A synthesis of levetiracetam based on (S)-N-phenylpantolactam as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2005.10.014

The synthesis of levetiracetam and its enantiomer by deracemization of (±)-2-bromobutyric acid using either (S)- or (R)-N-phenylpantolactam as chiral auxiliaries, followed by S_N2 substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and amidation of the carboxylic acid, is described.

Full text of DOI:10.1016/j.tetasy.2005.10.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3739–3745
A synthesis of levetiracetam based on (S)-N-phenylpantolactam
as a chiral auxiliary
Francesca Boschi,a Pelayo Camps,a,* Mauro Comes-Franchini,b Diego Munoz-Torrero,a,*
˜
b
a
´
Alfredo Ricci and Laura Sanchez
a
` `
Laboratori de Quı´mica Farmaceutica (Unitat Associada al CSIC), Facultat de Farmacia, Universitat de Barcelona,
Av. Diagonal 643, E-08028 Barcelona, Spain
bDepartment of Organic Chemistry ‘A. Mangini’, University of Bologna, Viale Risorgimento 4, I-40136 Bologna, Italy
Received 12 September 2005; accepted 7 October 2005
Abstract—The synthesis of levetiracetam and its enantiomer by deracemization of ( )-2-bromobutyric acid using either (S)- or (R)-
N-phenylpantolactam as chiral auxiliaries, followed by SN2 substitution of the bromine atom by a 2-oxopyrrolidin-1-yl group and
amidation of the carboxylic acid, is described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
expectations and the growing demand for Keppraꢁ
has made necessary new production installations and
adaptation of existing production plants.
Levetiracetam, (S)-1, or its racemic form (etiracetam)
have been used for the treatment of various disorders
since 1980. Etiracetam was first used as a piracetam-like
cognition-enhancing agent in memory disorders. How-
ever, epilepsy studies on etiracetam, initiated in 1992,
showed the outstanding pharmacokinetic and pharma-
cological profile for this new application of the (S)-enan-
tiomer, levetiracetam, which led to the fastest approval
of an antiepileptic drug (AED) by the FDA, at the
end of 1999, as an add-on therapy for partial onset sei-
zures in adults with epilepsy. Epilepsy is a common med-
ical disorder with a prevalence of around 1% of the
general population, requiring prolonged and sometimes
lifelong drug therapy.1 In this context, the effectiveness,
generally good tolerability, the lack of interactions with
other AEDs and especially the cost-effectiveness of the
add-on therapy with levetiracetam could afford substan-
tial benefits for patients with epilepsy as well as for
healthcare budgets. Indeed, since its launch in the
USA in April 2000, levetiracetam has become one of
the leading adjunctive antiepileptic drugs prescribed in
neurology clinics around the world, in such a way that
the worldwide sales of UCBꢀs Keppraꢁ have beaten
Different methods of preparation of levetiracetam have
been described. Several of these procedures start from
readily available enantiopure a-amino acids and deriva-
tives thereof: (1) from (S)-a-aminobutyramide by reac-
tion with ethyl c-bromobutyrate or c-chlorobutyryl
chloride, followed by cyclization of the resulting inter-
mediates;2,3 (2) from (S)-a-aminobutyric acid by esterifi-
cation, elaboration of the 2-pyrrolidinone ring and
conversion of the ester to the amide functionality;4 (3)
from (S)-a-amino-c-methylthiobutyramide by reaction
with ethyl c-bromobutyrate or c-chlorobutyryl chloride,
and Ra–Ni desulfurization.5 In other procedures, the
resolution of etiracetam, or an advanced racemic
intermediate thereof, is performed: (4) resolution of 2-(2-
oxopyrrolidin-1-yl)butyric acid with (R)-a-methyl-
benzylamine, followed by consecutive reaction of the
(S)-acid with ethyl chloroformate and ammonium
hydroxide;2 (5) resolution of etiracetam by preparative
chiral HPLC;6,7 (6) N-diethylaminomethylation of the
primary amide functionality of etiracetam followed by
resolution with L-(+)-tartaric acid, and hydrolysis of
the required enantiomer.8 Finally an enantioselective
catalytic synthesis of levetiracetam has also been
described: (7) the hydrogenation of (E)- or (Z)-2-(2-oxo-
pyrrolidin-1-yl)-2-butenamide with Rh(I) or Ru(II)
complexes of enantiopure diphosphines.9,10
*
Corresponding authors. Tel.: +34 93 4024536; fax: +34 93 4035941
(P.C.); tel.: +34 93 4024533; fax: +34 93 4035941 (D.M.-T.); e-mail
addresses: camps@ub.edu; dmunoztorrero@ub.edu
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.014

3740
F. Boschi et al. / Tetrahedron: Asymmetry 16 (2005) 3739–3745
We have described the preparation of (R)- and (S)-3-
hydroxy-4,4-dimethyl-1-phenylpyrrolidin-2-one11,12 [(R)-
and (S)-N-phenylpantolactam, (R)- and (S)-8] and their
efficient use as chiral auxiliaries in the deracemization of
different a-substituted carboxylic acids.13–18 Herein we
report the use of these chiral auxiliaries in a synthesis
of levetiracetam and its enantiomer.
samples of (aR,3S)-9 [>98:2 diastereomeric ratio (dr)]
and (aS,3S)-3 (>98:2 dr) could be isolated by silica gel
column chromatography and fully characterized.
Hydrolysis of each ester (aS,3S)-3 and (aR,3S)-9 with
LiOH/H2O2 gave the corresponding acids (S)- and
(R)-2 in 63% and 66% yield, respectively (Scheme 2).
The enantiomeric purity of these acids could not be
established by chiral HPLC. The specific rotation for
20
(S)-2 {½aŠ ¼ À28:0 (c 1.03, acetone)} was similar to
D
20
D
2. Results and discussion
that described {½aŠ ¼ À26:4 (c 1.00, acetone)}.2
Several possible routes for preparing levetiracetam
based on the use of (R)- and (S)-8 as chiral auxiliaries
are depicted in Scheme 1. The simplest possibility
involves the deracemization of the easily available 2-
(2-oxopyrrolidin-1-yl)butyric acid, ( )-2. Alternatively,
deracemization of 2-chloro- or 2-bromo-butyric acids,
( )-4 or ( )-5, provides (R)-4 or (R)-5, which on nucle-
ophilic substitution with 2-pyrrolidinone via an SN2
mechanism could provide acid (S)-2, whose conversion
into (S)-1 has previously been described.2 Deracemiza-
tions of a-substituted carboxylic acids with chiral
non-racemic alcohols has been proposed to take place
via ketene intermediates or by dynamic kinetic resolu-
tion processes.18 While the sense of asymmetric
induction in the deracemizations of a-halocarboxylic
acids is quite established [acids with an (R)-configura-
tion at the stereogenic centre being obtained using
(S)-pantolactone or (S)-N-phenylpantolactam as chiral
auxiliaries and Et3N as base],18 there is no rationale to
explain the outcome of these reactions.
4
O
O
2'
3
O
1'
3'
4'
ii
ii
2
N
N
1
O
N
CO2H
(S)-2
O
2"
5'
3"
O
CO2H
( )-2
N
i
(αS,3S)-3
1" Ph
4"
+
5"
HO
O
N
O
O
N
N
Ph
O
CO2H
(R)-2
O
(S)-8
O
N
(αR,3S)-9
Ph
Scheme 2. Resolution of acid ( )-2 using (S)-N-phenylpantolactam,
(S)-8, as chiral auxiliary. Reagents and conditions: (i) DCC/DMAP/
CH2Cl2, À78 ꢂC, overnight, quantitative yield of crude (aR,3S)-9/
(aS,3S)-3 in the ratio of 2:3; after silica gel column chromatography:
25% yield of (aR,3S)-9; 24% yield of (aS,3S)-3; (ii) LiOH/H2O2/THF,
0 ꢂC, 7 h; (S)-2: 63% yield; (R)-2: 66% yield.
As an alternative procedure, we studied the deracemiza-
tion of ( )-a-chlorobutyric acid, ( )-4. As expected,15,16
by reaction of the corresponding acid chloride with (R)-
N-phenylpantolactam, (R)-8, a diastereomeric mixture
of the esters (aS,3R)-6 and (aR,3R)-10 in an approxi-
mate ratio of 85:15 (1H NMRand HPLC) was obtained
(Scheme 3). Unfortunately, chromatographic purifica-
tion of the main diastereomer by silica gel column chro-
matography was not possible. Hydrolysis of the above
mixture using LiOH/H2O2 in THF at 0 ꢂC gave (S)-4
[95% yield, 70% optical purity (op)]. Assuming the op
to be similar to the ee, this result shows that hydrolysis
takes place without racemization. Reaction of (S)-4
(70% op) with the sodium salt of 2-pyrrolidinone in
THF overnight at room temperature gave the expected
O
O
O
N
N
N
( )-2
CONH2
levetiracetam, (S)-1
CO2H
O
O
O
O
(S)-2
N
(αS,3S)-3
Ph
Ph
( )-4
( )-5
X
X
CO2H
O
O
X = Cl, (R)-4
X = Br, (R)-5
N
X = Cl, (αR,3S)-6
X = Br, (αR,3S)-7
Scheme 1. Retrosynthetic analysis of levetiracetam based on (R)- or
(S)-N-phenylpantolactam.
4
3
i, ii
iii
2
1
Cl
Cl
Cl
CO2H
O
CO2H
O
2'
3'
In practice and contrary to our expectations,17
attempted deracemization of acid ( )-2 by reaction of
the corresponding acid chloride with (S)-8 under differ-
ent reaction conditions gave, in poor yield, a diastereo-
meric mixture of the corresponding esters (aS,3S)-3
and (aR,3S)-9 in ratios close to 1:1 (1H NMR). Not
unexpectedly, the reaction of acid ( )-2 with N,N0-
dicyclohexylcarbodiimide (DCC) and then with (S)-8 in
the presence of a catalytic amount of 4-dimethylamino-
pyridine (DMAP) at À78 ꢂC overnight, gave in quanti-
tative yield a diastereomeric mixture of (aR,3S)-9 and
(aS,3S)-3 in the approximate ratio of 2:3, due to partial
deracemization during esterification. From this mixture,
O
(S)-4 (70% op)
+ (R)-8 (88%; >99% ee)
( )-4
N
Ph
1'
4'
5'
(αS,3R)-6 / (αR,3R)-10
O
N
(dr = 85:15)
iv
CO2H
(R)-2 (64% op)
Scheme 3. Attempted synthesis of the enantiomer of levetiracetam via
deracemization of 2-chlorobutyric acid with (R)-8. Reagents and
conditions: (i) Cl2SO; (ii) (R)-8, CH2Cl2, Et3N, À20 ꢂC, 4 h: (aS,3R)-6/
(aR,3R)-10 (quantitative yield, 85:15 dr); (iii) LiOH/H2O2/THF, 0 ꢂC,
7 h: (S)-4 (95%, 70% op); (iv) NaH/2-pyrrolidinone/THF, rt, over-
night: (R)-2 (42%, 64% op).

F. Boschi et al. / Tetrahedron: Asymmetry 16 (2005) 3739–3745
3741
substitution product (R)-2, but in low yield (42%) and
i, ii
iii
lower op (64%) than that of the starting compound.
When the last reaction was carried out under reflux,
the yield increased to 52%, but the op decreased to
45%. These results show that some racemization takes
place in these transformations, which can be explained
by assuming a certain degree of participation of the car-
boxylate group in the substitution reaction, which would
take place with retention of the configuration, thus low-
ering the op of the main product arising from an SN2
reaction. Altogether, it seemed clear that a synthesis of
levetiracetam from ( )-2-chlorobutyric acid was not
adequate. In view of these results we discontinued this
approach to levetiracetam.
Br
Br
Br
(R)-5
CO2H
O
CO2H
O
O
( )-5
+ (S)-8 (99%; >99% ee)
[or (S)-5
+ (R)-8 (96%; >99% ee)]
N
Ph
(αR,3S)-7 / (αS,3S)-11 (dr = 9:1)
[or (αS,3R)-7 / (αR,3R)-11 (dr = 9:1)]
O
O
v
iv
N
N
CO2H
CONH2
(S)-1
[or (R)-1]
(S)-2
[or (R)-2]
Scheme 4. Synthesis of levetiracetam and its enantiomer via derace-
mization of 2-bromobutyric acid with (S)-8 or (R)-8. Reagents and
conditions: (i) Cl2SO; (ii) (S)-8 [or (R)-8], CH2Cl2, Et3N, À20 ꢂC, 4 h:
(aR,3S)-7 (67%, >98:2 dr) [or (aS,3R)-7 (71%, >98:2 dr)] from ( )-5,
after column chromatography; (iii) LiOH/H2O2/THF, 0 ꢂC, 7 h: (R)-5
(91%) [or (S)-5 (96%)]; (iv) NaH/2-pyrrolidinone/THF, rt, overnight:
(S)-2 (55%) [or (R)-2 (62%)]; (v) (a) ClCO2Et/CH2Cl2, Et3N, 0 ꢂC,
30 min, (b) NH4OH, rt, 16 h: (S)-1 (80% crude yield, 92% ee; 65%
yield, >99% ee, after recrystallization from acetone) [or (R)-1 (90%
crude yield, 91% ee; 63% yield, >99% ee, after recrystallization from
acetone)].
Finally, we studied the deracemization of ( )-2-bromo-
butyric acid, ( )-5. Reaction of ( )-5 with Cl2SO,
followed by reaction of the resulting racemic 2-bromo-
butyryl chloride with (S)-8, gave in a quantitative yield
a diastereomeric mixture of esters (aR,3S)-7 and
(aS,3S)-11 in the approximate ratio of 9:1 (1H NMR).
In this case, the main diastereomer (aR,3S)-7 was
isolated in 67% yield and >98:2 dr, after silica gel
column chromatography of the diastereomeric mixture.
Hydrolysis of (aR,3S)-7 using LiOH/H2O2 in THF
at 0 ꢂC afforded (R)-2-bromobutyric acid, (R)-5,
(62% yield), (R)-1 (90% crude yield, 91% ee; 63% yield
after recrystallization from acetone, >99% ee) was
obtained.
28
in 91% yield, with an ½aŠ ¼ þ33:6 (c 2.74, MeOH)
D
20
{described for (S)-5 ½aŠ ¼ À31:0 (c 2.50, MeOH)}.19
D
This result is in contrast with previous results obtained
in the hydrolysis of related a-bromo esters of N-phenyl-
pantolactam, such as a-bromopropionate and a-bromo-
b-methylbutyrate, carried out with 2 M HCl/AcOH
under reflux for 2 h or with LiOHÆH2O in THF from
À20 ꢂC to room temperature, which took place with
noticeable racemization of the a-bromo acid.15 How-
ever, we have previously observed a similar situation
in the hydrolysis of the a-chloropropionate of (R)-N-
phenylpantolactam.16 The reaction of (R)-5 with the
sodium salt of 2-pyrrolidinone in THF at room temper-
3. Conclusion
In conclusion, we have developed a synthesis of leveti-
racetam by deracemization of ( )-2-bromobutyric acid,
( )-5 to the (R)-enantiomer with (S)-N-phenylpantolac-
tam, (S)-8, followed by nucleophilic substitution with
the sodium salt of 2-pyrrolidinone to give (S)-2-(2-oxo-
pyrrolidin-1-yl)butyric acid, (S)-2, a known precursor of
levetiracetam. The key points of the synthesis are: (1) the
good diastereomeric ratio (9:1) in the esterification of
( )-5 with the chiral auxiliary and the easy purification
of the main diastereomer by column chromatography,
(2) the LiOH/H2O2 hydrolysis of the diastereopure ester
(aR,3S)-7 to give acid (R)-5 without racemization and
(3) the SN2 transformation of (R)-5 to the immediate
acid precursor of levetiracetam, (S)-2. This sequence
has also been applied to the preparation of the enantio-
mer of levetiracetam.
ature overnight gave the substitution product (S)-2 in
20
55% yield, showing an ½aŠ ¼ À27:3 (c 1.01, acetone),
D
20
similar to the described value, ½aŠ ¼ À26:4 (c 1.00, ace-
D
tone).2 This presumably shows that the substitution
reaction takes place by an SN2 mechanism. This com-
pound was transformed into the corresponding amide
(S)-1, by consecutive reaction with ethyl chloroformate
and ammonium hydroxide, following a known proce-
dure.2 The enantiomeric excess (ee) of the crude product
thus obtained (80% yield, 92% ee) was established by
chiral HPLC analysis. After recrystallization from ace-
tone, (S)-1 (>99% ee) was obtained in 65% overall yield.
This result shows that amidation of (S)-2 to levetirace-
tam (S)-1 takes place with partial racemization, which
may be due to the increased acidity of the a-carboxylic
proton in the intermediate mixed anhydride formed dur-
ing the amidation reaction and the basic reaction condi-
tions during the reaction with ammonium hydroxide.
Similarly, partial racemization during the amidation of
the ethyl ester of (S)-2 had been previously observed
(Scheme 4).4
4. Experimental
4.1. General
Melting points were determined in open capillary tubes
with an MFB 595010 M Gallenkamp melting point appa-
ratus. Unless otherwise stated, 1H NMR(300 MHz) and
13C NMR(75.4 MHz) spectra were recorded in CDCl 3 in
a Varian Gemini 300 spectrometer. Chemical shifts (d)
are reported in ppm related to internal tetramethylsilane
(TMS). For the numbering of representative pantolac-
tam esters, see Schemes 2 and 3. For the pantolactam
esters 3, 6, 7 and 9, the terms a or b are assigned to
In a similar way, by starting from ( )-5, via (aS,3R)-7
(71% yield, >98:2 dr), (S)-5 (96% yield) and (R)-2

3742
F. Boschi et al. / Tetrahedron: Asymmetry 16 (2005) 3739–3745
20
D
hydrogen atoms or groups of the pantolactam moiety,
which are cis or trans relative to the 3-carboxy substitu-
ent, respectively. Assignments given for the NMR
spectra are based on DEPT and comparison with related
compounds previously described by the research
group.13–15 MS spectra were taken on a Hewlett–Packard
5988A spectrometer using the chemical ionization (CH4)
technique; only significant ions are given. IRspectra were
recorded on a Perkin–Elmer Spectrum RX I equipment.
Absorption values are expressed as wave-numbers
(cmÀ1); only significant bands are given. Optical rota-
tions were measured on a Perkin–Elmer model 241 polar-
imeter. Chiral HPLC analyses were performed on a
Waters model 600 liquid chromatograph provided with
a Waters model 486 variable k detector, and using a CHI-
RALCEL OD-H column (25 · 0.46 cm) containing the
chiral stationary phase cellulose tris(3,5-dimethylphe-
nylcarbamate). Conditions A (mixture of hexane/ethanol
95:5 as eluent, flow 0.8 mL/min, k = 240 nm) were used
for the resolution of the enantiomers of etiracetam, 1.
Conditions B (mixture of hexane/isopropanol 93:7 as
eluent, flow 0.8 mL/min, k = 254 nm) were used for the
analysis of N-phenylpantolactam, 8, and the esters 6
and 10. Column chromatography was performed on
silica gel 60 AC.C. (35–70 mesh, SDS, ref. 2000027).
Thin-layer chromatography (TLC) was performed with
aluminium-backed sheets with silica gel 60 F254 (Merck,
ref. 1.05554), and spots were visualized with UV light
and 1% aqueous solution of KMnO4. NMRspectra were
(aS,3S)-3: ½aŠ ¼ À42:3 (c 0.96, CHCl3); Rf 0.30 (silica
gel, 8 cm, hexane/AcOEt 2:1); IR(NaCl) m: 1751 (C@O
1
st ester), 1714 and 1692 (C@O st lactams); H NMR d:
0.99 (dd, J3-Ha/4-H = J3-Hb/4-H = 7.2 Hz, 3H, 4-H3), 1.16
(s, 3H, 400a-CH3), 1.30 (s, 3H, 400b-CH3), 1.86 (ddq,
J3-Ha/3-Hb = 14.4 Hz, J2-H/3-Ha = 10.8 Hz, J3-Ha/4-H
=
7.2 Hz, 1H, 3-Ha), 1.97–2.22 (complex signal, 3H,
40-H2 and 3-Hb), 2.45 (m, 2H, 30-H2), 3.40 (m, 1H) and
3.70 (m, 1H) (50-H2), 3.54 (d, J5 a-H=5 b-H ¼ 9:6 Hz, 1H,
00
00
500a-H), 3.62 (d, J5 a-H=5 b-H ¼ 9:6 Hz, 1H, 500b-H), 4.81
00
00
(dd, J2-H/3-Ha = 10.8 Hz, J2-H/3-Hb = 4.8 Hz, 1H, 2-H),
5.39 (s, 1H, 300-H), 7.17 (tt, JHp/Hm = 7.5 Hz, JHp/Ho
=
1.2 Hz, 1H, Ar–Hpara N-phenyl), 7.38 (m, 2H, Ar–Hmeta
N-phenyl), 7.61 (m, 2H, Ar–Hortho N-phenyl); 13C
NMR d: 10.9 (CH3, C4), 18.4 (CH2, C3), 21.1 (CH3,
400a-CH3), 22.5 (CH2, C40), 24.7 (CH3, 400b-CH3), 30.9
(CH2, C30), 37.2 (C, C400), 43.7 (CH2, C50), 55.3 (CH,
C2), 57.7 (CH2, C500), 78.7 (CH, C300), 119.4 (CH, Ar–
Cortho N-phenyl), 124.9 (CH, Ar–Cpara N-phenyl),
128.9 (CH, Ar–Cmeta N-phenyl), 138.9 (C, Ar–Cipso N-
phenyl), 168.4 (C, C200), 170.5 (C, C20), 175.9 (C, C1).
MS (CI, CH4), m/z (%): 387 [(M+C2H5)+, 18], 360 (23),
359 [(M+H)+, 100], 154 (20), 126 (10). Elemental analysis:
calcd for C20H26N2O4Æ2/5H2O: C 65.70, H 7.39, N 7.66.
Found: C 65.94, H 7.76, N 7.24.
20
(aR,3S)-9: ½aŠ ¼ þ50:3 (c 1.03, CHCl3); Rf 0.38 (silica
D
gel, 8 cm, hexane/AcOEt 2:1); IR(NaCl) m: 1748
1
(C@O st ester), 1712 and 1692 (C@O st lactams); H
´
`
performed at the ꢁServeis Cientıfico-Tecnicsꢀ of the
University of Barcelona, while elemental analyses were
carried out at the Microanalysis Service of the IIQAB
(CSIC, Barcelona, Spain).
NMR d: 0.96 (dd, J3-Ha/4-H = J3-Hb/4-H = 7.2 Hz, 3H,
4-H3), 1.10 (s, 3H, 400a-CH3), 1.29 (s, 3H, 400b-CH3),
1.80 (ddq, J3-Ha/3-Hb = 14.4 Hz, J2-H/3-Ha = 10.5 Hz,
J3-Ha/4-H = 7.2 Hz, 1H, 3-Ha), 1.95–2.20 (complex sig-
nal, 3H, 40-H2 and 3-Hb), 2.33–2.51 (complex signal,
2H, 30-H2), 3.36 (m, 1H) and 3.62 (m, 1H) (50-H2),
4.2. (aR,3S)- and (aS,3S)-4,4-Dimethyl-2-oxo-1-phenyl-
pyrrolidin-3-yl 2-(2-oxopyrrolidin-1-yl)butyrate, (aR,3S)-
9 and (aS,3S)-3
3.52 (d, J5 a-H=5 b-H ¼ 9:6 Hz, 1H, 500a-H), 3.61 (d,
00
00
J5 a-H=5 b-H ¼ 9:6 Hz, 1H, 500b-H), 4.86 (dd, J2-H/3-Ha
=
00
00
10.5 Hz, J2-H/3-Hb = 4.8 Hz, 1H, 2-H), 5.40 (s, 1H,
300-H), 7.17 (tt, JHp/Hm = 7.5 Hz, JHp/Ho = 1.2 Hz, 1H,
Ar–Hpara N-phenyl), 7.38 (m, 2H, Ar–Hmeta N-phenyl),
7.59 (m, 2H, Ar–Hortho N-phenyl); 13C NMR d: 10.7
(CH3, C4), 18.4 (CH2, C3), 21.1 (CH3, 400a-CH3), 21.9
(CH2, C40), 24.6 (CH3, 400b-CH3), 30.9 (CH2, C30),
37.3 (C, C400), 43.6 (CH2, C50), 55.2 (CH, C2), 57.7
(CH2, C500), 78.7 (CH, C300), 119.4 (CH, Ar–Cortho N-
phenyl), 125.0 (CH, Ar–Cpara N-phenyl), 128.9 (CH,
Ar–Cmeta N-phenyl), 138.8 (C, Ar–Cipso N-phenyl),
168.4 (C, C200), 170.1 (C, C20), 176.0 (C, C1). MS (CI,
CH4), m/z (%): 387 [(M+C2H5)+, 19], 360 (22), 359
[(M+H)+, 100], 154 (51), 126 (30). Elemental analysis:
calcd for C20H26N2O4: C 67.02, H 7.31, N 7.82. Found:
C 66.66, H 7.45, N 7.45.
To a cold (0 ꢂC) solution of acid ( )-2 (1.40 g,
8.19 mmol, 1.1 equiv) in CH2Cl2 (20 mL), DCC
(1.69 g, 8.19 mmol, 1.1 equiv) was added in several por-
tions and the mixture stirred at this temperature for
20 min. The solution was cooled to À78 ꢂC, a solution
of (S)-8 (1.53 g, 7.46 mmol) in CH2Cl2 (18 mL) and
DMAP (46 mg, 0.38 mmol, 0.05 equiv) were successively
added and the reaction mixture was stirred at À78 ꢂC
for 16 h. The resulting solution was allowed to warm
to room temperature, the precipitated N,N0-
dicyclohexylurea (DCU) filtered off through a pad of
Celiteꢁ and the filtrate concentrated under reduced pres-
sure. Water (30 mL) and brine (5 mL) were added to the
residue and the mixture extracted with AcOEt
(3 · 60 mL). The combined organic extracts were dried
over Na2SO4 and concentrated in vacuo to give a mix-
ture of (aR,3S)-9 and (aS,3S)-3 [2.67 g, quantitative
yield, approximate diastereomeric ratio (dr) = 2:3, by
1H NMR] as a yellow oil. This mixture was submitted
to column chromatography [silica gel (54 g/g mixture),
hexane/Et2O mixtures]. On elution with hexane/Et2O
4.3. (S)-2-(2-Oxopyrrolidin-1-yl)butyric acid, (S)-2, by
hydrolysis of (aS,3S)-3
To a cold (0 ꢂC) solution of (aS,3S)-3 (466 mg,
1.30 mmol, >98:2 dr) in THF (23 mL), 30% w/v H2O2
(0.70 mL, 6.18 mmol, 4.7 equiv) and LiOHÆH2O
(165 mg, 3.93 mmol, 3.0 equiv) were added and the mix-
ture stirred at this temperature for 7 h. A solution of
Na2SO3 (0.75 M, 7.5 mL) was added, the final pH being
about 9. This mixture was extracted with CH2Cl2
1
30:70, (aR,3S)-9 (669 mg, 25% yield, >98:2 dr by H
NMR), mixtures of (aR,3S)-9 and (aS,3S)-3 (1.02 g,
35:65 dr) and (aS,3S)-3 (630 mg, 24% yield, >98:2 dr)
were successively isolated as yellow oils.

F. Boschi et al. / Tetrahedron: Asymmetry 16 (2005) 3739–3745
3743
(3 · 15 mL) and the combined organic extracts dried
over Na2SO4 and concentrated in vacuo to give (S)-8
(250 mg, 94% yield, >99% ee, by chiral HPLC, condi-
tions B). The aqueous phase was made acidic
(pH = 2–3) with 1 M HCl and extracted with AcOEt
(3 · 15 mL). The combined organic extracts were dried
J2-H/3-Ha = 7.5 Hz, J2-H/3-Hb = 6.0 Hz, 1H, 2-H), 5.43
(s, 1H, 30-H), 7.17 (tt, JHp/Hm = 7.5 Hz, JHp/Ho = 1.2 Hz,
1H, Ar–Hpara N-phenyl), 7.37 (m, 2H, Ar–Hmeta N-
phenyl), 7.62 (m, 2H, Ar–Hortho N-phenyl); 13C NMR
d: 10.5 (CH3, C4), 21.1 (CH3, 40a-CH3), 24.8 (CH3,
40b-CH3), 28.6 (CH2, C3), 37.5 (C, C40), 57.6 (CH2,
C50), 59.0 (CH, C2), 79.1 (CH, C30), 119.4 (CH, Ar–
Cortho N-phenyl), 125.0 (CH, Ar–Cpara N-phenyl),
128.9 (CH, Ar–Cmeta N-phenyl), 138.8 (C, Ar–Cipso
N-phenyl), 168.0 (C, C20), 168.7 (C, C1). MS (CI,
CH4), m/z (%): 338 [(M+C2H5)+, 14], 312 (33), 311
(23), 310 [(M+H)+, 100], 309 (15), 274 [(MÀCl)+, 22],
188 (24). Elemental analysis of the (aS,3R)-6/(aR,3R)-
10 mixture in the ratio of 85:15: calcd for C16H20ClNO3:
C 62.03, H 6.51, N 4.52, Cl 11.44. Found: C 61.73, H
6.64, N 4.40, Cl 11.78.
over Na2SO4 and concentrated in vacuo to give (S)-2
20
(140 mg, 63% yield) as a white solid, ½aŠ ¼ À28:0 (c
D
20
1.03 acetone) {described ½aŠ ¼ À26:4 (c 1.00, ace-
D
tone)}.2 The analytical and spectroscopic data of (S)-2
coincide with those obtained for the product of Section
4.12.
4.4. (R)-2-(2-Oxopyrrolidin-1-yl)butyric acid, (R)-2, by
hydrolysis of (aR,3S)-9
It was prepared as described for the preparation of (S)-2
from (aS,3S)-3. From (aR,3S)-9 (445 mg, 1.24 mmol,
>98:2 dr), (S)-8 (244 mg, 96% yield, >99% ee, by chiral
HPLC) and (R)-2 (141 mg, 66% yield) were obtained as
white solids. The analytical and spectroscopic data of
(R)-2 coincide with those obtained for the product from
Section 4.13.
4.6. (S)-2-Chlorobutyric acid, (S)-4
It was obtained in the same manner described for the
preparation of (S)-2 from its pantolactam ester (aS,3S)-
3. From the mixture (aS,3R)-6/(aR,3R)-10 in the ratio
85:15 (4.26 g, 13.8 mmol), (S)-4 (1.60 g, 95% yield, 70%
20
D
op) was obtained as a colourless liquid, ½aŠ ¼ À8:9
20
4.5. (aS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl
2-chlorobutyrate, (aS,3R)-6
(c 2.50, MeOH) {described for (R)-4 ½aŠ ¼ 12:7 (c 0.4,
MeOH)}.21 Furthermore, (R)-8 (2.50Dg, 88% yield,
>99% ee by chiral HPLC) was also recovered.
( )-2-Chlorobutyric acid, ( )-4 (7.0 mL, 8.33 g,
68.0 mmol) was added dropwise to cold (0 ꢂC) and mag-
netically stirred SOCl2 (7.25 mL, 11.9 g, 100 mmol,
1.5 equiv). Once the addition was complete, the mixture
was heated at reflux for 2 h. The excess of SOCl2 and the
acid chloride were fractionally distilled at atmospheric
pressure. In this way, ( )-2-chlorobutyryl chloride
(6.40 g, 67% yield, bp 100–120 ꢂC) was obtained as a
colourless liquid.
4.7. (R)-2 from (S)-4
A suspension of 2-pyrrolidinone (1.52 mL, 1.70 g,
20.0 mmol, 3 equiv) and NaH [55% oily dispersion,
872 mg, 20.0 mmol, 3.0 equiv, washed with hexane
(3 · 10 mL) prior to use] in anhydrous THF (15 mL)
was stirred at room temperature for 45 min. A solution
of chloroacid (S)-4 (815 mg, 6.65 mmol, 70% op) in
anhydrous THF (4 mL) was added and the reaction
mixture stirred at room temperature for 48 h. After acid-
ification with 10% aqueous HCl (6 mL), the organic
phase was separated and the aqueous layer extracted
with Et2O (4 · 25 mL). The combined organic phase
and extracts were dried (Na2SO4) and concentrated in
vacuo to give a residue (0.99 g), which on trituration
To a cold (À20 ꢂC) solution of (R)-8 (3.47 g, 16.9 mmol)
in anhydrous CH2Cl2 (50 mL), a solution of ( )-2-chlo-
robutyryl chloride (3.39 g, 24.1 mmol, 1.4 equiv) in
anhydrous CH2Cl2 (77 mL) and a solution of anhydrous
Et3N (7.8 mL, 5.66 g, 55.9 mmol, 3.3 equiv) in anhy-
drous CH2Cl2 (100 mL) were successively added, and
the reaction mixture stirred at À20 ꢂC for 2 h. [All of
the dichloromethane solutions were previously dried
with Et2O (5 mL) gave (R)-2 (474 mg, 42% yield, 64%
20
D
op) as a white solid, ½aŠ ¼ 17:5 (c 1.03, acetone)
20
by stirring with 3 A molecular sieves (about 0.3 g/mL)
{described ½aŠ ¼ 27:3 (c 1.00, acetone)}.20 Note: When
˚
D
at 0 ꢂC for 45 min.] The mixture was successively
washed with 1 M HCl (2 · 120 mL) and saturated aque-
ous solution of NaHCO3 (2 · 120 mL). The organic
phase was dried over Na2SO4 and concentrated in vacuo
to give a mixture of (aS,3R)-6 and (aR,3R)-10 [5.24 g,
quantitative yield, 85:15 dr, by 1H NMRand chiral
HPLC, conditions B: (aS,3R)-6, rt 17.34 min; (aR,3R)-
10, rt 19.43 min; k1 = 3.35, k2 = 3.87; a = 1.16;
Res = 1.75]. Column chromatography of this mixture
[silica gel (43 g/g mixture), hexane/AcOEt mixtures]
did not allow us to separate their components. IR
(KBr) m: 1753 (C@O st ester), 1716 (C@O st lactam);
NMRdata of [( aS,3R)-6]: 1H NMR d: 1.12 (dd,
J3-Ha/4-H = J3-Hb/4-H = 7.5 Hz, 3H, 4-H3), 1.17 (s, 3H,
40a-CH3), 1.31 (s, 3H, 40b-CH3), 1.96–2.25 (complex sig-
this reaction was carried out at reflux for 16 h, the yield
increased to 52% but the op was reduced to 45%.
4.8. (aR,3S)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl
2-bromobutyrate, (aR,3S)-7
It was prepared as described for (aS,3R)-6. Starting
from ( )-2-bromobutyric acid, ( )-5 (20.0 mL, 31.3 g,
187 mmol), ( )-2-bromobutyryl chloride (28.1 g, 81%
yield, bp 55–65 ꢂC/40 Torr) was obtained as a colourless
liquid, which on reaction with (S)-8 (4.84 g, 23.6 mmol)
for 4 h afforded a mixture of (aR,3S)-7 and (aS,3S)-11
(8.35 g, quantitative yield, approximate dr = 9:1, by
1H NMR). Column chromatography of this mixture [sil-
ica gel (50 g/g mixture), hexane/Et2O mixtures] allowed
us to isolate (aR,3S)-7 (5.23 g) as the first eluted product
(hexane/Et2O 85:15). Column chromatography of the
nal, 2H, 3-H2), 3.53 (d, J5 a-H=5 b-H ¼ 9:9 Hz, 1H, 50a-H),
0
0
3.63 (d, J5 a-H=5 b-H ¼ 9:9 Hz, 1H, 50b-H), 4.42 (dd,
0
0

3744
F. Boschi et al. / Tetrahedron: Asymmetry 16 (2005) 3739–3745
fractions corresponding to mixtures of both diaste-
4.11. (S)-2-Bromobutyric acid, (S)-5
reomers under similar conditions gave more (aR,3S)-7
1
(0.38 g, total yield 5.61 g, 67% yield, >98:2 dr, by H
It was obtained in a similar manner to that described for
(R)-5. From the same amount of starting materials, (R)-8
20
NMR). ½aŠ ¼ À36:6 (c 1.19, CHCl3); Rf 0.21 (silica
D
gel, 8 cm, hexane/Et2O 3:1); mp 64–65 ꢂC (hexane/
(1.57 g, 99% yield, >99% ee, by chiral HPLC) and acid
20
Et2O 85:15); IR(KBr) m: 1742 (C@O st ester), 1712
(S)-5 (1.24 g, 96% yield), ½aŠ ¼ À32:9 (c 2.50, MeOH)
D
28
D
(C@O st lactam); 1H NMR d: 1.11 (dd, J3-Ha/4-H
=
{described ½aŠ ¼ À31:0 (c 2.50, MeOH)},19 were ob-
J3-Hb/4-H = 7.2 Hz, 3H, 4-H3), 1.20 (s, 3H, 40a-CH3),
1.32 (s, 3H, 40b-CH3), 2.10 (ddq, J3-Ha/3-Hb = 14.4 Hz,
J2-H/3-Ha = J3-Ha/4-H = 7.2 Hz, 1H, 3-Ha), 2.24 (ddq,
J3-Ha/3-Hb = 14.4 Hz, J2-H/3-Hb = J3-Hb/4-H = 7.2 Hz, 1H,
tained as a white solid and a colourless oil, respectively.
4.12. (S)-2 from (R)-5
3-Hb), 3.54 (d, J5 a-H=5 b-H ¼ 9:6 Hz, 1H, 50a-H),
It was obtained as described for the preparation of (R)-2
from (S)-4. From (R)-5 (1.18 g, 7.07 mmol), after 16 h
at room temperature, crude acid (S)-2 (1.54 g) was
obtained, which on trituration with Et2O (6 mL) gave
0
0
3.63 (d, J5 a-H=5 b-H ¼ 9:6 Hz, 1H, 50b-H), 4.31 (dd,
J2-H/3-Ha = J2-H/3-Hb = 7.2 Hz, 1H, 2-H), 5.42 (s, 1H,
30-H), 7.17 (tt, JHp/Hm = 7.2 Hz, JHp/Ho = 1.2 Hz, 1H,
Ar–Hpara N-phenyl), 7.37 (m, 2H, Ar–Hmeta N-phen-
yl), 7.62 (m, 2H, Ar–Hortho N-phenyl); 13C NMR d:
11.9 (CH3, C4), 21.1 (CH3, 40a-CH3), 24.8 (CH3, 40b-
CH3), 28.6 (CH2, C3), 37.6 (C, C40), 47.7 (CH, C2),
57.7 (CH2, C50), 79.0 (CH, C30), 119.4 (CH, Ar–Cortho
N-phenyl), 124.9 (CH, Ar–Cpara N-phenyl), 128.9 (CH,
Ar–Cmeta N-phenyl), 138.8 (C, Ar–Cipso N-phenyl),
168.2 (C, C20), 168.8 (C, C1). MS (CI, CH4), m/z (%):
384 (13), 382 [(M+C2H5)+, 13], 357 (17), 356 (97), 355
(33), 354 [(M+H)+, 100], 274 [(MÀBr)+, 31], 206 (34),
188 (52), 69 (42). Elemental analysis: calcd for
C16H20BrNO3: C 54.25, H 5.69, N 3.95, Br 22.56.
Found: C 54.46, H 5.71, N 3.91, Br 22.48.
0
0
(S)-2 (660 mg, 55% yield) as
a
white solid,
20
20
½aŠ ¼ À27:3 (c 1.01, acetone) {described ½aŠ ¼ À26:4
D
D
(c 1.00, acetone)};2 mp 124–126 ꢂC (Et2O) [described
125.9 ꢂC (toluene)].2
4.13. (R)-2 from (S)-5
It was obtained as described for the preparation of (R)-2
from (S)-4. From (S)-5 (1.30 g, 7.78 mmol), (R)-2
(830 mg, 62% yield) was obtained as a white solid,
20
D
20
D
½aŠ ¼ 26:5 (c 1.02, acetone) {described ½aŠ ¼ 27:3 (c
1.00, acetone)};20 mp 124–126 ꢂC (Et2O) (described
126 ꢂC).20
4.9. (aS,3R)-4,4-Dimethyl-2-oxo-1-phenylpyrrolidin-3-yl
2-bromobutyrate, (aS,3R)-7
4.14. ( )-2-(2-Oxopyrrolidin-1-yl)butyramide, ( )-1
To a cold (0 ꢂC) solution of acid ( )-2 [500 mg,
2.92 mmol, prepared from ( )-5 as described for the
preparation of (S)-2 from (R)-5] and Et3N (0.43 mL,
0.31 g, 3.07 mmol, 1.05 equiv) in anhydrous THF
(2 mL), ethyl chloroformate (0.29 mL, 0.33 g,
3.04 mmol, 1.04 equiv) was added and the mixture stir-
red at 0 ꢂC for 30 min. Ammonium hydroxide (25%
w/v aqueous solution, 1.90 mL, 13.6 mmol, 4.6 equiv)
was added and the reaction mixture was stirred at room
temperature for 16 h. After the addition of K2CO3
(414 mg, 3.00 mmol, 1.03 equiv), the mixture was
filtered and the volatile materials (solvent and Et3N) dis-
tilled off in vacuo. The solid residue was extracted with
CH2Cl2 (3 · 8 mL) and the combined organic extracts
dried over Na2SO4 and concentrated in vacuo, to give
a crude amide ( )-1 (429 mg, 86% yield) as a yellowish
solid. Recrystallization from acetone (10 mL) gave
( )-1 (328 mg, 66% yield) as a white solid, mp 113–
114 ꢂC (acetone) [described 122 ꢂC (AcOEt)].22 Chiral
HPLC, conditions A: (R)-1, rt 21.13 min; (S)-1, rt
27.31 min; k01 ¼ 3:70, k20 ¼ 5:07; a = 1.37; Res = 3.38.
It was obtained as described for (aR,3S)-7. Starting
from the same amount of starting components, a mix-
ture of (aS,3R)-7 and (aR,3R)-11 (8.36 g, quantitative
1
yield, 9:1 dr, by H NMR) was obtained. After a first
column chromatography of the crude product,
(aS,3R)-7 (4.85 g) was isolated. After a second column
chromatography of the fractions corresponding to
mixtures of both diastereomers, a second crop of
(aS,3R)-7 (1.13 g, total yield 5.98 g, 71% yield, >98:2
20
dr, by 1H NMR) was isolated. ½aŠ ¼ 38:2 (c 1.15,
D
CHCl3); mp 65–66 ꢂC (hexane/Et2O 85:15). MS (CI,
CH4), m/z (%): 384 (13), 382 [(M+C2H5)+, 13], 357
(17), 356 (99), 355 (30), 354 [(M+H)+, 100], 353 (14),
274 [(MÀBr)+, 24], 206 (18), 188 (31), 69 (14). Elemental
analysis: calcd for C16H20BrNO3: C 54.25, H 5.69, N
3.95, Br 22.56. Found: C 53.76, H 5.69, N 3.78, Br
22.44. The Rf, IR ,1H NMRand 13C NMRdata of this
compound coincide with those of its enantiomer.
4.10. (R)-2-Bromobutyric acid, (R)-5
It was obtained in the same manner described for the
preparation of (S)-2 from its pantolactam ester (aS,3S)-
3. From (aR,3S)-7 (2.75 g, 7.77 mmol, >98:2 dr) in
THF (132 mL), H2O2 (30% w/v, 4.07 mL, 35.9 mmol,
4.6 equiv) and LiOHÆH2O (0.99 g, 23.6 mmol, 3.0 equiv),
4.15. (S)-2-(2-Oxopyrrolidin-1-yl)butyramide, (S)-1
It was obtained in a similar manner to that described
for ( )-1. From (S)-2 (454 mg, 2.65 mmol), (S)-1
(361 mg, 80% yield, 92% ee, by chiral HPLC, condi-
tions A) was obtained as a yellowish solid. On recrys-
tallization from acetone (10 mL), (S)-1 (293 mg,
(S)-8 (1.53 g, 96% yield, >99% ee, by chiral HPLC)
20
and (R)-5 (1.18 g, 91% yield), ½aŠ ¼ 33:6 (c 2.74, MeOH)
D
28
{described for (S)-5 ½aŠ ¼ À31:0 (c 2.50, MeOH)},19
65% yield, >99% ee, by chiral HPLC) was obtained
D
20
were obtained as a white solid and a colourless oil,
respectively.
as a white solid, ½aŠ ¼ À90:5 (c 0.99, acetone) {de-
D
25
D
scribed ½aŠ ¼ À90:0 (c 1.00, acetone)};2 chiral HPLC:

F. Boschi et al. / Tetrahedron: Asymmetry 16 (2005) 3739–3745
3745
4. Ates, C.; Surtees, J.; Burteau, A. C.; Marmon, V; Cavoy,
E. PCT Int. Appl. WO 2003/014080.
5. Cossement, E.; Motte, G.; Geerts, J. P. Gobert, J. UK Pat.
Appl., GB 2225322.
6. Futagawa, T.; Canvat, J. P.; Cavoy, E.; Deleers, M.;
Hamende, M.; Zimmermann, V. US patent 6107492.
7. Cavoy, E.; Hamende, M.; Deleers, M.; Canvat, J. P.;
Zimmermann, V. US patent 6124473.
rt 27.31 min; mp 115–117 ꢂC (acetone) [described
117 ꢂC (AcOEt)].2
4.16. (R)-2-(2-Oxopyrrolidin-1-yl)butyramide, (R)-1
It was obtained in a similar manner to that described for
( )-1. From (R)-2 (960 mg, 5.61 mmol), (R)-1 (859 mg,
90% yield, 91% ee, by chiral HPLC, conditions A) was
obtained as a yellowish solid. On recrystallization from
`
`
8. Artu´s, J. J.; Rafecas, J.; Garriga, L.; Pericas, M. A.; Sola,
Ll., PCT Int. Appl. WO 2004/076416.
acetone (3 mL), (R)-1 (605 mg, 63% yield, >99% ee,
9. Surtees, J.; Marmon, V; Differding, E.; Zimmermann, V.
PCT Int. Appl. WO 2001/64367.
10. Boaz, N. W.; Debenham, S. D. PCT Int. Appl. WO 2002/
26705.
20
by chiral HPLC) was obtained as a white solid, ½aŠ
tone)};20 chiral HPLC: rt 21.13 min; mp 114–116 ꢂC
¼
D
25
D
89:8 (c 1.00, acetone) {described ½aŠ ¼ 90:7 (c 1.00, ace-
´
11. Camps, P.; Gimenez, S.; Font-Bardia, M.; Solans, X.
(acetone) [described 115–117 ꢂC (AcOEt)].20
Tetrahedron: Asymmetry 1995, 6, 985–990.
´
12. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron Lett.
1999, 40, 6853–6856.
´
13. Camps, P.; Gimenez, S. Tetrahedron: Asymmetry 1995, 6,
Acknowledgements
991–1000.
´
14. Camps, P.; Gimenez, S. Tetrahedron: Asymmetry 1996, 7,
A fellowship from the Generalitat de Catalunya (GC) to
1227–1234.
´
´
L. Sanchez and financial support from the Direccion
´
15. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asym-
metry 1997, 8, 1877–1894.
16. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asym-
metry 1998, 9, 2065–2079.
17. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asym-
´
General de Investigacion of Ministerio de Ciencia y Tec-
´
nologıa and FEDER(project PPQ2002-01080) and
´
Comissionat per a Universitats i Recerca of the GC
(project 2001-SGR-00180) are gratefully acknowledged.
´
´
`
We thank the Serveis Cientıfico-Tecnics of the Univer-
metry 1999, 10, 493–509.
`
sity of Barcelona for NMRfacilities and Ms. P. Dome n-
18. Camps, P.; Munoz-Torrero, D. Curr. Org. Chem. 2004, 8,
˜
1339–1380.
ech from the IIQAB (CSIC, Barcelona, Spain) for
carrying out the elemental analyses.
19. Ferorelli, S.; Loiodice, F.; Tortorella, V.; Amoroso, R.;
Bettoni, G.; Conte-Camerino, D.; De Luca, A. Il Farmaco
1997, 52, 367–374.
20. Gobert, J.; Giurgea, C.; Geerts, J. P.; Bodson, G. Eur. Pat.
Appl. E0165919.
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