Asymmetric synthesis of the antiepileptic drug levetiracetam

Article abstract of DOI:10.3987/COM-08-S(N)106

Palladium-catalyzed asymmetric synthesis of levetiracetam of antiepileptic drug was expediently accomplished.

Full text of DOI:10.3987/COM-08-S(N)106

HETEROCYCLES, Vol. 76, No. 2, 2008
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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1627 - 1632. © The Japan Institute of Heterocyclic Chemistry
Received, 24th April, 2008, Accepted, 28th May, 2008, Published online, 5th June, 2008. COM-08-S(N)106
ASYMMETRIC SYNTHESIS OF THE ANTIEPILEPTIC DRUG
LEVETIRACETAM
Tatsushi Imahori, Keisuke Omoto, Yumi Hirose, and Hiroki Takahata*
Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Sendai
981-8558, Japan
E-mail:takahata@tohoku-pharm.ac.jp
Dedicated to Professor Ryoji Noyori on his 70th birthday.
Abstract – Palladium-catalyzed asymmetric synthesis of levetiracetam of
antiepileptic drug was expediently accomplished.
INTRODUCTION
®
Levetiracetam, [(S)-1] (Keppra , 38), was approved by the FDA, at the end of 1999 as an antiepileptic
drug for an add-on therapy for partial onset seizures in adults with epilepsy. Epilepsy is a common
medical disorder with a prevalence of around 1% in the general population and requires prolonged and
sometimes lifelong drug therapy.1 Many procedures for chiral synthesis of 1 have been developed.2
However, there have been few reports on its asymmetric synthesis.3 As a part of our ongoing interest in
synthesis of biologically important compounds based on palladium-catalyzed asymmetric allylic
alkylation,4 we describe an asymmetric synthesis of 1 through a dynamic kinetic asymmetric
transformation (DYKAT) reaction with butadiene monoepoxide (2) of succinimide (3) using the Trost
naphthyl ligand (4).5
O
N
CONH2
1 Levetiracetam
Keppra®, 38
Figure1

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RESULTS AND DISCUSSION
First, although a DYKAT reaction between 2 and pyrrolidone as a nucleophile under Trost’s condition
was examined, this reaction unfortunately afforded no desired product (5), resulting in recovery of
pyrrolidone. On the other hand, Figueredo very recently reported that the use of succinimide (3) as a
nucleophile was particularly successful. 6
[!3-C3H5PdCl2]2
4
Na2CO3
O
O
O
NH HN
O
O
N
N
H
CH2Cl2
rt
OH
2
5
PPh2 Ph2P
4
Scheme 1
[!3-C3H5PdCl2]2
4
Na2CO3
1) NaBH4
+
2
O
N
O
O
O
N
O
N
CH2Cl2
rt
2) Et3SiH/CF3CO2H
H
OH
OH
3
5
6
Cl3CCNHOCH2Ph
cat. CF3SO3H
H2/cat.Pd(OH)2
1) NaBH4
O
N
O
N
O
6
2) Et3SiH/CF3CO2H
OCH2Ph
OCH2Ph
8
7
i
1) ClCO2 Bu/Et3N
2) NH3
TEMPO/NaClO-NaClO2
phosphate buffer
O
O
N
N
O
N
OH
CONH2
CO2H
9
1
10
Scheme 2
DYKAT reaction with 2 of 3 using a π-allyl palladium chloride dimer in the presence of (R,R)- Trost
naphthyl ligand (4) provided the imide 6 in 85% yield. Half reduction of 6 with NaBH4 in methanol at
–4 °C followed by treatment with a combination of triethylsilane and TFA gave no amide 5. After
protection of hydroxyl, a similar transformation of imide to amide was examined. Benzylation of 6 with
benzyl bromide in the presence of NaH as a base afforded the benzyl-protected imide 7 in 57% yield. The
use of benzyl 2,2,2-trichloroacetimidate in the presence of CF3SO3H resulted in a higher yield (91%).7
The enantiomeric excess of 7 is 93%.8 A two-step sequence of imide 7 provided the amide 8 in 78%

HETEROCYCLES, Vol. 76, No. 2, 2008
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yield. Both hydrogenation and hydrogenolysis were simultaneously performed with cat. Pd(OH)2 under
hydrogen to give hydroxyl 9 in 92% yield. Oxidation of 9 with 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO) in the presence of sodium hypochlorite-sodium chlorite in acetonitrile buffer (pH 6.7)9 gave
carboxylic acid 10 and subsequent treatment with iso-butyl chloroformate and ammonium hydroxide
afforded 1 in 60% yield, the spectral data for which were found to be in good agreement with reported
values in the literature.10
In summary, an asymmetric synthesis of 1 has been performed in eight steps (34% overall yield) starting
from a DYKAT reaction with butadiene monoepoxide (2) of succinimide (3) under Trost’s condition.
EXPERIMENTAL
Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 series FT-IR spectrometer. Mass spectra
(MS) were recorded on a JEOL JMN-DX 303/JMA-DA 5000 spectrometer. Microanalyses were
performed on a Perkin-Elmer CHN 2400 Elemental Analyzer. Optical rotations were measured with a
JASCO DIP-360 or JASCO P-1020 digital polarimeter. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on JEOL JNM-AL 400 (400 MHz) spectrometer, using tetramethylsilane as an
internal standard. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, br = broad. Column chromatography was carried out on Merck Silica gel 60 (230-400 mesh)
or KANTO Silica Gel 60N (40-50 mm) for flash chromatography.
1-((S)-1-Hydroxybut-3-en-2-yl)pyrrolidin-2,5-dione [(S)-6]
To
a
mixture of (1R,2R)-(+)-1,2-diaminocyclohexan-N,N’-bis(2-diphenylphosphino-1-naphthoyl)
(R,R)-Trost ligand） (38 mg, 0.048 mmol),π-allyl palladium chloride dimer (5.9 mg, 0.016 mmol),
sodium carbonate (21 mg, 0.2 mmol), and succinimide (404 mg, 4 mmol) in CH2Cl2 (32 mL) was added
butadien monoepoxide (0.322 mL, 4 mmol) and then the mixture was stirred at rt for 23 h. After
addition of H2O, the mixture was successively extracted with Et2O (three times) and CH2Cl2 (nine times).
The extracts were dried over and Na2SO4 and evaporated. The residue was chromatographed on silica gel
27
using (hexane : EtOAc = 1 : 3) as eluant to give 6 (734 mg, 85 %) as an oil; [α]D -28.6 (CHCl3, c 1.0).
1H-NMR (400 MHz, CDCl3) δ: 2.62-2.63 (m, 1H), 2.70-2.75 (m, 4H), 3.85 (dt, J= 3.9, 11.7 Hz, 1H),
4.02-4.09 (m, 1H), 4.78 (dd, J= 7.8, 11.7 Hz, 1H), 5.23-5.30 (m, 2H), 6.10 (ddd, J= 7.3, 10.2, 17.5 Hz,
13
1H). C-NMR (100 MHz, CDCl3) δ: 28.06, 56.62, 61.89, 119.20, 131.20, 177.67. IR (neat) cm-1: 1694,
1771, 3444. EI-MS (m/z): 170 (M++1). HRMS Calcd for C8H12NO3: 170.0817, Found: 170.0816
1-((S)-1-(Benzyloxy)but-3-en-2-yl)pyrrolidine-2,5-dione (7)
To a solution of 6 (907 mg, 4.2 mmol) in hexane / CH２Cl２ (36 mL / 18 mL) were successively added

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benzyl 2,2,2-trichloroacetimidate (1.0 mL, 5.5 mmol) and CF3SO3H (0.040 mL, 0.45 mmol) and then the
whole was stirred at rt for 3.5 h. sat. aq. NaHCO3 (140 mL) was added to the solution and the mixture was
extracted with CH2Cl2 (180 mL x 3). The extracts were dried over Na2SO4 and evaporated. The residue
was chromatographed on silica gel using (hexane : EtOAc = 3 : 1) as eluant to give 7 (987 mg, 91 %) as
an oil; [α]D27 +16.9 (CHCl3, c 1.1). 1H-NMR (400 MHz, CDCl3) δ: 2.65 (s, 4H) 3.62 (dd, J= 5.8, 10.1 Hz,
1H), 4.07 (t, J= 10.1 Hz, 1H), 4.45 (d, J= 12.7, 1H), 4.55 (d, J= 12.7, 1H), 4.91-4.97 (m, 1H), 5.22-5.30
(m, 2H). 6.08 (ddd, J= 7.7, 10.1, 17.4 Hz, 1H), 7.26-7.38 (m, 7H). 13C-NMR (100 MHz, CDCl3) δ: 28.04,
53.89, 68.20, 72.76, 119.56, 127.62, 127.70, 128.38, 131.48, 137.90, 176.97. IR (neat) cm-1: 1702, 1774.
EI-MS (m/z): 259 (M+). HRMS Calcd for C14H15NO3: 259.1208, Found: 259.1202
1-((S)-1-(Benzyloxy)but-3-en-2-yl)pyrrolidin-2-one (8)
To a solution of 7 (160 mg, 0.62 mmol) in MeOH (20 mL) was added NaBH4 (0.137 mg, 3.26 mol) at –
4 °C and the whole was stirred at the same temperature for 2 h. After addition of sat. aq. NaHCO3 (20
mL), the mixture was extracted with CH2Cl2 (30 mL x 3). The extracts were dried over Na2SO4 and
evaporated. To the residue was added CH2Cl2 (15 mL). TFA (2 mL, 26.4 mmol) and Et3SiH (2 mL, 12.6
mmol) were successively added to the solution and the whole was stirred at rt for 1.5 h. After addition of
H2O(15 mL), the mixture was extracted with CH2Cl2 (30 mL x 2). The extracts were dried over Na2SO4
and evaporated. The residue was chromatographed on silica gel using (hexane: EtOAc = 5 : 1) as eluant
to give 8 (118 mg, 78%) as an oil; [α]D +19.2 (CHCl3, c 1.0). 1H-NMR (400 MHz, CDCl3) δ: 1.60 (br s,
27
5H), 1.95-2.03 (m, 2H), 2.40-2.44 (m, 2H), 3.37 (t, J= 7.2 Hz, 2H). 3.58-3.66 (m, 2H), 4.47 (d, J= 12.1
Hz, 1H), 4.58 (d, J= 12.1 Hz, 1H), 4.90-4.94 (m, 1H), 5.18-5.24 (m, 2H), 5.79 (ddd, J= 5.8, 10.6, 16.4 Hz,
1H). 13C-NMR (100 MHz, CDCl3) δ: 18.22, 31.13, 43.74, 52.60, 69.44, 72.75, 117.87, 127.63, 127.66,
128.35, 132.57, 137.89, 175.42. IR (neat) cm-1: 1103, 1683. EI-MS (m/z): 245 (M+) HRMS Calcd for
C15H19NO2: 245.1416, Found: 245.1426.
1-((S)-1-Hydroxybutan-2-yl)pyrrolidin-2-one (9)
A mixture of 8 (190 mg, 0.77 mmol) and Pd(OH)2 (81.1 mg, 0.12 mmol) in MeOH (2.6 mL) under
hydrogen atmosphere for 1 h. The mixture was filtered through Celite and the filtrate was evaporated. The
residue was chromatographed on silica gel using (Et2O : MeOH = 5 : 1) as eluant to give 9 (113 mg, 92%)
as an oil.
[α]D28 -11.8 (CHCl3, c 0.9). 1H-NMR (400 MHz, CDCl3) δ: 0.91 (t, J= 7.7 Hz, 3H), 1.43-1.67
(m, 3H), 2.00-2.09 (m, 2H), 2.43-2.47 (m, 2H), 2.74 (br s, 1H), 3.31-3.45 (m, 2H), 3.61 (dd, J= 8.7, 11.6
Hz, 1H), 3.75 (dd, J= 3.9, 11.6 Hz, 1H), 3.86-3.93 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ: 10.54, 18.11,
21.02, 31.45, 43.43, 55.64, 62.62, 176.58. IR (neat) cm-1: 1668, 3384. EI-MS (m/z): 157 (M+). HRMS
Calcd for C8H15NO2: 157.1103, Found: 157.1096.
(S)-2-(2-Oxopyrrolidin-1-yl)butanoic acid (10)
Alcohol 9 (59 mg, 0.38 mmol) was dissolved in MeCN (1.9 mL) and pH 6.7 NaH2PO4 aq. buffer (0.67M

HETEROCYCLES, Vol. 76, No. 2, 2008
1631
phosphate) (1.4 mL) and warmed to 40 °C. TEMPO (4.2 mg, 0.027 mmol) and a solution of sodium
chlorite (68.7 mg, 0.76 mmol) in H2O (0.35 mL) were successively added to the reaction mixture. A
diluted solution of bleach (9.8 mL) was added to the mixture and the whole was stirred at 40 °C for 91 h.
The reaction was cooled to rt and quenched with sat. aq. Na2SO3. The mixture was basified with 2N
NaOH and the whole was extracted with CH2Cl2. The aqueous layer was acidified with 2N HCl and
extracted with CH2Cl2. The extract was dried over Na2SO4 and evaporated to give 10 (54 mg, 84%) as a
solid. mp 124-125 ˚C [lit.,2b mp 124-6 ˚C]; [α]19 -23.0 (c 1, acetone) [lit.,2d [α]25D -24.32 (c 1, acetone)];
D
1H-NMR (400 MHz, CDCl3) δ: 0.93 (t, J = 7.7 Hz, 3H), 1.67-1.76 (m, 1H), 1.99-2.13 (m, 3H), 2.49 (t, J =
7.7 Hz, 2H), 3.37 (td, J = 8.7, 5.8 Hz, 1H), 3.52-3.58 (m, 1H), 4.64 (dd, J = 10.6, 4.8 Hz, 1H); 13C-NMR
(100 MHz, CDCl3) δ: 10.8, 18.2, 21.9, 30.9, 44.1, 55.6, 174.2, 177.1; IR (neat): 2880, 1719 cm-1; EI-Ms
(m/z): 171 (M+); HRMS: Calcd for C8H13NO3: 171.0895, Found: 171.0903.
(S)-2-(2-Oxopyrrolidin-1-yl)butanamide (levetiracetam) (1)
Isobutyl chloroformate (0.43 mL, 0.328 mmol) was added to a solution of 10 (54 mg, 0.315 mmol) and
triethylamine (0.046 mL, 0.33 mmol) in THF (0.2 mL) at 0 °C and the whole was stirred for 0.5 h. 28%
NH4OH (0.1 mL, 1.45 mmol) was added to reaction mixture at 0 °C and the whole was stirred at rt for 11
h. K2CO3 (44.8 mg, 0.324 mmol) was added to the reaction. The mixture was filtered off and the filtrate
was evaporated. The residue was chromatographed on silica gel using (Et2O : MeOH = 10 : 1) as eluant to
give 1 (39 mg, 72%) as a solid. mp 114-115˚C [lit.,2b mp 115-117 ˚C]; [α]24D -95.3 (c 1, acetone) [lit.,2b
[α]25D -90.5 (c 0.99, acetone)]; 1H-NMR (400 MHz, CDCl3) δ: 0.89 (t, J = 7.7 Hz, 3H), 1.62-1.73 (m, 1H),
1.90-2.08 (m, 3H), 2.34-2.48 (m, 2H), 3.35-3.48 (m, 2H), 4.46 (dd, J = 8.7, 6.8 Hz, 1H), 5.77 (br s, 1H),
6.45 (br s, 1H); 13C-NMR (100 MHz, CDCl3) δ: 10.5, 18.1, 21.0, 31.0, 43.8, 56.0, 172.3, 176.0; IR (neat):
3359, 3188, 1675, 1653, 1432 cm-1; EI-Ms (m/z): 170 (M+); HRMS: Calcd for C8H14N2O2: 170.1055,
Found: 170.1052.
ACKNOWLEDGEMENTS
This work was supported in part by High Technology Research Program from the Ministry of Education,
Sciences, Sports and Culture of Japan.
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