Synthesis of the antiepileptic (R)-Stiripentol by a combination of lipase catalyzed resolution and alkene metathesis

Article abstract of DOI:10.1016/j.tetasy.2013.02.006

The enantiopure (ee >99%) antiepileptic (R)-(+)-Stiripentol has been stereoselectively synthesized via cross metathesis of 5-vinylbenzo[d][1,3] dioxole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2. A novel one-pot two-step pathway for the synthesis of 5-vinylbenzo[d][1,3]dioxole 1 starting from 3,4-dihydroxycinnamic acid has been introduced. A lipase catalyzed kinetic resolution access to enantiopure (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 (ee >99%) has also been developed.

Full text of DOI:10.1016/j.tetasy.2013.02.006

Tetrahedron: Asymmetry 24 (2013) 285–289
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Tetrahedron: Asymmetry
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Synthesis of the antiepileptic (R)-Stiripentol by a combination of lipase
catalyzed resolution and alkene metathesis
⇑
,
Mohammed Farrag El-Behairy , Eirik Sundby
Department of Chemistry, South-Trøndelag University College, N-7004 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 December 2012
Accepted 7 February 2013
The enantiopure (ee >99%) antiepileptic (R)-(+)-Stiripentol has been stereoselectively synthesized via
cross metathesis of 5-vinylbenzo[d][1,3]dioxole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2. A
novel one-pot two-step pathway for the synthesis of 5-vinylbenzo[d][1,3]dioxole 1 starting from 3,4-
dihydroxycinnamic acid has been introduced. A lipase catalyzed kinetic resolution access to enantiopure
(R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 (ee >99%) has also been developed.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
OH
O
Stiripentol (STP) (DiacomitÒ) is an antiepileptic drug pioneered
by Biocodex (Gentilly, France). With respect to chemical structure,
it is dissimilar to all market available antiepileptic drugs as it be-
longs to the group of aromatic allylic alcohols.1 The European Un-
ion has approved Stiripentol orphan drug status for the treatment
of severe myoclonic epilepsy in infants (Dravet syndrome). In addi-
tion, it has long been used as co-therapy for the treatment of epi-
lepsy.2 A recent report stated that STP acts at the neuronal level,
increasing inhibitory GABAergic neurotransmission through posi-
tive allosteric modulation of GABAA receptors.3 STP has long been
considered to be an indirect antiepileptic, as it inhibits the en-
zymes responsible for metabolism of other antiepileptic drugs.4
Stereochemically, Stiripentol is a secondary alcohol containing
one asymmetric center (Fig. 1). Despite the marked differences in
pharmacokinetics and antiepileptic potency between the enantio-
mers, it is still marketed as a racemic mixture.4
Over the last few years, biocatalysis has been recognized as a
viable and popular technique in organic synthesis, especially in
the production of enantiopure molecules and pharmaceutical com-
pounds.5 Most lipases have a wide range of non-natural substrates
and are thus very versatile for applications in organic synthesis.
They do not require cofactors and are commercially available in
free and immobilized forms; in many cases, they exhibit good to
excellent stereoselectivity6.
O
(R)-(+)-Stiripentol
Figure 1. Structure of (R)-(+)-Stiripentol.
groups on alkenes are exchanged, has grown to be a powerful syn-
thetic tool for C@C bond formation due to the development of a
range of very stable ruthenium-based catalysts introduced by
Grubbs et al.7
In a previous study,8 Stiripentol has been subjected to thorough
investigations aimed at a resolution of the racemic mixture to its
enantiomers using lipase catalyzed kinetic resolution technology.
Careful selection of the lipases used and subsequent reaction opti-
mization resulted in enantioenriched (R)-Stiripentol that was ob-
tained in ee = 94%. Although the achieved result was acceptable,
further enhancement was required to obtain enantiopure (R)-Sti-
ripentol. The difficulties in these lipase-catalyzed resolution reac-
tions have been attributed to the bulky substrate (Stiripentol)
which pushed most of the lipases used to be completely inactive
or in the best case very slow. Thus herein, it has been assumed that
using a less bulky substrate could be helpful in the attainment of
very high selectivity and enantiomeric purity. Hence, (RS)-( )-
4,4-dimethylpent-1-en-3-ol has been subjected to intensive ki-
netic resolution reactions catalyzed by lipases in order to afford
(R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 which by further cou-
pling with 5-vinylbenzo[d][1,3]dioxole 1 in a cross metathesis
reaction could yield the desired enantiopure (R)-Stiripentol
(Scheme 1).
Recently, olefin metathesis has become more generally utilized
in synthetic organic chemistry. The process, by which alkylidene
⇑
Corresponding author. Tel.: +2 01227163094; fax: +2 33370931.
E-mail address: mohabeha@gmail.com (M.F. El-Behairy).
Present address: Medicinal and Pharmaceutical Chemistry Department, Pharma-
ceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza
12622, Egypt.
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.02.006

286
M. F. El-Behairy, E. Sundby / Tetrahedron: Asymmetry 24 (2013) 285–289
O
HO
O
bio-catalyzed
hydrolysis
kinetic
HO
resolution
(RS)-( )-4,4-dimethylpent-1-
en-3-ol( )-2
(R)-4,4-dimethylpent-1-
(R)-(+)-4,4-dimethylpent-1-
en-3-ol(+)-2
en-3-yl butyrate
OH
Cross
Metathesis
O
O
+
(R)-(+)-Stiripentol
HO
COOH
O
O
K2CO3/CH2Cl2/ DMF
reflux over night
HO
5-vinylbenzo[d][1,3]dioxole
Scheme 1. Synthesis of (R)-(+)-Stiripentol.
(E)-3,4-dihydroxycinnamic acid
bromide in the presence of palladium acetate20 has also provided
styrenes.
2. Results and discussion
Herein, we focused on the synthesis of 5-vinyl-
benzo[d][1,3]dioxole 1 starting from dihydroxybenzaldehyde or
dihydroxycinnamic acid. According to the starting material many
pathways could be followed in order to attain the desired com-
pound 1 (Scheme 2).
2.1. Synthesis of 5-vinylbenzo[d][1,3]dioxole 1
5-Vinylbenzo[d][1,3]dioxole 1 is a functionalized styrene, which
is one of the most comprehensively investigated set of compounds
due to its broad applications in the food and flavoring industries.9
Also, it can act as an intermediate in the synthesis of various bio-
active molecules10 and many biological activities have been as-
cribed to these compounds.11
Synthetic strategies toward styrenes or vinyl phenols are ubiq-
uitous and mainly depend on the starting material. For instance,
starting with trans-cinnamic acids, decarboxylation at 240–
260 °C in the presence of quinoline and metal salts is reported.12
For ethylphenols catalytic dehydrogenation is the preferred strat-
egy,13 or alternatively achieved via Wittig synthesis14 or from phe-
nol in five steps as reported by Corson et al.15 Starting with
benzaldehyde derivatives, Knoevenagel condensation–decarboxyl-
ation16,17 or Grignard addition–dehydration approaches18 are also
useful. Recently, the cross coupling of aryl halides and 2,4,6-trivi-
nylcyclotriboroxane pyridine,19 or arylboronic acids with vinyl
At the inception, the recently reported microwave assisted
techniques for Knoevenagel condensation–decarboxylation of
3,4-dihydroxybenzaldehyde17 or the decarboxylation of 3,4-
dihydroxycinnamic acid21 were attempted. Unfortunately, all
microwave assisted experiments failed in our hands and resulted
in charred reaction mixtures. We then shifted the investigations
toward conventional decarboxylation methodology whereby high
temperatures and basic catalysis are used. Accordingly, the re-
ported procedure by Saga et al.22 for the decarboxylation of cin-
namic acid using cupric chloride, DBU and heating at 240 °C for
30 min was carried out, and resulted in 4-vinylbenzene-1,2-diol
in a low 10% yield. The pure 4-vinylbenzene-1,2-diol was then sub-
jected for further methylene bridge formation reaction according
to the reported procedures by Aboul-Enein et al.23 whereby 5-
CHO
O
O
CHO
O
O
1. Knoevenagel-
Doebner
Wittig reaction
2. Decarboxylation
1.Knoevenagel-
Doebner
3. K2CO3/CH2Cl2
DMF
HO
HO
CHO
O
O
2. Decarboxylation
1. K2CO3/CH2Cl2
DMF
1. Decarboxylation
2. Decarboxylation
COOH
2. K2CO3/CH2Cl2
DMF
HO
HO
COOH
HO
HO
Scheme 2. Postulated pathways toward 5-vinylbenzo[d][1,3]dioxole 1.

M. F. El-Behairy, E. Sundby / Tetrahedron: Asymmetry 24 (2013) 285–289
287
vinylbenzo[d][1,3]dioxole 1 has been obtained in 55% yield as a
2.3. Lipase-catalyzed resolution of (R)-(+)-4,4-dimethylpent-1-
en-3-ol (R)-(+)-2
light yellow oil, giving 1 in a total yield of 5.5% over two steps.
However, this method was still superior to the reported procedures
for the synthesis of 1 by Sinha et al.17 which afforded 4% yield.
In order to improve the yield of 1, reversing the sequence of the
reactions was investigated, by performing the methylene bridging
reaction first, followed by the decarboxylation. Somewhat surpris-
ingly, a one-pot two-step reaction was discovered whereby the
methylene bridging and decarboxylation reactions occurred in
the same pot when 3,4-dihydroxycinnamic acid was subjected to
reaction conditions intended to introduce the methylene bridge.
The product obtained was verified by spectroscopic analysis which
showed data identical to those of 5-vinylbenzo[d][1,3]dioxole 1.10
It could be that anhydrous potassium carbonate, used in the meth-
ylene bridging reaction as a base, plays the role of DBU in the
decarboxylation reaction. Also, it has been reported22 that DMF
could be used as a reaction medium where the high boiling point
solvent will provide the heat needed for decarboxylation.
The one-pot two-step synthesis of 5-vinylbenzo[d][1,3]dioxole
1 provided the pure product in 61% yield and required no sophisti-
cated purification procedures. This new procedure has been proved
to be superior over the previously reported synthesis of 5-vinyl-
benzo[d][1,3]dioxole 1 by Sinha et al.17 giving an improved yield.
In addition, it is better than the reported procedures by Aslam
et al.10 being simpler and using more economic starting materials
and catalysts (Scheme 3).
After optimizing the chiral analyses for racemic 4,4-dimethyl-
pent-1-en-3-ol 2 and the corresponding butanoate 3, the screening
of different lipases (11 lipases) for the enantioselective transesteri-
fication of (RS)-4,4-dimethylpent-1-en-3-ol (RS)-2 was then per-
formed (Scheme 5).
Screening all available lipases for activity in n-hexane and using
vinyl butanoate as the acyl donor showed that three lipases gave
mediocre to excellent enantiomeric ratios (E). Lipase immobilized
on immobead 150 from Candida rugosa (E = 19.9), AMANO lipase
AY30 (E = >300), and lipase A from Candida antarctica (CAL-A)
(E = >300) gave in all cases (R)-2 as the faster reacting enantiomer.
This was then subsequently esterified selectively to afford (R)-3
leaving the second enantiomer of the substrate (S)-2 in an enanti-
omerically enriched form.
Further investigations have been performed in order to test the
performance of these three enzymes in different organic solvents
such as toluene, methyl tertbutyl ether (MTBE), ethyl acetate
(EtOAc), tetrahydrofuran (THF), and chloroform. Switching to other
solvents or changing the acyl donor gave no major differences in
the enantiomeric ratio in reactions using AMANO lipase AY30 or li-
pase A from Candida antarctica. Unfortunately, no improvement
was observed when testing Candida rugosa lipase in these solvents
or by attempting acyl donors other than vinyl butyrate.
The best process was based on a minimum reaction time and
the best enantiomeric ratio was determined to be lipase A from
Candida antarctica in toluene (Fig. 2). Using this procedure, the
reaction was scaled up to 1 g of substrate which, after separation
of the (R)-ester and (S)-alcohol by column chromatography using
silica gel and CHCl3 (100%) afforded (S)-alcohol (S)-(ꢀ)-2 (0.4 g,
HO
HO
COOH
O
O
K2CO3/CH2Cl2/DMF
reflux over night
ee = 75%), ½a 2D0
¼ ꢀ6:2 (c 10, CHCl3), and (R)-butyrate (R)-(+)-3
ꢁ
Scheme 3. One-pot two-step synthesis of 5-vinylbenzo[d][1,3]dioxole 1.
(0.33 g, ee >99%), ½a D20
¼ þ5:1 (c 10, CHCl3) which was subjected
ꢁ
to further lipase A catalyzed hydrolysis in phosphate buffer pH
7.0 to afford (R)-alcohol (R)-(+)-2 (0.1 g, ee >99%), ½a D20
¼ þ8:3 (c
ꢁ
2.2. Synthesis of ( )-4,4-dimethylpent-1-en-3-ol ( )-2
10, CHCl3).
Typical Grignard reaction procedures were followed24 for the
synthesis of ( )-4,4-dimethylpent-1-en-3-ol ( )-2. Thus an equi-
molar amount of vinyl magnesium bromide and pivaldehyde was
allowed to react in dry ethyl ether at reflux. The resulting magne-
sium complex was decomposed using saturated ammonium chlo-
ride solution and the reaction product was purified to afford
racemic 2 as yellow oil in 75% yield (Scheme 4).
O
OH
+
BrMg
H
(RS)-( )-4,4-
dimethylpent-1-en-3-ol
( )-2
pivaldehyde
vinylmagnesium
bromide
Figure 2. Progress of the kinetic resolution of rac-2 by esterification with vinyl
butanoate catalyzed by CALA, (X) product fraction (R)-3, ( ) substrate fraction (S)-2.
Scheme 4. Grignard synthesis of (RS)-( )-4,4-dimethylpent-1-en-3-ol (RS)-( )-2.
D
O
OH
OH
R
O
Lipase
+
organic solvent
acyl donor
(RS)-4,4-dimethylpent-1-
en-3-ol( )-2
(S)-4,4-dimethylpent-1-en-3-ol
Scheme 5. Lipase catalyzed transestrification of ( )-4,4-dimethylpent-1-en-3-ol ( )-2.

288
M. F. El-Behairy, E. Sundby / Tetrahedron: Asymmetry 24 (2013) 285–289
2.4. Synthesis of (R)-(+)-1-(benzo[d][1,3]dioxol-5-yl)-4,4-
dimethylpent-1-en-3-ol (R)-(+)-4, (R)-(+)-Stiripentol using
olefin metathesis
4.2.2. Chiral HPLC analysis8
Stiripentol was separated according to the reported procedures
by Jacobsen et al.8 using an Agilent 1100 HPLC system (Agilent,
USA) with a quaternary pump and a variable wavelength UV detec-
tor and equipped with Chiracel OD-HÒ column ([cellulose tris (3,5
The high selectivity and reactivity of Grubbs’ catalyst for car-
bon-carbon
p-bond formation enable the use of cross metathesis
dimethylphenylcarbamate) coated on 5
lm silica-gel], i.d. 4.6 mm,
(CM) as an excellent alternative to other alkene forming reactions.
The reported cross metathesis procedures by Nagarapu et al.25
have been utilized in the synthesis of (R)-(+)-Stiripentol. Equimolar
amounts of 5-vinylbenzo[d][1,3]dioxole (1) and (R)-(+)-4,4-dim-
ethylpent-1-en-3-ol (R)-(+)-2 were treated with 5 mol % of Grubbs’
2nd generation catalyst in dry dichloromethane. The product was
purified using preparative thin layer chromatography (silica gel
and CHCl3) to give 5 mg of (R)-(+)-Stiripentol (15%, ee >99%). The
low yield could be attributed to the occurrence of the homo-cou-
pling reaction affording dimers of the starting materials instead
of reacting further the cross-coupling product. Based on the ob-
served coupling constant (3J = 15.3 Hz, CH@CHPh) and coincident
chromatographic behavior with a Stiripentol standard, it was con-
cluded that no Z-isomers were formed. The ee was determined by
chiral HPLC8 and all spectroscopic data were in accordance with
those reported earlier.8
25 cm, film density 5 m). n-Hexane, tert-butyl methyl ether
l
(MTBE) and 2-propanol (2-PrOH) were used as eluents, flow rate
1 mL minꢀ1. Retention time Stiripentol (mobile phase 95:5:1)
27.9, 30.3 min.
4.3. Synthesis of 5-vinylbenzo[d][1,3]dioxole 1
4.3.1. One-pot two-step reaction
A solution of 3,4-dihydroxycinnamic acid (2 g, 0.011 mol) in
DMF (20 mL) was added dropwise to a suspension of CH2Cl2
(1.4 mL, 0.02 mol) and K2CO3 (4 g, 0.028 mol) in DMF (30 mL).
The mixture was stirred and heated at reflux for 18 h then cooled
and filtered. The filtrate was concentrated, diluted with water,
and extracted with ethyl acetate (3 ꢂ 100 mL). The filter cake
was washed with ethyl acetate (25 mL). The organic layer was
washed with 10% NaOH (25 mL), water (25 mL), dried (Na2SO4),
and evaporated to afford 1.0 g (61%) of 1 as a yellow oil.10 1H
NMR (CDCl3, 400 MHz): d 5.0 (d, J = 10.86 Hz, 1H, CHCH2), 5.5 (d,
J = 17.43 Hz, 1H, CHCH2), 5.9 (s, 2H, OCH2O), 6.5 (dd, J = 10.86,
17.43 Hz, 1H, CHCH2), 6.5 (d, J = 8.08 Hz, 1H, Har), 6.75 (dd,
J = 1.52, 7.83 Hz, 1H, Har), 6.9 (d, J = 1.52 Hz, 1H, Har).
13C NMR (CDCl3, 100 MHz): 101, 105, 109, 112, 121, 132, 136,
147,148.
3. Conclusion
By employing the cross-metathesis of 5-vinylbenzo[d][1,3]diox-
ole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 using Grub-
bs’ second generation catalyst, access toward enantiopure (R)-(+)-
Stiripentol has been achieved. 5-Vinylbenzo[d][1,3] dioxole 1 has
been synthesized in 61% yield using a new concise, and straightfor-
ward pathway from 3,4-dihydroxycinnamic acid. The first lipase-
catalyzed enantioselective resolution of (RS)-( )-4,4-dimethyl-
pent-1-en-3-ol (RS)-( )-2 has been reported to afford enantiopure
(R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 in ee >99%.
4.3.2. Two step reaction
4.3.2.1. Synthesis of 4-vinylbenzene-1,2-diol.
dihydroxycinnamic acid (1 g, 5.5 mmol),
A mixture of
1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) (1.7 g, 11 mmol), and CuCl2 (0.08 g,
0.59 mmol) was heated at 240 °C for 30 min. The mixture was
cooled, dissolved in water, acidified with HCl (10%, aqueous) until
pH 1, filtered, extracted with ethyl acetate (3 ꢂ 50 mL), then evap-
orated under vacuum, and purified using column chromatography
(silica gel, CHCl3/CH3OH 4/1 v/v) to afford 80 mg (10%) of 4-vinyl-
benzene-1,2-diol as yellow oil.29 1H NMR (CDCl3, 400 MHz): d 4.9
(d, J = 10.86 Hz, 1H, CHCH2), 5.4 (d, J = 17.43 Hz, 1H, CHCH2), 6.5
(dd, J = 10.86, 17.43 Hz, 1H, CHCH2), 6.7 (m, 3H, Har). 13C NMR
(CDCl3, 100 MHz): 110, 112, 115, 119, 120, 130, 137, 145.
4. Materials and methods
4.1. General
All solvents used were analytical grade (p.a.) and purchased
from Sigma–Aldrich (Steinheim, Germany). Immobilized Candida
antarctica lipase B (Novozym 435, activity 10,000 PLU/g, lot No.
LC 200205) was from Novozymes (Bagsværd, Denmark). Lipase A
from Candida antarctica immobilized on Immobead 150, (activity
500 U/g, lot No. 1388471) was bought from Sigma–Aldrich.
1H NMR and 13C NMR spectra were carried out on Bruker
400 MHz Spectrophotometer using TMS as an internal standard.
Chemical shift values are recorded in the ppm d scale. Optical rota-
tions (½aꢁD) were determined at 20 °C using a Perkin–Elmer 341
instrument, concentrations are given in g/100 mL. AIKA KS 4000
shaker incubator was used for the enzyme reactions. Enantiomeric
ratios, E, were calculated based on ping–pong bi–bi kinetics using
the computer program E & K Calculator 2.1b0 PCC26 based on the
calculations of Chen and Rakes.27,28 GC system was Varian 3400
gas chromatograph equipped with a chiral CP-Chirsil Dex CB col-
umn (25 m, 0.32 mm i.d., 0.25 lm film thickness).
4.3.2.2. Synthesis of 5-vinylbenzo[d][1,3]dioxole 1.
A solu-
tion of 4-vinylbenzene-1,2-diol (50 mg, 0.36 mmol) in DMF
(1 mL) was added dropwise to a suspension of CH2Cl2 (0.35 mL,
0.005 mol) and K2CO3 (150 mg, 0.028 mol) in DMF (10 mL). The
mixture was stirred and heated at reflux for 4 h then cooled and fil-
tered. The filtrate was concentrated, diluted with water, and ex-
tracted with ethyl acetate (3 ꢂ 10 mL). The filter cake was
washed with ethylacetate (10 mL). The organic layer was washed
with 10% NaOH (10 mL), water (10 mL), dried (Na2SO4), and evap-
orated to afford 30 mg (55%) of 1 as a yellow oil.10 1H NMR (CDCl3,
400 MHz): d 5.2 (d, J = 10.8 Hz, 1H, CHCH2), 5.6 (d, J = 17.4 Hz, 1H,
CHCH2), 6.0(s, 2H, OCH2O), 6.7 (dd, J = 10.8, 17.4 Hz, 1H, CHCH2),
6.8 (d, J = 8.0 Hz, 1H, Har), 6.9 (dd, J = 1.52, 7.83 Hz, 1H, Har), 7.0
(d, J = 1.52 Hz, 1H, Har). 13C NMR (CDCl3, 100 MHz): 101, 105,
108, 112, 121, 132, 136, 147,148.
4.2. Chiral chromatography analysis
4.2.1. Chiral GC analysis
4.4. Synthesis of ( )-4,4-dimethylpent-1-en-3-ol ( )-2
Varian 3400 gas chromatograph equipped with a chiral CP-Chir-
sil Dex CB column (25 m, 0.32 mm i.d., 0.25 lm film thickness),
temperature program 50–85 °C, 5 °C/min, 85–97 °C, 1 °C/min, 97–
200 °C, 20 °C/min. Retention times, (R)-(+)-2 = 12.9 min, (S)-(ꢀ)-
2 = 13.2 min, (R)-(+)-3 = 22.0.
To an ice cooled stirred solution of vinyl magnesium bromide
(25 ml of 1.0 mol solution in THF, 2.3 g, 17 mmol) in tetrahydrofu-
ran was added dropwise a solution of pivaldehyde (2.0 ml, 1.5 g,
17 mmol) in dry ether. The mixture was allowed to heat at reflux

M. F. El-Behairy, E. Sundby / Tetrahedron: Asymmetry 24 (2013) 285–289
289
overnight. The reaction was cooled and saturated ammonium chlo-
ride solution was added until no more solid in the aqueous phase
was observed, the organic layer was separated, dried over anhy-
drous sodium sulfate anhydrous, and evaporated under vacuum
to afford 1.5 g (75%) of racemic-2 as a pale yellow oil.24 1H NMR
(CDCl3, 400 MHz): d 0.9 (s, 9H, t-butyl), 5.0 (d, J = 6.82 Hz, 1H,
CHOH), 5.2 (m, 2H, CH@CH2), 5.8 (m, 1H, CH@CH2). 13C NMR
(CDCl3, 100 MHz): 26, 36, 81, 116, 138.IR: 3500 (OH).
product purified using preparative thin layer chromatography (sil-
ica gel and CHCl3) to afford 5 mg of (R)-(+)-Stiripentol (15%, ee
>99%). The enantiomeric excess was calculated according to the re-
ported procedures by Jacobsen et al.8
Acknowledgements
We thank The Research Council of Norway (RCN) for a research
fellowship to Mohammed Farrag El-Behairy. (Contract Grant num-
ber 202903/11).
4.5. Synthesis of ( )-4,4-dimethylpent-1-en-3-yl butyrate ( )-3
To a stirred solution of ( )-2 (0.5 g, 0.004 mol) in pyridine
(30 mL), was added butanoic anhydride (1.95 mL, 1.89 g,
0.012 mol). The mixture was heated at reflux overnight, cooled,
poured over HCl (200 mL, 10% aq), and extracted with diethyl ether
(2 ꢂ 50 mL). The ethereal layer was separated, dried (Na2SO4), and
evaporated to afford 0.5 g (62%) of ( )-4,4-dimethylpent-1-en-3-yl
butyrate ( )-3 as a brown oil. 1H NMR (400 MHz, CDCl3): d 0.9 (s,
9H, t-butyl), 0.95 (t, J = 7.33, 7.58 Hz, 3H, OCOCH2CH2CH3), 1.7
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(m,
2H,
OCOCH2CH2CH3),
2.3
(t,
J = 7.33,
7.07 Hz,
2H,OCOCH2CH2CH3), 5.0 (d, J = 6.82 Hz, 1H, CHOCO), 5.2 (m, 2H,
CH@CH2), 5.8 (m, 1H, CH@CH2). 13C NMR (CDCl3, 100 MHz): 14,
19, 26, 34, 36, 81, 118, 133, 172.
4.6. Lipase-catalyzed synthesis of (R)-(+)-4,4-dimethylpent-1-
en-3-ol (R)-(+)-2
( )-4,4-Dimethylpent-1-en-3-ol ( )-2 (1 g, 8.7 mmol) was dis-
solved in n-hexane (25 mL) in a 50 mL round bottom flask followed
by the addition of vinyl butanoate (2.3 mL, 17 mmol, 2.0 g, 2 equiv)
and Lipase A from Candida antarctica (2 g) immobilized on Immo-
bead 150. The mixture was heated to 35 °C, stirred at 300 rpm,
and monitored by GC. After 9 h, the reaction was stopped by en-
zyme filtration and the solvent together with the excess of vinyl
butyrate was evaporated under reduced pressure. The residual
(R)-ester and (S)-alcohol mixture was separated by column chro-
matography using silica gel and CHCl3 (100%) to afford (S)-alcohol
(S)-(ꢀ)-2 (0.4 g, ee = 75%), ½a D20
¼ ꢀ6:2 (c 10, CHCl3), and (R)-but-
ꢁ
anoate (R)-(+)-3 (0.33 g, ee >99%), ½a D20
¼ þ5:1 (c 10, CHCl3) which
ꢁ
was subjected to further lipase catalyzed hydrolysis in phosphate
buffer pH 7.0 to afford (R)-alcohol (R)-(+)-2 (0.1 g, ee >99%),
½
a 2D0
ꢁ
¼ þ8:3 (c 10, CHCl3).
4.7. Synthesis of (R)-(+)-1-(benzo[d][1,3]dioxol-5-yl)-4,4-
dimethylpent-1-en-3-ol (R)-(+)-4, (R)-(+)-Stiripentol
26. Anthonsen, H. W.; Hoff, B. H.; Anthonsen, T. Tetrahedron: Asymmetry 1996, 7,
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43, 411–422.
To a stirred solution of 5-vinylbenzo[d][1,3]dioxole 1 (22 mg,
0.15 mmol) and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2
(17 mg, 0.15 mmol) in dry DCM (5 mL), Grubbs’ second generation
catalyst (7 mg, 5 mol %) was added and the mixture was heated at
overnight under argon, the reaction mixture was cooled, and the
28. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104,
7294–7299.
29. Terpinc, P.; Polak, T.; Šegatin, N.; Hanzlowsky, A.; Ulrih, N. P.; Abramovic, H.
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