Scalable Synthesis of Both Enantiomers of Vigabatrin, an Antiepileptic Drug

Article abstract of DOI:10.1002/ejoc.201801617

Vigabatrin is a potent inhibitor of gamma-aminobutyric acid (GABA) catabolism used for the treatment of epilepsy. Here we have synthesized both enantiomers of the drug vigabatrin in five steps from known intermediates using Wittig olefination and pyrolytic elimination as key steps. The target compounds are synthesized in gram scale amounts with >98 % enantiopurity.

Full text of DOI:10.1002/ejoc.201801617

A Journal of
Accepted Article
Title: Scalable Synthesis of Both Enantiomers of Vigabatrin, an
Antiepileptic Drug
Authors: Gorakhnath R. Jachak and D Srinivasa Reddy
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801617
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10.1002/ejoc.201801617
European Journal of Organic Chemistry
Full Paper
Scalable Synthesis of Both Enantiomers of Vigabatrin, an
Antiepileptic Drug
Gorakhnath R. Jachaka, b and Dr. D. Srinivasa Reddy*a, b
Abstract: Vigabatrin is a potent inhibitor of gamma-aminobutyric acid
(GABA) catabolism used for the treatment of epilepsy. Here we have
synthesized both enantiomers of the drug vigabatrin in five steps from
known intermediates using Wittig olefination and pyrolytic elimination
as key steps. The target compounds are synthesized in gram scale
with >98% enantiopurity.
Introduction
Epilepsy is estimated to universally affect one percent of the entire
population.1 Though the biochemical mechanisms responsible for
epilepsy, are not fully understood, it is known that GABA is a
major inhibitory neurotransmitter present in the mammalian
central nervous system (CNS) that prevents seizures.2 Indeed,
convulsions occur when GABA level diminishes below a specific
threshold in the brain, so increase in the brain concentration of
GABA prevents the same.3 The low lipophilicity of this compound
is probably responsible for its inefficiency as an anticonvulsant
when administered orally or intravenously. The brain
concentration of GABA can also beraised using selective
inhibitors of GABA catabolism such as Gabapentin, Pregabalin,
Figure 1: Structure of GABA and their analogues.
and Pivagabine. The most important enzyme in this catabolic
process is GABA-aminotransferase (GABA-T) which degrades
GABA to succinic semialdehyde. One of the most effective and
selective inhibitors of GABA-T is 4-amino-5-hexenoic acid known
as vigabatrin which is an important anticonvulsant drug marketed
Results and Discussion
We planned to access Vigabatrin starting from methionine which
as Sabril (Figure 1).4 The pharmacological properties of
vigabatrin have been studied extensively which demonstrate its
absolute configuration to be highly crucial for the concerned
biological activity of the drug. Although racemic vigabatrin is used
in clinical practice, (S)-vigabatrin is the pharmacologically active
enantiomer.5 Since stereochemistry is a key important facet in the
efficacy and safety of a drug molecule, synthesis of chirally pure
drugs is presently an area of major interest in the domain of
medicinal chemistry and drug discovery.6 Hence the asymmetric
synthesis of vigabatrin holds a critical standpoint in this context.
Several methods for the racemic as well as asymmetric synthesis
of this anti-convulsive drug have been reported in the literature,7
some of them having certain disadvantages like more number of
reaction sequences and expensive catalysts coupled with low
enantiomeric purity. In this letter, we report an efficient and
scalable route, which can furnish both the enantiomers of
vigabatrin with impressive enantiopurity. A route by Knaus to
prepare vigabatrin is worth mentioning here, which also uses
methionine as the starting material.7d, e
is readily available in both enantiomeric forms. Two carbon
homologation was planned using Wittig olefination followed by
hydrogenation, which is in turn prepared from methionine. Vinyl
moiety was planned through pyrolytic elimination of
corresponding sulfoxide (Figure 2). Accordingly, the synthesis of
(S)-vigabatrin 1a commenced with a known D-methionine
aldehyde 3a8 which on two carbon Wittig olefination reaction with
ethyl 2-(triphenyl-l5-phosphaneylidene) acetate in CH2Cl2 gave
the desired -unsaturated ester 4a in 81% yield.9 To our delight,
compound 4a upon hydrogenation using catalytic amount of 10%
Pd/C in ethanol under 60 psi pressure of H2 gave saturated ester
2a with quantitative yield. It was reported in the literature that
reduction of -unsaturated ester having methylthio group is
difficult because of its interference in catalytic hydrogenation
[a]
[b]
Organic Chemistry Division, CSIR-National Chemical Laboratory,
Dr. Homi Bhabha Road, Pune, 411008, India
E-mail: ds.reddy@ncl.res.in (D. S. Reddy)
http://academic.ncl.res.in/ds.reddy
Academy of Scientific and Innovative Research (AcSIR), New Delhi,
110 025, India
Figure 2: Synthetic plan towards vigabatrin
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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10.1002/ejoc.201801617
European Journal of Organic Chemistry
Full Paper
Scheme 1. Gram scale synthesis of vigabatrin enantiomers
reaction or poisoning of catalyst.10 In this context it is worth
mentioning that we have performed hydrogenation on a gram
scale in single batch operation without any complicacies. The next
task was to install olefin by converting it to sulfoxide followed by
elimination. One possible way to make sulfoxide is by the use of
sodium metaperiodate, however, it generates a considerable
amount of solid waste. But here we have utilized ozonolysis
reaction to convert sulphur to sulphoxide in CH2Cl2 at -78˚C which
also makes it a greener approach.11 Crude sulphoxide thus
obtained was subjected for pyrolytic elimination in the presence
of calcium carbonate in ODCB (o-dichloro benzene) as solvent
under reflux condition to result in compound 5a with an overall
yield of 40% over two steps.12 The product was characterized by
all the spectral data and it is in agreement with the depicted
structure as 5a. Essentially following the same sequence, we
have prepared corresponding enantiomer starting from 3b. The
enantiomeric excess of compound 5a and its enantiomer was
determined by using chiral HPLC method which came out to be
>98%.13 The next task was to hydrolyze the ethyl ester which was
achieved using LiOH.H2O in THF:H2O mixture which gave N-Boc
protected (S)-vigabatrin 6a with a 96% yield in gram scale. Finally
Boc deprotection using 4M HCl in dioxane followed by passing
through Dowex resin resulted in (S)-vigabatrin (1a) with a yield of
90%. After the successful synthesis of 1a, we turned our attention
to its enantiomer 1b. The gram scale synthesis of (R)-vigabatrin
(1b) was achieved by repeating essentially the same scheme
used for 1a (Scheme 1). Both the enantiomers of vigabatrin are
well characterized using spectroscopic techniques, which are in
well accordance with the literature data.7
Conclusions
In conclusion, we have developed a novel enantiospecific route to
access both the R and S isomers of an antiepileptic drug
vigabatrin from known intermediates which in turn was prepared
from methionines. A two carbon homologation through Wittig
olefination and hydrogenation followed by pyrolytic elimination are
key features of the synthesis. The developed route discussed
herein is simple and amenable to scale up to access the
enantiopure drugs in a gram scale. Although this synthesis is not
the best one, it can be an alternate synthetic route to access
vigabatrin and related compounds. During the course of synthesis,
Wittig olefination reaction furnished chiral -amino--
unsaturated ester which can be a useful building block for the
synthesis of biologically important compounds, as peptide
isosteres or peptide mimics.
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10.1002/ejoc.201801617
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Full Paper
4.12 (q, J = 6.7 Hz, 2H), 3.72 - 3.66 (m, 1H), 2.56 - 2.48 (m, 2H), 2.37
(t, J = 7.3 Hz, 2H), 2.09 (s, 3H), 1.87 - 1.81 (m, 1H), 1.78 - 1.73 (m,
1H), 1.68 - 1.65 (m, 2H), 1.42 (brs, 9H), 1.25 (t, J = 7.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3): 173.5, 155.6, 79.2, 60.5, 49.9, 35.4, 31.0,
30.6, 30.3, 28.3, 15.6, 14.2; HRMS calculated for C14H28O4NS
[M+H]+ : 306.1734, found 306.1721.
Experimental Section
General Information: All reactions were carried out in oven-dried
glassware under a positive pressure of argon or nitrogen unless
otherwise mentioned with magnetic stirring. Air sensitive reagents and
solutions were transferred via syringe or cannula and were introduced
to the apparatus via rubber septa. All reagents, starting materials and
solvents were obtained from commercial suppliers and used as such
without further purification. Reactions were monitored by thin layer
chromatography (TLC) with 0.25 mm pre-coated silica gel plates (60
F254). Visualization was accomplished with either UV light, or by
immersion in ethanolic solution of phosphomolybdic acid (PMA), para-
anisaldehyde, 2,4-DNP, KMnO4 solution or Iodine adsorbed on silica
gel followed by heating with a heat gun for ~15 sec. Column
chromatography was performed on silica gel (100-200 or 230-400
mesh size). Melting points (mp) were determined using a Bruker
capillary melting point apparatus. Deuterated solvents for NMR
Ethyl (S)-4-((tert-butoxycarbonyl)amino)hex-5-enoate (5a):
To a solution of compound 2a (15.3 g, 50.09 mmol) in CH2Cl2 (250
mL) ozone was bubbled at -78 °C until the color becames blue, once
the blue color appeared oxygen was bubbled to remove excess ozone,
then reaction mixture was allowed to warm to room temperature and
stirred for 1 h. After concentration under vacuocrude sulfoxide
compound was taken in 1,2 dichloro benzene (500 mL), followed by
addition of CaCO3 (5 g, 50.09 mmol) and refluxed for 6 h. The crude
reaction mixture was purified by column chromatography (silica gel
230-400 mesh 10% ethyl acetate – pet ether) to afford 5a as a
colorless powder (5.20 g, 40% yield). Mp = 61 - 63 °C; []D22 + 13.5 (c
0.95, CHCl3); IR υmax(film): cm-1 3557, 2979, 2933, 1711, 1692, 1513,
1
1
spectroscopic analyses were used as received. All H NMR and 13C
1366; H NMR (500 MHz, CDCl3):  5.74 (ddd, J = 5.7, 10.6, 16.9
NMR spectra were obtained using a 400 MHz or 500 MHz
spectrometer. Coupling constants were measured in Hertz. Chemical
shifts were quoted in ppm, relative to TMS, using the residual solvent
peak as a reference standard. The following abbreviations were used
to explain the multiplicities: s = singlet, d = doublet, dd = doublet of
doublets, ddd = doublet of doublet of doublets, dt = doublet of triplets,
t = triplet, q = quartet, m = multiplet. HRMS (ESI) were recorded on
ORBITRAP mass analyser (Thermo Scientific, Q Exactive). Infrared
(IR) spectra were recorded on a FT-IR spectrometer as a thin film.
Chemical nomenclature was generated using Chem Bio Draw Ultra
14.0.
Hz, 1H), 5.19 - 5.10 (m, 2H), 4.56 (brs, 1H), 4.13 (q, J = 7.0 Hz, 3H),
2.36 (t, J = 7.6 Hz, 2H), 1.91 - 1.87 (m, 1H), 1.80 - 1.76 (m, 1H), 1.43
(s, 9H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3): 173.3,
155.3, 138.2, 115.0, 79.4, 60.5, 52.4, 30.8, 29.9, 28.3, 14.2; HRMS
calculated for C13H23O4NNa [M+H]+ : 280.1519, found 280.1513.
(S)-4-((tert-Butoxycarbonyl)amino)hex-5-enoic acid (6a):
To a solution of compound 5a (4.00 g, 15.54 mmol) in ethanol (30 mL)
was added LiOH.H2O (1.27 g, 31.08 mmol) in H2O (30 mL) drop wise
at 0 °C and stirred for 5 h at room temperature. Reaction mass was
evaporated to dryness, diluted with H2O (50 mL), washed with diethyl
ether (50 mL), acidified with citric acid (20% solution). The suspension
thus formed was extracted with EtOAc (3 x 70 mL), washed with H2O
(50 mL), brine (50 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give 6a as a yellow solid
(3.36 g, 96% yield). IR υmax(film): cm-1 3325, 2979, 2932, 1702, 1512,
1393; 1H NMR (400 MHz, DMSO-d6): 11.99 (brs, 1H), 6.87 (d, J =
7.9 Hz, 1H), 5.71 (ddd, J = 6.1, 10.4, 17.1 Hz, 1H), 5.07- 4.99 (m, 2H),
3.91 (brs, 1 H), 2.19 (t, J = 7.3 Hz, 2H), 1.69 - 1.56 (m, 2H), 1.37 (s,
9H); 13C NMR (100 MHz, DMSO-d6): 174.1, 155.1, 139.3, 114.1, 77.6,
51.9, 30.3, 29.4, 28.2; HRMS calculated for C13H24O4N [M+H]+ :
130.0861, found 130.0863.
Ethyl (R,E)-4-((tert-butoxycarbonyl)amino)-6-(methylthio)hex-2-
enoate (4a):
To a solution of compound 3a (15.0 g, 64.29 mmol) in anhydrous
dichloromethane (250 mL) at 0 °C under the nitrogen atmosphere
(ethyl 2-(triphenyl-l5-phosphaneylidene)propanoate) Wittig ylide
(40.31 g, 115.72 mmol) was added in portion wise. The progress of
reaction was monitored by TLC. After the completion of reaction (8 h)
CH2Cl2 was evaporated and product was purified by column
chromatography (silica gel 230-400 mesh 8% ethyl acetate - pet
ether) to afford compound 4a as an oily liquid (15.7 g, 81% yield).
[]D22 + 5.23 (c 0.6, CHCl3); IR υmax(film): cm-1 3345, 2978, 2918, 1690,
1515, 1366; 1H NMR (400 MHz, CDCl3): 6.80 (dd, J = 4.9, 15.9 Hz,
1H), 5.89 (d, J = 15.3 Hz, 1H), 4.87 (brs, 1H), 4.39 (brs, 1H), 4.15 (q,
J = 7.3 Hz, 2H), 2.54 - 2.49 (m, 2H), 2.05 (s, 3H), 1.84 - 1.74 (m, 2H),
1.39 (s, 9H), 1.24 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
166.1, 155.0, 147.5, 121.0, 79.7, 60.5, 60.4, 50.7, 33.8, 30.2, 28.2,
15.4, 14.1; HRMS calculated for C14H26O4NS [M+H]+ : 304.1577,
found 304.1571.
(S)-4-Aminohex-5-enoic acid (1a):
To a solution of compound 6a (300 mg, 1.31 mmol), 4M HCl in
dioxane (5 mL) was added and stirred at room temperature for 2 h.
The solvent was then removed in vacuo, and the residue was washed
with diethyl ether (10 mL) to give a yellow colorled solid, which
happened to be the hydrochloride salt. 1H NMR (200 MHz, D2O): 
5.80 (m, 1H), 5.47 - 5.36 (m, 2H), 3.82 (m, 1H), 2.46 (m, 2H), 2.08 (m,
1H), 1.94 (m, 1H). The compound was introduced in water (1 mL)
solution was passed through a column of Dowex 50WX8 ion
exchange resin (4 g, 200–400 mesh, H+ form). The column was eluted
with H2O until the eluent pH was neutral. Further elution with 2N aq.
NH4OH, and removal of the latter in vacuo, afforded (S)-vigabatrin
(1a) (151 mg, 90%) as a colorless solid. The spectroscopic data for
this compound was in full agreement with that reported. Observed Mp
= 173 - 175 °C, Literature7e Mp = 164 - 165 °C; Observed []D22 + 14.23
(c 0.94, H2O), Literature7e []D25 +12.00 (c 2.5, H2O).
Ethyl
(S)-4-((tert-butoxycarbonyl)amino)-6-
(methylthio)hexanoate (2a):
To a solution of compound 4a (15.5 g, 51.08 mmol) in ethanol (70 mL),
10% Pd/C (~ 300 mg) was added and stirred in reactor with 60 psi
pressure of H2 atmosphere for 8 h. The reaction mixture was then
filtered through a pad of celite, concentrated to afford saturated ester
22
compound 2a as a colorless liquid with quantitative yield. []D
+
Ethyl (S,E)-4-((tert-butoxycarbonyl)amino)-6-(methylthio)hex-2-
enoate (4b):
16.18 (c 0.67, CHCl3); IR υmax(film): cm-1 3351, 2977, 2919, 1711, 1687,
1516, 1447; 1H NMR (400 MHz, CDCl3): 4.40 (d, J = 8.5 Hz, 1H),
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10.1002/ejoc.201801617
European Journal of Organic Chemistry
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[4]
a) R. W. Olsen, M. Avoli, Epilepsia.1997, 38, 399; b) E. Roberts, Biochem.
Pharmacol. 1974, 23, 2637; c) L. L. Iversen, G. A. R. Johnston, Journal
of Neurochemistry 1971, 18, 1939.
Compound 4b was synthesized from 3b by following similar
procedure for the synthesis of compound 4a. []D22 - 6.03 (c 0.81,
CHCl3); 1H NMR (400 MHz, CDCl3): 6.80 (dd, J = 4.9, 15.9 Hz, 1H),
5.89 (d, J = 15.3 Hz, 1H), 4.87 (brs, 1H), 4.39 (brs, 1H), 4.15 (q, J =
7.3 Hz, 2H), 2.54 - 2.49 (m, 2H), 2.05 (s, 3H), 1.84 - 1.74 (m, 2H), 1.39
(s, 9H), 1.24 (t, J = 7.0 Hz, 3H)
[5]
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B. W. Metcalf, M. J. Jung, Molecular. Pharmacol. 1979, 16, 539.
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Shanmugam, K. Harlos, M. Yogavel, A. Sharma, D. S. Reddy, J. Med.
Chem. 2018, 61, 5664.
Ethyl
(R)-4-((tert-butoxycarbonyl)amino)-6-
(methylthio)hexanoate (2b):
Compound 2b was synthesized from 4b by following similar
procedure for the synthesis of compound 2a. []D22 - 15.37 (c 0.57,
CHCl3); 1H NMR (500 MHz, CDCl3):  4.40 (d, J = 8.8 Hz, 1H), 4.12
(q, J = 7.2 Hz, 2H), 3.72 - 3.59 (m, 1H), 2.54 - 2.49 (m, 2H), 2.37 (t, J
= 7.6 Hz, 2H), 2.09 (s, 3H), 1.87 - 1.83 (m, 1H), 1.78 - 1.74 (m, 1H),
1.69 - 1.65 (m, 2H), 1.42 (s, 9H), 1.27 - 1.20 (m, 3H)
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Ethyl (R)-4-((tert-butoxycarbonyl)amino)hex-5-enoate (5b):
Compound 5b was synthesized from 2b by following similar
22
procedure for the synthesis of compound 5a. []D +12.6 (c 0.82,
CHCl3); 1H NMR (200 MHz, CDCl3): 5.74 (ddd, J = 5.7, 10.6, 16.9
Hz, 1H), 5.22 - 5.09 (m, 2H), 4.52 (brs, 1H), 4.13 (q, J = 7.0 Hz, 3H),
2.37 (t, J = 7.6 Hz, 2H), 1.91 - 1.87 (m, 1H), 1.80 - 1.76 (m, 1H), 1.44
(s, 9H), 1.26 (t, J = 7.2 Hz, 3H).
(R)-4-((tert-Butoxycarbonyl)amino)hex-5-enoic acid (6b):
Compound 6b was synthesized from 5b by following similar
procedure for the synthesis of compound 6a. 1H NMR (200 MHz,
DMSO-d6): 12.0 (brs, 1H), 6.88 (d, J = 7.9 Hz, 1H), 5.71 (ddd, J =
6.1, 10.4, 17.1 Hz, 1H), 5.09 - 4.98 (m, 2H), 3.91 (brs, 1H), 2.20 (t, J
= 7.3 Hz, 2H), 1.69 - 1.52 (m, 2H), 1.38 (s, 9H).
(R)-4-Aminohex-5-enoic acid (1b):
Compound 1b was synthesized from 6b by following similar
22
procedure for the synthesis of compound 1a. Mp = 170 - 173 °C; []D
-12.81 (c 0.56, H2O); 1H NMR (200 MHz, D2O): 5.80 (m, 1H), 5.47
[8]
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- 5.36 (m, 2H), 3.82 (m, 1H), 2.46 (m, 2H), 2.08 (m, 1H), 1.94 (m, 1H).
Supporting Information (see footnote on the first page of this
article): 1HNMR, 13C NMR spectra and HPLC chromatograms.
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Conflict of Interest The authors declare no conflict of interest.
[11] K. Kashinath, S. Dhara, D. S. Reddy, Org. Lett. 2015, 17, 2090 and
references cited therein.
Acknowledgements
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Airiau, T. Span genberg, N. Girard, B. Breit, A. Mann, Org. Lett. 2010, 12,
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Gonnade, D. S. Reddy, Org. Lett. 2016, 18, 3178.
The following are acknowledged for supporting this work:
SERB, New Delhi (EMR/2016/001045) for financial support
CSIR-NCL for providing research infrastructures and G. R.
J. thanks CSIR, New Delhi, for the award of senior research
fellowship.
(13) HPLC performed on Daicel Chiralpak AD-H column, n-hexane/2-
propanol (95:5), flow rate = 0.6 mL/min, 210 nm UV detector, tR = 15.5
for Ethyl (S)-4-((tert-butoxycarbonyl)amino)hex-5-enoate (5a) and tR =
19.4 min for Ethyl (R)-4-((tert-butoxycarbonyl)amino)hex-5-enoate (5b).
Keywords: Vigabatrin • Epilepsy • Wittig reactions •
Hydrogenation • Elimination.
[1]
[2]
K.Gale, Epilepsia1989, 30, S1–11.
a) B. Lippert, B. W. Metcalf, M. J. Jung, P. Casara, Eur. J. Biochem. 1977,
74, 441; b) S. M. Nanavati, R. B. Silverman, J. Am. Chem. Soc.1991,
113, 9341.
[3]
a) E. Roberts, T. N. Chase, D. B. Tower, GABA in Nervous System
Function, Raven, New York (1975); b) T. J. Hayashi, Physiol. 1959, 145,
570.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801617
European Journal of Organic Chemistry
Full Paper
Layout 2:
Key Topic*
Gorakhnath R. Jachak,a,band Dr. D.
Srinivasa Reddy* a,b
Page No. – Page No.
Scalable
Enantiomers
Synthesis
of
Both
an
.
of Vigabatrin,
*Scalable synthesis of drug vigabatrin
*Scalable synthesis of drug vigabatrin
Antiepileptic Drug
*Scalable synthesis of drug vigabatrin
This article is protected by copyright. All rights reserved.