigabatrin, Gabapentin (GBP, Neurontin), Pregabalin (Lyrica, Pfizer's blockbuster drug, β-i-Bu-GABA) (Figure 1).
Enantiomers of a drug are often known to play an important role in pharmacological actions, pharmacokinetics, toxicities and metabolism.The biological activity of some drugs depends on their absolute configuration.Therefore, the use of a single isomer of a given drug is usually recommended for clinical use [4].It has reported that (R)-enantiomer of GABA derivatives is much more active than (S)-enantiomer [5] [6] [7].For example, 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.In the forced swimming test, at a dose of 100 mg/kg only (R)-phenibut significantly decreased immobility time.Consequently, obtaining enantiomerically pure GABA derivatives as a new modulators has become one of the most effective approaches for the development of extracellular GABA homeostasis in the CNS.
In this paper, 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.And their transformations into biologically attractive chiral GABA derivatives 6 via reduction/cyclization/hydrolysis cascade reactions were reported.

Materials
Trans-β-nitroolefins, benzotrifluoride, TiCl 3 were purchased from commercial Figure 1.GABA and its analogs used as CNS depressants.Journal of Materials Science and Chemical Engineering suppliers and were used without further purification.S, S'-diphenyldithiomalonate 2 and cinchona alkaloid-derived thioureas 3 were previously synthesized in our laboratory.Zinc powder was freshly activated before usage.DCM and toluene were freshly distilled before usage.Analytical thin layer chromatography (TLC) was performed on Kiselgel 60 F 254 plates. 1 H NMR or 13 C NMR spectra were recorded in CDCl 3 and CD 3 OD, and the solvent signals (7.26/77.0 and 3.31/ 49.0 ppm) were used as reference.The yields are isolated by column chromatographygel plates.Percent enantiomeric excess (ee %) was determined by Agilent 1260 interfaced to a HP 71 series computer workstation with Chiralpak OD-H column.Optical rotations were determined on a polarimeter at 589 nm.Melting points were determined by using a XRC-1 microferrometer and are uncorrected.Specific rotations were measured in a Perkin-Elmer 343 polarimeter at room temperature and λ = 589 nm.The purification of all compounds was carried out by column chromatography using (silica gel 200 -300).

Synthesis of β-Aryl-γ-Nitroalkanes 4 Vis Asymmetric Michael Addition
For the synthesis of the important intermediates β-aryl-γ-nitroalkanes 4, asymmetric Michael addition was studied.We initially examined two kinds of cinchona alkaloid-derived bifunctional thioureas 3a-b as potential organocatalysts for the asymmetric Michael addition of S, S'-diphenyldithiomalonate 2 to trans-β-nitroolefins 1 in benzotrifuoride at room temperature, leading to the expected γ-nitroalkanes derivative 4 in good yield and excellent stereoselectivity (Table 1).Quinidine-derived thiourea 3b, pseudoenantiomer of 3a, effectively catalyzed the reaction and gave 4a, 4b and 4c with opposite absolute configuration in similar enantioselectivities (Table 1, entries 2, 4, 6 vs 1, 3, 5).Upon screening the various solvents, we found that benzotrifluoride produced better results than any other polar or less polar solvents, such as DCM, diethyl ether, touene and methanol.
Thus, the best reaction conditions was obtained when carrying out the reaction with 1.0 equiv of trans-β-nitroolefins 1 and 1.0 equiv of S, S'-diphenyldithiomalonate 2 in benzotrifluoride (1mL) at room tempreature in the presence of 10% mol of 3a/b as catalysts for 12 h (Table 1).
After filtration, the products were furnished.

Conclusion
In conclusion, we have developed the first example of cinchona alkaloid-derived thioureas-catalyzed asymmetric Michael addition of S, S'-diphenyldithiomalonate to trans-β-nitroolefins.An efficient asymmetric synthesis of biologically attractive chiral GABA derivatives (S) or (R)-Phenibut was readily accomplished by reduction/cyclization/ hydrolysis sequential reactions.Easily obtained substrates, catalysts and a simple experimental procedure constitute peculiar advantages of this method.Investigations aimed at developing more effective transformation of β-aryl-γ-nitroalkanes adducts to GABA derivatives without any effect on enantioselectivities are currently ongoing in our laboratory.