Total synthesis of levetiracetam

Article abstract of DOI:10.1039/C9OB00111E

Total synthesis of levetiracetam, an active ingredient of epilepsy treatment medications, is reported. The reported method is based on a one-pot dehydration/sigmatropic rearrangement of (R,E)-hept-4-en-3-ol carbamate to the corresponding allylamine derivative, an advanced precursor of levetiracetam.

Full text of DOI:10.1039/C9OB00111E

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DOI: 10.1039/C9OB00111E
Total synthesis of levetiracetam
Aleksandra Narczyk, Michał Mrozowicz, and Sebastian Stecko*
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw, Poland
e-mail: sebastian.stecko@icho.edu.pl
Graphical abstract:
ONE-POT
O
dehydration
rearrangement
hydrolysis
NH2
O
N
N
H2N
O
O
acylation
O
N-alkylation
Levetiracetam
antiepileptic drug
Abstract: Total synthesis of levetiracetam, an active ingredient of epilepsy treatment
medications, is reported. The reported method is based on a one-pot
dehydration/sigmatropic rearrangement of (R,E)-hept-4-en-3-ol carbamate to the
corresponding allylamine derivative, an advanced precursor of levetiracetam.
Keywords:, levetiracetam, [3,3]-sigmatropic rearrangements, isocyanates, epilepsy
Introduction:
Epilepsy is a chronic condition characterized by recurrent unprovoked epileptic
seizures. These, in turn, are clinical manifestations including symptoms and signs of
an abnormal and excessive activity of neurons in the brain.1 It is estimated that this
disease affects over 50 million people around the world, and additional hundreds of
thousands of people are diagnosed with epilepsy every year.
1

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γ-Butyrolactam derivatives are an important structural family oDfOIb: 1i0o.1a03c9t/iCv9eOB00111E
molecules used in the treatment of epilepsy2-5 and brain-related disorders (including
bipolar disorder, migraines, chronic and neuropathic pain, Figure 1).6, 7 Among them,
an interesting representative is levetiracetam (1),7-9 marketed under the trade name
KeppraTM, which is dedicated for the treatment of people with the above-mentioned
disorder. The mechanism of action of levetiracetam (1) is probably connected with its
binding to a synaptic vesicle glycoprotein (SV2A) and inhibition of presynaptic calcium
channels, reducing neurotransmitter release and acting as a neuromodulator.10-12 This
is believed to impede impulse conduction across synapses.13
O
O
O
O
NH2
O
NH2
O
NH2
O
NH2
O
N
N
N
N
F
F
Brivaracetam
Seletracetam
Piracetam
(Nootropil
Levetiracetam

(Keppra

Figure 1. Examples of racetam-based drugs used in the treatment of epilepsy and
related disorders.
Since 2010, levetiracetam (1)14, 15 is on the list of top best-selling medicines,16
which renders the development of new protocols for the preparation of this bioactive
molecule of high interest to the medicinal chemist. Reported methods for the synthesis
of 1 typically involve chiral pool approaches starting from enantiopure 훼-amino acids14,
17-19 and their derivatives.20-26 Other methods involve the resolution of etiracetam (rac-
1), or advanced racemic intermediates, either by the crystallization of diastereomeric
salts (with chiral amines or acids), kinetic resolution of the racemate, or separation by
chiral chromatography.27-31
Several asymmetric strategies have been also reported, for example metal-
catalyzed asymmetric hydrogenation,32, 33 deracemization of 2-bromobutyric acid with
N-phenyl pantolactam as a chiral auxiliary,34 chiral auxiliary-controlled alkylation of
2

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36
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DOI: 10.1039/C9OB00111E
amino acids,35,
alkylation.23
proline-catalyzed asymmetric α-aminooxylation37 or allylic
Herein, we report a practical and efficient asymmetric synthesis of levetiracetam
(1) through enantiospecific cyanate-to-isocyanate rearrangement as a key step. The
retrosynthetic analysis of 1 is outlined in Scheme 1. We envisioned that secondary
amine 3 would be an ideal key intermediate for the synthesis of levetiracetam 1, which
can be prepared easily from alcohol 4 by an isocyanate-to-cyanate rearrangement. In
the past, we have proved that this mild, rapid, and catalyst-free process is an attractive
tool for the preparation of non-racemic allylamines and their derivatives in an
enantiospecific fashion through efficient chirality transfer.38-41 It was also applied in the
total synthesis of lacosamide, another anti-epilepsy drug.42 The key intermediate 3 can
be elaborated to the advanced amide precursor 2 by an addition/cyclization reaction
sequence leading to the formation of a 2-pyrrolidone ring.
O
oxygen-to-nitrogen
rearrangement
NH2
oxidation
N
O
N
O
NH2
with
OH
chirality transfer
1
2
3
4
levetiracetam
Scheme 1
Accordingly, our synthesis began with the preparation of enantiomerically
enriched (R,E)-hept-4-en-3-ol (4) by Pd-catalyzed deracemization of allylic carbonate
5 via protocol reported by Lussem and Gais.43 The racemic carbonate 5 was obtained
in two steps by the addition of EtMgBr to (E)-pent-2-enal followed by treatment of the
resulting alcohol rac-4 with methyl chloroformate (74%, 2 steps). Treatment of the
.
racemic carbonate 5 with 2 mol% Pd2(dba)3 CHCl3 and (R,R)-DACH-phenyl Trost
ligand in a H2O/CH2Cl2 mixture furnished the (R)-allylic alcohol 4 with 96% ee (Scheme
2). Due to its volatility, alcohol 4 was not isolated but, after filtration and drying, was
3

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directly subjected to the tin-catalyzed transcarbamoylation process44 to obtain allyl
DOI: 10.1039/C9OB00111E
carbamate 6 with 70% after 2 steps. The overall yield of 6 was 58% after 4 steps from
rac-4.
O
Pd2(dba)3.CHCl3
PhO
NH2
(R,R)-DACH-phenyl
DBTM (10 mol%)
H2N
O
OH
MeO
O
CH2Cl2/H2O
rt
PhMe, 90 o
C
O
O
5
4
6
96% ee
70%
(after 2 steps)
O
O
O
O
(R,R)-DACH-phenyl
DBTM:
Sn
Ph2P
NH HN
PPh2
O
O
Scheme 2
Next, carbamate 6 was treated with TFAA in the presence of Et3N to provide
allyl cyanate 7, which spontaneously underwent [3,3]-sigmatropic rearrangement to
afford allyl isocyanate 8. In the initial experiments, isocyanate 8 was directly treated
with organolithium or Grignard reagents of type 9 (Scheme 3). Unfortunately, products
10 were formed in poor to medium yields. Disappointingly, the subsequent synthesis
of alcohol 11, considered as a precursor in the formation of the pyrrolidone ring,
proceeded in poor yield, ca. 25%, which forced us to redesign the synthetic strategy.
TFAA, Et3N
THF, 0 o
C
H2N
O
O
NCO
N
O
M
6
7
8
9
( )
OR
C
AcCl (1 mol%)
MeOH, rt
THF, _78 o
HN
HN
OR
OH
for R = THP
O
O
M: Li, MgBr
R: TBS, THP
10
11
10a
10b
, R: THP, ~70%
, R: TBS, traces
25%
Scheme 3
Independently, isocyanate 8 was treated with Grignard reagent 12 to provide
product 13 in 50% yield after 3 steps (Scheme 4). Next, 13 was subjected to cyclization
4

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by treatment with Et3SiH and Al(OTf)3 according to a very recent report byDWOI:a10n.1g039a/Cn9dOB00111E
co-workers.45 Disappointingly, under the reported conditions, complete decomposition
of starting material 13 was observed.
Al(OTf)3 (0.5 eq)
Et3SiH (2 eq)
TFAA, Et3N
i.
THF, 0 o
C
HN
N
H2N
O
O
O
MeCN
reflux
12
O
ii.
O
O
MgBr
O
O
THF, _78 o
C
6
13
2
one-pot
50% (3 steps)
Scheme 4
Finally, isocyanate 8 was directly treated with TMSOLi and, subsequently, with
TBAF solution to obtain free allylamine 15. Alternative quenching of isocyanate 8 with
water (to provide amine 3) is not rapid enough and the resulting amine 3 reacts with
unreacted 8 to provide an unwanted urea derivative. Amine 3 was not isolated but
acylating agent 14 was directly added to the reaction mixture to afford chloro-amide 16
in 65% overall yield after 5 steps (Scheme 5). It is noteworthy that the transformation
of 6 to 16 was carried out in a one-pot fashion in order to minimize the loss of any
unstable, volatile or highly polar intermediates during the work-up and isolation
operations.
1) TFAA, Et3N, THF
2) TMSOLi, THF
3) TBAF, THF
NaH
15-crown-5
O
4)
THF, rt
85%
N
HN
O
H2N
O
O
14
(
)
Cl
Cl
O
Cl
2
65%
6
16
(after 5 steps)
one-pot
TFAA
Et3N
14
then
14
NaOH, TBABr
60% (after 6 steps)
one-pot
TMSOLi
then TBAF
N
NH2
15
C
O
8
Scheme 5
Next, amide 16 was subjected to a cyclization process to generate the 2-
pyrrolidone ring. Upon treatment with NaH in the presence of 15-crown-5 chloro-amide
5

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16 cyclized to product 2 in 85% yield (Scheme 5). To our delight, we fouDnOdI: 1t0h.1a03t9/tCh9eOB00111E
cyclization step can be also directly combined with the previous sequence involving
the transformation of carbamate 6 to amide 16 and performed in one-pot fashion. Thus,
after the acylation reaction is completed, NaOH, H2O, and a phase-transfer catalyst
were added to the reaction mixture, in order to perform intramolecular N-alkylation.
After aqueous work-up and purification, product 2 was obtained in 60% overall yield
after 6 steps.
1) O3, CH2Cl2, -78 o
C
O
O
2) 2-methyl-2-butene, NaH2PO4,
3) ClCOOEt, Et3N, THF
4) aq. NH3
OH
O
NH2
O
NaClO2, t-BuOH/H2O, rt
N
N
N
O
62%
(after 4 steps)
one-pot
17
97% ee
1
2
Scheme 6
Finally, amide 2 was subjected to the oxidative transformation of the double
bond. Thus, ozonolysis of 2 followed by subsequent Pinnick-Lindgren oxidation
provided amino acid 17. This acid was activated by treatment with ClCOOEt/Et3N and
then directly subjected to a reaction with aq. NH3, furnishing the desired amide 1 in
62% overall yield after 4 steps (Scheme 6).
Conclusions
In conclusion, a new route for the synthesis of the antiepileptic drug
levetiracetam through functionalization of enantiopure (S)-allylamine 3. This chrial
building block was obtained via rearrangement of (R)-alcohol 4, readily and highly
enantioselectively prepared via Pd-catalyzed deracemization of the corresponding
allylic carbonate 5. Alcohol 4 was transformed to the corresponding allyl carbamate 6
and then was subjected to highly efficient one-pot dehydration/rearrangement/
addition/hydrolysis/acylation/alkylation sequence to provide non-racemic pyrrolidone
6

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derivative 2. This 6 steps sequence proceeded with excellent overall 60% yield and
DOI: 10.1039/C9OB00111E
with complete chirality transfer. Such approach let to minimize loss of volatile or polar
intermediates during the work-up and purification operations. Compound 2 was then
transformed into levetiracetam 1 by oxidative transformation of a double bond and the
formation of an amide group. Also in this case single steps were realized in one-pot
manner or without isolation of intermediates to maximize the overall efficiency of the
synthesis.
Experimental section:
(E)-hept-4-en-3-ol (rac-4): To a cooled (0 °C) solution of EtMgBr (3 M in Et2O, 48
mmol, 16 mL) was added dropwise (E)-pent-2-enal (40 mmol, 3.36 g, 3.9 mL) in Et2O
(25 mL). After refluxing for 2 h, the mixture was cooled to 0 °C and carefully quenched
with aqueous saturated NH4Cl, after which 10% aqueous HCl was added to dissolve
any precipitate. The aqueous layer was extracted with Et2O and the combined organic
layers were dried over Na2SO4. Careful removal of the solvent gave 4.4 g (83%) of rac-
5 as a colorless liquid; Spectral data in agreement with literature:46 1H NMR (400 MHz,
CDCl3) δ 5.67 (dtd, J = 15.4, 6.3, 1.0 Hz, 1H), 5.42 (ddt, J = 15.4, 7.1, 1.6 Hz, 1H), 4.00
– 3.88 (m, 1H), 2.14 – 1.94 (m, 2H), 1.71 (br s, 1H), 1.62 – 1.39 (m, 2H), 0.98 (t, J =
7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 133.8, 131.7, 74.5,
30.1, 25.2, 13.5, 9.7.
(E)-hept-4-en-3-yl methyl carbonate (5): To a cooled (0 °C) solution of alcohol rac-4
(24 mmol, 2.74 g) and pyridine (72 mmol, 5.6 g, 5.8 mL) in CH2Cl2 (0.4 M, 60 mL),
methyl chloroformate (48 mmol, 4.4 g, 3.70 mL) was added. The reaction mixture was
warmed to room temperature, and stirred overnight. The progress of the reaction was
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followed by TLC. After that, the mixture was washed with brine and extracted with Et2O.
DOI: 10.1039/C9OB00111E
The combined organic layers were washed with 1M aqueous HCl and dried over
anhydr. Na2SO4. The solvent was carefully removed under reduced pressure
(200 mBar). The crude residue was purified by column chromatography on silica gel
(1-3% Et2O in pentane) to provide 4 g (99%) of carbonate 5 as a colorless liquid;
Spectral data in agreement with literature:47 1H NMR (400 MHz, CDCl3) δ 5.81 (dtd, J
= 15.5, 6.2, 0.9 Hz, 1H), 5.39 (ddt, J = 15.5, 7.7, 1.6 Hz, 1H), 5.01 – 4.88 (m, 1H), 3.76
(s, 3H), 2.14 – 1.98 (m, 2H), 1.78 – 1.67 (m, 1H), 1.67 – 1.57 (m, 1H), 0.99 (t, J = 7.4
Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 155.3, 136.8, 126.5,
80.6, 54.3, 27.5, 25.1, 13.1, 9.4.
(R,E)-hept-4-en-3-ol (4):43 In a glovebox, a Schlenk flask was charged with
.
Pd2(dba)3 CHCl3 (0.212 mmol, 220 mg, 2 mol%), (R,R)-DACH-phenyl Trost ligand
(0.848 mmol, 585 mg, 4 mol%) and CH2Cl2 (80 mL). During stirring for 15 min, the
resulting brown solution turned orange, then water (9.2 mL) and carbonate 5
(10.8 mmol, 1.84 g) was added. After stirring at rt for 48 h, the reaction mixture was
poured into a pentane/ether mixture (1:1 v/v, 500 mL) and filtered through a silica gel
pad. The filtrate was dried over anhydr. Na2SO4 and the solvent was carefully removed
under reduced pressure (500 mbar). Due to its volatility, alcohol 4 was not isolated but,
after filtration and drying, was directly subjected to the next step; Yield ca. 95%
1
determined by H NMR of crude product; e.e. 96%; (determined by HPLC of 4-
nitrobenzoate of 4: Rt 33.4 min); HPLC (for 4-nitrobenzoate, racemate) Chiralcel OD-
H, hexanes, flow 1 mL/min, det. 254 nm; 30.6 min (S-enantiomer) and Rt 34.3 min (R-
enantiomer).
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(R,E)-hept-4-en-3-yl carbamate (6): A solution of alcohol 4 (10.68 mmol, 1.22 g),
DOI: 10.1039/C9OB00111E
phenyl carbamate (16.0 mmol, 2.2 g), and dibutyltin maleate (3.0 mol%, 0.32 mmol,
112 mg) in dry toluene (55 mL) was kept at 90 °C for 5 h. The reaction mixture was
cooled to ambient temperature and then to 0 °C and diluted with 2M aqueous NaOH.
After stirring at 0 °C for 10 min, CH2Cl2 and H2O were added. The organic layer was
separated and washed with 2M aqueous NaOH, H2O, and brine and dried over anhydr.
Na2SO4. After the removal of the solvent, the crude residue was purified by column
chromatography on silica gel deactivated with Et3N (0-40% AcOEt in hexanes) to
provide 1.16 g (70% after 2 steps) of carbamate 4 as a white solid; [α]D22 +23.2 (c 1.10,
CHCl3), e.e. 96%; 1H NMR (400 MHz, CDCl3) δ 5.75 (dtd, J = 15.5, 6.3, 1.0 Hz, 1H),
5.37 (ddt, J = 15.5, 7.2, 1.6 Hz, 1H), 5.08 – 4.92 (m, 1H), 4.68 (br s, 2H), 2.13 – 1.96
(m, 2H), 1.74 – 1.48 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 157.1, 135.4, 127.3, 76.8, 27.7, 25.2, 13.2, 9.4; FTIR (film) v:
3425, 3333, 3264, 3211, 2965, 2935, 2876, 1682, 1610, 1394, 1326, 1032, 969, 786,
574 cm-1; HRMS (EI) m/z calcd for C8H15NO2 [M] 157.1103; found 157.1093.
(S,E)-4-chloro-N-(hept-4-en-3-yl)butanamide (16): To a solution of carbamate 6
(2.56 mmol, 400 mg) and Et3N (15.2 mmol, 1.55 g, 2.2 mL) in dry THF (65 mL) cooled
to 0 °C, TFAA (5.2 mmol, 1.07 g, 720 µL) was added. The resulting mixture was slowly
warmed to room temperature and stirred for 1 h. In a separate flask, a 1 M solution of
LiHMDS (15.2 mmol, 15.2 mL) was added to a solution of TMS-OH (15.2 mmol, 1.37
g, 1.7 mL) in dry THF (25 mL). After 1 h, the solution of TMSOLi was transferred to the
generated allyl isocyanate and the reaction mixture was left to stand for 5 h. Next, the
mixture was cooled to 0 °C and 1 M soln. of TBAF in THF (18 mmol, 18 mL) was added
dropwise. The reaction mixture was slowly warmed to room temperature and left to
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stand overnight. After that, 4-chlorobutyryl chloride (3.04 mmol, 430 mg, 340 µL) was
DOI: 10.1039/C9OB00111E
added and the mixture was left to stand overnight. Then, the volatiles were removed
under reduced pressure. The residue was purified by flash chromatography on silica
gel: 5-30% AcOEt in hexanes to provide 360 mg (63%, 5 steps) of amide 16 as a waxy
solid; [α]D22 –29.2 (c 1.12, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.74 – 5.51 (m, 2H),
5.37 – 5.17 (m, 1H), 4.42 – 4.19 (m, 1H), 3.56 (t, J = 6.2 Hz, 2H), 2.33 (t, J = 7.1 Hz,
2H), 2.16 – 2.04 (m, 2H), 2.04 – 1.92 (m, 2H), 1.60 – 1.42 (m, 2H), 0.94 (t, J = 7.5 Hz,
3H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.8, 133.3, 128.7, 52.3,
44.5, 33.4, 28.2, 28.2, 25.2, 13.5, 10.2; FTIR (film) v: 3276, 2965, 2933, 1641, 1547,
969 cm-1; HRMS (EI) m/z calcd for C11H20NOCl [M] 217.1233; found 217.1240.
(S,E)-1-(hept-4-en-3-yl)pyrrolidin-2-one (2), method 1: To a solution of amide 16
(325 mg, 1.5 mmol) in dry THF (7.5 mL) cooled to 0 °C, NaH (60% dispersion in oil,
2.25 mmol, 90 mg) was added portionwise, after that a catalytic amount of 15-crown-
5 (75 µmol, 17 mg, 15 µL) was added. The reaction mixture was slowly warmed to
room temperature and left to stand overnight. Next, water was added and the resulting
mixture was extracted with AcOEt. The combined organic layers were dried over
anhydr. Na2SO4. After the removal of the solvents, the residue was purified by column
chromatography on silica gel: 20-50% AcOEt in hexanes. Yield: 230 mg (85%); yellow
oil; [α]D21 –95.1 (c 1.08, CHCl3), 1H NMR (400 MHz, CDCl3) δ 5.59 (dtd, J = 15.4, 6.3,
1.3 Hz, 1H), 5.29 (ddt, J = 15.4, 6.5, 1.6 Hz, 1H), 4.54 – 4.32 (m, 1H), 3.36 – 3.11 (m,
2H), 2.45 – 2.25 (m, 2H), 2.11 – 1.86 (m, 4H), 1.64 – 1.41 (m, 2H), 0.93 (t, J = 7.5 Hz,
3H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 174.6, 134.8, 126.5, 54.0,
42.4, 31.4, 25.3, 24.7, 18.1, 13.5, 10.7; FTIR (film) v: 3291, 2964, 2931, 2874, 1685,
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1423, 1284, 970 cm-1; HRMS (ESI-TOF) m/z calcd for C11H19NONaDO[(I:M10+.10N39a/C)9O]B00111E
204.1364; found 204.1355.
(S,E)-1-(hept-4-en-3-yl)pyrrolidin-2-one (2), method 2 (one-pot six steps mode):
To a solution of carbamate 6 (2.56 mmol, 400 mg) and Et3N (15.2 mmol, 1.55 g,
2.2 mL) in dry THF (65 mL) cooled to 0 °C, TFAA (5.2 mmol, 1.07 g, 720 µL) was
added. The resulting mixture was slowly warmed to room temperature and stirred for
1 h. In a separate flask, a 1 M solution of LiHMDS (15.2 mmol, 15.2 mL) was added to
a solution of TMS-OH (15.2 mmol, 1.37 g, 1.7 mL) in dry THF (25 mL). After 1 h, the
solution of TMSOLi was transferred to the generated allyl isocyanate and the reaction
mixture was left to stand for 5 h. Next, the mixture was cooled to 0 °C and 1 M soln. of
TBAF in THF (18 mmol, 18 mL) was added dropwise. The reaction mixture was slowly
warmed to room temperature and left to stand overnight. After that, 4-chlorobutyryl
chloride (3.04 mmol, 430 mg, 340 µL) was added and the mixture was left to stand
overnight. Next, water (35 mL), NaOH (12 mmol, 480 mg) and TBABr (0.25 mmol, 85
mg) was added and the reaction mixture was stirred overnight. Next, water was added
and the resulting mixture was extracted with AcOEt. The combined organic layers were
dried over anhydr. Na2SO4. After the removal of the solvents, the residue was purified
by column chromatography on silica gel: 20-50% AcOEt in hexanes. Yield: 280 mg
(60%, 6 steps).
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (1): Ozone was passed through a solution of
pyrrolidin-2-one 2 (1 mmol, 180 mg) in dry CH2Cl2 (40 mL) at −78 °C until the solution
turned blue. Then, excess of ozone was removed by bubbling oxygen through the
mixture. After the addition of Me2S (8 mL), the resulting mixture was warmed to room
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temperature and stirred for 1 h. After that, the solvent was removed undDeOrI:r1e0.d10u39c/Ce9dOB00111E
pressure. The residue was dissolved in t-BuOH/H2O (4:1 v/v, 30 mL), followed by the
addition of NaH2PO4·H2O (5 mmol, 730 mg), 2-methyl-2-butene (480 μL) and NaClO2
(pur. 80%, 5 mmol, 610 mg). The resulting mixture was stirred overnight. Next, the
solvents were removed and crude acid was dissolved in AcOEt and dried over anhydr.
Na2SO4. After the removal of the solvent, the residue was dissolved in dry THF (8 mL),
Et3N (1.04 mmol, 105 mg, 150 µL) was added and the mixture was cooled to 0 °C.
Ethyl chloroformate (1.04 mmol, 112 mg, 100 µL) was added dropwise and the mixture
was stirred at 0 °C. After 30 min, 25% aq NH3 solution (4 mL) was added and the
mixture was stirred at room temperature overnight. Next, K2CO3 (1.52 mmol, 210 mg)
was added and the reaction mixture was filtered through Celite and washed with
AcOEt. After the removal of the solvent, the crude product was purified by flash column
chromatography: 0-1% MeOH in AcOEt. Yield: 104 mg (62%, 4 steps); yellowish solid;
22
m.p. 113-115 °C [Lit. 113-114 °C,26 115-117 °C24]; [α]D19 –148.0 (c 0.59, CHCl3), [α]D
–89.2 (c 1.1, acetone) [Lit.: –85.6 (c 0.97, acetone),26 –90.5 (c 1.0, acetone)24] e.e.
97% (HPLC: Rt 21.4 min); Spectral data in agreement with literature:26 1H NMR (400
MHz, CDCl3) δ 6.48 (br s, 1H), 5.84 (br s, 1H), 4.45 (dd, J = 9.0, 6.7 Hz, 1H), 3.52 –
3.29 (m, 2H), 2.46 – 2.33 (m, 2H), 2.09 – 1.85 (m, 3H), 1.75 – 1.58 (m, 1H), 0.88 (t, J
= 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.0, 172.4, 56.1, 43.9, 31.1, 21.1, 18.1,
10.5; HPLC (racemate) Chiralcel OD-H, 10% i-PrOH in hexanes, flow 1 mL/min, det.
210 nm; Rt 15.5 min (R-enantiomer) and 21.5 min (S-enantiomer).
Acknowledgments: The authors are grateful to National Science Center of Poland for
financial support of the project (research grant OPUS No. 2014/15/B/ST5/04398). A.N.
is grateful to the Institute of Organic Chemistry of the Polish Academy of Sciences and
12

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Scientists and PhD Students.
References:
1.
2.
3.
B. Abou-Khalil, Neuropsychiatr. Dis. Treat., 2008, 4, 507-523.
M. A. Rogawski, Br. J. Pharmacol., 2008, 154, 1555-1557.
S. D. Shorvon and K. V. J. Rijckevorsel, Neurol. Neurosurg. Psychiatry, 2002, 72,
426-429.
4.
5.
6.
K. A. Lyseng-Williamson, Drugs, 2011, 71, 489-514.
A. Z. Crepeau and D. M. Treiman, Expert Rev. Neurother., 2010, 10, 159-171.
J. L. Tucker, L. Xu, W. Yu, R. W. Scott, L. Zhao and N. Ran, PCT Int. Appl, WO
2009009117, 2009.
7.
R. Olszanecki, G. B. Bujak, R. Korbut and M. Gajda, PCT Int. Appl, WO 2011049475,
2011.
8.
J. Prous, N. Mealy and J. Castaner, Drugs Future, 1994, 19, 11-14.
M. J. Brodie and J. A. French, Epileptic. Disord., 2003, 5 Suppl 1, S65-72.
M. Bialer and H. S. White, Nat. Rev. Drug Discov., 2010, 9, 68-82.
B. A. Lynch, N. Lambeng, K. Nocka, P. Kensel-Hammes, S. M. Bajjalieh, A. Matagne
and B. Fuks, Proc. Natl. Acad. Sci. USA, 2004, 101, 9861-9866.
D. G. Kasteleijn-Nolst Trenite and E. Hirsch, Epileptic Disord., 2003, 5 Suppl 1, S39-
44.
9.
10.
11.
12.
13.
14.
B. A. Lynch, N. Lambeng, K. Nocka, P. Kensel-Hammes, S. M. Bajjalieh, A. Matagne
and B. Fuks, Proc. Natl. Acad. Sci. USA, 2004, 101, 9861-9866.
B. M. Kenda, A. C. Matagne, P. E. Talaga, P. M. Pasau, E. Differding, B. I.
Lallemand, A. M. Frycia, F. G. Moureau, H. V. Klitgaard, M. R. Gillard, B. Fuks and P.
Michel, J. Med. Chem., 2004, 47, 530-549.
13

Organic & Biomolecular Chemistry
Page 14 of 15
View Article Online
DOI: 10.1039/C9OB00111E
15.
16.
17.
18.
19.
20.
21.
22.
J. Gobert, J. P. Geerts and G. Bodson, US Patent 4696943, 1990.
Top 200 Drugs for 2010 by Sales, www.drugs.com.
J. Gobert, J.-P. Geerts and G. Bodson, US4696943A, 1987.
D. S. Koushik, Z. Ji, H. Yun and D. J. G., Eur. J. Org. Chem., 2006, 3730-3737.
G. Minghua, S. Qi, L. Guangshun and Z. Zhibin, CN108239016, 2018.
J. Gobert, J. P. Geerts and G. Bodson, EP 162036, 1985.
E. Cossement, G. Motte, J. P. Geerts and J. Gobert, GB 2225322, 1990.
A. K. Mandal, S. W. Mahajan, M. K. Sharma, A. Chetia and N. D. Chauhan,
WO2006095362A1, 2006.
23.
24.
25.
T. Imahori, K. Omoto, Y. Hirose and H. Takahata, Heterocycles, 2008, 76, 1627-
1632.
M. Mujahid, P. Mujumdar, M. Sasikumar, S. S. Kunte and M. Muthukrishnan,
Tetrahedron: Asymmetry, 2012, 23, 1512-1515.
J. Surtees, D. Bouvy, A. Thomas, Y. Combret, M. Frank, G. Schmidt and G. Duchene,
US8338621B2, 2012.
26.
27.
M. Liniger, Y. Liu and B. M. Stoltz, J. Am. Chem. Soc., 2017, 139, 13944-13949.
T. Futagawa, J.-P. Canvat, E. Cavoy, M. Deleers, M. Hamende and V. Zimmermann,
US6107492A, 1998.
28.
29.
30.
31.
32.
C. Ates, J. Surtees, A. C. Burteau, V. Marmon and E. Cavoy, PCT Int. App. WO
2003014080, 2003.
E. Cavoy, M. Hamende, M. Deleers, J.-P. Canvat and V. Zimmermann, US6124473A,
2000.
A. K. Mandal, S. W. Mahajan, M. K. Sharma, A. Chetia and N. D. Chauhan,
WO2006095362A1, 2006.
H. Cai, T. J. Mangner, O. Muzik, M.-W. Wang, D. C. Chugani and H. T. Chugani, ACS
Med. Chem. Lett., 2014, 5, 1152-1155.
J. Surtees, V. Marmon, E. Differding and V. Zimmermann, WO 2001064637 2001.
14

Page 15 of 15
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C9OB00111E
33.
34.
35.
36.
M. R. Friedfeld, H. Zhong, R. T. Ruck, M. Shevlin and P. J. Chirik, Science, 2018,
360, 888-893.
F. Boschi, P. Camps, M. Comes-Franchini, D. Muñoz-Torrero, A. Ricci and L.
Sánchez, Tetrahedron: Asymmetry, 2005, 16, 3739-3745.
K. Chandra Babu, R. Buchi Reddy, K. Mukkanti, K. Suresh, G. Madhusudhan and S.
Nigam, Journal of Chemistry, 2013, Article ID 176512.
V. Raju, S. Somaiah, S. Sashikanth, E. Laxminarayana and K. Mukkanti, Drug
Invention Today, 2014, 6, 32-34.
37.
38.
S. P. Kotkar and A. Sudalai, Tetrahedron Lett., 2006, 47, 6813-6815.
P. Szcześniak, A. Październiok-Holewa, U. Klimczak and S. Stecko, J. Org. Chem.,
2014, 79, 11700-11713.
39.
40.
41.
42.
43.
44.
M. Chwastek, M. Pieczykolan and S. Stecko, J. Org. Chem., 2016, 81, 9046-9074.
P. Szcześniak, M. Pieczykolan and S. Stecko, J. Org. Chem., 2016, 81, 1057-1074.
M. Pieczykolan, A. Narczyk and S. Stecko, J. Org. Chem., 2017, 82, 5636-5651.
S. Stecko, J. Org. Chem., 2014, 79, 6342-6346.
B. J. Lüssem and H.-J. Gais, J. Am. Chem. Soc., 2003, 125, 6066-6067.
Y. Ichikawa, Y. Morishita, S. Kusaba, N. Sakiyama, Y. Matsuda, K. Nakano and H.
Kotsuki, Synlett, 2010, 2010, 1815-1818.
45.
46.
47.
T. Liu, W. Jia, Q. Xi, Y. Chen, X. Wang and D. Yin, J. Org. Chem., 2018, 83, 1387-
1393.
P. Y. Hayes, S. Chow, F. Rahm, P. V. Bernhardt, J. J. De Voss and W. Kitching, J.
Org. Chem., 2010, 75, 6489-6501.
Y. Dai, F. Wu, Z. Zang, H. You and H. Gong, Chem. Eur. J., 2012, 18, 808-812.
15