Synthesis of vigabatrin

Article abstract of DOI:10.3987/COM-06-10837

A concise synthesis of vigabatrin has been achieved from trans-(2S,4R)-4-hydroxyproline via the key regioselective Baeyer-Villiger lactonization reaction.

Full text of DOI:10.3987/COM-06-10837

HETEROCYCLES, Vol. 68, No. 10, 2006
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HETEROCYCLES, Vol. 68, No. 10, 2006, pp. 2031 - 2036. © The Japan Institute of Heterocyclic Chemistry
Received, 5th July, 2006, Accepted, 27th July, 2006, Published online, 1st August, 2006. COM-06-10837
SYNTHESIS OF VIGABATRIN®
Meng-Yang Chang,*,a Chun-Yu Lin,b and Chi-Wi Ongb
aDepartment of Applied Chemistry, National University of Kaohsiung,
b
Kaohsiung 811, Taiwan. Department of Chemistry, National Sun Yat-Sen
University, Kaohsiung 804, Taiwan. Email: mychang@nuk.edu.tw
Abstract – A concise synthesis of vigabatrin® has been achieved from
trans-(2S,4R)-4-hydroxyproline via the key regioselective Baeyer-Villiger
lactonization reaction.
Based on the structural framework of trans-(2S,4R)-4-hydroxyproline (1), it possesses three functional
groups that can be easily modified.1 The skeleton represents the significant feature for producing a series
of different carbon framework using an efficient modification technique.2 Recently we have introduced
some approaches toward anisomycin,2l epibatidine,2m pancracine,2n streptorubin B core,2o and statine2p
employing trans-(2S,4R)-4-hydroxyproline (1) as the starting material.
CO H
HO
2
CO H
N
H
2
H N
2
trans-(2S,4R)-4-hydroxyproline (1)
vigabatrin (2)
Figure 1. Structures of trans-(2S,4R)-4-hydroxyproline (1) and vigabatrin® (2)
Vigabatrin® (2, γ-vinyl-GABA, 4-amino-5-hexenoic acid, Sabril®), which is a highly selective
enzyme-activated inhibitor of GABA-T in mammalian brain,3a-b crosses the BBB and is used clinically
primarily to control seizures refractory to other anticonvulsant drugs. Although racemic vigabatrin® is
used in clinical practice, S-isomer is the pharmacologically active, whereas R-isomer is inactive.
Vigabatrin® is therefore useful for treating disorders associated with depletion of GABA levels in central
nervous system such as schizophrenia and epilepsy.3c-d Methodologies4-5 for the synthesis of vigabatrin®
(2) have been described so far based on thermal rearrangement,4c-d catalytic palladium-mediated
enantioselective syntheses,5a-d asymmetric syntheses starting from α-amino acids5e-j (e.g. methionine,

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HETEROCYCLES, Vol. 68, No. 10, 2006
glutamic acid, and pyroglutamate) and other chiral materials,5k-l and large scale enzyme-catalyzed
resolution.5m The other related vigabatrin® derivatives were synthesized as the potential biological
inhibitors.6 In continuing the previous investigations and building upon these observations on
trans-(2S,4R)-4-hydroxyproline (1) as the chiral material, we are interested in developing an easy
approach to vigabatrin® (2) via the key regioselective Baeyer-Villiger lactonization reaction.
As shown in Scheme 1, we studied the approach to vigabatrin® (2) from 1-tosyl-2-vinylpyrrolidin-4-one
(3), which was prepared from trans-(2S,4R)-4-hydroxyproline (1) by our preliminary report.2m
Regioselective Baeyer-Villiger lactonization2p,7 of ketone (3) was treated with m-chloroperoxybenzoic
acid and sodium carbonate to afford sole tetrahydro-1,3-oxazin-6-one (4). During the lactonization
process, the other ring-expanded framework was not observed. While poring over the related literature of
Baeyer-Villiger ring expansion reaction, we found that Young and co-workers had developed copper(II)
acetate-mediated ring expansion of 4-ketoprolines with m-chloroperoxybenzoic acid in modest yield. The
most likely explanation would be that it is controlled by involvement of the nitrogen lone pair on
substituted pyrrolidin-4-one.7 Reduction of the regioisomer (4) with lithium aluminum hydride was
provided 1,3-aminoalcohol (5). Treatment of alcohol (5) with pyridinium chlorochromate was yielded
aldehyde (6). One-carbon elongation of compound (6) was achieved via Wittig olefination of compound
(6) and followed by Jones oxidation of the resulting enol ether to give an acid (7). Finally, synthesis of
vigabatrin® (2) was accomplished via desulfonation8 and acidification.9
OH
O
O
MCPBA
PCC
LAH
O
Na2CO3
(86%)
(82%)
(89%)
HN
Ts
N
N
Ts
Ts
3
4
5
O
CO2H
CO2H
Ph3P=CHOMe
sodium naphthalenide
H
then Jones ox.
(68%)
then 12N HCl
(71%)
HN
Ts
HN
Ts
H2N
HCl
vigabatrin (2)
6
7
Scheme 1. Synthesis of vigabatrin® (2)
In summary, we succeeded in accomplishing the synthesis of vigabatrin® (2) from the chiral starting
material trans-(2S,4R)-4-hydroxyproline (1) via the key regioselective Baeyer-Villiger lactonization
reaction. Currently studies are in progress in this direction.

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ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council (NSC-95-2113-M-390-003-MY2) of the
Republic of China for financial support.
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9. For experimental details: General. Tetrahydrofuran (THF) was distilled prior to use from a
deep-blue solution of sodium-benzophenone ketyl. All other reagents were obtained from
commercial sources and used without further purification. Reaction was routinely carried out under
an atmosphere of dry nitrogen with magnetic stirring. Extract was dried with anhydrous MgSO4
before concentration in vacuo. Crude product was purified using column chromatography on SiO2
(MN Kieselgel 60, 70~230 mesh).
3-(4-Methylphenylsulfonyl)-4-vinyl-[1,3]oxazinan-6-one (4).
A solution of m-chloroperoxybenzoic acid (600 mg, 75%, 2.6 mmol) in CH2Cl2 (10 mL) was added
a solution of ketone (3) (265 mg, 1.0 mmol) and Na2CO3 (420 mg, 4.0 mmol) in CH2Cl2 (20 mL) at
0 oC. The reaction mixture was stirred at rt for 40 h. Saturated aqueous Na2CO3 (10 mL) was added
to the reaction mixture and the solvent was concentrated under reduced pressure. The residue was
extracted with AcOEt (3 x 20 mL). The combined organic layers were washed with brine, dried,
filtered and evaporated to afford crude product. Purification on silica gel (hexane/AcOEt = 4/1~2/1)
afforded compound (4) (242 mg, 86%). [α]31.4 -174.31o (c 0.025, CHCl3); HRMS (ESI, M++1)
D
calcd for C13H16NO4S 282.0800, found 282.0803; 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz,
2H), 7.29 (d, J = 8.0 Hz, 2H), 5.83 (ddd, J = 5.0, 10.5, 17.0 Hz, 1H), 5.77 (dd, J = 1.0, 11.5 Hz, 1H),

HETEROCYCLES, Vol. 68, No. 10, 2006
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5.29 (dd, J = 1.5, 17.0 Hz, 1H), 5.25 (dd, J = 1.5, 10.5 Hz, 1H), 5.12 (d, J = 11.5 Hz, 1H), 4.35-4.31
13
(m, 1H), 2.58 (dd, J = 7.5, 16.5 Hz, 1H), 2.50 (dd, J = 9.0, 16.5 Hz, 1H), 2.37 (s, 3H); C NMR
(125 MHz, CDCl3) δ 167.57, 144.72, 135.07, 134.79, 129.91 (2x), 127.58 (2x), 117.18, 74.00, 52.50,
33.72, 21.36; Anal. Calcd for C13H15NO4S: C, 55.50; H, 5.37; N, 4.98. Found: C, 55.69; H, 5.60; N,
5.12.
N-[1-(2-Hydroxyethyl)allyl]-4-methylbenzenesulfonamide (5).
A solution of compound (4) (200 mg, 0.71 mmol) in THF (10 mL) was added to a rapidly stirred
o
suspension of lithium aluminum hydride (76 mg, 2.0 mmol) in THF (20 mL) at 0 C. The reaction
mixture was stirred at rt for 2 h. Aqueous NH4Cl solution (15%, 2 mL) was added to the reaction
mixture and filtered through a short silica gel column. The filtrate was dried, filtered and evaporated
to yield crude compound. Purification on silica gel (hexane/EtOAc = 2/1) afforded aminoalcohol (5)
(162 mg, 89%). [α]31.2 +22.94o (c 0.017, CHCl3); HRMS (ESI) m/z calcd for C12H18NO3S (M++1)
D
256.1007 found 256.1010; 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0
Hz, 2H), 5.57 (ddd, J = 6.0, 9.5, 16.5 Hz, 1H), 5.24 (d, J = 8.0 Hz, 1H), 4.97 (d, J = 16.5 Hz, 1H),
4.95 (d, J = 9.5 Hz, 1H), 3.99 (br s, 1H), 3.86 (dt, J = 3.5, 12.5 Hz, 1H), 3.69-3.65 (m, 1H), 2.42 (s,
3H), 2.37 (br s, 1H), 1.84-1.78 (m, 1H), 1.61-1.55 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 143.39,
137.61, 137.22, 129.58 (2x), 127.12 (2x), 115.78, 58.82, 53.48, 37.22, 21.50; Anal. Calcd for
C12H17NO3S: C, 56.45; H, 6.71; N, 5.49. Found: C, 56.59; H, 6.54.; N, 5.85.
N-[1-(2-Oxoethyl)allyl]-4-methylbenzenesulfonamide (6).
A solution of compound (5) (130 mg, 0.51 mmol) in CH2Cl2 (5 mL) was added to a stirred mixture
of pyridinium chlorochromate (431 mg, 2.0 mmol) and Celite (1.0 g) in CH2Cl2 (20 mL). After being
stirred at rt for 20 h, the mixture was filtered through a short silica gel column. The filtrate was dried,
filtered and evaporated to yield crude compound. Purification on silica gel (hexane/EtOAc = 5/1)
afforded compound (6) (106 mg, 82%). [α]30.9 +31.37o (c 0.005, CHCl3); HRMS (ESI) m/z calcd
D
1
for C12H16NO3S (M++1) 254.0851, found 254.0852; H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H),
7.73 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 5.66 (ddd, J = 6.0, 10.5, 17.5 Hz, 1H), 5.28 (d, J =
8.5 Hz, 1H), 5.02 (dd, J = 1.0, 17.5 Hz, 1H), 5.01 (dd, J = 1.0, 10.5 Hz, 1H), 4.25-4.19 (m, 1H),
13
2.79-2.70 (m, 2H), 2.42 (s, 3H); C NMR (125 MHz, CDCl3) δ 199.93, 143.58, 137.50, 135.97,
129.65 (2x), 127.13 (2x), 116.84, 51.43, 48.46, 21.50.
4-Aminohex-5-enoic acid (Vigabatrin®, 2).
n-Butyllithium (1.0 mL, 1.6 M in hexane, 1.6 mmol) was added to a stirred solution of
o
(methoxymethyl)triphenylphosphonium chloride (686 mg, 2.0 mmol) in THF (20 mL) at –78 C.
o
The orange red colored mixture was stirred at –78 C for 1 h. A solution of aldehyde (6) (100 mg,

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HETEROCYCLES, Vol. 68, No. 10, 2006
o
0.4 mmol) in THF (5 mL) was added to the reaction mixture at –78 C via a syringe and further
o
stirred at –78 C for 2 h. The reaction was quenched with aqueous NH4Cl (15%, 10 mL) and the
mixture was extracted with Et2O (3 x 20 mL) and the combined organic layers were washed with
brine, dried, filtered and evaporated to yield the crude product. Excess Jones reagent (2 mL) was
added to a solution of the resulting compound in acetone (10 mL) at rt. The mixture was stirred for
20 min and treated with 2-propanol (1 mL) to destroy the unreacted oxidation reagent. After the
solvent was removed, the residue was diluted with water (5 mL) and extracted with Et2O (4 x 10
mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford
crude product. Purification on silica gel (hexane/EtOAc = 1/1~1/2) afforded product (7) (76 mg,
1
68% of two steps). HRMS (ESI) m/z calcd for C13H18NO4S (M++1) 284.0957, found 284.0961; H
NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 5.82-5.70 (m, 1H),
5.44-5.20 (m, 3H), 3.72-3.65 (m, 1H), 3.20 (br s, 1H), 2.45 (s, 3H), 2.28-2.10 (m, 2H), 2.00-1.82 (m,
2H).
A freshly prepared solution of sodium naphthalenide (1.0 M in THF, 2 mL, 2.0 mmol) was added to
o
a solution of compound (7) (140 mg, 0.5 mmol) in THF (20 mL) at 0 C for 2h. Water (5 mL) was
poured into the reaction mixture and evaporated to afford the residue. Water (10 mL) was poured
into the residue and extracted with Et2O (3 x 20 mL). Hydrochloric acid (12N, 5 mL) was added to
the water layer at rt. Then the water was evaporated under reduced pressure to give the crude
hydrochloride. The crude salt was purified by ion exchange chromatography to give the vigabatrin®
1
(2) (58 mg, 71%). [α]28.2 +12.02o (c 0.026, H2O); H NMR (300 MHz, D2O) δ 5.75-5.63 (m, 1H),
D
13
5.32-5.26 (m, 2H), 3.69-3.61 (m, 1H), 2.21-2.07 (m, 2H), 1.94-1.71 (m, 2H); C NMR (75 MHz,
D2O) δ 181.46, 132.92, 121.18, 54.06, 33.41, 28.94. The NMR spectral data were in accordance with
those reported in the literature.5e